An inherited disorder characterized by hypotonia, obesity, prominent incisors, and nonprogressive psychomotor retardation.
Norio Syndrome; Pepper Syndrome; Hypotonia-Obesity-Prominent Incisors Syndrome; Obesity-Hypotonia Syndrome.
More than 200 cases have been described. An increased frequency has been reported in Finland and in the Ashkenazi Jewish population. Consanguinity is a known, but not constant risk factor. No sexual predilection has been reported.
Autosomal recessive. The disorder is caused by mutations in the COH1 (Cohen 1), also known as VPS13B (Vacuolar Protein Sorting 13 Homolog B) gene, which has been mapped to chromosome 8q22-q23. This gene encodes a protein of the Golgi apparatus that is involved in the glycosylation of proteins and plays a crucial role in the normal growth and development of neurons and adipocytes.
The wide clinical variability of this disorder can make the diagnosis difficult. There are significant differences in the frequency of certain features among different cohorts (eg, Finnish, Greek/Mediterranean, Amish, and Irish travelers). The diagnosis is primarily based on the clinical findings of microcephaly with the characteristic facial appearance, nonprogressive psychomotor retardation, and isolated, intermittent neutropenia (<1.5 × 109/mm3). Due to the highly variable features, the diagnosis is often not made until later in infancy or even childhood when visual disturbances lead to the diagnosis of chorioretinal dystrophy and subsequent molecular genetic testing for VPS13B gene mutations, which will confirm the diagnosis. It has been suggested that for the diagnosis the significant mental delay should be accompanied by at least two of the following findings: typical facial appearance, pigmentary retinopathy, or neutropenia.
Pregnancy is most often uneventful and birth occurs at term; however, poor fetal movement and growth and oligohydramnios have been described in some patients. Poor feeding in the first year of life is common. During that time, the facial features may be subtle and non-characteristic. However, after the second year of life, the facial features become more obvious and should allow for an early diagnosis. One study reported that the great majority of Cohen Syndrome patients are correctly diagnosed after 6 years of age, in adolescence or in even later in adulthood. In fact, only a few reports exist of children appropriately diagnosed before 6 years of age and even less before 3 years of age. Facial features are characterized by postnatal microcephaly, thick scalp hair with low hairline, long, dysplastic ears, thick eyebrows and eyelashes, wave-shaped and downward slanting palpebral fissures, epicanthic folds, ptosis, prominent nasal bridge and beak-shaped nose, full cheeks, maxillary hypoplasia, prominent appearing incisors (mainly due to the short and thin upper lip, and becoming even more pronounced with smiling), short and upturned philtrum, (usually mild) micrognathia, high-narrow palate, small and open ...