Pitt-Hopkins syndrome (PTHS, OMIM 610954) is
characterized by facial dysmorphisms and developmental and intellectual delay
in all cases and, in some patients, by episodes of hyperventilation and/or breath-holding
while awake. Behavioral problems, stereotypic movements, epilepsy, constipation
and severe myopia may also be present. PTHS can be caused by heterozygous mutation
in the TCF4 gene.
Recently, a similar phenotype has been
described by some authors and called Pitt-Hopkins syndrome (PTHSL). Two types
of PTHSL have been so far classified: type 1 (PTHSL1) and type 2 (PTHSL2).
PTHSL1 (OMIM 610042) is characterized by a
neuropathologic phenotype with mild gross motor delay, deterioration of social
behavior (with possibility of autistic or stereotypic behavior), severe
intractable seizures and subtle limitations in motor skills. Distinguishing
physical features may be absent, although some patients may have relatively
large heads, coarse facial features, short stature, short great toes and
hypertrichosis. Diminished or absent deep-tendon reflexes and overbreathing are
described. Brain MRI may show focal malformations. Homozygous or compound
heterozygous mutations in the CNTNAP2 gene can cause PTHSL1.
PTHSL2 (OMIM 614325) is also characterized by
psychomotor retardation (typically appearing as a regression of development
after the first years). Hyperbreathing and autistic behavior are described also
in PTHSL2, but seizures and brain MRI abnormalities may not be present. Mild
facial dysmorphism (including broad mouth, strabismus, and protruding tongue
with drooling) are described. Hypotonia can be diagnosed at birth. Compound
heterozygosity for point mutations or, very interestingly, for different large
deletions have been reported in the NRXN1 gene to cause PTHSL2.
Of note, CNTNAP2 and NRXN1 are two distantly
related members of the neurexin superfamily.
So, the first difference between PTHS and PTHSL
is about inheritance: PTHS is inherited in an autosomal dominant manner, while
PTHSL1 and 2 are inherited in an autosomal recessive manner. This difference,
however, may be of little help in the first evaluation of the patient, as most PTHS
patients have a de novo mutation and
thus have unaffected parents. Although facial dysmorphisms may be present in
PTHSL, the characteristic facial features of PTHSL1 or PTHSL2 are reportedly
different and this should help in the differential diagnosis.
References: see text.
