|Classification and external resources|
Pitt–Hopkins syndrome is a rare genetic disorder characterized by developmental delay, a wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea. It is associated with an abnormality within chromosome 18: specifically, it is caused by an insufficient expression of the TCF4 gene.
The condition was first described in 1978 by Pitt and Hopkins in two unrelated patients.
The genetic cause of this disorder was described in 2007. This disorder is due to a haploinsufficiency of the transcription factor 4 (TCF4) gene which is located on the long arm of chromosome 18 (18q21.2) The mutational spectrum appears to be 40% point mutations, 30% small deletions/insertions and 30% deletions. All appear to be de novo mutations and to date no risk factors have been identified.
A Pitt–Hopkins like phenotype has been assigned to autosomal recessive mutations of the contactin associated protein like 2 (CNTNAP2) gene on the long arm of chromosome 7 (7q33-q36) and the neurexin 1 alpha (NRXN1) gene on the short arm of chromosome 2 (2p16.3).
Approximately 100 cases have been described in the literature to date.
The facial features are characteristic and include
- Deep set eyes
- Marked nasal root
- Broad and/or beaked nasal bridge
- Prominent Cupid's bow
- Everted lower lip
- Tented upper lip
- Large mouth
- Widely spaced teeth
- Wide and shallow palate
- Ears with thick and overfolded helix
Most have a smiling appearance.
Intellectual disability is severe. Language is absent or limited to only a few words. Stereotypic movements particularly of the arms, wrists and fingers is almost universal. Hypotonia is common (75%) as is an unsteady gait. All have delayed walking. Other features include a single (simian) palmar crease, long, slender fingers, flat feet and cryptorchidism (in males). Finger clubbing and the presence of fetal pads is common. Hyperventilation occurs in over half and is frequently followed by apnea and cyanosis. During these episodes aerophagia may occur. Constipation is common. Microcephaly and seizures may occur. Hypopigmented skin macules have occasionally been reported.
Around 50% of those affected show abnormalities on brain imaging. These include hypoplastic corpus callosum with a missing rostrum and posterior part of the splenium with bulbous caudate nuclei bulging towards the frontal horns.
Electroencephalograms show an excess of slow components.
All have low levels of immunoglobulin M (IgM) but features of an immunodeficiency are absent.
Diagnosis is made by showing a mutation in the TCF4 gene.
Currently there is no specific treatment for this condition. Management is supportive.
- Zweier C, Peippo MM, Hoyer J, et al. (May 2007). "Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt–Hopkins syndrome)". American Journal of Human Genetics. 80 (5): 994–1001. doi:10.1086/515583. PMC . PMID 17436255.
- "PITT-HOPKINS SYNDROME; PTHS". National Center for Biotechnology Information. Retrieved 2009-12-08.
- Pitt D, Hopkins I (1978) A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paed J 14(3):182-184
- Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, Colleaux L (2007) Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am. J. Hum. Genet. 80: 988-993
- Peippo M, Ignatius J (2012) Pitt-Hopkins Syndrome. Mol Syndromol 2(3-5):171-180
- Megan Lane (8 August 2011). "Who was Peter the Wild Boy?". BBC News Magazine. BBC. Retrieved 2011-08-09.