Pitt–Hopkins syndrome

Pitt–Hopkins syndrome
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.
Specialty	Psychiatry, 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. 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.

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

PTHS can be seen as early as childhood.

The earliest signs in infants is the lower face and the high nasal root.

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

When it comes to adults who has PTHS, they have trouble with their speech. Carniofacial features, which is important when diagnosing PTHS, becomes more visible as the person gets older.

PTHS is characterized by developmental delay, possible breathing problems of episodic hyperventilation and/or breath-holding while awake, recurrent seizures/epilepsy, gastrointestinal issues, 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.

Genetics

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. The risks are low, but higher in the general population due to parental germline mosaicism.

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).

Malformations in the CNS can be seen by doing a MRI and can be seen in about 60 to 70% of patients.

There is a chance people with a TCF4 deletion can lack characteristic facial features.

Diagnosis

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

Gene-targeted testing can be used to diagnosis PTHS.

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.

According to the clinical diagnosis. PTHS is in the same group as Pervasive Developmental Disorders.

Evaluations

• Developmental assessment
• Assessment for communication devices
• Talk to a child behavior specialist
• Pulmonary consultation
• Child neurology consultation
• Ophthalmology evaluation
• Gastroenterology
• Musculoskeletal evaluation
• Talk to a clinical geneticist

Differential diagnosis

Differential diagnosis includes Angelman syndrome, Rett syndrome, and Mowat- Wilson syndrome.

Angelman syndrome is the one closest to PTHS. Both have absent speech and happy disposition. One thing that they do not have in common is the face abnormalities. Rett syndrome is the least closest to PTHS. This syndrome is seen as a progressive encephalopathy. Mowat-Wilson syndrome is seen in early infancy and is characterized by distinctive facial abnormalities.

Treatment

Currently there is no specific treatment for this condition. It is based on symptomatology. Since there is a lack of treatment, people with PTHS use behavioral and training approaches.

Recommendations for developmental delay and intellectual disability in the U.S (could change depending on the country)

• Early intervention program from newborn to age 3. It will help them get access to different therapies (occupational, physical, speech, and feeding).
• Developmental preschool through your public school system from the ages 3 to 5 years. The child will have to have an evaluation before getting into the program, to see what kind of therapy they would need.
• From the ages 5–21 your child's school should have create an IEP (based on your child's functions). Children are encouraged to stay in school until at least the age of 21.

History

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

See also

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