Pitt–Hopkins syndrome

Pitt–Hopkins syndrome is a genetic disorder characterized by developmental delay, a wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea.^[1] It is associated with an abnormality within chromosome 18: specifically, it is caused by an insufficient expression of the TCF4 gene.^[2]

Genetics

The condition was first described in 1978 by Pitt and Hopkins in two unrelated patients.^[3]

The genetic cause of this disorder was described in 2007.^[4] 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).^[5]

Clinical

Approximately 100 cases have been described in the literature to date.

The facial features are characteristic and include

• Deep set eyes
• Strabismus
• Myopia
• 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.

Investigations

~50% 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.

Differential diagnosis

This includes Angelman syndrome, Mowat–Wilson syndrome and Rett syndrome.

Diagnosis

This is made by showing a mutation in the TGF4 gene.

Treatment

Currently there is no specific treatment for this condition. Management is supportive.

Miscellaneous

Peter the Wild Boy, showing some of the physical traits of Pitt–Hopkins syndrome, including coarse, curly hair, drooping eyelids and large, thick lipped mouth.

Professor Phillip Beales, of the Institute of Child Health, has speculated that Peter the Wild Boy suffered from Pitt–Hopkins syndrome.^[6] The boy was brought to Britain in 1725 as a feral child.

See also

• Distal 18q-
• Peter the Wild Boy – an 18th-century feral child now believed to have had the syndrome

References

1. ^ Zweier C, Peippo MM, Hoyer J, et al. (May 2007). "Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt–Hopkins syndrome)".  
2. ^ "PITT-HOPKINS SYNDROME; PTHS".  
3. ^ Pitt D, Hopkins I (1978) A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paed J 14(3):182-184
4. ^ 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
5. ^ Peippo M, Ignatius J (2012) Pitt-Hopkins Syndrome. Mol Syndromol 2(3-5):171-180
6. ^ Megan Lane (8 August 2011). "Who was Peter the Wild Boy?". BBC News Magazine. BBC. Retrieved 2011-08-09.