Pitt-Hopkins syndrome: Mental retardation, psychomotor and developmental delays with facial dysmorphism

The Pitt-Hopkins syndrome is a very rare and severe genetic disease characterized by mental retardation, psychomotor and developmental delays with facial dysmorphism. It was first described in 1978 in patients with mental retardation and crisis of intermittent hyperventilation. The genetic cause is haploinsufficiency of the TCF4 (transcription factor 4) gene that affects the neurodevelopment in both sexes; the majority of patients have spontaneous molecular defects by point mutations or deletions in chromosome 18 at the region 18q21. The syndrome is characterized by neurological abnormalities that affect the motor coordination and balance, in patients with mental and developmental delays. The phenotype includes a peculiar face by specific craniofacial anomalies: prominent square forehead, deep-set eyes with ocular hypertelorism; prominent large nose beaked and broad flat nasal bridge; mouth wide and large, thick fleshy lips, tented bow-shaped upper lip and everted lower lip; cup-shaped ears with dysplastic broad overfolded helix. We review the literature and the photographs of 44 published patients from 2007 to 2012, to resume the principal features of craniofacial anomalies, attempting to delineate the syndrome phenotype and score the specific dysmorphism than help to achieve the early clinical diagnosis.