Description

Pitt-Hopkins syndrome (PHS) is characterized by the association of mental retardation, characteristic facial dysmorphism and abnormal and irregular breathing. About 50 cases have been described. The disease affects males and females equally. Facial signs include macrosomia, with spaced teeth, broad and shallow palate, thick lips, sunken eyes, nose with flared nostrils and ears with thick helix. Psychomotor disorders are early and severe and include hypotonia, instability of walking, which is acquired late, and absence of language. Voluntary retention is maintained and there are no related malformations. Constipation, gastroesophageal reflux, microcephaly, postnatal developmental delay and tonic-clonic seizures are frequent. In isolated cases, hypopigmented skin areas, severe myopia, penile hypoplasia and cryptorchidism have been described. In early childhood or during adolescence, limited to the waking phase, respiratory disorders may occur, consisting of episodes of hyperventilation, sometimes followed by apnea and cyanosis. The syndrome is due to heterozygous de novo mutations in the TCF4 gene (18p21), which encodes a ubiquitous b-HLH transcription factor. Transmission is autosomal dominant. A case of parental somatic mosaicism has been described. The diagnosis is based on the clinical examination, the electroencephalogram and brain imaging by magnetic resonance, which shows a reduction of the hippocampus, a dedifferentiation of the temporal lobes and, sometimes, a hypoplasia of the corpus callosum and a ventricular dilatation. The main differential diagnoses are Angelman, Rett and Mowat-Wilson syndrome (see these terms). In the case of new pregnancies, the possibility of carrying out the amniocentesis should be discussed with the parents of an index case in order to find the mutation. Management takes a multidisciplinary approach. The course of the disease is not progressive.