Pitt-Hopkins Syndrome

Abstract

Pitt-Hopkins syndrome (PTHS, MIM #610954) is characterized by severe intellectual disability, typical facial features and tendency to epilepsy, panting-and-holding breathing anomaly, stereotypic movements, constipation, and high myopia. Growth is normal or only mildly retarded, but half of the patients have postnatal microcephaly. Remarkably, congenital malformations are practically nonexistent. The cause of PTHS is de novo haploinsufficiency of the TCF4 gene (MIM *602272) at 18q21.2. Altogether 78 PTHS patients with abnormalities of the TCF4 gene have been published since 2007 when the etiology of PTHS was revealed. In addition, 27 patients with 18q deletion encompassing the TCF4 gene but without given PTHS diagnosis have been published, and thus, the number of reported patients with a TCF4 abnormality exceeds 100. The mutational spectrum includes large chromosomal deletions encompassing the whole TCF4 gene, partial gene deletions, frameshift (including premature stop codon), nonsense, splice site, and missense mutations. So far, almost all patients have a private mutation and only 2 recurrent mutations are known. There is no evident genotype-phenotype correlation. No familial cases have been reported. Diagnosis of PTHS is based on the molecular confirmation of the characteristic clinical features. Recently, a Pitt-Hopkins-like phenotype has been assigned to autosomal recessive mutations of the CNTNAP2 gene at 7q33q36 and the NRXN1 gene at 2p16.3.

Fig. 1

Facial features of patients with TCF4-related Pitt-Hopkins syndrome. Patient 1 in A (6 months), B (18 months) and C (14 years). Patient 6 in D and H (29 years). Patient 2 in E, F (6 months) and G (11 years). Patient 3 in I (3 years), J (6 years) and K (8.75 years). Patient 4 in L and M (12.5 years). Note the deep-set eyes, broad and beaked nasal bridge with down-turned, pointed nasal tip, and flaring nostrils; the wide mouth with widely spaced teeth, and Cupid-bowed and everted lower lip; the mildly cup-shaped, fleshy ears; as well as increased coarsening of the facial features with age (by courtesy of [Zweier et al., 2007]).

Fig. 2

The boy's Pitt-Hopkins syndrome is due to a splice-cite mutation in the TCF4 gene. In photo 1, he is half-a-year old, in photos 2–4 three years old, and in photo 5 five years old. Note the broad nose, flared and anteverted nostrils, protruding philtrum, large mouth, bow-shape upper lip, broad lips, broad ear helices, and the development of myopia by the age of 5.