DiagnosisThe following information on the diagnosis Pitt-Hopkins syndrome (PTHS) is based on a detailed review of all the published reports and available photos to date of 117 individuals with a diagnosis of PTHS and a confirmed mutation or deletion in TCF4 [Zweier et al 2008, dePontual et al 2009, Rosenfeld et al 2009, Marangi et al 2011, Armani et al 2012, Ghosh et al 2012, Maini et al 2012, Whalen et al 2012, Steinbusch et al 2013]. Ages at the time the reports were published range from 20 months to 32 years. The diagnosis PTHS is suggested by the following: Characteristic facial features which become more apparent with age are listed below. The craniofacial features are an important aspect for the diagnosis of PTHS, but may be less obvious in the infant. In many individuals, the prominence of the nose and lower face may be the earliest clue to PTHS in an infant with developmental concerns (see Figure 1, Figure 2):Deep-set eyes with prominence of the supraorbital ridgeMildly upslanting palpebral fissuresHigh nasal root with prominent nasal bridgeOverhanging or depressed nasal tip which may be pointedWide nostrilsShort philtrumFull lower lip (which may be everted) with thick vermillion borderIn some individuals, wide mouth with downturned corners and tented or cupid bowed upper lipWidely spaced teethProminence of the lower face with a well-developed chin. With age, the lower face becomes more prominent and facial features may coarsen.In some individuals, mildly cupped ears with thick or fleshy helicesDevelopmental delay/intellectual disability. Delayed milestones are reported in all, with hypotonia in most. Intellectual disability is typically severe; speech is severely limited or absent. Episodic hyperventilation and/or breath-holding while awake. Unusual episodes of hyperventilation (which may be followed by apnea) may occur while awake. When present, this finding (in combination with the characteristic facial features and developmental history) is highly suggestive of PTHS; however, the absence of a breathing abnormality should not eliminate consideration of the diagnosis of PTHS as the breathing abnormality may begin sometime in the second half of the first decade, later, or not at all [Zweier et al 2008, Marangi et al 2011].
Note: Information about the presence of the breathing abnormality must be elicited directly: parents may not realize the diagnostic importance of this finding as it would not typically prompt them to seek medical attention [Takano et al 2011, personal observation]. Growth that tends to be normal. However, microcephaly is rather common. Absence of serious congenital malformations.FigureFigure 1. Newborn male with Pitt-Hopkins syndrome. Note high nasal root with prominent nasal bridge, and depressed nasal tip. FigureFigure 2. 7-year-old male with Pitt-Hopkins syndrome (same individual as in Figure 1). Note prominence of the lower face with a well-developed chin. He has a cheerful disposition, deep-set eyes, prominent nasal bridge with depressed nasal tip, and wide (more...)Molecular Genetic TestingGene. TCF4 is the only gene in which mutations are known to cause Pitt-Hopkins syndrome.Clinical testingSequence analysis. Sequencing of all 18 TCF4 coding exons (exons 2 to 19), splice junctions, and immediate intronic flanking regions detects approximately 70% of mutations [Whalen et al 2012].Deletion/duplication analysis. Approximately 30% of TCF4 mutations are whole- or partial-gene deletions, varying in size from a single exon to ~12 Mb [Whalen et al 2012]. Of these, at least ten reports describe single-exon or partial-gene deletions, detectable only by deletion/duplication analysis (Table 1) [Brockschmidt et al 2007, Rosenfeld et al 2009, Lehalle et al 2011, Whalen et al 2012]. Chromosome microarray analysis (CMA) (also known as array comparative genomic hybridization [aCGH]) detects a deletion in about one third of individuals with PTHS. Note: High-resolution chromosome analysis is required to determine if a translocation is present in these individuals.Cytogenetic testing. Cytogenetically visible deletions or chromosomal rearrangements disrupting TCF4 have been detected in at least seven individuals with PTHS [Gustavsson et al 1999, Giurgea et al 2008, Kalscheur et al 2008, Kato et al 2010, Marangi et al 2011]. In addition, the size of a number of the deletions detected by CMA would make them cytogenetically visible [Whalen et al 2012]. Table 1. Summary of Molecular Genetic Testing Used in Pitt-Hopkins SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityTCF4Sequence analysisSequence variants 270%ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletions30% 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis of Pitt-Hopkins syndrome in a proband1.Perform TCF4 sequence analysis. Note: Whalen et al [2012] propose a tiered sequencing strategy, beginning with exon 18, which harbors 25% of mutations; however, such testing may not be widely available. 2.If a mutation is not found by sequence analysis, perform exon-level deletion/duplication analysis. 3.If a mutation or deletion is not found by deletion/duplication analysis and a strong clinical suspicion of PTHS remains, perform a karyotype to look for an apparently balanced translocation involving the 18q21.2 region (which would not be detected by either sequence analysis or CMA). Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in TCF4.}

Natural History Children with Pitt-Hopkins syndrome (PTHS) typically present in the first year of life with hypotonia and developmental delays. Some infants have been described as being quiet and "unusually good" with excessive sleeping [Giurgea et al 2008].Craniofacial. In addition to the craniofacial features discussed in Diagnosis, cherry red lips have been noted infrequently [Ghosh et al 2012, personal observation]. Developmental delay/intellectual disability. Global developmental delays are significant and intellectual disability is moderate to severe. Motor skills are delayed with a mean age of walking of four to six years (range 27 months to seven years); some affected individuals may walk only with assistance and others do not acquire independent walking skills [Whalen et al 2012]. Those who walk independently often have a wide-based, unsteady gait. Self-care skills are also delayed and few are reported to develop dressing or toileting skills. Speech is significantly delayed in all individuals with PTHS. Some are reported to have developed a few words; most are nonverbal. Respiratory. Episodic hyperventilation and/or breath-holding while awake are reported in 55%-60% of individuals [Whalen et al 2012]. This breathing abnormality is often associated with anxiety or excitement [Giurgea et al 2008, Steinbusch et al 2013] and is not present during sleep [Maini et al 2012]. Breath-holding may be associated with cyanosis. In some children, hyperventilation and/or breath-holding episodes are only observed for a few months; in others they occur for many years. They are not related to seizure activity. Behavioral. Many individuals with PTHS are described as having a happy disposition [Zweier et al 2008, Marangi et al 2011]. Others are described as being difficult to handle as they develop outbursts of aggression or bouts of shouting associated with frustration or unanticipated changes in routine [Andrieux et al 2008, Giurgea et al 2008, dePontual et al 2009]. They may be shy or anxious in new situations and self-aggression can occur. Unprovoked laughter may occur; sleep disturbance in childhood is reported in fewer than half of affected individuals [Whalen et al 2012]. Stereotypic hand movements commonly observed include flapping, clapping, washing movements, hand to mouth, and finger crossing [Takano et al 2010, Marangi et al 2011, Whalen et al 2012]. Two individuals have been reported to have lost the use of hand skills [Zweier et al 2008, Armani et al 2012].Neurologic. Seizures, reported in 40%-50% of individuals with PTHS, vary in type and severity. They are usually controlled with anticonvulsant therapy. Onset of seizures is reported from early infancy to as late as age 18 years [dePontual et al 2009]. If present, seizures typically are not associated with the breathing abnormality. In those individuals who have had a brain MRI, a variety of findings have been reported, most commonly hypoplasia/agenesis of the corpus callosum, ventricular dilatation, and posterior fossa abnormalities. A number of individuals have had normal studies [Marangi et al 2011, Whalen et al 2012]. Eyes. Myopia, strabismus, and/ or astigmatism are present in 50%-60%. Myopia can be severe (>6 diopters) and evident before age two years [Giurgea et al 2008, Stavropoulos et al 2010].Gastrointestinal. Early feeding issues may occur, although most resolve with age. Constipation is common (75%) and may be severe. Hirschsprung disease is rare (only one individual reported [Peippo et al 2006]). Gastroesophageal reflux is reported in less than half of individuals with PTHS. Musculoskeletal. Minor hand and foot anomalies such as slender or small hands and feet, broad fingertips, absent flexion creases of the thumbs, clinodactyly, tapered fingers, flat feet with hindfoot valgus deformity, overriding fifth toe, and short metatarsals have been reported. Hands and feet are reported to be cold and cyanosed in some individuals. Scoliosis has been noted in about 25% although no information regarding severity is given. Club feet are uncommon [Whalen et al 2012]. Skin. Many have had prominent pads on the fingertips and/or toes (persistent fetal pads) [Lehalle et al 2011]. Supernumerary nipples have been observed in at least ten individuals [Rosenfeld et al 2009, Takano et al 2010, Marangi et al 2011].Growth. Growth is typically in the normal range for size at birth; slower postnatal growth is noted in about 25%. Head growth slows postnatally with true or relative microcephaly reported in 10%-65% [Marangi et al 2011, Whalen et al 2012].OtherHodgkin lymphoma has been reported in a 29-year-old with PTHS [Zweier et al 2007]. While TCF4 has a role in lymphocyte development [Zhuang et al 1996], it is unknown if lymphoma in one person is related to the diagnosis of PTHS or coincidental. Relatively few older teens or adults have been reported with PTHS; thus it is not yet known what, if any, other adult-onset disorders may be of concern in PTHS.

Differential DiagnosisDisorders with features that overlap those of Pitt-Hopkins syndrome (PTHS) include the following:Mowat-Wilson syndrome (MWS). Similar developmental delay, absent speech, and hypotonia with some overlap in facial features; however, MWS is associated with an unusual uplifted earlobe configuration and hypertelorism. MWS is more likely than PTHS to be associated with a variety of malformations (Hirschsprung disease, genitourinary anomalies, heart defects, and structural eye anomalies).Angelman syndrome (AS). Similar developmental delay with absent speech, seizures, microcephaly, wide-based gait, happy disposition. Two percent of 86 individuals suspected of having AS actually had PTHS with a TCF4 mutation [Takano et al 2010].Joubert syndrome (JS). Associated with hypotonia, developmental delays, and episodic tachypnea and/or apnea. It can be distinguished by the distinctive cerebellar vermis hypoplasia associated with the molar tooth sign on brain MRI, oculomotor apraxia, and truncal ataxia. In addition, the breathing abnormalities of JS are noted in early infancy and improve with age.Rett syndrome. Associated with episodic hyperventilation/apnea, but unlike PTHS, it is progressive and seen in females only. Normal early development is followed by stagnation and regression of language and motor skills. Rett syndrome also lacks the facial characteristics associated with PTHS. Mutation of the X-linked gene MECP2 is causative. ARX-related intellectual disability syndrome. Recurrent hyperventilation episodes reported in a single individual with an ARX mutation [Demos et al 2009]. This X-linked condition associated with global developmental delay, severe speech disorder, and seizures can be distinguished by the presence of hand and lower-limb dystonia and lack of the characteristic facial features seen in PTHS.NRXN1-associated autosomal recessive intellectual disability disorder. Severe global delays, lack of speech, stereotypies, and episodic breathing differences reported in three individuals (two with hyperventilation episodes and one with breath-holding episodes) [Zweier et al 2009, Harrison et al 2011]. These individuals lack the characteristic facial features seen in PTHS and have abnormal sleep-wake cycles, which are not commonly reported with PTHS.CNTNAP2 -associated autosomal recessive intellectual disability disorder. Severe global delays, lack of speech, stereotypies, seizures, and episodic hyperventilation episodes reported in three individuals [Zweier et al 2009]. These individuals lack the characteristic facial features seen in PTHS. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Pitt-Hopkins syndrome (PTHS), the following evaluations are recommended:Developmental assessment to determine the types of services and educational strategies needed. In school-aged children this information is important for the child’s individual education program (IEP).Assessment for the use of nonverbal communication devices and strategies (given that most patients do not develop useful speech)Child behavior specialist to aid with behavioral concernsPulmonary consultation if history of respiratory pattern abnormality is identified on directed questioning. Polysomnography may be indicated if there is a history of episodic apnea especially when associated with cyanosis (typically alternating with episodes of hyperventilation).Child neurology evaluation if there are concerns about seizure episodesOphthalmology evaluation to evaluate for myopia, astigmatism, and/or strabismusGastroenterology evaluation to establish treatment regimen for chronic constipationMusculoskeletal evaluation to evaluate ambulatory skills and need for special mobility equipment and/or orthotics to aid in foot positionMedical genetics consultationTreatment of ManifestationsDevelopmental. Early infant developmental services (physical, occupational, speech therapies):Infant feeding assessment to address early hypotonia as neededSpecial education services to address delays with focus on life skillsBehavioral modification for self-injurious behavior or anxietyPulmonary. Some reports indicate that antiepileptic medications control seizures while leaving the unusual respiratory patterns unchanged Peippo et al [2006] and others have noted some decrease in the frequency of the episodes with the use of anticonvulsants [Takano et al 2010]. Improvement of an abnormal respiratory pattern after treatment with sodium valproate has been reported in a person with PTHS with frequent apneic episodes associated with hypoxemia [Maini et al 2012]. A recent study in two patients with PTHS demonstrated that daily treatment with acetazolamide resulted in decreased frequency and duration of hyperventilatory and apneic episodes and improved oxygen saturation [Verhulst et al 2012]. Neurologic. Treatment of epilepsy appropriate to type of seizure and individualized to the patientOphthalmologic. Eyeglasses or surgery as needed for amblyopiaGastrointestinal. In most patients, regular use of high-fiber diet and/or laxative regimen to address constipationMusculoskeletal: Orthotics for abnormal foot position to aid in ambulation. Orthopedic treatment of scoliosis as indicated.Other. Standard care for other medical issuesSurveillanceAppropriate surveillance includes:Ongoing developmental assessments to tailor educational services to an individual’s strengthsRegular follow up with an ophthalmologist to monitor for high myopia and strabismusPeriodic reevaluation with medical geneticist and/or genetic counselor to review the most current information and recommendations for individuals with PTHSEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Pitt-Hopkins Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTCF418q21​.2Transcription factor 4TransCription Factor 4 (TCF4) @ LOVDTCF4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Pitt-Hopkins Syndrome (View All in OMIM) View in own window 602272TRANSCRIPTION FACTOR 4; TCF4 610954PITT-HOPKINS SYNDROME; PTHSNormal allelic variants. TCF4 has 18 coding exons (exons 2-19) spanning 360 kb with exons 1 and 20 being non-coding. However, a recent bioinformatic analysis of mRNA and expressed sequence tag sequences demonstrates that TCF4 uses numerous alternative 5’ exons, potentially yielding many isoforms with different N-termini and different subcellular distribution [Sepp et al 2011]. TCF4 mRNAs are ubiquitously expressed but the levels differ considerably between different tissues, with the highest levels present in fetal brain [Sepp et al 2011].Pathologic allelic variants. At least 115 PTHS-associated mutations have been described in the literature to date; with the exception of five recurrent mutations, all are private. PTHS-associated TCF4 variants are either null mutations or missense mutations, mostly affecting the bHLH domain (see Normal gene product) encoded by exon 18 [Brockschmidt et al 2007, Zweier et al 2007, Whalen et al 2012]. Whalen et al [2012] summarized the frequency of various types of TCF4 mutations:30% are deletions including one or more exons and varying in size from a single exon to several megabases. Deletions result in either a frameshift or removal of the bHLH domain.30% are small intra-exonic insertions or deletions.40% are point mutations:Nonsense mutations account for 20% of all point mutations reported and are spread throughout the gene between exons 7 and 18. They are presumed to result in nonsense-mediated RNA decay. Splice mutations account for 14% of point mutations and affect mostly donor or acceptor consensus sites. Splice mutations in TCF4 are thought to result in frameshifts, and no splice mutations affecting exon 15 (the only in-frame exon) have been reported to date.Missense mutations represent 19% of point mutations in TCF4 and mostly affect conserved residues in the bHLH domain, several of which have been seen in multiple families.A mutation hot spot in the nucleotides encoding the basic domain of TCF4 accounts for 25% of mutations. [Whalen et al 2012].Evidence suggests that less severe mutations may result in milder or atypical presentations: A patient with mild to moderate intellectual disability and minor facial abnormalities but without classic PTHS was reported to have a balanced translocation t(18:20)(q21.1;q11.2) disrupting TCF4 upstream to exon 4. Fusion transcripts between TCF4 and CHD6 produced in the patient’s cell line may result in a partially functional TCF4 protein [Kalscheur et al 2008]. Normal gene product. TCF4 (also known as ITF2, E2-2, and SEF2) encodes a member of the class I basic helix-loop-helix (bHLH) family of transcription factors, which regulate multiple processes including cellular differentiation and proliferation and lineage commitment [Atchley & Fitch 1997, Kageyama & Nakanishi 1997, Ross et al 2003, de Pontual et al 2009]. During early development, TCF4 is highly expressed in the central nervous system, genital bud, peribronchial and kidney mesenchyme, and sclerotome [de Pontual et al 2009]. Homozygous Tcf4 knock-out mice exhibit early lethality, suggesting an important role in development [Zhuang et al 1996].Class I bHLH proteins are also known as E-proteins because they bind DNA as homo or heterodimers, at Ephrussi box (E-box) sequences (CANNTG) [Ephrussi et al 1985, Massari & Murre 2000]. E-proteins have two conserved transactivation domains, AD1 and AD2 [Aronheim et al 1993, Quong et al 1993], a repression domain, RD [Markus et al 2002], as well as a common bHLH structural motif that mediates homo- and heterodimerization between bHLH proteins via their HLH domain, while the adjacent basic region mediates the DNA binding to the E-box [Ross et al 2003].The interaction of TCF4 with other bHLH proteins indicates a potential role in development of specific parts of the central and peripheral nervous system. Such bHLH partners include Atoh1 (Math1) in pontine development in mice [Flora et al 2007] and ASCL1 in neuroblastoma cells [Persson et al 2000].Several TCF4 isoforms have been reported, the longest of which encodes a protein of 671 amino acids [Sepp et al 2011]. See Table A.Abnormal gene product. PTHS is caused by haploinsufficiency of TCF4 protein [Amiel et al 2007]. The clinical features observed in patients with PTHS are consistent with haploinsufficiency of TCF4 having a negative effect on development, particularly affecting specific parts of the central and peripheral nervous system [Persson et al 2000]. Tcf4 knockout mice have disrupted development of the pontine nucleus [Flora et al 2007]. Deregulation of other bHLH protein partners such as Atoh1 or ASCL1 could also potentially cause a related phenotype; this has yet to be demonstrated.