Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex. Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (Kousseff et al., 1976).

NTRK1 congenital insensitivity to pain with anhidrosis (NTRK1-CIPA) is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of NTRK1-CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.

Hereditary sensory and autonomic neuropathy type V (HSAN5) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN5.\n\nThe signs and symptoms of HSAN5 appear early, usually at birth or during infancy. People with HSAN5 lose the ability to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with HSAN5. Because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. Repeated trauma can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed.

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Pallister-Killian syndrome (PKS) is a dysmorphic condition involving most organ systems, but is also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).

Bjornstad syndrome (BJS) is an autosomal recessive disorder characterized by sensorineural hearing loss and pili torti. The hearing loss is congenital and of variable severity. Pili torti (twisted hairs), a condition in which the hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair very brittle, is usually recognized early in childhood (Selvaag, 2000).

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Cockayne syndrome (referred to as CS in this GeneReview) spans a continuous phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal (COFS) syndrome; CS type III, a milder and later-onset form; COFS syndrome, a fetal form of CS. CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years. CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I. COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia).

Cockayne syndrome (referred to as CS in this GeneReview) spans a continuous phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal (COFS) syndrome; CS type III, a milder and later-onset form; COFS syndrome, a fetal form of CS. CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years. CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I. COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia).

Syndrome that is characterised by intellectual deficit, choroideraemia, acrokeratosis verruciformis, anhidrosis, and skeletal deformities. It has been observed in a single kindred. The syndrome is transmitted as an X-linked recessive trait and may be caused by a small X-chromosome deletion.

Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

Ectodermal dysplasia/skin fragility syndrome (EDSFS) is an autosomal recessive genodermatosis characterized by widespread skin fragility, alopecia, nail dystrophy, and focal keratoderma with painful fissures. Hypohidrosis and cheilitis are sometimes present (summary by Ersoy-Evans et al., 2006).

Any tooth agenesis in which the cause of the disease is a mutation in the PAX9 gene.

EDAID2 is characterized by variable features of ectodermal dysplasia (e.g., hypo/anhidrosis, sparse hair, tooth anomalies) and various immunologic and infectious phenotypes of differing severity (summary by Boisson et al., 2017). Some patients may also have neutrophilia and autoinflammatory disease, such as liver disease (Tan et al., 2020). Mutations in the NFKBIA gene result in functional impairment of NFKB (see 164011), a master transcription factor required for normal activation of immune responses. Interruption of NFKB signaling results in decreased production of proinflammatory cytokines and certain interferons, rendering patients susceptible to infection (McDonald et al., 2007). For discussion of genetic heterogeneity of ectodermal dysplasia and immune deficiency, see 300291.

Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

Hereditary sensory and autonomic neuropathy type IC (HSAN1C) is an autosomal dominant neurologic disorder characterized by sensory neuropathy with variable autonomic and motor involvement. Most patients have adult onset of slowly progressive distal sensory impairment manifest as numbness, tingling, or pain, as well as distal muscle atrophy. Complications include ulceration and osteomyelitis. Some patients may have a more severe phenotype with onset in childhood. Electrophysiologic studies show a predominantly axonal neuropathy with some demyelinating features. Some patients may have evidence of central nervous system involvement, including macular telangiectasia type 2 and/or pyramidal signs. Affected individuals have increased levels of plasma 1-deoxysphingolipids (1-deoxySLs), which are thought to be neurotoxic. (summary by Rotthier et al., 2010, Gantner et al., 2019, and Triplett et al., 2019). Oral supplementation with serine decreases 1-deoxySL and may offer some clinical benefits (Fridman et al., 2019). For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400).

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Multiple system atrophy (MSA) is a distinct clinicopathologic entity that manifests as a progressive adult-onset neurodegenerative disorder causing parkinsonism, cerebellar ataxia, and autonomic, urogenital, and pyramidal dysfunction in various combinations. Two main subtypes are recognized: 'subtype C,' characterized predominantly by cerebellar ataxia, and 'subtype P,' characterized predominantly by parkinsonism. MSA is characterized pathologically by the degeneration of striatonigral and olivopontocerebellar structures and glial cytoplasmic inclusions (GCIs) that consist of abnormally phosphorylated alpha-synuclein (SNCA; 163890) or tau (MAPT; 157140) (Gilman et al., 1998; Gilman et al., 2008; Scholz et al., 2009). 'Subtype C' of MSA has been reported to be more prevalent than 'subtype P' in the Japanese population (65-67% vs 33-35%), whereas 'subtype P' has been reported to be more prevalent than 'subtype C' in Europe (63% vs 34%) and North America (60% vs 13%, with 27% of cases unclassified) (summary by The Multiple-System Atrophy Research Collaboration, 2013). MSA is similar clinically and pathologically to Parkinson disease (PD; 168600) and Lewy body dementia (127750). See also PARK1 (168601), which is specifically caused by mutation in the SNCA gene. Pure autonomic failure manifests as orthostatic hypotension and other autonomic abnormalities without other neurologic involvement. Although there is some phenotypic overlap, the relationship of pure autonomic failure to MSA is unclear (Vanderhaeghen et al., 1970; Schatz, 1996).

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.

HELIX syndrome is an autosomal recessive disorder characterized by Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia (summary by Hadj-Rabia et al., 2018).

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).

Erythrokeratodermia variabilis et progressiva-7 (EKVP7) is characterized by palmoplantar keratoderma that extends to the dorsal surface of the hands and feet (transgrediens), as well as erythematous annular skin lesions. Pruritis, woolly hair, and dystrophic nails may also be present (Duchatelet et al., 2019; Patel et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of EKVP, see EKVP1 (133200).

Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder characterized by childhood onset of failure to thrive, skin manifestations, pancytopenia, and susceptibility to recurrent infections (Harapas et al., 2022).

Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.