Unilateral atrophy of facial tissues, including muscles, bones and skin.

A condition characterized by recurrent, self-limiting episodes of vomiting associated with intense nausea, pallor, and lethargy. It is commonly a migraine precursor.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.

Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated.

Episodic ataxia is a genetically heterogeneous neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia. Episodic ataxia type 2 is the most common form of EA (Jen et al., 2007). For a discussion of genetic heterogeneity of episodic ataxia, see EA1 (160120).

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started.

Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started.

Familial adult myoclonic epilepsy-2 (FAME2) is an autosomal dominant neurologic disorder characterized by onset of tremor affecting the fingers, hand, and voice in adolescence or young adulthood with somewhat later onset of rhythmic myoclonic jerks and generalized tonic-clonic seizures. Electrophysiologic studies are consistent with cortical reflex myoclonus. Some patients may show cognitive decline or migraines; photosensitivity is common (summary by De Fusco et al., 2014; Crompton et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of familial adult myoclonic epilepsy, see FAME1 (601068).

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").

PHACE is an acronym for a neurocutaneous syndrome encompassing the following features: posterior fossa brain malformations, hemangiomas of the face (large or complex), arterial anomalies, cardiac anomalies, and eye abnormalities. The association is referred to as PHACES when ventral developmental defects, such as sternal clefting or supraumbilical raphe, are present (summary by Bracken et al., 2011).

Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness.

PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) include paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), and hemiplegic migraine (HM). In addition, PRRT2 pathogenic variants have been identified in other childhood-onset movement disorders and different types of seizures, suggesting that the understanding of the spectrum of PRRT2-PxMD is still evolving. The paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and less commonly ballismus. The seizures of BFIE are usually focal with or without generalization. Thirty percent of PRRT2-associated PKD is associated with BFIE and is referred to as PKD/IC.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a small-vessel disease that affects highly vascularized tissues including the retina, brain, liver, and kidneys. Age of onset is often between 35 and 50 years. The most common presenting finding is decreased visual acuity and/or visual field defects. Neurologic manifestations may include hemiparesis, facial weakness, aphasia, and hemianopsia. Migraines and seizures are less frequently described. Renal manifestations may include mild-to-moderate increase in serum creatinine and mild proteinuria; progression to end-stage renal disease (ESRD) is uncommon. Hepatic manifestations frequently include mildly elevated levels of alkaline phosphatase and gamma-glutamyltransferase (GGT). Less common findings include psychiatric disorders, hypertension, mild-to-moderate anemia, and Raynaud phenomenon.

Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).

Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia.

People with familial paroxysmal nonkinesigenic dyskinesia experience episodes of abnormal movement that are brought on by alcohol, caffeine, stress, fatigue, menses, or excitement or develop without a known cause. Episodes are not induced by exercise or sudden movement and do not occur during sleep. An episode is characterized by irregular, jerking or shaking movements that range from mild to severe. In this disorder, the dyskinesia can include slow, prolonged contraction of muscles (dystonia); small, fast, "dance-like" motions (chorea); writhing movements of the limbs (athetosis); and, rarely, flailing movements of the limbs (ballismus). The dyskinesia also affects muscles in the torso and face. The type of abnormal movement varies among affected individuals, even among affected members of the same family. Individuals with familial paroxysmal nonkinesigenic dyskinesia do not lose consciousness during an episode. Most people do not experience any neurological symptoms between episodes.\n\nIndividuals with familial paroxysmal nonkinesigenic dyskinesia usually begin to show signs and symptoms of the disorder during childhood or their early teens. Episodes typically last 1 to 4 hours, and the frequency of episodes ranges from several per day to one per year. In some affected individuals, episodes occur less often with age.\n\nFamilial paroxysmal nonkinesigenic dyskinesia is a disorder of the nervous system that causes episodes of involuntary movement. Paroxysmal indicates that the abnormal movements come and go over time. Nonkinesigenic means that episodes are not triggered by sudden movement. Dyskinesia broadly refers to involuntary movement of the body.

Phosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (Shirakawa et al., 2006).

An exceedingly rare form of hereditary episodic ataxia with varying degrees of ataxia and associated findings including slurred speech, headache, confusion and hemiplegia.

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.

AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by Smith et al., 2010).

Women show menstrual cycle-dependent physiologic changes in relation to sex hormone levels. Because ovulation triggers a significant change in the hormonal milieu that is similar to local inflammation, a 0.5 to 1.0 degree Celsius increase in basal body temperature after ovulation is commonly associated with progesterone secretion and is believed to be triggered by the induction of several inflammatory cytokines. Rare menstrual cycle-dependent febrile episodes have been reported, some of which have shown a luteal-phase-dependent pattern (summary by Jiang et al., 2012).

PBD14B is an autosomal recessive peroxisome biogenesis disorder characterized clinically by mild intellectual disability, congenital cataracts, progressive hearing loss, and polyneuropathy (Ebberink et al., 2012), all of which had been observed in patients with mild peroxisomal biogenesis disorders (e.g., Kelley et al., 1986; Poll-The et al., 1987). Additionally, recurrent migraine-like episodes following mental stress or physical exertion, not a common feature in peroxisome disorders, was reported. Thoms and Gartner (2012) classified the disorder described by Ebberink et al. (2012) in their patient as a mild 'Zellweger syndrome (214100) spectrum' (ZSS) disorder. See PBD1B (601539) for a phenotypic description and discussion of genetic heterogeneity of less severe phenotypes on the Zellweger syndrome spectrum. See PBD9B (614879) for another atypical peroxisome biogenesis disorder.

Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present.

Advanced sleep phase syndrome is characterized by very early sleep onset and offset (summary by Jones et al., 1999). For a discussion of genetic heterogeneity of advanced sleep phase syndrome, see FASPS1 (604348).

Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, a history of migraine with aura, mood disturbance, apathy, and diffuse white matter lesions and subcortical infarcts on neuroimaging.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years.

The spectrum of COL4A1-related disorders includes: small-vessel brain disease of varying severity including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and systemic findings (kidney involvement, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia). On imaging studies, small-vessel brain disease is manifest as diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages. Clinically, small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability; however, on occasion it can be an incidental finding. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome usually associates asymptomatic small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye. Two additional phenotypes include isolated retinal artery tortuosity and nonsyndromic autosomal dominant congenital cataract.

Hennekam lymphangiectasia-lymphedema syndrome-3 (HKKLLS3) is characterized by widespread congenital edema that is more severe in more dependent areas of the body. Associated features include facial dysmorphism and protein-losing enteropathy of variable severity (Brouillard et al., 2017). For a discussion of genetic heterogeneity of Hennekam lymphangiectasia-lymphedema syndrome, see HKLLS1 (235510).

Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome (ROSAH) is an autosomal dominant disorder in which affected individuals present in childhood with reduced vision associated with papilledema and low-grade ocular inflammation. Progressive deterioration of visual acuity results in counting fingers to no light perception by the third decade of life. Patients also show anhidrosis, as well as splenomegaly and mild pancytopenia, and most experience headaches that may be migraine-like in nature (Williams et al., 2019).

Autosomal recessive idiopathic basal ganglia calcification-7 is a neurologic disorder characterized by onset of symptoms in adulthood. Patients present with dysarthria, gait abnormalities, various movement abnormalities, and often cognitive decline. Brain imaging shows abnormal accumulation of calcium deposits in deep brain regions, including the basal ganglia, thalamus, dentate nuclei, cerebellum, and sometimes other areas of the brain and spinal cord. Some patients with brain imaging abnormalities may be clinically asymptomatic (summary by Yao et al., 2018). For a detailed phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (213600).

Nabais Sa-de Vries syndrome type 2 (NSDVS2) is characterized by global developmental delay apparent from birth and distinctive dysmorphic facial features. Most patients have additional anomalies, including congenital heart defects, sleep disturbances, hypotonia, and variable endocrine abnormalities, such as hypothyroidism (summary by Nabais Sa et al., 2020).

Sulfide:quinone oxidoreductase-deficiency (SQORD) is characterized by a variable phenotype ranging from no clinical symptoms to episodes of encephalopathy and Leigh syndrome-like (see 256000) brain lesions, with acute symptoms triggered by infections and fasting. Other features may include lactic acidosis and decreased mitochondrial respiratory chain complex IV activity in tissues. Most affected individuals are asymptomatic. Patients with encephalopathy may recover or die in childhood (Friederich et al., 2020).

Baralle-Macken syndrome (BARMACS) is an autosomal recessive disorder characterized by global developmental delay apparent from infancy, difficulty walking or inability to walk, and impaired intellectual development with poor or absent speech. Affected individuals develop early-onset cataracts; some may have microcephaly. Additional more variable features may include dysmorphic facial features, metabolic abnormalities, spasticity, and lymphopenia (summary by Macken et al., 2021).

Multifocal fibromuscular dysplasia (FMDMF) is characterized histologically by medial fibroplasia and angiographically by multiple arterial stenoses with intervening mural dilations. Arterial tortuosity, macroaneurysms, dissections, and rupture may occur (summary by Richer et al., 2020).

Axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH) is an autosomal dominant peripheral neuropathy characterized predominantly by onset of vocal cord weakness resulting in stridor in infancy or early childhood. The vocal cord paresis remains throughout life and may be severe enough to require tracheostomy. Additional features of the disorder usually include pes cavus and scoliosis. Some patients have mild distal muscle weakness and atrophy primarily affecting the lower limbs, although the upper limbs may also be involved, and distal sensory impairment, often with hyporeflexia (Sullivan et al., 2020). For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.

Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by Hochberg et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA) is characterized by global developmental delay apparent from infancy. Affected individuals show delayed walking with an unsteady gait, variably impaired intellectual development, learning disabilities, and speech difficulties. Abnormal eye movements, which are often noted in early childhood, include opsoclonus, nystagmus, and strabismus. Some patients have seizures, which may be refractory (Lu et al., 2022).

The basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, is characterized by numerous basal cell cancers and epidermal cysts of the skin, calcified dural folds, keratocysts of the jaws, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, fetal rhabdomyomas, and various stigmata of maldevelopment (e.g., rib and vertebral abnormalities, cleft lip or cleft palate, and cortical defects of bones) (summary by Koch et al., 2002). For a discussion of genetic heterogeneity of BCNS, see BCNS1 (109400).

Combined oxidative phosphorylation deficiency-59 (COXPD59) may present as a lethal infantile form of Leigh syndrome (see 256000) or as a milder disorder with hypertrophic cardiomyopathy, lactic acidosis, attention deficit-hyperactivity disorder (ADHD) and survival into adulthood (summary by Amarasekera et al., 2023). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Familial partial lipodystrophy type 9 (FPLD9) is an autosomal recessive metabolic disorder characterized by the loss of adipose tissue resulting in a lean appearance with muscular hypertrophy, usually most apparent in the limbs and trunk. Some patients have more generalized lipoatrophy, whereas others have abnormal fat accumulation in the face and neck regions and show cushingoid or acromegalic facial features. The disorder is associated with insulin-resistant diabetes mellitus, dyslipidemia, low HDL, and hepatic steatosis. Symptom onset is usually in the first decade. Females tend to have hirsutism and polycystic ovary syndrome, whereas males have gynecomastia. Most patients also have neurologic involvement, including demyelinating polyneuropathy (in most) and delayed development with intellectual disability (in about half) (Schuermans et al., 2023). For a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

Moyamoya disease-7 (MYMY7) is a cerebrovascular disease that leads to strokes and neurologic deficits. The age at symptom onset is highly variable, ranging from childhood to adulthood. Brain imaging shows progressive occlusion and stenosis of the distal internal carotid arteries with collateral vessel formation. Intracranial aneurysms and involvement of the posterior circulation, including the basilar artery, may also be observed (Pinard et al., 2023). For a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).

Autosomal recessive idiopathic basal ganglia calcification-9 (IBGC9) is characterized by a combination of features including ataxia, parkinsonism, headache, and psychiatric and cognitive deficits, with high intrafamilial phenotypic variability and age at onset (Chelban et al., 2024). For a phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (213600).