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A rare developmental defect during embryogenesis characterized by microcephaly, characteristic facial features, hypotonia, non-progressive intellectual deficit, myopia and retinal dystrophy, neutropenia and truncal obesity.
ORPHA:193Classification level: Disorder
The prevalence is unknown. Approximately 200 cases have been reported to date. It is overrepresented in the Finnish population and in certain Amish, Greek/Mediterranean and Irish families.
Clinical manifestations seen between families are variable. At birth newborns appear normal as characteristic facial features are not yet present but neutropenia may be. The first manifestations include feeding difficulties, hypotonia, microcephaly, delayed developmental milestones (rolling over, sitting independently) and joint hypermobility. The majority of patients have a short stature with small or narrow hands and feet (compared to normal) and truncal obesity in the teen years. Characteristic facial features (high-arched or wave-shaped eyelids, thick hair, low hairline, short philtrum as well as long-thick eyelashes, prominent nasal root and upper central incisors) start to appear around the age of 5 and become more evident between the ages of 7-14 and into adulthood. Speech development is delayed. Aphthous ulcers are present in some. Recurrent upper respiratory infections are also seen in certain patients, possibly due to neutropenia. Intellectual deficiency is noted but is not progressive and the learning of new concepts is possible. Patients are often very sociable with a cheerful disposition. In adolescence, myopia and strabismus are present along with signs of retinochoroidal dystrophy in most cases. Nyctalopia and a narrowed visual field develop with time, and vision progressively begins to deteriorate after the age of 30. Patients over 45 suffer from severe retinochoroidal atrophy and posterior subcapsular cataracts. Although visual abnormalities are severe they do not lead to blindness.
CS is caused by a mutation in the vacuolar protein sorting 13B (VPS13B) gene on locus 8q22-8q23 which is thought to have a role in vesicle mediated sorting and intracellular protein trafficking. More than 100 different null mutations (resulting in the truncation of the final protein) have been identified in the gene.
Characteristic clinical findings along with molecular genetic testing for the presence of mutations in the VPS13B gene are required for a definite diagnosis of CS.
Differential diagnoses include Bardet-Biedl syndrome, Prader-Willi syndrome, Cri-du-chat syndrome, Alström syndrome, Angelman syndrome, Williams syndrome, MORM syndrome and monosomy 1p36 (see these terms). Mirhosseini-Holmes-Walton syndrome is considered allelic to CS and is clinically indistinguishable.
Antenatal diagnosis is possible if mutations in family members have been identified.
CS is transmitted autosomal recessively and genetic counseling is recommended for at-risk individuals.
Management and treatment
Spectacles/eyeglasses are necessary. Intellectual deficiency requires special education and children often attend specialized schools. Speech therapy is important during the preschool years to foster speech development as well as physical therapy for motor delay, hypotonia and motor clumsiness. Respiratory infections should be treated with antibiotics. Granulocyte-colony stimulating factor (G-CSF) has been given to some patients to treat neutropenia. Ophthalmologic evaluation is needed to determine visual acuity. No effective treatment has been developed to halt the progression of the retinal disease. In later years, training for the visually impaired can be offered. Psychosocial support should be offered to patients and their families.
There is no evidence of the decrease in life expectancy but quality of life is reduced due to visual impairment.