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Pitt-Hopkins syndrome (PHS) is characterized by the association of intellectual deficit, characteristic facial dysmorphism and problems of abnormal and irregular breathing.
About 50 cases have been reported worldwide. Males and females are equally affected.
The facial features are recognizable by macrostomia with widely spaced teeth, a wide and shallow palate, thick lips, deep-set eyes, splayed nostrils and ears with wide helices. Psychomotor disorders are early and severe with hypotonia, late-acquired unstable walking and an absence of language. Voluntary prehension is preserved and there are no associated malformations. Severe constipation and gastro-esophageal reflux are common. Microcephaly, postnatal underdevelopment and severe tonic-clonic epileptic attacks are also frequent. Hypopigmented skin macules, high-grade myopia, a small penis and cryptorchidism have been observed in isolated cases. Breathing disorders can appear during early childhood or adolescence and occur only when the patient is awake. They are characterized by fits of hyperventilation, often followed by apnea and cyanosis.
The syndrome is caused by heterozygous de novo mutations in the TCF4 gene (18q21), coding for a ubiquitous b-HLH transcription factor.
Diagnosis is based on clinical examination, EEG and cerebral MRI showing a reduced hippocampus, dedifferentiation of the temporal lobes and, sometimes, hypoplasia of the corpus callosum and ventricular dilation.
The principal differential diagnosis includes Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome (see these terms).
Detection of the mutation by amniocentesis should be discussed with the parents of an index case during subsequent pregnancies.
Transmission is autosomal dominant. A case with a somatic mosaic parent has been described.
Management and treatment
Management requires a multidisciplinary approach.
The course of the disease is non-progressive.
- Clinical genetics review
- English (2012)