INDICE Chromosomal 1q21.1 recurrent microdelection 3q29 recurrent delection 7q11.23 duplication syndrome 15q13.3 microdelection 16p11.2 recurrent delection 16p11.2 recurrent delection 17 q12 recurrent duplication 17q12 recurrent delection syndrome 21-hydroxylase-deficient congenital adrenal hyperplasia 22q11.2 dlection syndrome A ACTG2 Visceral Myopathy ADAMTSL4-Related Eye Disorders ADCY5 Dyskinesia ADNP-Related Disorder AIP Familial Isolated Pituitary Adenomas ALK-Related Neuroblastic Tumor Susceptibility ALS2-Related Disorder ANKRD17-Related Neurodevelopmental Syndrome ANKRD26-Related Thrombocytopenia ANO5 Muscle Disease AP-4-Associated Hereditary Spastic Paraplegia APC-Associated Polyposis Conditions APOB-Related Familial Hypobetalipoproteinemia ARID1B-Related Disorder ARSACS ASAH1-Related Disorders ASPM Primary Microcephaly ASXL3-Related Disorder ATN1-Related Neurodevelopmental Disorder ATP1A3-Related Neurologic Disorders ATP6V0A2-Related Cutis Laxa ATP7A-Related Copper Transport Disorders ATP8B1 Deficiency Abetalipoproteinemia Aceruloplasminemia Achondrogenesis Type 1B Achondroplasia Achromatopsia Acid Sphingomyelinase Deficiency Acute Intermittent Porphyria Adenine Phosphoribosyltransferase Deficiency Adenosine Deaminase 2 Deficiency Adenosine Deaminase Deficiency Adult Refsum Disease Aicardi Syndrome Aicardi-Goutières Syndrome Alagille Syndrome Alexander Disease Alkaptonuria Allan-Herndon-Dudley Syndrome Alpha-1 Antitrypsin Deficiency Alpha-Mannosidosis Alpha-Thalassemia X-Linked Intellectual Disability Syndrome Alpha-Thalassemia Alport Syndrome Alström Syndrome Alzheimer Disease Overview Amyotrophic Lateral Sclerosis Overview Andersen-Tawil Syndrome Androgen Insensitivity Syndrome Angelman Syndrome Apert Syndrome Arginase Deficiency Argininosuccinate Lyase Deficiency Aromatic L-Amino Acid Decarboxylase Deficiency Arrhythmogenic Right Ventricular Cardiomyopathy Overview Arterial Tortuosity Syndrome Arylsulfatase A Deficiency Asparagine Synthetase Deficiency Ataxia with Oculomotor Apraxia Type 1 Ataxia with Oculomotor Apraxia Type 2 Ataxia with Vitamin E Deficiency Ataxia-Telangiectasia Au-Kline Syndrome Autoimmune Lymphoproliferative Syndrome Autosomal Dominant Epilepsy with Auditory Features Autosomal Dominant Robinow Syndrome Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Autosomal Dominant TRPV4 Disorders Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1 Autosomal Dominant Tubulointerstitial Kidney Disease – REN Autosomal Dominant Tubulointerstitial Kidney Disease – UMOD Autosomal Recessive Congenital Ichthyosis Aymé-Gripp Syndrome B BAP1 Tumor Predisposition Syndrome BCL11A-Related Intellectual Disability BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer BSCL2-Related Neurologic Disorders / Seipinopathy Bachmann-Bupp Syndrome Baller-Gerold Syndrome Baraitser-Winter Cerebrofrontofacial Syndrome Bardet-Biedl Syndrome Overview Barth Syndrome Beckwith-Wiedemann Syndrome Berardinelli-Seip Congenital Lipodystrophy Bestrophinopathies Beta-Propeller Protein-Associated Neurodegeneration Beta-Thalassemia Bietti Crystalline Dystrophy Biotin-Thiamine-Responsive Basal Ganglia Disease Biotinidase Deficiency Birt-Hogg-Dubé Syndrome Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome Bloom Syndrome Bohring-Opitz Syndrome Branchiooculofacial Syndrome Branchiootorenal Spectrum Disorder Brugada Syndrome Bryant-Li-Bhoj Neurodevelopmental Syndrome C 1q21.1 Recurrent Microdeletion The 1q21.1 recurrent microdeletion itself does not appear to lead to a clinically recognizable syndrome as some persons with the deletion have no obvious clinical findings and others have variable findings that most commonly include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, autistic features, and sleep disturbances. 3q29 Recurrent Deletion 3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations including mild-to-moderate intellectual disability (ID), autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), executive function deficits, graphomotor weakness, and psychosis/schizophrenia. Age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Neurodevelopmental and psychiatric conditions are responsible for the majority of the disability associated with the 3q29 deletion. Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, gastrointestinal disorders (including constipation and gastroesophageal reflux disease [GERD]), ocular issues, dental anomalies, and congenital heart defects (especially patent ductus arteriosus). Structural anomalies of the posterior fossa may be seen on neuroimaging. To date more than 200 affected individuals have been identified. 7q11.23 Duplication Syndrome 7q11.23 duplication syndrome is characterized by delayed motor, speech, and social skills in early childhood; neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior issues including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention-deficit/hyperactivity disorder, oppositional disorders, physical aggression, and autism spectrum disorder; and intellectual disability in some individuals. Distinctive facial features are common. Cardiovascular disease includes dilatation of the ascending aorta. Approximately 30% of individuals have one or more congenital anomalies. 15q13.3 Recurrent Deletion ndividuals with the 15q13.3 recurrent deletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the recurrent deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete. A little over half of individuals diagnosed with this recurrent deletion have intellectual disability or developmental delay, mainly in the areas of speech acquisition and cognitive function. In the majority of individuals, cognitive impairment is mild. Other features reported in diagnosed individuals include epilepsy (in ~30%), mild hypotonia, and neuropsychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, mood disorder, schizophrenia, and aggressive or self-injurious behavior). Congenital malformations are uncommon. 3q29 Recurrent Deletion Synonyms: 3q29 Deletion Syndrome, 3q29 Microdeletion Syndrome 3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations including mild-to-moderate intellectual disability (ID), autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), executive function deficits, graphomotor weakness, and psychosis/schizophrenia. Age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Neurodevelopmental and psychiatric conditions are responsible for the majority of the disability associated with the 3q29 deletion. Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, gastrointestinal disorders (including constipation and gastroesophageal reflux disease [GERD]), ocular issues, dental anomalies, and congenital heart defects (especially patent ductus arteriosus). Structural anomalies of the posterior fossa may be seen on neuroimaging. To date more than 200 affected individuals have been identified. 7q11.23 Duplication Syndrome 7q11.23 duplication syndrome is characterized by delayed motor, speech, and social skills in early childhood; neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior issues including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention-deficit/hyperactivity disorder, oppositional disorders, physical aggression, and autism spectrum disorder; and intellectual disability in some individuals. Distinctive facial features are common. Cardiovascular disease includes dilatation of the ascending aorta. Approximately 30% of individuals have one or more congenital anomalies. 16p11.2 Recurrent Deletion The 16p11.2 recurrent deletion phenotype is characterized by motor speech disorder, language disorder, motor coordination difficulties, psychiatric conditions, and autistic features. While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, the severity varies significantly. Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years. Seizures are observed in approximately 25% of individuals with the recurrent deletion. Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each been observed in some individuals. Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems. 17q12 Recurrent Duplication The 17q12 recurrent duplication is characterized by intellectual abilities ranging from normal to severe disability and other variable clinical manifestations. Speech delay is common, and most affected individuals have some degree of hypotonia and gross motor delay. Behavioral and psychiatric conditions reported in some affected individuals include autism spectrum disorder, schizophrenia, and behavioral abnormalities (aggression and self-injury). Seizures are present in 75%. Additional common findings include microcephaly, ocular abnormalities, and endocrine abnormalities. Short stature and renal and cardiac abnormalities are also reported in some individuals. Penetrance is incomplete and clinical findings are variable. 17q12 Recurrent Deletion Syndrome The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturityonset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85% to 90% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years). 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia Synonyms: 21-OHD CAH, Virilizing Adrenal Hyperplasia 21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by the adrenal cortex. In 21-OHD CAH, excessive adrenal androgen biosynthesis results in virilization in all individuals and salt wasting in some individuals. A classic form with severe enzyme deficiency and prenatal onset of virilization is distinguished from a non-classic form with mild enzyme deficiency and postnatal onset. The classic form is further divided into the simple virilizing form (~25% of affected individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with salt-wasting 21-OHD CAH are at risk for life-threatening salt-wasting crises. Individuals with the non-classic form of 21OHD CAH present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth. 22q11.2 Deletion Syndrome Synonym: 22q11.2DS Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. 15q13.3 Recurrent Deletion Individuals with the 15q13.3 recurrent deletion may have a wide range of clinical manifestations. The deletion itself may not lead to a clinically recognizable syndrome and a subset of persons with the recurrent deletion have no obvious clinical findings, implying that penetrance for the deletion is incomplete. A little over half of individuals diagnosed with this recurrent deletion have intellectual disability or developmental delay, mainly in the areas of speech acquisition and cognitive function. In the majority of individuals, cognitive impairment is mild. Other features reported in diagnosed individuals include epilepsy (in ~30%), mild hypotonia, and neuropsychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, mood disorder, schizophrenia, and aggressive or self-injurious behavior). Congenital malformations are uncommon. 16p11.2 Recurrent Deletion The 16p11.2 recurrent deletion phenotype is characterized by motor speech disorder, language disorder, motor coordination difficulties, psychiatric conditions, and autistic features. While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, the severity varies significantly. Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years. Seizures are observed in approximately 25% of individuals with the recurrent deletion. Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each been observed in some individuals. Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems. The 16p11.2 recurrent deletion phenotype is characterized by motor speech disorder, language disorder, motor coordination difficulties, psychiatric conditions, and autistic features. While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, the severity varies significantly. Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years. Seizures are observed in approximately 25% of individuals with the recurrent deletion. Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each been observed in some individuals. Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems. A ACTG2 Visceral Myopathy Synonyms: Berdon Syndrome, Familial Visceral Myopathy ACTG2 visceral myopathy is a disorder of smooth muscle dysfunction of the bladder and gastrointestinal system with phenotypic spectrum that ranges from mild to severe. Bladder involvement can range from neonatal megacystis and megaureter (with its most extreme form of prune belly syndrome) at the more severe end, to recurrent urinary tract infections and bladder dysfunction at the milder end. Intestinal involvement can range from malrotation, neonatal manifestations of microcolon, megacystis microcolon intestinal hypoperistalsis syndrome, and chronic intestinal pseudoobstruction (CIPO) in neonates at the more severe end to intermittent abdominal distention and functional intestinal obstruction at the milder end. ADAMTSL4-Related Eye Disorders The spectrum of ADAMTSL4-related eye disorders is a continuum that includes the phenotypes known as "autosomal recessive isolated ectopia lentis" and "ectopia lentis et pupillae" as well as more minor eye anomalies with no displacement of the pupil and very mild displacement of the lens. Typical eye findings are dislocation of the lens, congenital abnormalities of the iris, refractive errors that may lead to amblyopia, and early-onset cataract. Increased intraocular pressure and retinal detachment may occur on occasion. Eye findings can vary within a family and between the eyes in an individual. In general, no additional systemic manifestations are observed, although skeletal features have been reported in a few affected individuals. ADCY5 Dyskinesia ADCY5 dyskinesia is a hyperkinetic movement disorder (more prominent in the face and arms than the legs) characterized by infantile to late-adolescent onset of chorea, athetosis, dystonia, myoclonus, or a combination of these. To date, affected individuals have had overlapping (but not identical) manifestations with wide-ranging severity. The facial movements are typically periorbital and perioral. The dyskinesia is prone to episodic or paroxysmal exacerbation lasting minutes to hours, and may occur during sleep. Precipitating factors in some persons have included emotional stress, intercurrent illness, sneezing, or caffeine; in others, no precipitating factors have been identified. In some children, severe infantile axial hypotonia results in gross motor delays accompanied by chorea, sometimes with language delays. The overall tendency is for the abnormal movements to stabilize in early middle age, at which point they may improve in some individuals; less commonly, the abnormal movements are slowly progressive, increasing in severity and frequency. ADNP-Related Disorder Synonyms: Helsmoortel-Van der Aa Syndrome, ADNP-Related ID/ASD ADNP-related disorder is characterized by hypotonia, severe speech and motor delay, mild-tosevere intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip) based on a cohort of 78 individuals. Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, brain abnormalities, seizures, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, endocrine issues including short stature and hormonal deficiencies, cardiac and urinary tract anomalies, and hearing loss. AIP Familial Isolated Pituitary Adenomas AIP familial isolated pituitary adenoma (AIP-FIPA) is defined as the presence of an AIP germline pathogenic variant in an individual with a pituitary adenoma (regardless of family history). The most commonly occurring pituitary adenomas in this disorder are growth hormone-secreting adenomas (somatotropinoma), followed by prolactin-secreting adenomas (prolactinoma), growth hormone and prolactin co-secreting adenomas (somatomammotropinoma), and nonfunctioning pituitary adenomas (NFPA). Rarely TSH-secreting adenomas (thyrotropinomas) are observed. Clinical findings result from excess hormone secretion, lack of hormone secretion, and/or mass effects (e.g., headaches, visual field loss). Within the same family, pituitary adenomas can be of the same or different type. Age of onset in AIP-FIPA is usually in the second or third decade. ALK-Related Neuroblastic Tumor Susceptibility ALK-related neuroblastic tumor susceptibility is characterized by increased risk for neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Neuroblastoma is a more malignant tumor and ganglioneuroma a more benign tumor. Depending on the histologic findings, ganglioneuroblastoma can behave in a more aggressive fashion, like neuroblastoma, or in a benign fashion, like ganglioneuroma. Preliminary data from the ten reported families with ALK-related neuroblastic tumor susceptibility suggest an overall penetrance of approximately 57% with the risk for neuroblastic tumor development highest in infancy and decreasing by late childhood. ALS2-Related Disorder ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes: -Infantile ascending hereditary spastic paraplegia (IAHSP), characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome caused by progressive cranial nerve involvement -Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. -Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years. ANKRD17-Related Neurodevelopmental Syndrome Synonym: Chopra-Amiel-Gordon Syndrome (CAGS) ANKRD17-related neurodevelopmental syndrome is characterized by developmental delay – particularly affecting speech – and variable intellectual disability. Additional features include autism spectrum disorder, attention-deficit/hyperactivity disorder, ophthalmologic abnormalities (strabismus and refractive errors), growth deficiency, feeding difficulties, recurrent infections, gait and/or balance disturbances, and epilepsy. Characteristic craniofacial features include triangular face shape, high anterior hairline, deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils, full cheeks, and thin vermilion of the upper lip. Less common but distinctive features include cleft palate with Pierre Robin sequence, renal agenesis, and scoliosis. ANKRD26-Related Thrombocytopenia Synonym: Thrombocytopenia 2 (THC2) ANKRD26-related thrombocytopenia is characterized by lifelong mild-to-moderate thrombocytopenia with a normal platelet size and no syndromic associations. Most individuals have normal hemostasis or a mild bleeding phenotype and do not develop severe spontaneous bleeding. Some individuals may have concomitant erythrocytosis and leukocytosis. The risk for myeloid malignancies (including myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelogenous leukemia) is increased in individuals with ANKRD26 pathogenic variants. ANO5 Muscle Disease Synonym: Anoctaminopathy The spectrum of ANO5 muscle disease is a continuum that ranges from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. The most typical presentation is limb-girdle muscular dystrophy type 2L (LGMD2L) with late-onset proximal lower-limb weakness in the fourth or fifth decade (range 15-70 years). Less common is Miyoshi-like disease (Miyoshi muscular dystrophy 3) with early-adult-onset calf distal myopathy (around age 20 years). Incidental hyperCKemia may be present even earlier. Initial symptoms are walking difficulties, reduced sports performance, and difficulties in standing on toes as well as nonspecific exercise myalgia and/or burning sensation in the calf muscles. Muscle weakness and atrophy are frequently asymmetric. Cardiac findings can include cardiomyopathy and arrhythmias and/or left ventricular dysfunction. Bulbar or respiratory symptoms have not been reported. Females have milder disease manifestations than males. Disease progression is slow in both the LGMD and distal forms; ambulation is preserved until very late in the disease course. Life span is normal. AP-4-Associated Hereditary Spastic Paraplegia Synonyms: Adaptor Protein Complex 4 Deficiency (AP-4 Deficiency), AP-4-Associated HSP, AP-4 Deficiency Syndrome AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. APC-Associated Polyposis Conditions APC-associated polyposis conditions include (classic or attenuated) familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). -FAP is a colorectal cancer (CRC) predisposition syndrome that can manifest in either classic or attenuated form. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, beginning on average at age 16 years (range 7-36 years). For those with the classic form of FAP, 95% of individuals have polyps by age 35 years; CRC is inevitable without colectomy. The mean age of CRC diagnosis in untreated individuals is 39 years (range 34-43 years). The attenuated form is characterized by multiple colonic polyps (average of 30), more proximally located polyps, and a diagnosis of CRC at a later age than in classic FAP. For those with an attenuated form, there is a 70% lifetime risk of CRC and the mean age of diagnosis is 50-55 years. Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions, desmoid tumors, adrenal masses, and other associated cancers. -GAPPS is characterized by proximal gastric polyposis, increased risk of gastric adenocarcinoma, and no duodenal or colonic involvement in most individuals reported. APOB-Related Familial Hypobetalipoproteinemia Individuals with biallelic APOB-related familial hypobetalipoproteinemia (APOB-FHBL) may present from infancy through to adulthood with a range of clinical symptoms including deficiency of fat-soluble vitamins and gastrointestinal and neurologic dysfunction. Affected individuals typically have plasma total cholesterol, LDL cholesterol, and apo B levels below the fifth centile for age and sex. Acanthocytosis, elevated liver enzymes, and hyperbilirubinemia may also be found. The most common clinical findings are hepatomegaly, steatorrhea, and failure to thrive / growth deficiency. In the absence of treatment, affected individuals can develop atypical pigmentation of the retina; progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle pain or weakness; dysarthria; ataxia; tremors; and steatohepatitis, fibrosis, and rarely, cirrhosis of the liver. Individuals with a heterozygous, typically truncating pathogenic variant in APOB are usually asymptomatic with mild liver dysfunction and hepatic steatosis. However, about 5%-10% of individuals with heterozygous APOB-FHBL develop relatively more severe nonalcoholic steatohepatitis requiring medical attention and occasionally progressing to cirrhosis, albeit very rarely. ARID1B-Related Disorder ARID1B-related disorder (ARID1B-RD) constitutes a clinical continuum, from classic Coffin-Siris syndrome to intellectual disability with or without nonspecific dysmorphic features. Coffin-Siris syndrome is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hypertrichosis, and sparse scalp hair. Frequencies of other features, such as developmental delay (with speech often more affected than motor development), is consistent across the clinical spectrum, and may include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings seen in individuals with ARID1BRD include feeding difficulties, slow growth, ophthalmologic abnormalities, hearing impairment, seizures, attention-deficit/hyperactivity disorder, and autistic features. ARSACS Synonyms: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay, Autosomal Recessive Spastic Ataxia Type 6, ATX/HSP-SACS Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is clinically characterized by a progressive cerebellar ataxia, peripheral neuropathy, and spasticity. Disease onset of classic ARSACS is often in early childhood, leading to delayed walking because of gait unsteadiness in very young toddlers, while an increasing number of individuals with disease onset in teenage or early-adult years are now being described. Typically the ataxia is followed by lower-limb spasticity and later by peripheral neuropathy – although pronounced peripheral neuropathy has been observed as a first sign of ARSACS. Oculomotor disturbances, dysarthria, and upper-limb ataxia develop with slower progression than the other findings. Brain imaging demonstrates atrophy of the superior vermis and the cerebellar hemisphere with additional findings on MRI, such as linear hypointensities in the pons and hyperintense rims around the thalami. Many affected individuals (though not all) have yellow streaks of hypermyelinated fibers radiating from the edges of the optic disc noted on ophthalmologic exam, and thickened retinal fibers can be demonstrated by optical coherence tomography. Mild intellectual disability, hearing loss, and urinary urgency and incontinence have been reported in some individuals. ASAH1-Related Disorders The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). -Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. -SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years. ASPM Primary Microcephaly Synonyms: ASPM Microcephalia Vera, Microcephaly Primary Hereditary 5 (MCPH5) ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (>3 standard deviations [SD] below the mean for age) usually present at birth and always present before age one year and (2) the absence of other congenital anomalies. While developmental milestones are usually normal in young children, older children have variable levels of intellectual disability. Neurologic examination is usually normal except for mild spasticity. Seizures are not common. ASXL3-Related Disorder Synonym: Bainbridge-Ropers Syndrome (BRPS) ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies. ATN1-Related Neurodevelopmental Disorder Synonyms: ATN1-Related Neurodevelopmental Condition; CHEDDA (Congenital Hypotonia, Epilepsy, Developmental Delay, Digit Abnormalities) ATN1-related neurodevelopmental disorder (ATN1-NDD) is characterized by developmental delay / intellectual disability. Other neurologic findings can include infantile hypotonia, brain malformations, epilepsy, cortical visual impairment, and hearing loss. Feeding difficulties, present in some individuals, may require gastrostomy support when severe; similarly, respiratory issues, present in some, may require respiratory support after the neonatal period. Distinctive facial features and hand and foot differences are common. Other variable findings can include cardiac malformations and congenital anomalies of the kidney and urinary tract (CAKUT). To date, 18 individuals with ATN1-NDD have been identified. ATP1A3-Related Neurologic Disorders ATP1A3-related neurologic disorders represent a clinical continuum in which at least three distinct phenotypes have been delineated: rapid-onset dystonia-parkinsonism (RDP); alternating hemiplegia of childhood (ACH); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). However, some affected individuals have intermediate phenotypes or only a few features that do not fit well into one of these major phenotypes. -RDP has been characterized by: abrupt onset of dystonia over days to weeks with parkinsonism (primarily bradykinesia and postural instability); common bulbar involvement; and absence or minimal response to an adequate trial of L-dopa therapy, with few exceptions. Often fever, physiologic stress, or alcoholic binges trigger the onset of symptoms. After their initial appearance, symptoms often stabilize with little improvement; occasionally second episodes occur with abrupt worsening of symptoms. Rarely, affected individuals have reported a more gradual onset of symptoms over weeks to months. Anxiety, depression, and seizures have been reported. Age of onset ranges from four to 55 years, although a childhood variation of RDP with onset between ages nine and 14 months has been reported. -AHC is a complex neurodevelopmental syndrome most frequently manifesting in infancy or early childhood with paroxysmal episodic neurologic dysfunction including alternating hemiparesis or dystonia, quadriparesis, seizure-like episodes, and oculomotor abnormalities. Episodes can last for minutes, hours, days, or even weeks. Remission of symptoms occurs with sleep and immediately after awakening. Over time, persistent neurologic deficits including oculomotor apraxia, ataxia, choreoathetosis, dystonia, parkinsonism, and cognitive and behavioral dysfunction develop in the majority of those affected; more than 50% develop epilepsy in addition to their episodic movement disorder phenotype. -CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is characterized by episodes of ataxic encephalopathy and/or weakness during and after a febrile illness. Onset is between ages six months and four years. Some acute symptoms resolve; progression of sensory losses and severity vary. ATP6V0A2-Related Cutis Laxa Synonyms: ATP6V0A2-CDG, Autosomal Recessive Cutis Laxa Type 2A (ARCL2A) ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression. ATP7A-Related Copper Transport Disorders Menkes disease, occipital horn syndrome (OHS), and ATP7A-related distal motor neuropathy (DMN) are disorders caused by pathogenic variants in the ATP7A, the X-linked gene that encodes a copper-transporting ATPase. Classic Menkes disease typically presents after a six- to 12-week period of good health following a normal pregnancy and birth. Feeding difficulties and/or a seizure event are the usual initial presenting features. In the absence of a known or suspected positive family history, these issues prompt a diagnostic evaluation that may consume months, by which time hypotonia and significant neurodevelopmental delays are evident. OHS is milder neurologically and is not recognized until late childhood or adolescence. Both phenotypes involve subnormal serum copper levels and other manifestations of perturbed copper metabolism, including connective tissue weakness. In contrast, ATP7A-related DMN typically presents in early adulthood with isolated muscle weakness and atrophy, in the absence of overt copper metabolism abnormalities. -While nonspecific temperature instability and hypoglycemia in the neonatal period may be noted retrospectively, infants with classic Menkes disease appear healthy until age 1.5 to three months, when loss of developmental milestones, hypotonia, seizures, and failure to thrive occur. The diagnosis is usually suspected when infants exhibit neurologic findings and concomitant characteristic changes of the hair (short, sparse, coarse, twisted, and often lightly pigmented). Without treatment, premature death is typical, often by age three years. -OHS is characterized by "occipital horns," distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticula, inguinal hernias, and vascular tortuosity. Intellect is normal or slightly reduced. -ATP7A-related DMN, an adult-onset disorder resembling Charcot-Marie-Tooth disease, shares none of the clinical or biochemical abnormalities characteristic of Menkes disease or OHS. ATP8B1 Deficiency Synonym: FIC1 Deficiency The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. Abetalipoproteinemia Synonym: Bassen-Kornzweig Syndrome Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life. Aceruloplasminemia Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition. Achondrogenesis Type 1B Synonym: ACG1B, SLC26A2-Related Achondrogenesis Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. Death occurs prenatally or shortly after birth. Achondroplasia Synonym: FGFR3-Related Achondroplasia Achondroplasia is the most common cause of disproportionate short stature. Affected individuals have rhizomelic shortening of the limbs, macrocephaly, and characteristic facial features with frontal bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. Additional complications include obstructive sleep apnea, middle ear dysfunction, kyphosis, and spinal stenosis. Achromatopsia Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middlewavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have complete achromatopsia, with total lack of function of all three types of cones. Rarely, individuals have incomplete achromatopsia, in which one or more cone types may be partially functioning. The manifestations are similar to those of individuals with complete achromatopsia, but generally less severe. Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography. Acid Sphingomyelinase Deficiency The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type. As more affected individuals are treated with ERT for longer periods of time, the natural history of ASMD is likely to change. The most common presenting symptom in untreated NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Growth failure typically becomes evident by the second year of life. Psychomotor development progresses no further than the 12month level, after which neurologic deterioration is relentless. This feature may not be amenable to ERT. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children, although it is unclear if ERT will have an impact on this. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most untreated children succumb before the third year of life. NPD-B generally presents later than NPDA, and the manifestations are less severe. NPD-B is characterized in untreated individuals by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some central nervous system manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B, even when untreated. Acute Intermittent Porphyria Synonyms: PBGD Deficiency, Porphobilinogen Deaminase Deficiency Acute intermittent porphyria (AIP), an autosomal dominant disorder, occurs in heterozygotes for an HMBS pathogenic variant that causes reduced activity of the enzyme porphobilinogen deaminase. AIP is considered "overt" in a heterozygote who was previously or is currently symptomatic; AIP is considered "latent" in a heterozygote who has never had symptoms, and typically has been identified during molecular genetic testing of at-risk family members. Note that GeneReviews does not use the term "carrier" for an individual who is heterozygous for an autosomal dominant pathogenic variant; GeneReviews reserves the term "carrier" for an individual who is heterozygous for an autosomal recessive disorder and thus is not expected to ever develop manifestations of the disorder. -Overt AIP is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia. Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 3%-8% (mainly women) have recurrent attacks (defined as >3 attacks/year) that may persist for years. Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. -Latent AIP. While all individuals heterozygous for an HMBS pathogenic variant that predisposes to AIP are at risk of developing overt AIP, most have latent AIP and never have symptoms. Adenine Phosphoribosyltransferase Deficiency Synonyms: 2,8-Dihydroxyadeninuria; APRT Deficiency Adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production and renal excretion of 2,8-dihydroxyadenine (DHA), which leads to kidney stone formation and crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD). Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age; in at least 50% of affected persons symptoms do not occur until adulthood. If adequate treatment is not provided, approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD), usually in adult life. Adenosine Deaminase 2 Deficiency Synonyms: ADA2 Deficiency, Deficiency of Adenosine Deaminase 2 (DADA2) Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2. Adenosine Deaminase Deficiency Synonyms: ADA Deficiency, ADA-SCID Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes: -Severe combined immunodeficiency disease (SCID), often diagnosed by age six months and usually by age 12 months; -Less severe "delayed" onset combined immune deficiency (CID), usually diagnosed between age one and ten years; -"Late/adult onset" CID, diagnosed in the second to fourth decades; -Benign "partial ADA deficiency" (very low or absent ADA activity in erythrocytes but greater ADA activity in nucleated cells), which is compatible with normal immune function. Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADAdeficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection. Adult Refsum Disease Synonym: Classic Refsum Disease Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life. Aicardi Syndrome Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis. Aicardi-Goutières Syndrome Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known. Alagille Syndrome Synonyms: Arteriohepatic Dysplasia, Syndromic Bile Duct Paucity Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability; this variability is seen even among individuals from the same family. The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects (primarily involving the pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Renal abnormalities, growth failure, developmental delays, splenomegaly, and vascular abnormalities may also occur. Alexander Disease Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous GFAP pathogenic variant, comprises a continuous clinical spectrum most recognizable in infants and children and a range of nonspecific neurologic manifestations in adults. This chapter discusses the spectrum of Alexander disease as four forms: neonatal, infantile, juvenile, and adult. The neonatal form begins in the first 30 days after birth with neurologic findings (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive), followed by severe developmental delay and regression, seizures, megalencephaly, and typically death within two years. The infantile form is characterized by variable developmental issues: initially some have delayed or plateauing of acquisition of new skills, followed in some by a loss of gross and fine motor skills and language during in the first decade or in others a slow disease course that spans decades. Seizures, often triggered by illness, may be less frequent/severe than in the neonatal form. The juvenile form typically presents in childhood or adolescence with clinical and imaging features that overlap with the other forms. Manifestations in early childhood are milder than those in the infantile form (e.g., mild language delay may be the only developmental abnormality or, with language acquisition, hypophonia or nasal speech may alter the voice, often prior to appearance of other neurologic features). Vomiting and failure to thrive as well as scoliosis and autonomic dysfunction are common. The adult form is typically characterized by bulbar or pseudobulbar findings (palatal myoclonus, dysphagia, dysphonia, dysarthria or slurred speech), motor/gait abnormalities with pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign), or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). Others may have hemiparesis or hemiplegia with a relapsing/remitting course or slowly progressive quadriparesis or quadriplegia. Other neurologic features can include sleep apnea, diplopia or disorders of extraocular motility, and autonomic dysfunction. Alkaptonuria Synonym: Alcaptonuria Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are dark urine or urine that turns dark on standing, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Ochronosis generally occurs after age 30 years; arthritis often begins in the third decade. Other manifestations can include pigment in the sclera, ear cartilage, and skin of the hands; aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation; renal stones; prostate stones; and hypothyroidism. Allan-Herndon-Dudley Syndrome Synonyms: MCT8 Deficiency, MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities. Alpha-1 Antitrypsin Deficiency Synonyms: AAT Deficiency, A1AT Deficiency, AATD, Alpha-1 Antiprotease Deficiency Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD. Alpha-Mannosidosis Synonym: α-Mannosidosis Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1) A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2) A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (type 3) Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease – mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome Synonym: ATR-X Syndrome Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants. Alpha-Thalassemia lpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome (caused by deletion/inactivation of all four alpha globin [α-globin] genes; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three α-globin genes; --/-α). Hb Bart syndrome, the more severe form, is characterized by prenatal onset of generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Death usually occurs in the neonatal period. HbH disease has a broad phenotypic spectrum: although clinical features usually develop in the first years of life, HbH disease may not present until adulthood or may be diagnosed only during routine hematologic analysis in an asymptomatic individual. The majority of individuals have enlargement of the spleen (and less commonly of the liver), mild jaundice, and sometimes thalassemia-like bone changes. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to infections or exposure to oxidant drugs. Alport Syndrome Synonyms: Familial Nephritis, Hereditary Nephritis, Thin Basement Membrane Disease, Thin Basement Membrane Nephropathy In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare. Alström Syndrome Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family. Alzheimer Disease Overview Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory (often called mild cognitive impairment or MCI) and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, visual complaints, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. Approximately 95% of all AD is late onset (age >60-65 years) and 5% is early onset (age <60-65 years). Establishing the diagnosis of Alzheimer disease relies on clinical-neuropathologic assessment. Neuropathologic findings of β-amyloid plaques, intraneuronal neurofibrillary tangles (containing tau protein), and amyloid angiopathy remain the gold standard for diagnosis. -The plaques should stain positively with β-amyloid antibodies and negative for prion antibodies (which are diagnostic of prion diseases). -The numbers of plaques and tangles must exceed those found in age-matched controls without dementia. Guidelines for the quantitative assessment of these changes exist [Montine et al 2012]. -Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala; frequently there is accumulation of TDP-43 protein [James et al 2016, Lemstra et al 2017]. The clinical diagnosis of AD, based on clinical signs of slowly progressive dementia and neuroimaging findings of gross cerebral cortical atrophy, is correct approximately 80%-90% of the time. Greater precision can be obtained by use of more sophisticated studies such as amyloid PET imaging, CSF concentrations of amyloid and tau, and (in the near future) tau PET imaging and plasma concentration of β amyloid [Dubois et al 2014, Gabelle et al 2015, Sutphen et al 2015, Mattsson et al 2018]. Differential diagnosis of Alzheimer disease includes the following: -Treatable forms of cognitive decline including depression, chronic drug intoxication, chronic CNS infection, thyroid disease, vitamin deficiencies (especially B12 and thiamine), CNS angiitis, and normal-pressure hydrocephalus [Bird & Miller 2008]. CT and MRI can identify some of these other causes of dementia, including neoplasms, normal-pressure hydrocephalus, and cerebral vascular disease. -Other degenerative disorders associated with dementia, such as frontotemporal dementia (including frontotemporal dementia with parkinsonism-17; FTDP-17), Picks disease, Parkinson disease, diffuse Lewy body disease (LBD), Creutzfeldt-Jakob disease, and CADASIL [Loy et al 2014, Ferrari et al 2018]. Amyotrophic Lateral Sclerosis Overview Synonym: Lou Gehrig Disease Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease involving both the brain and spinal cord. While it has traditionally been perceived to be a syndrome primarily affecting motor neurons, there is increasing recognition that additional areas within the frontal and temporal lobes are involved to varying degrees in a subset of individuals. In addition, other systems outside the nervous system may be involved, such as bone (Paget disease of the bone) and muscle (inclusion body myopathy). The location and extent of the degeneration determines the clinical picture, which by definition includes motor decline, and may include cognitive and/or behavioral symptoms as well. There is wide variability in presentation, progression, and survival [Hardiman et al 2017]. Motor Involvement Motor symptoms occur as the result of degeneration of both upper and lower motor neurons. Upper motor neurons (UMNs), located in the motor cortex of the frontal lobe, send their axons through the great corticofugal tracts to the brain stem (corticobulbar neurons) and the spinal cord (corticospinal neurons) to influence patterned activity of the lower motor neurons (LMNs). Additional UMN influences on the LMN are carried over descending pathways of the brain stem. UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone. LMNs, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations. Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and lability of affect, but not necessarily mood. A diagnostic feature of ALS, typically not seen in other neurodegenerative disorders, is the presence of hyperreflexia in segmental regions of muscle atrophy, unaccompanied by sensory disturbance. At presentation, limb involvement occurs more often than bulbar involvement. Various subtypes of ALS have been identified: "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties: Limb-onset ALS. -Progressive muscular atrophy, where lower motor neurons are primarily involved. -UMN-predominant ALS Neuropsychological Involvement Recent studies of both the genetics and neuropathology of ALS have reinforced the understanding that while the syndrome of ALS by definition involves the motor system, wider frontotemporal degeneration may give rise to at least some degree of cognitive and behavioral dysfunction. White matter structural abnormalities in the frontal and temporal lobes of individuals with ALS who do not demonstrate evidence of cognitive decline have also been identified [Abrahams et al 2005]. It has been reported that upwards of 45% of individuals with ALS have some degree of cognitive impairment at some time during their illness [Raaphorst et al 2012, Beeldman et al 2016]. Several neuropsychological domains may be affected. The most common deficits are in executive function (demonstrated by difficulties with emotional and impulse control, flexible thinking, self-monitoring, planning and prioritizing, organization, task initiation, and working memory), verbal fluency, and social cognition (demonstrated by difficulties interpreting the emotional states of others and lack of insight in social situations) [Beeldman et al 2016]. Symptoms can range from mild to severe. In the severe end of the spectrum, frontotemporal dementia (FTD), particularly the behavioral variant of FTD (bvFTD), marked by severe apathy and progressive declines in socially appropriate behavior, judgment, and self-control, as well as personality change, has been reported to range from 5% to 27% in various series [Raaphorst et al 2012]. However, a more recent Italian population-based study suggests that the incidence may be closer to 10% [Montuschi et al 2015], or perhaps close to 5%. Additionally, individuals with ALS with FTD (ALS/FTD) experience more language disturbance (difficulty with grammar and sentence and syntactic comprehension) than is generally associated with bvFTD alone [Saxon et al 2017]. Generally, visuospatial dysfunction is not present. ALS/FTD tends to be associated with bulbar-onset ALS, with its incidence reported to be 39%61% [Raaphorst et al 2012]. Either motor or neuropsychological manifestations may appear first in individuals with ALS/FTD. When features of ALS appear first, FTD becomes apparent on average 16 months later, whereas when features of FTD appear first, ALS becomes apparent on average 18 months later [Raaphorst et al 2012]. Individuals with ALS with milder neuropsychological manifestations may exhibit executive dysfunction and deficits in verbal and nonverbal fluency and concept formation early in the disease course, particularly in the presence of bulbar onset of disease [Schreiber et al 2005]. These more subtle manifestations may well be missed with routine mental status examination. Formal neuropsychological testing can be helpful in identifying subtle alterations, particularly alterations that may be masked by socially favorable traits such as empathy and optimism. These favorable traits, well known to specialists dealing with ALS, may lead to considerable bonding between the health care team and persons with ALS. Affected individuals are also generally well liked by their families, as social connections are retained and their "positive" attitudes are appreciated. Course Regardless of the initial manifestations, atrophy and weakness eventually spread to other muscles in additional regions. Oculomotor neurons are generally resistant to degeneration in ALS but may be affected in individuals with a long disease course, particularly when life is extended by ventilatory support. Once all muscles of communication and expression are paralyzed, the individual is "locked in." In some instances, eye movements may remain intact, allowing communication by way of special devices. Death most often results from failure of the respiratory muscles, but other causes, such as pulmonary embolism or cardiac arrhythmias, may supervene. Overall, ALS is a highly heterogeneous disorder with widely varying ages of onset, ranging from childhood to the ninth decade. Males are more commonly affected than females in a ratio of about 1.3/1. The mean age of onset in males is approximately 55 years, while females are most commonly affected in their mid-60s. Individuals with genetic forms of ALS tend to have an earlier onset of symptoms. Disease duration is similarly variable, ranging from months to several decades. About half of affected individuals expire within five years of symptom onset. Individuals (both male and female) younger than age 55 years at onset tend to survive longer [Magnus et al 2002]. Traditionally, ALS has been discussed in light of the individual's family history, with "familial ALS" indicating that two or more close relatives are known to be affected with ALS and "sporadic ALS" indicating that no other relatives are known to have ALS. As genetic research in ALS has evolved and the clinical use of genetic testing has increased, this terminology is shifting. In this GeneReview, "genetic ALS" refers to ALS caused by a pathogenic variant in a known ALS gene, regardless of family history. "ALS of unknown cause" will refer to ALS in which a pathogenic variant in a known ALS gene has not been identified, regardless of family history. It is estimated that about 10%-15% of individuals with ALS have genetic ALS. Some of the genetic forms of ALS may confer particular clinical characteristics, although intra- and interfamilial variability of age at onset and disease progression is common (see Table 2a and Table 2b). Establishing the Diagnosis of ALS The diagnosis of ALS requires characteristic clinical features and specific findings on electrodiagnostic testing, as well as exclusion of other health conditions with related manifestations (see Differential Diagnosis of ALS). The most commonly employed consensus criteria for its diagnosis are the revised Escorial criteria [Brooks et al 2000]. Additional evaluation of electromyographic information as outlined in the Awaji criteria [de Carvalho et al 2008] may establish the diagnosis more quickly than the Escorial criteria alone. Due to variability in clinical presentation and the lack of biomarkers for the disease, it is not uncommon for several months to a year to pass from symptom onset to a firm diagnosis. Andersen-Tawil Syndrome Synonym: Long QT Syndrome Type 7 (LQTS Type 7) Andersen-Tawil syndrome (ATS) is characterized by a triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described. Androgen Insensitivity Syndrome Synonym: Testicular Feminization Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes: -Complete androgen insensitivity syndrome (CAIS), with typical female external genitalia. -Partial androgen insensitivity syndrome (PAIS) with predominantly female, predominantly male, or ambiguous external genitalia. -Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia. Angelman Syndrome Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. Apert Syndrome Synonym: Acrocephalosyndactyly Type I Apert syndrome is characterized by the presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails. Almost all affected individuals have coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures. The midface in Apert syndrome is underdeveloped as well as retruded; a subset of affected individuals have cleft palate. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger are sometimes also involved. Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae) are also common. Multilevel airway obstruction may be present and can be due to narrowing of the nasal passages, tongue-based airway obstruction, and/or tracheal anomalies. Nonprogressive ventriculomegaly is present in a majority of individuals, with a small subset having true hydrocephalus. Most individuals with Apert syndrome have normal intelligence or mild intellectual disability; moderateto-severe intellectual disability has been reported in some individuals. A minority of affected individuals have structural cardiac abnormalities, true gastrointestinal malformations, and anomalies of the genitourinary tract. Arginase Deficiency Synonyms: ARG1 Deficiency, Arginase-1 Deficiency, Hyperargininemia rginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms. Argininosuccinate Lyase Deficiency Synonyms: Argininosuccinic Acid Lyase Deficiency, Argininosuccinic Aciduria, ASLD eficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form or a late-onset form: -The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. -In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency that appear to be unrelated to the severity or duration of hyperammonemic episodes: -Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability) -Liver disease (hepatitis, cirrhosis) -Trichorrhexis nodosa (coarse brittle hair that breaks easily) -Systemic hypertension Aromatic L-Amino Acid Decarboxylase Deficiency Synonym: AADC Deficiency Individuals with aromatic L-amino acid decarboxylase (AADC) deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life. The most common initial symptoms are often nonspecific, and include feeding difficulties, hypotonia, and developmental delay. More specific symptoms include oculogyric crises (which occur in the vast majority of affected individuals, typically starting in infancy), movement disorders (especially dystonia), and autonomic dysfunction (excessive sweating, temperature instability, ptosis, nasal congestion, hypoglycemic episodes). Sleep disturbance is present in a majority of affected individuals and can include insomnia, hypersomnia, or both. Mood disturbance, including irritability and anxiety, are also common. Brain MRI is typically either normal or may demonstrate nonspecific abnormalities, such as mild diffuse cerebral atrophy or delayed myelination. Seizures are an uncommon finding, occurring in fewer than 5% of affected individuals. Arrhythmogenic Right Ventricular Cardiomyopathy Overview Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary cardiomyopathy that is often diagnosed after an individual presents with arrhythmia findings. Presenting manifestations include heart palpitations, syncope, or even sudden death. ARVC typically presents in adults (mean age of first presentation in one large cohort study was 36 ± 14 years [Groeneweg et al 2015]), although it may less commonly be seen in children, most often during the late second decade. ARVC typically affects the right ventricular apex, the base of the right ventricle, and the right ventricle outflow tract. The arrhythmias in ARVC most frequently arise from the right ventricle and have left bundle branch block morphology. The disease is progressive and is characterized by fibrofatty replacement of the myocardium. Pathology in ARVC may also extend to involve the left ventricle, resulting in regional left ventricular dysfunction. Note: There is a movement within clinical cardiology to merge ARVC with other arrhythmogenic cardiomyopathies because the left ventricle can become involved, or even become predominantly involved, especially in individuals with DSP pathogenic variants; left ventricular involvement has also been reported in individuals with variants in genes encoding other desmosomal proteins (e.g., DSC2) that were previously associated with ARVC. The 2010 Task Force Criteria (see Diagnosis) are still used to establish a clinical diagnosis of ARVC [Marcus et al 2010], and these criteria do not incorporate other arrhythmogenic cardiomyopathies, leading to potential underdiagnosis. An international expert panel convened to reevaluate the diagnostic approach to arrhythmogenic cardiomyopathies and developed new criteria, the Padua Criteria [Corrado et al 2020]. There are ongoing studies to evaluate the proposed Padua Criteria in larger cohorts. Readers should be aware of the potential overlap/differentiation between ARVC and other arrhythmogenic cardiomyopathies. Progression. The four described stages of ARVC are the following [Te Riele et al 2021, Wallace & Calkins 2021]: 1.The concealed phase is the earliest phase and is without electrical, structural, or histologic changes as typically seen in ARVC. If scar formation is present, it can be so minimal that it goes undetected by cardiac MRI. However, affected individuals might experience sustained ventricular arrhythmias, and there is a potential risk of sudden cardiac death. 2.An overt electrical disorder characterized by symptomatic arrhythmias including palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia 3.Right ventricular failure 4.A biventricular pump failure (resembling dilated cardiomyopathy) [Dalal et al 2006] Cardiomyopathy in ARVC is not always isolatedto right ventricular involvement. There is evidence that the left ventricle can often become involved as well. The cohort of individuals with ARVC followed by Bhonsale et al [2015] had an overall incidence of left ventricular dysfunction of 14% over the follow-up interval, with 5% experiencing heart failure. In a separate cohort, 55% of individuals with DSP pathogenic variants experienced left ventricular predominant cardiomyopathy [Smith et al 2020]. Arrhythmia. The principal characteristic of arrhythmogenic cardiomyopathies is the tendency for ventricular arrhythmia in the absence of overt ventricular dysfunction. Arrhythmias in ARVC include ventricular tachycardia and ventricular fibrillation. Atrial fibrillation has also been described in ARVC. One recent study identified atrial fibrillation occurring in one in seven individuals with a diagnosis of definite ARVC (by 2010 Task Force Criteria), with atrial fibrillation onset at a median age of 51 years [Baturova et al 2020]. The risk of atrial fibrillation increases with severity of the ARVC phenotype compared to individuals who have an ARVC-related pathogenic variant but do not have clinical manifestations of ARVC (and thus do not meet 2010 Task Force Criteria). Prognosis. Two long-term studies of individuals with ARVC suggested that survival was greater than 72% at six years following diagnosis. In individuals with ARVC, cardiac mortality and need for transplant are less than 5% [Bhonsale et al 2015, Groeneweg et al 2015]. An individual with a prior history of sustained ventricular tachycardia or fibrillation is at increased risk for subsequent ventricular arrhythmias and sudden cardiac death. Prognosis is worse for individuals with more than one ARVC-related pathogenic variant, with an increased propensity to arrhythmias and progression to cardiomyopathy [Bao et al 2013, Rigato et al 2013, Bhonsale et al 2015, Groeneweg et al 2015]. Prevalence. The prevalence of clinical ARVC is estimated at 1:1,000-1,250 in the general population, although most of this data derives from cohorts of European ancestry [Wallace & Calkins 2021]. The prevalence of ARVC is greater in certain regions; in Italy and Greece (island of Naxos), it can be as high as 0.4%-0.8% [Thiene & Basso 2001]. Arterial Tortuosity Syndrome Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder, which may include soft or doughy hyperextensible skin, joint hypermobility, inguinal hernia, and diaphragmatic hernia. Skeletal findings include pectus excavatum or carinatum, arachnodactyly, scoliosis, knee/elbow contractures, and camptodactyly. The cardiovascular system is the major source of morbidity and mortality with increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree, and for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs). Arylsulfatase A Deficiency Synonyms: ARSA Deficiency, Metachromatic Leukodystrophy Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the lateinfantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms. Asparagine Synthetase Deficiency Synonym: ASNS Deficiency Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern. Ataxia with Oculomotor Apraxia Type 1 Synonym: AOA1 Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed. Ataxia with Oculomotor Apraxia Type 2 Synonym: AOA2 Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset of ataxia between age three and 30 years after initial normal development, axonal sensorimotor neuropathy, oculomotor apraxia, cerebellar atrophy, and elevated serum concentration of alpha-fetoprotein (AFP). Ataxia with Vitamin E Deficiency Synonyms: Ataxia with Isolated Vitamin E Deficiency, AVED Untreated ataxia with vitamin E deficiency (AVED) generally manifests between ages five and 15 years. The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. Although age of onset and disease course are more uniform within a given family, disease manifestations and their severity can vary even among sibs. When lifelong high-dose vitamin E supplementation is initiated in presymptomatic individuals, manifestations of AVED do not develop. Ataxia-Telangiectasia The phenotypic spectrum of ataxia-telangiectasia (A-T), a multisystem disorder, is a continuum ranging from classic A-T at the severe end and variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant A-T on this spectrum helps understand differences in disease course, rate of progression, and life expectancy. Classic A-T is characterized by childhood onset of progressive neurologic manifestations (initially cerebellar ataxia, followed typically by extrapyramidal involvement and peripheral sensorimotor neuropathy), immunodeficiency (variably associated with abnormalities of humoral immunity, cellular immunity, or combined immune deficiency), pulmonary disease (resulting from recurrent infections, immune deficiency, aspiration, interstitial lung disease, and neurologic abnormalities), and increased risk of malignancy. Although it is generally accepted that intellectual disability is not common in A-T, disturbances in cerebellar as well as non-cerebellar brain areas and networks may result in cognitive deficits. Increased sensitivity to ionizing radiation (x-ray and gamma ray) can result in severe side effects from such treatments. Life expectancy is significantly reduced due to cancer, pulmonary disease, and infections. Variant A-T has a significantly milder disease course. While cerebellar ataxia can be absent, extrapyramidal movement disorders are common (typically dystonia and dystonic tremor) and most individuals have manifestations of axonal sensorimotor polyneuropathy. In contrast to classic A-T, immune function is generally normal, respiratory infections are not increased, and pulmonary disease is not a major feature. However, risk of developing malignancies is increased, particularly in premenopausal females who have an increased risk of developing breast cancer and hematologic malignancies. Au-Kline Syndrome Au-Kline syndrome is characterized by developmental delay and hypotonia with moderate-tosevere intellectual disability, and typical facial features that include long palpebral fissures, ptosis, shallow orbits, large and deeply grooved tongue, broad nose with a wide nasal bridge, and downturned mouth. There is frequently variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating). Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are also reported in the majority of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, osteopenia, and other skeletal anomalies. Autoimmune Lymphoproliferative Syndrome Synonym: ALPS Autoimmune lymphoproliferative syndrome (ALPS), homeostasis, is characterized by the following: caused by defective lymphocyte •Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age •Autoimmune disease, mostly directed toward blood cells •Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (α/β-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published. Autosomal Dominant Epilepsy with Auditory Features Synonyms: ADEAF, Autosomal Dominant Lateral Temporal Epilepsy (ADLTE) Autosomal dominant epilepsy with auditory features (ADEAF) is a focal epilepsy syndrome with auditory symptoms and/or receptive aphasia as prominent ictal manifestations. The most common auditory symptoms are simple unformed sounds including humming, buzzing, or ringing; less common forms are distortions (e.g., volume changes) or complex sounds (e.g., specific songs or voices). Ictal receptive aphasia consists of a sudden onset of inability to understand language in the absence of general confusion. Less commonly, other ictal symptoms may occur, including sensory symptoms (visual, olfactory, vertiginous, or cephalic) or motor, psychic, and autonomic symptoms. Most affected individuals have focal to bilateral tonic-clonic seizures, usually accompanied by "focal aware" and "focal impaired-awareness" seizures, with auditory symptoms as a major focal aware seizure manifestation. Some persons have seizures precipitated by sounds such as a ringing telephone. Age at onset is usually in adolescence or early adulthood (range: age 4-50 years). The clinical course of ADEAF is benign. Seizures are usually well controlled after initiation of medical therapy. Autosomal Dominant Robinow Syndrome Synonym: Fetal Face Syndrome Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above. Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Synonym: Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), ADSHE Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is a seizure disorder characterized by clusters of nocturnal motor seizures that are often stereotyped and brief (<2 minutes). They vary from simple arousals from sleep to dramatic, often hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Age of onset ranges from infancy to adulthood. About 80% of individuals develop ADSHE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidities, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. Autosomal Dominant TRPV4 Disorders The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: a) CharcotMarie-Tooth disease type 2C. b) Scapuloperoneal spinal muscular atrophy. c) Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: 1)Familial digital arthropathy-brachydactyly. 2) Autosomal dominant brachyolmia. 3) Spondylometaphyseal dysplasia, Kozlowski type. 4) Spondyloepiphyseal dysplasia, Maroteaux type. 5)Parastremmatic dysplasia. 6) Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias. Autosomal Dominant Tubulointerstitial Kidney Disease – MUC1 Synonyms: ADTKD-MUC1, Medullary Cystic Kidney Disease Type 1 (MCKD1), MUC1 Kidney Disease (MKD) Autosomal dominant tubulointerstitial kidney disease – MUC1 (ADTKD-MUC1) is characterized by slowly progressive tubulointerstitial disease that leads to end-stage renal disease (ESRD) and the need for dialysis or kidney transplantation. The rate of loss of kidney function for individuals is variable within and between families, with a median age of onset of end-stage renal disease (ESRD) of 46 years (range: ages 20-70 years). There are no other systemic manifestations. Autosomal Dominant Tubulointerstitial Kidney Disease – REN Synonyms: ADTKD-REN, Familial Juvenile Hyperuricemic Nephropathy Type 2 (FJHN2) The two clinical presentations observed in autosomal dominant tubulointerstitial kidney disease – REN (ADTKD-REN) correlate with the renin protein domains affected by the causative REN variants. -Childhood/adolescent onset, the more common presentation (caused by REN variants encoding the signal peptide or prosegment domains), is characterized by decreased estimated glomerular filtration rate, acidosis, hyperkalemia, and anemia early in life, followed by slowly progressive chronic kidney disease (CKD) and gout. -Adult onset, the less common presentation (caused by REN variants encoding the mature renin peptide), is characterized by gout or mild slowly progressive CKD, beginning in the third decade. Anemia, hyperkalemia, and acidemia do not occur. Autosomal Dominant Tubulointerstitial Kidney Disease – UMOD Synonyms: ADTKD-UMOD, Uromodulin Kidney Disease Autosomal dominant tubulointerstitial kidney disease – UMOD (ADTKD-UMOD) is characterized by normal urinalysis and slowly progressive chronic kidney disease (CKD), usually first noted in the teen years and progressing to end-stage renal disease (ESRD) between the third and seventh decades. Hyperuricemia is often present from an early age, and gout (resulting from reduced kidney excretion of uric acid) occurs in the teenage years in about 8% of affected individuals and develops in 55% of affected individuals over time. Autosomal Recessive Congenital Ichthyosis Autosomal recessive congenital ichthyoses (ARCI) are lifelong skin disorders with generalized scaling and variable erythema that typically manifest at birth or early infancy. ARCI encompass several forms of nonsyndromic ichthyosis, which vary significantly in clinical presentation and severity, including the most severe and sometimes fatal form, harlequin ichthyosis; lamellar ichthyosis (LI); (nonbullous) congenital ichthyosiform erythroderma (CIE); and intermediate phenotypes with variable degrees of erythema and size and quality of scale. While these phenotypes fall on a continuum, the phenotypic descriptions are clinically useful for clarifying prognosis and management for affected individuals. Presentation at Birth Children with ARCI are often born prematurely encased in a collodion membrane, a taut, shiny, transparent membrane formed by the thickened cornified layers of the skin, resembling plastic wrap. They can experience high levels of transepidermal water loss with resultant dehydration and hypernatremia. They are at increased risk for skin infections and sepsis during the neonatal period. Tautness of collodion membrane often leads to ectropion, eclabium, and underdeveloped nasal and auricular cartilage. Impaired sucking and pulmonary ventilation may lead to dehydration, malnutrition, hypoxia, and pneumonia. Gradually, within two to four weeks, the collodion membrane dries and peels off, transitioning to generalized scaling and erythema characteristic of the underlying form of ARCI, predominantly LI and CIE. In the rarest form of ARCI, harlequin ichthyosis, babies are born prematurely covered in thick, hard, armor-like plates of cornified skin separated by deep fissures. The taut skin results in deformation of facial features, microcephaly, lack of eyelashes and eyebrows, and sometimes alopecia. Circular bands of hardened skin can lead to vascular constriction, ischemia, and distal edema with a mitten-like casing of hands and feet. Babies are at risk for life-threatening complications in the neonatal and postnatal period, including respiratory insufficiency, dehydration, electrolyte imbalance, temperature instability, feeding issues, bacterial infections, and sepsis, potentially with fatal consequences. A survival rate of 56% has been reported, although that is expected to further increase with improved neonatal intensive care and treatment options, such as early topical and/or systemic retinoids [Ahmed & O'Toole 2014, Glick et al 2017]. Babies with ichthyosis-prematurity syndrome (IPS) are born prematurely between 29 and 35 weeks' gestation. Polyhydramnios is common, and fetal ultrasound may reveal echogenic sediment in the amniotic fluid. The skin at birth is erythrodermic, swollen, and massively thickened with a vernix-like appearance. The most severely affected skin is the scalp, often with cobblestone-like hyperkeratosis. Neonates suffer from severe, sometimes fatal asphyxia due to reduced lung function from intrauterine amniotic fluid aspiration. They have poor Apgar scores and require intensive care and prolonged hospitalization. Nevertheless, the prognosis of IPS is generally excellent. After a few days, the skin sheds and improves significantly, regressing to a mild ichthyosis with underlying erythema that eventually resolves [Khnykin et al 2012]. Postnatal Features Lamellar ichthyosis (LI). LI Typically presents at birth with a collodion membrane, which is replaced by large, whitish, and later brown, plate-like scales in a generalized distribution. Erythroderma (generalized redness of the skin) may be present but is usually mild and not a predominant feature. Other frequent findings are ectropion, eclabium, and scarring alopecia involving the scalp and eyebrows. Built-up scale leads to sweat duct constriction and severe heat intolerance. Accumulation of scale in the external ear canals can lead to occlusion, bacterial colonization, and recurrent infections. Thickening and fissuring of the skin on palms and soles (palmoplantar keratoderma) and curved nails are common. Whole-body scaling and other associated features persist throughout life. Congenital ichthyosiform erythroderma (CIE). At birth, more than 90% of infants with CIE present with a collodion membrane, which gives way to prominent generalized erythroderma and fine, white, semiadherent scales. Palms and soles are often severely thickened (palmoplantar keratoderma), with painful fissures and digital contractures. Ectropion, eclabium, scalp involvement, and loss of eyebrows can occur, although less frequently than in LI. Severe exfoliative erythroderma causes significant metabolic stress through very high caloric loss from inflammation and scaling of the skin, often leading to poor weight gain and growth deficiency if the caloric needs cannot be adequately met [Moskowitz et al 2004]. Similar to LI, scaling, hypohidrosis, and heat intolerance may persist lifelong. Intermediate and rare phenotypes. Many affected individuals with ARCI fall between the LI-CIE spectrum and may be classified as having mild LI or mild CIE, or have overlapping, variable features. In a rare form of congenital ichthyosis, skin involvement may be limited to the trunk and scalp ("bathing suit ichthyosis") due to a temperature-sensitive effect [Marukian et al 2017]. In about 10% of babies with a collodion membrane, a milder "self-healing" phenotype known as "self-improving collodion ichthyosis" occurs [Traupe et al 2014]. Residual skin findings after infancy include generalized dry skin (xerosis), mild or focal scaling, hyperlinear palms, red cheeks, or anhidrosis [Raghunath et al 2003, Vahlquist et al 2010]. Individuals with ARCI born with erythroderma but mostly without collodion membrane who later develop generalized LI and hyperlinear palms and soles have been reported as having LI type 3 [Lefèvre et al 2006]. Harlequin ichthyosis is the most severe form of ARCI. Morbidity and mortality in neonates are high, which can be improved by intensive neonatal care and oral/topical retinoid therapy. However, harlequin ichthyosis remains a serious and chronic skin disorder throughout life. Surviving children gradually shed the armor-like skin plates and develop generalized scaling and intense redness and inflammation of the skin (erythroderma), with a very severe CIE phenotype. Significant growth delay, hypohidrosis and anhidrosis, heat intolerance, and vitamin D deficiency are common. Other features include ocular issues related to persistent severe ectropion, alopecia, palmoplantar keratoderma with painful fissures and digital contractures, chronic constipation, anemia, arthralgia or arthritis, and joint contractures [Ahmed & O'Toole 2014]. Skin cancer. Atypical melanocytic nevi, malignant melanoma, squamous cell carcinoma, and basal cell carcinoma have been reported [Fernandes et al 2010, Natsuga et al 2011]. Albeit the true incidence of skin malignancies among individuals with ARCI has not been established, several case reports indicate that adults with ARCI are at increased risk to develop multiple squamous cell carcinoma and basal cell carcinoma at an unusually young age (between age 25 and 51 years). Other skin malignancies, such as malignant melanoma, malignant fibrous histiocytoma, and cutaneous lymphoma, were rarely observed. Skin biopsy: -Histologic findings in ARCI are mostly nonspecific, showing epidermal hyperplasia and ortho-hyperkeratosis (thickened stratum corneum, the uppermost layer of the epidermis) with an underlying acanthosis. -Harlequin ichthyosis is characterized by extreme hyperkeratosis and follicular plugging. Electron microscopy shows absence of lamellar bodies and lipid bilayers. Aymé-Gripp Syndrome Aymé-Gripp syndrome is classically defined as the triad of bilateral early cataracts, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities. The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears. Hearing loss is often congenital. Other features may include postnatal short stature, seizure disorder, nonspecific brain abnormalities on head imaging, skeletal abnormalities, and joint limitations. A subset of individuals have been found to have pericarditis or pericardial effusion during the neonatal or infantile period. All affected individuals have had developmental delay, but the degree of cognitive impairment is extremely variable. Other features including gastrointestinal and endocrine abnormalities, ectodermal dysplasia (i.e., nail dystrophy and mammary gland hypoplasia), dental anomalies, and chronic glomerulopathy with proteinuria have been reported in rare affected individuals. B BAP1 Tumor Predisposition Syndrome Synonyms: BAP1 Cancer Syndrome; Cutaneous/Ocular Melanoma, Atypical Melanocytic Proliferations, and Other Internal Neoplasms (COMMON Syndrome) BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a specific skin lesion, BAP1-inactivated melanocytic tumors (BIMT; formerly called atypical Spitz tumors), and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC). Hepatocellular carcinoma, cholangiocarcinoma, and meningioma may also be associated with BAP1-TPDS. Affected individuals can have more than one type of primary cancer. In general, the median age of onset of these tumors is younger than in the general population. UM tends to be a more aggressive class 2 tumor with higher risk for metastasis and reduced survival compared to UM occurring in the general population. Due to the limited number of families reported to date, the penetrance, natural history, and frequencies of BAP1-associated tumors are yet to be determined. Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetic order): breast cancer, neuroendocrine carcinoma, non-smallcell lung adenocarcinoma, thyroid cancer, and urinary bladder cancer. BCL11A-Related Intellectual Disability Synonyms: Dias-Logan Syndrome, Intellectual Developmental Disorder with Persistence of Fetal Hemoglobin BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer Synonym: BRCA1- and BRCA2-Associated HBOC BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The risk of developing an associated cancer varies depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant. BSCL2-Related Neurologic Disorders / Seipinopathy The spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and pes cavus and other foot deformities. Disease severity is variable among and within families. Bachmann-Bupp Syndrome Synonym: ODC1-Related Neurodevelopmental Disorder Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties. Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life. Rare findings may include seizures with onset in later childhood and conductive hearing loss. Baller-Gerold Syndrome Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean. Baraitser-Winter Cerebrofrontofacial Syndrome Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common. Bardet-Biedl Syndrome Overview Bardet-Biedl syndrome (BBS) is a multisystem non-motile ciliopathy primarily characterized by retinal cone-rod dystrophy, obesity and related complications, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism and/or genitourinary malformations, and renal malformations and/or renal parenchymal disease. Individuals with BBS can also have other eye abnormalities (strabismus, astigmatism, cataracts), subtle craniofacial dysmorphisms, hearing loss, anosmia, oral/dental abnormalities (crowding, hypodontia, high-arched palate), gastrointestinal and liver disease, brachydactyly/syndactyly, musculoskeletal abnormalities, dermatologic abnormalities, and neurodevelopmental abnormalities including mild hypertonia, ataxia/poor coordination/imbalance, developmental delay(s), seizures, speech abnormalities, and behavioral/psychiatric abnormalities (Table 1). The motile ciliary structure and function is essentially normal in BBS, but affected individuals have an increased prevalence of manifestations associated with motile ciliopathies, such as neonatal respiratory distress, asthma, otitis media, and thoraco-abdominal laterality defects [Shoemark et al 2015]. BBS exhibits variable expressivity and both inter- and intrafamilial variation. Barth Syndrome Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies. Beckwith-Wiedemann Syndrome Synonyms: Wiedemann-Beckwith Syndrome, Beckwith-Wiedemann Spectrum (BWSp) Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by macroglossia, hemihyperplasia, omphalocele, neonatal hypoglycemia, macrosomia, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, kidney abnormalities (e.g., medullary dysplasia, nephrocalcinosis, and medullary sponge kidney), and ear creases / posterior helical ear pits. BWS is considered a clinical spectrum, in which affected individuals may have many or only one or two of the characteristic clinical features. Although most individuals with BWS show rapid growth in late fetal development and early childhood, growth rate usually slows by age seven to eight years. Adult heights are typically within the normal range. Hemihyperplasia (also known as lateralized overgrowth) is often appreciated at birth and may become more or less evident over time. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. Hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral). Macroglossia is generally present at birth and can obstruct breathing or interfere with feeding in infants. Neonatal hypoglycemia occurs in approximately 50% of infants with BWS; most episodes are mild and transient. However, in some cases, persistent hypoglycemia due to hyperinsulinism may require consultation with an endocrinologist for therapeutic intervention. With respect to the increased risk for embryonal tumor development, the risk for Wilms tumor appears to be concentrated in the first seven years of life, whereas the risk for developing hepatoblastoma is concentrated in the first three to four years of life. Cognitive and neurobehavioral development is usually normal. After childhood, prognosis is generally favorable, although some adults experience issues requiring medical management (e.g., for renal or skeletal concerns). Berardinelli-Seip Congenital Lipodystrophy Synonym: Berardinelli-Seip Congenital Generalized Lipodystrophy Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality. Bestrophinopathies Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in BEST1, are typically characterized by retinal degeneration. The four recognized phenotypes are the three autosomal dominant disorders: Best vitelliform macular dystrophy (BVMD), BEST1 adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC); and autosomal recessive bestrophinopathy (ARB). Onset is usually in the first decade (except AVMD in which onset is age 30 to 50 years). Slow visual deterioration is the usual course. Choroidal neovascularization can occur in rare cases. ADVIRC is also associated with panophthalmic involvement including nanophthalmos, microcornea, hyperopia, and narrow anterior chamber angle with angle closure glaucoma. Beta-Propeller Protein-Associated Neurodegeneration Synonyms: BPAN, Neurodegeneration with Brain Iron Accumulation 5 (NBIA5) Beta-propeller protein-associated neurodegeneration (BPAN) is typically characterized by earlyonset seizures, infantile-onset developmental delay, intellectual disability, absent-to-limited expressive language, motor dysfunction (ataxia), and abnormal behaviors often similar to autism spectrum disorder. Seizure types including generalized (absence, tonic, atonic, tonic-clonic and myoclonic), focal with impaired consciousness, and epileptic spasms, as well as epileptic syndromes (West syndrome and Lennox-Gastaut syndrome) can be seen. With age seizures tend to resolve or become less prominent, whereas cognitive decline and movement disorders (progressive parkinsonism and dystonia) emerge as characteristic findings. Beta-Thalassemia Synonyms: Cooley's Anemia, Mediterranean Anemia Beta-thalassemia (β-thalassemia) has two clinically significant forms, β-thalassemia major and βthalassemia intermedia, caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain). Individuals with β-thalassemia major present between ages six and 24 months with pallor due to severe anemia, poor weight gain, stunted growth, mild jaundice, and hepatosplenomegaly. Feeding problems, diarrhea, irritability, and recurrent bouts of fever may occur. Treatment with regular red blood cell transfusions and iron chelation therapy allows for normal growth and development and improves prognosis. Long-term complications associated with iron overload include stunted growth, dilated cardiomyopathy, liver disease, and endocrinopathies. Individuals with β-thalassemia intermedia have a more variable age of presentation due to milder anemia that does not require regular red blood cell transfusions from early childhood. Additional clinical features may include jaundice, cholelithiasis, hepatosplenomegaly, skeletal changes (long bone deformities, characteristic craniofacial features, and osteoporosis), leg ulcers, pulmonary hypertension, extramedullary masses of hyperplastic erythroid marrow, and increased risk of thrombotic complications. Individuals with β-thalassemia intermedia are at risk for iron overload secondary to increased intestinal absorption of iron as a result of dysregulation of iron metabolism caused by ineffective erythropoiesis. Bietti Crystalline Dystrophy Synonyms: Bietti Crystalline Corneoretinal Dystrophy, Bietti Crystalline Retinopathy Bietti crystalline dystrophy (BCD) is a chorioretinal degeneration characterized by the presence of yellow-white crystals and/or complex lipid deposits in the retina and (to a variable degree) the cornea. Progressive atrophy and degeneration of the retinal pigment epithelium (RPE) / choroid lead to symptoms similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa and allied disorders, namely: reduced visual acuity, poor night vision, abnormal retinal electrophysiology, visual field loss, and often impaired color vision. Marked asymmetry between eyes is not uncommon. Onset is typically during the second to third decade of life, but ranges from the early teenage years to beyond the third decade. With time, loss of peripheral visual field, central acuity, or both result in legal blindness in most if not all affected individuals. Biotin-Thiamine-Responsive Basal Ganglia Disease Synonyms: Biotin-Responsive Basal Ganglia Disease (BBGD), BTBGD, Thiamine Metabolism Dysfunction Syndrome-2, Thiamine Transporter-2 Deficiency Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in childhood, early infancy, or adulthood. -The classic presentation of BTBGD occurs in childhood (age 3-10 years) and is characterized by recurrent subacute encephalopathy manifest as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia which, if left untreated, can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or stress. Simple partial or generalized seizures are easily controlled with anti-seizure medication. -An early-infantile Leigh-like syndrome / atypical infantile spasms presentation occurs in the first three months of life with poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis. -An adult-onset Wernicke-like encephalopathy presentation is characterized by acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia in the second decade of life. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in the childhood and adult presentations, but most with the infantile presentation have had poor outcome even after supplementation with biotin and thiamine. Biotinidase Deficiency Synonym: Late-Onset Multiple Carboxylase Deficiency ndividuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development. Symptoms including seizures, developmental delay, cutaneous manifestations (skin rash, alopecia), optic atrophy, hearing loss, and respiratory problems occur only in those individuals with biotinidase deficiency prior to biotin treatment. Symptoms of untreated profound biotinidase deficiency (<10% mean normal serum biotinidase activity) usually appear between ages one week and ten years, typically with optic atrophy, hypotonia, seizures, hair loss, and skin rash. Affected children often have ataxia and developmental delay. Individuals with partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection. Some symptoms, such as feeding issues, cutaneous manifestations, and respiratory issues, usually resolve with biotin therapy, whereas other manifestations presenting prior to biotin treatment, such as optic atrophy, hearing loss, and developmental delay, may improve but are usually not completely reversible with the initiation of biotin therapy. Untreated adolescents and adults usually exhibit myelopathy and optic neuropathy and are often initially diagnosed with multiple sclerosis. Most of these individuals experience improvement in their symptoms with biotin supplementation. Birt-Hogg-Dubé Syndrome Synonym: Hornstein-Knickenberg Syndrome The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are often bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Individuals with BHDS are at a sevenfold increased risk for renal tumors that can be bilateral and multifocal; median age of renal tumor diagnosis is 48 years. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor) and chromophobe histologic cell types. Some families have renal tumor(s) and/or spontaneous pneumothorax without cutaneous manifestations. Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome Synonyms: Blepharophimosis Syndrome, BPES Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by a complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and primary ovarian insufficiency; BPES type II includes only the four major features. Other ophthalmic manifestations that can be associated with BPES include dysplastic eyelids, lacrimal duct anomalies, strabismus, refractive errors, and amblyopia. Other craniofacial features may include a broad nasal bridge and low-set ears. Bloom Syndrome Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include cancer of a wide variety of types and anatomic sites, diabetes mellitus as a result of insulin resistance, chronic obstructive pulmonary disease, and hypothyroidism. Bohring-Opitz Syndrome Synonym: Oberklaid-Danks Syndrome Bohring-Opitz syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia. The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted. Branchiooculofacial Syndrome Synonym: BOF Syndrome Branchiooculofacial syndrome (BOFS) is characterized by branchial (cervical or infra- or supraauricular) skin defects that range from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; ocular anomalies that can include microphthalmia, anophthalmia, coloboma, cataract, and nasolacrimal duct stenosis/atresia; and facial anomalies that can include dolichocephaly, hypertelorism or telecanthus, broad nasal tip, upslanted palpebral fissures, cleft lip or prominent philtral pillars that give the appearance of a repaired cleft lip (formerly called "pseudocleft lip") with or without cleft palate, upper lip pits, and lower facial weakness (asymmetric crying face or partial weakness of cranial nerve VII). Malformed and prominent pinnae and hearing loss from inner ear and/or petrous bone anomalies are common. Intellect is usually normal. Branchiootorenal Spectrum Disorder Branchiootorenal spectrum disorder (BORSD) is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Some individuals progress to end-stage renal disease (ESRD) later in life. Extreme variability can be observed in the presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality from right side to left side in an affected individual and also among individuals in the same family. Brugada Syndrome Synonym: Sudden Unexpected Nocturnal Death Syndrome Brugada syndrome is characterized by cardiac conduction abnormalities (ST segment abnormalities in leads V1-V3 on EKG and a high risk for ventricular arrhythmias) that can result in sudden death. Brugada syndrome presents primarily during adulthood, although age at diagnosis may range from infancy to late adulthood. The mean age of sudden death is approximately 40 years. Clinical presentations may also include sudden infant death syndrome (SIDS; death of a child during the first year of life without an identifiable cause) and sudden unexpected nocturnal death syndrome (SUNDS), a typical presentation in individuals from Southeast Asia. Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Bryant-Li-Bhoj Neurodevelopmental Syndrome Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability (typically in the severe range) and nonspecific craniofacial abnormalities. Many affected individuals do not achieve independent sitting, walking, or speaking, although there is a range of developmental outcomes. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia – forward flexion of the spine when standing that resolves when lying down), growth abnormalities (most commonly poor growth), craniosynostosis (of any suture), and ocular involvement. Congenital anomalies are rare but can include congenital heart defects, brain malformations, and genitourinary abnormalities in males. C
