Summary
Pitt-Hopkins syndrome (PHS) is characterized by the association of intellectual deficit, distinctive facial features and an abnormal breathing pattern. About 150 patients have been reported worldwide. Males and females seem to be equally affected. The facial dysmorphism is characterized by a wide mouth with widely spaced teeth, a wide and shallow palate, full upper and lower lip vermilion borders, deep-set eyes, a large convex nose, and cup-shaped ears with broad helices. The wide heart-shaped upper vermillion border is especially characteristic. Broad or clubbed fingertips may develop with time. In addition to early and severe psychomotor retardation, microcephaly, postnatal growth retardation and epilepsy with severe grand mal seizures are frequent. Speech is usually absent. Pronounced muscle hypotonia and ataxia may be present. Hypopigmented skin macules, high-grade myopia, a small penis and cryptorchidism, severe constipation, and gastroesophageal reflux have been reported in isolated cases. Breathing abnormalities usually appear in childhood, after the onset of seizures, and are present only when the children are awake. They consist of abrupt paroxysmal tachypnea and hyperventilation followed by apnea and even overt cyanosis. In some patients hyperbreathing develops later, with onset during adolescence in some cases. Breathing abnormalities are found in most but not all patients. PHS is transmitted in an autosomal dominant manner and is caused by heterozygous mutations in the gene encoding transcription factor 4 (TCF4; 18q21). Diagnosis is based on clinical history, physical findings and MRI findings (cerebellar and vermis hypoplasia, hypoplasia of the corpus callosum, a small hippocampus and bulging caudate nuclei). The main differential diagnosis is Rett syndrome, however, the Angelman, Mowat-Wilson and Goldberg-Shprintzen syndromes, together with submicroscopic deletions of chromosome 22q13 should also be considered (see these terms). Management requires a multidisciplinary approach. Though some patients may experience periods of clinical stability, the disease has a progressive course. *Author: Orphanet (November 2008)*.
