macrocephaly

Watson Syndrome

Clinical Characteristics

Ocular Features

Lisch iris nodules similar to those seen in neurofibromatosis are found in some but not all patients with Watson syndrome.

Systemic Features

Short stature and low normal intelligence are the most consistent features.  Pulmonic stenosis and caf√©-au-lait spots are also common.   The macrocephaly is relative and not striking.  Neurofibromas have been seen in a minority of patients.

Genetics

Mutations in the NF1(17q11.2) gene have been identified in members of several large pedigrees with an apparent autosomal dominant pattern.

It remains uncertain if this condition is allelic to neurofibromatosis I(162200) or if Watson syndrome is the result of mutations in contiguous genes.

The LEOPARD syndrome(151100) shares some clinical similarities such as short stature, pulmonic stenosis, cognitive deficits and caf√©-au-lait spots but is caused by mutations in PTPN11.   The phenotype also resembles Noonan syndrome in some aspects.

Treatment Options

There is no known treatment for this condition but multidisciplinary management is recommended for isolated problems.

References

Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991 Nov;28(11):752-6.

PubMed ID: 
1770531

Sandhoff Disease

Clinical Characteristics

Ocular Features

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. 

Systemic Features

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.  

Genetics

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. 

Treatment Options

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. 

References

Myerowitz R, Lawson D, Mizukami H, Mi Y, Tifft CJ, Proia RL. Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. Hum Mol Genet. 2002 May 15;11(11):1343-50.

PubMed ID: 
12019216

Neufeld EF. Natural history and inherited disorders of a lysosomal enzyme, beta-hexosaminidase. J Biol Chem. 1989 Jul 5;264(19):10927-30. Review.

PubMed ID: 
2525553

Gilbert F, Kucherlapati R, Creagan RP, Murnane MJ, Darlington GJ, Ruddle FH. Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes. Proc Natl Acad Sci U S A. 1975 Jan;72(1):263-7.

PubMed ID: 
1054503

Strømme Syndrome

Clinical Characteristics

Ocular Features

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.

Systemic Features

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.

Genetics

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.

Treatment Options

Infants do well following intestinal surgery.  Ocular surgery has not been reported.

References

Castori M, Laino L, Briganti V, Pedace L, Zampini A, Marconi M, Grammatico B, Buffone E, Grammatico P. Jejunal atresia and anterior chamber anomalies: Further delineation of the Stromme syndrome. Eur J Med Genet. 2010 May-Jun;53(3):149-52.

PubMed ID: 
20219704

van Bever Y, van Hest L, Wolfs R, Tibboel D, van den Hoonaard TL, Gischler SJ. Exclusion of a PAX6, FOXC1, PITX2, and MYCN mutation in another patient with apple peel intestinal atresia, ocular anomalies and microcephaly and review of the literature. Am J Med Genet A. 2008 Feb 15;146A(4):500-4. Review.

PubMed ID: 
18203155

Str√∏mme P, Dahl E, Flage T, Stene-Johansen H. Apple peel intestinal atresia in siblings with ocular anomalies and microcephaly. Clin Genet. 1993 Oct;44(4):208-10.

PubMed ID: 
8261651