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J Pediatr Genet 2015; 04(03): 168-176
DOI: 10.1055/s-0035-1564570
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Pitt–Hopkins Syndrome and Differential Diagnosis: A Molecular and Clinical Challenge

Giuseppe Marangi
1   Department of Laboratory Medicine, Institute of Medical Genetics, Catholic University, Rome, Italy
,
Marcella Zollino
1   Department of Laboratory Medicine, Institute of Medical Genetics, Catholic University, Rome, Italy
› Author Affiliations
Further Information

Publication History

12 June 2015

16 June 2015

Publication Date:
25 September 2015 (online)

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Abstract

Pitt–Hopkins syndrome is an emerging neurodevelopmental disorder caused by haploinsufficiency of the TCF4 gene on chromosome 18q21. It is characterized by severe intellectual disability, seizures, microcephaly, constipation and a distinctive facial gestalt. Although the overlapping phenotype of microcephaly, epilepsy, absent speech and constipation represents a challenge for the differential diagnosis with Angelman syndrome, Rett syndrome and Mowat–Wilson syndrome, distinctive of Pitt–Hopkins syndrome are breathing abnormalities, that can occur as either hyperventilation episodes or apnea crises, and a typical facial dysmorphism, including bitemporal narrowing, squared forehead, deep-set eyes, peculiar nose conformation, with broad nasal bridge, down-turned nasal tip and flaring nostrils, typical shape of the mouth, with a tented and M shaped upper lip, and widely spaced teeth. The occurrence of these signs in variable association of uncoordinated movements, microcephaly of postnatal onset, eye abnormalities, constipation, epilepsy and subtle brain abnormalities is highly predictive of a TCF4 mutation, making it possible to plan a genetic test of choice among severe encephalopathies. Angelman syndrome represents the nosological condition closest to Pitt–Hopkins syndrome.

Keywords

Pitt-Hopkins syndrome - TCF4 - differential diagnosis
 

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