Clinical differential diagnosis of PTHS includes distinguishing PTHS versus the following syndromes: AS, Rett Syndrome, Mowat–Wilson Syndrome, Joubert Syndrome, ATR-X-related ID syndrome, Neurexin 1 (NRXN1)-associated autosomal recessive ID disorder, and contactin-associated protein-like 2 (CNTNAP2)-associated autosomal recessive ID disorder. A more complete guide to differential diagnosis among these various possibilities is given in references 1, 34 and 35. Fortunately, all these disorders have genetic screening tests available in order to allow distinguishing among them, which I will discuss in more detail in the following section.
A landmark step forward for our understanding of PTHS came in 2007 with the simultaneous independent discovery by three different research groups in Europe that disruption of the TCF4
located at 18q21.1, (OMIM 602272)) is the basis for PTHS.40, 41, 42
These groups discovered that point mutations, intragenic deletions or broader deletions in Chromosome 18 that disrupt the TCF4 gene are diagnostic for PTHS, and thus by definition PTHS is a disorder of disrupted TCF4 function. These pioneering human genetic studies and a wide variety of subsequent studies have clearly demonstrated that heterozygous deficiency (haplo-insufficiency, or loss of function of one of the two cellular copies of TCF4) is sufficient to cause PTHS in humans. Mosaicism of TCF4 mutation, variability in deletion/insertion mutations and the cellular locales wherein the TCF4 deficiency resides is also an important when considering the variable phenotypes observed in PTHS patients.21, 41
The breakthrough discovery of TCF4 as the PTHS gene provided a rationale for clinical genetic screening for mutation of TCF4 as an unambiguous means of diagnosis of the syndrome. This is not a trivial consideration, as PTHS shares considerable phenotypic similarity with the (presumably) more broadly occurring Angelman Syndrome (AS, (OMIM 105830)), Rett Syndrome (RTT, OMIM 312750) and Mowat–Wilson Syndrome (MWS, OMIM 235730).14, 33, 35
Clinically, one should consider Angelman, Rett and Mowat–Wilson Syndromes in the differential diagnosis of Pitt–Hopkins Syndrome because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly and constipation.
Indeed, a recent study has demonstrated that in a quasi-random sampling of patients diagnosed with AS, approximately 2% of individuals thought to have AS instead had TCF4 deficiency, that is, PTHS.14
Regarding Rett Syndrome, Armani et al.42
identified a frameshift mutation in TCF4 in a patient who had previously been diagnosed clinically with ‘variant' RTT. Takano et al.33
have also suggested that PTHS be included in the differential diagnosis of X-linked α-thalassemia Intellectual Disability (ATR-X (OMIM 301040)) due to phenotypic similarities to this syndrome, as well as identifying at least one bona fide
case of mis-diagnosis of a presumed ATR-X patient under their care. Lehalle et al.36
have observed prominent fetal pads, on the fingers and toes, as a feature in several individuals with PTHS and have suggested that this phenotype can be used to help distinguish PTHS from other similar conditions during differential diagnosis, and thus this characteristic may be useful in suggesting specific genetic testing for PTHS.
Given the rarity of PTHS itself, co-morbidity with another genetic disorder is indeed highly unlikely. However, Ghosh et al.37
have observed the co-occurrence of Charcot-Marie-Tooth Disease Type 1 (CMT1A, OMIM 118220) with PTHS in one individual, with PTHS diagnosis confirmed by genetic screening.
Although the majority of cases of PTHS arise as a result of sporadic, spontaneous mutations in the TCF4 gene, Steinbusch et al.43
have reported somatic mosaicism of the TCF4 gene in a mother with two children manifesting PTHS. In both children, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4: the same mutation was found at low levels in DNA from the mother. As Steinbusch et al.43
suggest, the possibility of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling of PTHS families. This consideration may also explain an early report of possible PTHS in two siblings,28
although an alternative explanation could be the more recently characterized possibility of manifestation of a PTHS-like ID disorder manifesting autosomal recessive inheritance through NRXN1 and CNTNAP2 mutations, as will be described in the next paragraph.
Differential diagnoses versus novel ‘Pitt–Hopkins-like' syndromes
Recent studies of a few patients16, 44, 45, 46
have demonstrated the existence of two autosomal recessive disorders that are characterized by phenotypes very similar to PTHS: NRXN1-associated intellectual disability disorder
, and CNTNAP2-associated intellectual disability disorder.
This has led to these two disorders being categorized as Pitt–Hopkins-like
Indeed it has been hypothesized that TCF4, NRXN1 and CNTNAP2 (a Neurexin homolog) may all lie within a common signaling pathway that when disrupted leads to PTHS and related ID disorders.16, 44
Similar to PTHS, both NRXN1-associated ID disorder and CNTNAP2 -associated ID disorder manifest pervasive developmental delay, lack of speech, stereotypic movements and episodic hyperventilation or breath-holding. In one instance, a patient in this category exhibited epilepsy. However, these individuals lack the characteristic facial features seen in PTHS.
CNTNAP2 and NRXN1 are two distantly related members of the neurexin superfamily, and disruption of these genes has been implicated in a wide spectrum of neuropsychiatric disorders, such as developmental language disorders, ASDs, epilepsy and schizophrenia.16
In pioneering studies, Zweier et al.16
identified deletions and mutations in CNTNAP2 and NRXN1 in four patients with severe ID and variable features, such as autistic behavior, epilepsy and breathing anomalies, phenotypically overlapping with Pitt–Hopkins Syndrome. Although PTHS is an autosomal dominant disorder caused by haplo-insufficiency in the TCF4 gene, NRXN1- and CNTNAP2-associated ID are autosomal recessive disorders.16, 44
Interestingly, the known function of NRXN1 to serve as a synaptic cell adhesion molecule linking the presynaptic terminal with the postsynaptic compartment suggests that synaptic defects contribute to NRXN1-associated ID and by implication CNTNAP2-associated ID and PTHS as well.16, 44
Especially intriguing is the linkage of CNTNAP2 as an autism-susceptibility gene47, 48, 49
and its known contribution as a gene controlling human auditory language cognition.50, 51