Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (a-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% a-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% a-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack.

Hallermann-Streiff syndrome is characterized by a typical skull shape (brachycephaly with frontal bossing), hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia, skin atrophy, dental anomalies, and proportionate short stature (Hallermann, 1948; Streiff, 1950; Francois, 1958). Mental retardation is present in a minority of cases (Gorlin et al., 1990).

PNPLA6 disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia; upper motor neuron involvement manifesting as spasticity and/or brisk reflexes; chorioretinal dystrophy associated with variable degrees of reduced visual function; and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). The hypogonadotropic hypogonadism occurs either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting); hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia); short stature; and impaired cognitive functioning (learning disabilities in children; deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia).

Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this GeneReview) is characterized by a triad of major clinical features including partial-to-complete alopecia, nail dystrophy, and palmoplantar hyperkeratosis. Sweating is preserved and there are usually no dental anomalies. Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is fine, sparse, and brittle. Progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. Associated features may include cutaneous hyperpigmentation (particularly over the joints) and finger clubbing. The clinical manifestations are highly variable even within the same family.

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.

Dermochondrocorneal dystrophy, or Francois syndrome, is a rare disorder characterized by the development of skin nodules, acquired deformities of the extremities, and a corneal dystrophy. The corneal dystrophy is central and superficial with whitish subepithelial opacities (summary by Bierly et al., 1992).

Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other possible associations include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence.

Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder characterized by hair loss followed by progressive macular degeneration and early blindness. Scalp hair is lost during the first months of life, with onset of retinal degeneration and vision loss a few years to 2 decades later (summary by Sprecher et al., 2001 and Indelman et al., 2002).

A rare primary bone dysplasia characterised by severe early-onset dysplasia of the proximal femurs, with almost complete absence of the secondary ossification centres and abnormal development of the femoral necks (short and broad with irregular metaphyses). It is associated with gait abnormality, mild short stature, arthralgia, and joint stiffness with limited mobility of the hips and irregular acetabula, and hip and knee pain. Coxa vara and mild spinal changes are also associated.

Severely hypoplastic and triangular-shaped tibiae and absence of the fibulae.Two sporadic cases have been described. Moderate mesomelia of the upper limbs, proximal widening of the ulnas, pelvic anomalies and marked bilateral glenoid hypoplasia also reported.

FATCO syndrome comprises fibular aplasia, tibial campomelia, and oligosyndactyly (Courtens et al., 2005). See also ectrodactyly (split-hand/foot malformation) associated with fibular hypoplasia/aplasia (113310).

This syndrome has characteristics of anophthalmia or microphthalmia, retinal dystrophy, and/or myopia, associated in some cases with cerebral anomalies. It has been described in two families. Polydactyly may also be present. Linkage analysis allowed identification of mutations in the BMP4 gene, which has already been shown to play a role in eye development.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. The clinical course of PLOSL can be divided into four stages: 1. The latent stage is characterized by normal early development. 2. The osseous stage (3rd decade of life) is characterized by pain and tenderness, mostly in ankles and feet, usually following strain or injury. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities. 3. In the early neurologic stage (4th decade of life), a change of personality begins to develop insidiously. Affected individuals show a frontal lobe syndrome (loss of judgment, euphoria, loss of social inhibitions, disturbance of concentration, and lack of insight, libido, and motor persistence) leading to serious social problems. 4. The late neurologic stage is characterized by progressive dementia and loss of mobility. Death usually occurs before age 50 years.