Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.

Sjogren-Larsson syndrome (SLS) is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, impaired intellectual development, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (summary by Lossos et al., 2006).

Pili annulati, or 'ringed hair,' is a disorder in which scalp hairs show alternating light and dark bands. It is often an incidental finding, and the hair usually does not show increased fragility (Green et al., 2004). See also pseudopili annulati (613241), a distinct entity.

Trichodentoosseous syndrome (TDO) is an autosomal dominant disorder with complete penetrance characterized by abnormalities involving hair, teeth, and bone (summary by Nguyen et al., 2013).

Pseudovaginal perineoscrotal hypospadias is a form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum.

Geroderma osteodysplasticum (GO) is an autosomal recessive disorder characterized by skin wrinkling limited to the dorsa of hands and feet and to the abdomen, bowed long bones, and osteopenia with frequent fractures. There is a distinctive facial appearance with droopy skin at the cheeks, maxillary hypoplasia, and large ears. Adult patients appear prematurely aged (summary by Rajab et al., 2008).

Any inherited isolated nail anomaly in which the cause of the disease is a mutation in the PLCD1 gene.

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).

A rare, congenital malformation syndrome characterized by the association of anterior ocular chamber cleavage disorder with developmental delay, short stature and congenital hypothyroidism. Additional manifestations include cerebellar hypoplasia, tracheal stenosis, narrow external auditory meatus, and hip dislocation. There have been no further description in the literature since 1995.

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.

A very rare hereditary skin disease with manifestation of irregularly distributed epidermal hyperkeratosis of the palms and soles. Reported in 35 families worldwide to date. The lesions usually start to develop in early adolescence but can also present later in life. Mutations in the AAGAB gene (15q22.33-q23) have recently been identified as one of the causes. Mutations in the COL14A1 gene (8q23) have also been identified as causal in some cases in Asia that seem to have a similar phenotype

A rare clinical variant of epidermolytic ichthyosis, with manifestations of blistering phenotype at birth and the development from early infancy of annular polycyclic erythematous scales on the trunk and extremities. It has been reported in less than 10 families. The disease is caused by mutations in the KRT1 (12q11-q13) and KRT10 (17q21-q23) genes, encoding keratins 1 and 10 respectively. These mutations impair keratin filament formation and weaken the structural stability of the keratinocyte cytoskeleton. Transmission is autosomal dominant.

PPKS2 is characterized by linear hyperkeratosis of the palms, which is particularly evident in affected individuals who perform manual labor. Hyperkeratosis of the soles primarily involves pressure points, and diffuse background palmoplantar thickening may also be present. (Armstrong et al., 1999; Whittock et al., 1999). For a discussion of genetic heterogeneity of the striate form of palmoplantar keratoderma, see PPKS1 (148700).

Variant Vohwinkel syndrome is a rare genodermatosis characterized by hyperkeratosis of the palms and soles, with a honeycomb appearance; constricting bands encircling the digits of the hands and feet, which frequently lead to autoamputation of the fifth digits; starfish-shaped, salmon-colored hyperkeratotic lesions, or knuckle pads, on the dorsal surface of the hands; and ichthyosiform dermatosis. The pathognomonic histologic finding is markedly thickened stratum corneum, hypergranulosis, and particularly, hyperkeratosis with round nuclei retained in the stratum corneum. Unlike classic Vohwinkel syndrome, hearing loss is not a feature (summary by Maestrini et al., 1996).

Familial multiple discoid fibromas (FMDF) is an autosomal dominant dermatologic condition characterized by the appearance of multiple skin-colored, firm, flat or dome-shaped papules on the pinnae and the central area of the face in childhood or adolescence. Most lesions show a hair at or just outside the periphery, and many have a telangiectatic surface (summary by Starink et al., 2012). Trichodiscoma, as this lesion was first described by Pinkus et al. (1974), is a small benign fibrovascular tumor of the dermal part of the hair disc. The hair disc is a richly vascularized dermal pad in close association with a hair. It is supplied by a thick myelinated nerve and is considered to be a slow-adapting mechanoreceptor. Trichodiscomas are small, flat or dome-shaped, skin-colored, firm papules with a telangiectatic surface. Many of the lesions show a hair at the periphery or just outside it. Starink et al. (2012) renamed the lesion 'discoid fibroma' as a clarification of the histologic findings. FMDF is similar to, but histologically and genetically distinct from, Birt-Hogg-Dube syndrome (BHD; 135150), which is characterized by fibrofolliculomas as well as renal and pulmonary cysts.

A rare genetic multiple congenital anomalies/dysmorphic syndrome with characteristics of dysmorphic facial features including high forehead, elongated and flattened midface, arched and sparse eyebrows, short palpebral fissures, telecanthus, long nose with hypoplastic nostrils, long philtrum, high and narrow palate and microstomia with downturned corners. Ears are characteristically malformed, large, low-set and posteriorly rotated and nasal speech is associated.

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

An extremely rare genetic disorder characterized by corneal anesthesia, retinal abnormalities, bilateral hearing loss, distinct facies, patent ductus arteriosus, Hirschsprung disease, short stature and intellectual disability. The phenotype is variable. Some affected individuals have only mild disease manifestations. The etiology of this syndrome is not yet known. Mutations in an as of yet unidentified gene, involved in autonomic nervous system function, are suspected. Follows an autosomal dominant pattern of inheritance, probably with variable expressivity.

Any striate palmoplantar keratoderma in which the cause of the disease is a mutation in the KRT1 gene.

A rare intestinal disease characterized by dilated intestinal lacteals which cause lymph leakage into the small bowel lumen. Clinical manifestations include edema related to hypoalbuminemia (protein-losing gastro-enteropathy), asthenia, moderate diarrhea, lymphedema, serous effusion and failure to thrive in children.

Cole disease (COLED) is a rare autosomal dominant disorder characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show nonspecific changes including hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer (summary by Eytan et al., 2013). Some patients also exhibit calcinosis cutis or early-onset calcific tendinopathy (Eytan et al., 2013).

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.

Peeling skin syndrome-3 (PSS3) is characterized by asymptomatic lifelong and continuous shedding of the stratum corneum of the epidermis. Symptoms start during the second half of the first decade of life and consist of generalized white scaling occurring over the upper and lower extremities (Cabral et al. (2012)). For a discussion of genetic heterogeneity of peeling skin syndrome, see PSS1 (270300).

Erythrokeratodermia variabilis et progressiva-5 (EKVP5) is an autosomal recessive skin disorder characterized by progressive development of symmetrically distributed hyperkeratotic plaques with palmoplantar hyperkeratosis and nail thickening (Shah et al., 2017).

EKVP6 is characterized by erythematous hyperkeratotic plaques that develop within the first year of life, beginning on distal extremities and progressing to involve the face, wrists, and ankles, with sparing of volar surfaces. Intrafamilial variation in severity has been observed, and most affected individuals experience slowly progressive spontaneous remission after puberty (Wang et al., 2019). For a general phenotypic description and discussion of genetic heterogeneity of EKVP, see EKVP1 (133200).

Isolated anhidrosis with normal sweat glands (ANHD) is characterized by absence of perspiration and subsequent heat intolerance with normal morphology and number of sweat glands. Teeth, hair, nails, and skin are normal (Klar et al., 2014).