Pitt–Hopkins syndrome

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Pitt–Hopkins syndrome
Peter the Wild Boy.jpg
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.
SpecialtyPsychiatry, Medical genetics

Pitt–Hopkins syndrome is a rare genetic disorder characterized by developmental delay, epilepsy, distinctive facial features, and possible intermittent hyperventilation followed by apnea.[1] As more is learned about Pitt Hopkins, the developmental spectrum of the disorder is widening, and can also include difficulties with anxiety and ADHD, and sensory disorders. It is associated with an abnormality within chromosome 18: specifically, it is caused by an insufficient expression of the TCF4 gene.[2]

PTHS has traditionally been associated with severe cognitive impairment, however true intelligence is difficult to measure given motor and speech difficulties. Thanks to augmentative communication and more progressive therapies, many individuals can achieve much more than initially thought. It has become clearer that there is a wider range of cognitive abilities in Pitt Hopkins than reported in much of the scientific literature.

Signs and symptoms[edit]

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.

PTHS is characterized by developmental delay, possible breathing problems of episodic hyperventilation and/or breath-holding while awake, recurrent seizures/epilepsy, gastrointestinal issues, lack of speech, and distinctive facial features. Stereotypic movements particularly of the arms, wrists and fingers is almost universal. Hypotonia is common (75%) as is an unsteady gait. Other features include a single (simian) palmar crease, long, slender fingers, flat feet and cryptorchidism (in males). The presence of fetal pads is common. Hyperventilation may occur and is sometimes followed by apnea and cyanosis. Constipation is common. Microcephaly and seizures may occur. Hypopigmented skin macules have occasionally been reported. Individuals with Pitt-Hopkins syndrome typically have a happy, excitable demeanor with frequent smiling and laughter.


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]


Diagnosis is made by showing a mutation in the TCF4 gene.

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.[citation needed]

Differential diagnosis[edit]

Differential diagnosis includes Angelman syndrome, and Rett syndrome.[citation needed]


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


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[edit]


  1. ^ 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 1852727. PMID 17436255.
  2. ^ "PITT-HOPKINS SYNDROME; PTHS". National Center for Biotechnology Information. Retrieved 2009-12-08.
  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.

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