Mount Sinai Medical Center
New York, New York
What Is It?
Pitt-Hopkins syndrome (PHS), first reported by Drs. Pitt and Hopkins in two unrelated patients, in 1978, is a genetic disorder characterized by severe intellectual disability, epilepsy, speech absence or impairment, distinctive facial features, microcephaly and constipation. Breathing abnormalities including hyperventilation and tachypnea followed by apnea and cyanosis differentiate this syndrome from Angelman, Mowat-Wilson and Rett syndromes.1-3 A fuller description of the disorder is emerging as more genetic mutations are discovered; characteristics may include anxiety, sensory disorders and attention-deficit/hyperactivity disorder. It is considered an autism spectrum disorder, although there may be atypical autistic characteristics. An abnormality within chromosome 18q21, specifically, a haploinsufficiency of the TCF4 gene, has been identified.
Because of the evolving spectrum of PHS, the incidence is unknown. However, approximately 500 people worldwide have been genetically identified as sufferers of PHS as originally described. Males and females are equally affected. It’s now suspected that Peter the Wild Boy—a historical feral child who was found in a German forest by the British King George I in 1726 and later brought to the Royal Court in London—had the TCF mutation.
Diagnosis ultimately is made by demonstrating a mutation in the TCF4 gene. Fifty percent of those with PHS have abnormalities on brain imaging, including a hypoplastic corpus callosum with missing rostrum and posterior part of the splenium, and bulbous caudate nuclei. Levels of immunoglobulin M are low, and EEG shows an excess of slow components.4 Clinical features include developmental delay, coarse curly hair, large lips, drooping eyelids, strabismus, a shallow palate, widely spaced teeth, hypotonia, foot pads and a single palmar crease. Seizures are common, and the child (or adult) may only crawl and be unable to speak. Laughter and constant smiling are other features.
There is no specific treatment. Management is supportive for epilepsy control and breathing abnormalities, and affected individuals may live for many years. (Peter the Wild Boy was said to be 72 when he died.) Aripiprazole and risperidone have been used successfully in the management of problem behavior in children.5 Acetazolamide has been advocated for central apnea.
Obtaining consent may be difficult in patients who are mentally impaired, cannot see or speak. No study has identified a superior anesthetic techniq ue, which should be chosen based on history and physical examination. Difficult intubation and airway management have been reported, due not only to anatomic abnormalities but gum hypertrophy from antiepileptic medications.6 Gastrointestinal abnormalities (reflux and constipation) would indicate a preference for rapid sequence intubation. Succinylcholine is best omitted in hypotonic patients and those with strabismus. Opioids should be used at a minimum or avoided because of the risk for apnea and worsening constipation. Nursing in a monitored setting postoperatively is indicated. The child is probably not a candidate for outpatient or same-day surgery. Massachusetts General Hospital for Children has a clinic dedicated to the care of patients with PHS.