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The eyebrows appear bushy. Inflammation of the limbus and keratoconjunctivitis sicca are often present and reported to resemble Sjögren syndrome.
Infants appear large at birth with a large forehead and macrocephaly. Birth weight, length, and head circumference are usually above the 97th percentile. The mandible appears large and the lips are full and ‘fleshy’. Dentition is delayed. Recurrent stomatitis and gastroesophageal reflux have been noted. Closure of the fontanels is delayed. Hypotonia and hyperflexible joints can be a feature.
Multiple brain anomalies have been described including cortical atrophy, dilated and asymmetrical ventricles, and mild hydrocephalus. Psychomotor development and milestones are delayed. Intellectual disabilities, syncope, hypoglycemia, seizures, apneic episodes, mood anomalies, abnormal gait, and general clumsiness may be present. There was considerable clinical variation among the six reported patients.
Heterozygous mutations in RNF125 (18q12.1) are responsible for this syndrome.
No treatment is known.
Lisch iris nodules similar to those seen in neurofibromatosis are found in some but not all patients with Watson syndrome.
Short stature and low normal intelligence are the most consistent features. Pulmonic stenosis and cafe-au-lait spots are also common. The macrocephaly is relative and not striking. Neurofibromas have been seen in a minority of patients.
Mutations in the NF1(17q11.2) gene have been identified in members of several large pedigrees with an apparent autosomal dominant pattern.
The LEOPARD syndrome(151100) shares some clinical similarities such as short stature, pulmonic stenosis, cognitive deficits and cafe-au-lait spots but is caused by mutations in PTPN11. The phenotype also resembles Noonan syndrome in some aspects.
There is no known treatment for this condition but multidisciplinary management is recommended for isolated problems.
Retinal ganglion cells become dysfunctional as a result of the toxic accumulation of intra-lysosomal GM2 ganglioside molecules causing early visual symptoms. These cells in high density around the fovea centralis create a grayish-white appearance. Since ganglion cells are absent in the foveolar region, this area retains the normal reddish appearance, producing the cherry-red spot. Axonal decay and loss of the ganglion cells leads to optic atrophy and blindness.
Sandhoff disease may be clinically indistinguishable from Tay-Sachs disease even though the same enzyme is defective (albeit in separate subunits A and B that together comprise the functional enzymes). The presence of hepatosplenomegaly in Sandoff disease may be distinguishing. The infantile form of this lysosomal storage disease seems to be the most severe. Infants appear to be normal until about 3-6 months of age when neurological development slows and muscles become weak. Seizures, loss of interest, and progressive paralysis begin after this together with loss of vision and hearing. An exaggerated startle response is considered an early and helpful sign in the diagnosis. Among infants with early onset disease, death usually occurs by 3 or 4 years of age.
Ataxia with spinocerebellar degeneration, motor neuron disease, dementia, and progressive dystonia are more common in individuals with later onset of neurodegeneration. The juvenile and adult-onset forms of the disease also progress more slowly.
Sandhoff disease results from mutations in the beta subunit of the hexosaminidase A and B enzymes. It is an autosomal recessive disorder caused by mutations in HEXB (5q13).
Tay-Sachs disease (272800) can be clinically indistinguishable from Sandoff disease and they are allelic disorders. However, the mutation in Tay-Sachs (272800) is in HEXA resulting in dysfunction of the alpha subunit of hexosaminidase A enzyme.
No specific treatment is available beyond general support with proper nutrition and maintainence of airways. Anticonvulsants may be helpful in some stages. Gene therapy in fibroblast cultures has achieved some restoration of hexosaminidase A activity in Tay-Sachs disease and may have potential in Sandhoff disease as well.
The core complex of Strømme syndrome consists of intestinal atresia and ocular abnormalities of the anterior segment. The ocular anomalies seem to be limited to the anterior segment with variable amounts of angle dysgenesis, anterior synechiae, corneal leukoma, and sometimes megalocornea. Posterior chamber and optic nerve anomalies have been ruled out in a few cases. Glaucoma has not been reported. Only about 10 cases have been reported since Strømme 's first report in 1993. Most patients have been too young for reliable acuity testing.
The intestinal atresia seems to involve the jejunum primarily and is usually surgically correctable. Some developmental delay is common while the microcephaly seems to be progressive. Short stature has been noted and the amount of developmental delay is highly variable.
This disorder is presumed to be autosomal recessive but only one family with sibs has been reported and other single cases have been found around the world. No locus has been identified.
Infants do well following intestinal surgery. Ocular surgery has not been reported.