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Pitt-Hopkins syndrome (PTHS) 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 syndrome, the developmental spectrum of the disorder is widening, and can also include anxiety, autism⁽²⁾, 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⁽³⁾. The neurobiological implications give the rarity of this neurodevelopmental disorder. Pitt-Hopkins syndrome arises from the haploinsufficiency of TCF4 (ITF2, SEF2, E2-2) as a result of autosomal dominant mutations at this gene locus on chromosome 18^(4,5). The severe and systemic neurodevelopmental phenotypes of PTHS determined the specialized researchers and clinicians to develop and implement effective therapies to enhance the quality of life for these patients. The evidence that the expression of TCF4 is maintained in the brain, showing an untimely of expression during development⁽⁶⁾, suggests that the treatment of PTHS cognitive deficits may be possible if TCF4 plays a significant role in the maintenance of neuronal function through adulthood.

At the time of presentation, those that attract attention are the facial features of the child:

• deep set eyes

• strabismus

Microcephaly and seizures may occur. Hypopigmented skin macules have occasionally been described. Children with Pitt-Hopkins syndrome typically have a happy, excitable disposition with nearly constant smiling and laughter. Affected children are described as very sociable; laughter may occur spontaneously or at inappropriate times. In any case, some children may be quiet or withdrawn into their own world (self-absorption). Episodes of aggression or shouting or agitation, often in response to unexpected changes in routine, occur as well. Additional behavioral issues are common and can include hyperactivity, anxiety, self-injury and shyness. Children with Pitt-Hopkins syndrome also exhibit stereotypic hand movements, which include hand clapping, hand flapping, flicking hands, hand washing, fingers crossing and frequent hand-to-mouth movements. Head shaking, head banging, body rocking, teeth grinding (bruxism) and hair pulling may also be seen. Children may repeatedly and repetitively play with a toy, and may show a fascination with one specific part of a toy⁽⁷⁾.

Seizures can occur in under half of the individuals and usually begin in childhood, but sometimes are present from birth or develop late, as teenagers. Most children experience constipation, which can be severe. Gastro­esophageal reflux has been reported in less than half of the affected individuals. Most patients have a high pain threshold.

Additional symptoms can include excessive drooling (especially when younger), severe nearsightedness (myopia), crossed eyes (strabismus), and abnormal curving of the lens of the eye (astigmatism). Abnormal curving of the spine (scoliosis) has occurred in a small number of individuals. Approximately one third of affected males experience failure of one or both testicles to descend into the scrotum (cryptorchidism)⁽⁸⁾.
 

Diagnostic criteria

The clinical diagnostic criteria for PTHS are defined by cardinal (highly specific) features and supportive features. With a score of ≥9, the diagnosis of PTHS can be clinically confirmed (although molecular confirmation remains desirable)⁽⁹⁾. This score can only be reached if at least two of the three cardinal features are present. A score of 6-8 needs further confirmation by molecular testing (Table 1). Also, Bayley Scales of Infant Development, readapted according to the autonomy of the clinic or research center, is used in order to asses mental and motor functioning⁽¹⁰⁾. The Vineland Adaptive Behavior Scales – Survey Form (VABS) was used to assess personal and social self-sufficiency⁽¹¹⁾.
 

Differential diagnosis

In the differential diagnosis, the following diseases will be discussed, such as:

• Angelman syndrome

• Rett syndrome

• Mowat-Wilson syndrome

• Autism spectrum disorder.

Neuropsychiatry

Like many neurological diseases with a psychiatric impact, the neuropsychiatric features must be studied and taken into account carefully, separately, and not in bulk.

Neurological signs: distinctive facial characteristics, stereotype movements, impaired motor coordination, ataxia, hypotonia, atypical sensory profile.

Psychiatric symptoms: intellectual disability, very low cognitive abilities, behavioral impairments, social impairments, aggression, self-injurious behavior (e.g., pinching, hand biting, biting oneself), hyperexcitability.

In case of patients with Pitt-Hopkins syndrome, a multidisciplinary approach is needed:

• Pediatrician/pediatric neurologist/pediatric psychia­trist.

• Medical genetics specialist/genetic map/genetic counseling.

• Clinical laboratory testing.

Treatment

Because of the differences between ill people, currently there is no pharmacological treatment for this syndrome. Seizures and breathing problems represent the first important symptoms that need to be controlled and monitored. Early intervention services for infants and young children – which may include occupational, physical, speech and feeding therapies – are welcomed. An individualized education plan (IEP) for preschool and school-aged children is necessary. Behavioral therapies: children may benefit from treatments for autism spectrum disorder (such as applied behavioral analysis; ABA) or medications. Consider medication for important breathing problems. Some individuals with PTHS have reported the improvement of breathing problems with antiepileptic drugs or with acetazolamide.

Conclusions

Pitt-Hopkins syndrome is almost a forgotten disease, but with all of a sudden potential to be a diagnostic pitfall or a “hidden surprise”, masking other neuropediatric pathologies. This article tries to summarize and concentrate the primordial aspects of the disease. Because the diseases is like a condemnation, future research and studies to systematically investigate the cognitive, behavioral and neuropsychological profiles in an objective, quantitative and prospective manner, together with the natural history of PTHS, are needed in order to identify potential clinical biomarkers and outcome measures for testing future novel therapeutic interventions, all in the benefit of the little patients.

Conflicts of interests: The author declares no conflict of interests.