Pitt–Hopkins syndrome in two patients and further definition of the phenotype

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Abstract
Pitt-Hopkins syndrome is a rare dysmorphic mental retardation syndrome marked by daytime spells of overbreathing interrupted by apnoea. The dysmorphism consists of a large beaked nose, cup-shaped ears with broad helices, a wide mouth, Cupid's bow upper lip, wide and shallow palate and broad or clubbed fingertips. The four patients described so far have been sporadic and represented both sexes. In addition, a pair of sibs with atypical features has been reported as possible Pitt-Hopkins syndrome cases. We describe two unrelated Pitt-Hopkins syndrome patients in order to further define the phenotype. In addition to severe developmental retardation, hypotonia, postnatal growth retardation, microcephaly, abnormal breathing and characteristic dysmorphic features, both had epilepsy and intestinal problems with severe constipation in one and Hirschsprung disease in the other. Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp-wave discharges on electroencephalography. Magnetic resonance imaging in both showed a similar hypoplastic corpus callosum with missing rostrum and posterior part of the splenium and bulbous caudate nuclei bulging towards the frontal horns. Chromosomal analysis and subtelomere fluorescence in-situ hybridization studies were normal. No mutations were found in the MECP2 or ZFHX1B genes. Extensive metabolic and mitochondrial screens were normal. The electroencephalography and brain magnetic resonance imaging findings appear to be further diagnostic signs in Pitt-Hopkins syndrome, which is also one of the syndromes associated with Hirschsprung disease.