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The ocular features have not been fully described. The most consistent features are long eyelashes, thick or bushy eyebrows, and ‘visual disturbance’. Most individuals have a facial dysmorphism which includes a broad nasal base suggestive of hypertelorism. Optic atrophy and proptosis have been noted.
Intrauterine growth retardation is sometimes seen. Microcephaly, short stature, syndactyly, intellectual disability (often labeled mental retardation), and a dysmorphic face are characteristic. Some individuals have cryptorchidism, seizures, and ectodermal abnormalities including nail hypoplasia, hirsutism, and microdontia. Mental and physical delays are common. The syndactyly usually involves only soft tissue between toes 2, 3, and 4 and fingers 3 and 4 accompanied by clinodactyly of the 5th finger. Polydactyly is sometimes present while radiologically the radial head may show evidence of hypoplasia.
Homozygosity or compound heterozygosity in the CKAP2L gene (2q13) segregates with this phenotype.
No treatment is known.
Eyelashes are described as ‘long’, and the eyebrows are bushy. The majority of individuals have poor vision secondary to severe receptor dysfunction. Night blindness and severe photophobia are features in some cases. Both retinal and choroidal atrophy have been diagnosed in the first 5 years of life and most patients have a progressive and extensive pigmentary retinopathy.
Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes. Frontal bossing has been noted in some patients. Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.
Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded. There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life. The peripheral neuropathy includes both sensory and motor components. Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period. Several patients have had evidence of progressive cerebellar ataxia.
Compund heterozygous mutations in PNPLA6 (19p13.2), coding for neuropathy target esterase, have been found in several patients presumed to have this condition. Autosomal recessive inheritance has been proposed on the basis of a single family in which an affected brother and sister were born to first cousin parents.
The relationship of this disorder to that found in two cousins, offspring of consanguineous matings, described as ‘cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition’ (204110 ) is unknown. They were described as having visual impairment from birth and profound photophobia. Fundus changes were minimal with a bull’s eye pattern of pigment changes in the macula described as indicative of a rod-cone congenital amaurosis. ERG responses were unrecordable. These individuals apparently did not have other somatic, psychomotor or neurologic deficits.
Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome in this database.
No treatment is available for this condition although growth hormone and testosterone supplementation have been reported to have the appropriate selective effects.
There is considerable clinical heterogeneity in this disorder. Few patients have all of the clinical features and there is much variation in the severity of these. Almost all segments of the eye can be involved. The lashes are often lush and the eyebrows may be highly arched and bushy. Lid fissures are often downward slanting (88%). Congenital glaucoma, nystagmus, cataracts, lacrimal duct obstruction (37%), ptosis (29%), colobomas and numerous corneal abnormalities including keratoglobus, sclerocornea, and megalocornea have been reported. Abnormal VEP waveforms and cone and cone-rod dysfunction have been found in the majority (78%) of patients tested. Retinal pigmentary changes have been seen in some patients. Refractive errors (usually myopia) occur in 56% of patients. Visual acuities vary widely but about 20% of patients are visually handicapped.
Fluorescein angiography in a single patient revealed generalized vascular attenuation and extensive peripheral avascularity. The AV transit time was prolonged with delayed venous filling and late small vessel leakage.
The facial features are reported to be characteristic but there are few distinctive signs. The face is often broad and round, the nose is beaked, the mouth is small, and the lower lip appears to pout and protrudes beyond a short upper lip. Smiles have been described as ‘grimacing’. It is common for the columella to protrude beyond the alae nasi. The palate is narrow and highly arched and the laryngeal walls collapse easily which may lead to feeding problems and respiratory difficulties. The ears may be rotated posteriorly. The anterior hairline can appear low.
Among the more distinctive signs are the broad thumbs and great toes which are often deviated medially. However, the distal phalanges of all fingers may be broad as well. Bone fractures are common and patellar dislocations can be present as seen in the first two decades of life. Hypotonia is a feature. Numerous dental anomalies have been reported including crowded teeth, enamel hypoplasia, crossbite, and abnormal numbers of teeth.
Developmental delays are common. Infancy and childhood milestones are often delayed. Many patients have cognitive delays and some are mildly retarded. Postnatal growth is subnormal and obesity is common. A third of patients have a cardiac abnormality including septal defects, valvular defects, coarctation of the aorta, pulmonic stenosis, and patent ductus arteriosus. Renal abnormalities occur frequently and almost all males have undescended testes. Patients are at increased risk of tumors, both malignant and benign, many of which occur in the central nervous system. Other problems are constipation and hearing loss.
Evidence points to an autosomal dominant mode of inheritance secondary to mutations in CREBBP (16p13.3) but there is some genetic heterogeneity as mutations in EP300 (22q13) have also been associated with this disease.
Treatment is directed at specific clinical features such as glaucoma and strabismus. Special education and vocational training may be helpful. Hearing loss may respond to standard treatment. Fractures and dislocations should receive prompt attention. Cardiac anomalies may require surgical correction.