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Pitt-Hopkins Syndrome

, MD, , MS, and , PhD.

Author Information
, MD
Section of Genetics
Department of Pediatrics
Children’s Mercy Hospitals and Clinics
School of Medicine
University of Missouri - Kansas City
Kansas City, Missouri
, MS
Section of Genetics
Department of Pediatrics
Children’s Mercy Hospitals and Clinics
School of Medicine
University of Missouri - Kansas City
Kansas City, Missouri
, PhD
Clinical Molecular Genetics Laboratory
Department of Pathology
Children’s Mercy Hospitals and Clinics
School of Medicine
University of Missouri - Kansas City
Kansas City, Missouri

Initial Posting: .

Summary

Disease characteristics. Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features which become more apparent with age (100%), developmental delay/intellectual disability (100%), and episodic hyperventilation and/or breath-holding while awake (55%-60%). Global developmental delays are significant and intellectual disability is moderate to severe: mean age of walking is four to six years; most affected individuals are nonverbal. Other common findings are behavioral issues, hand stereotypic movements, seizures (40%-50%), constipation, and severe myopia.

Diagnosis/testing. The diagnosis is suspected on clinical findings and confirmed on molecular genetic testing of TCF4.

Management. Treatment of manifestations: Developmental services for infants (physical, occupational, speech therapies); special education services focused on life skills for older children; behavioral modification as needed for self-injurious behavior or anxiety; possible treatment of abnormal respiratory pattern with sodium valproate. Routine management of seizures, myopia, constipation, scoliosis, and abnormal foot positioning.

Surveillance: Ongoing developmental assessments to tailor educational services to individual needs; regular follow up with an ophthalmologist to monitor for high myopia and strabismus; periodic reevaluation with a medical genetics professional regarding current information and recommendations.

Genetic counseling. PTHS is caused by haploinsufficiency of TCF4 resulting from either a mutation in TCF4 or a deletion of the chromosomal region in which TCF4 is located (18q21.2). Most affected individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo mutation or deletion. The risk to sibs of a proband is low, but higher than that of the general population because of the possibility of parental germline mosaicism. Prenatal diagnosis of pregnancies at increased risk is possible if the genetic diagnosis has been established in an affected family member.

Diagnosis

The 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 ridge
    • Mildly upslanting palpebral fissures
    • High nasal root with prominent nasal bridge
    • Overhanging or depressed nasal tip which may be pointed
    • Wide nostrils
    • Short philtrum
    • Full lower lip (which may be everted) with thick vermillion border
    • In some individuals, wide mouth with downturned corners and tented or cupid bowed upper lip
    • Widely spaced teeth
    • Prominence 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 helices
  • Developmental 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.
Figure 1

Figure

Figure 1. Newborn male with Pitt-Hopkins syndrome. Note high nasal root with prominent nasal bridge, and depressed nasal tip.

Figure 2

Figure

Figure 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 Testing

Gene. TCF4 is the only gene in which mutations are known to cause Pitt-Hopkins syndrome.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Pitt-Hopkins Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
TCF4Sequence analysisSequence variants 270%
Deletion / 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 gene

2. 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 proband

1.

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.

Clinical Description

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].

Other

  • Hodgkin 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.

Genotype-Phenotype Correlations

The phenotype associated with PTHS appears to be independent of TCF4 mutation type.

Comparisons between individuals with PTHS with a chromosome 18q21.2 deletion and those with an intragenic TCF4 mutation have not identified any consistent clinical differences, further suggesting that the phenotype can be explained by haploinsufficiency for the TCF4 protein product [Stavropoulos et al 2010].

No genotype-phenotype correlation exists for chromosome 18q21.2 deletions of varying sizes [Andrieux et al 2008]. However, the phenotype in individuals with large deletions that include TCF4 may be influenced by the haploinsufficiency of other genes in close proximity. Giurgea et al [2008] could not identify clinical differences between individuals with point mutations and those with large cytogenetic deletions in TCF4.

Some genotype-phenotype relationships that have been suggested:

Two individuals with mosaicism for chromosome 18q21.2 deletions (11.9 Mb and 7.5 Mb in size) demonstrated the typical PTHS phenotype [Giurgea et al 2008, Stavropoulos et al 2010].

Genetic and epigenetic modifiers as well as environmental factors may also influence the phenotype. Two brothers with the same TCF4 mutation demonstrated different severity of phenotype: one brother showed the typical characteristics of PTHS; the other brother had milder physical features and less severe intellectual disability. Their unaffected mother was somatic mosaic for the TCF4 mutation [Steinbusch et al 2013].

Prevalence

Overall prevalence of PTHS is unknown. However, one laboratory estimated that the frequency of chromosome 18q21 deletions associated with PTHS is between one in 34,000 and one in 41,000 [Rosenfeld et al 2009].

If deletions are found in approximately one third of individuals with PTHS, the frequency of the condition could be as high as one in 11,000. It has been suggested that PTHS is underdiagnosed [Taddeucci et al 2010].

PTHS occurs in both males and females and is not limited to a specific ethnic background.

Differential Diagnosis

Disorders 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations 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 concerns
  • Pulmonary 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 episodes
  • Ophthalmology evaluation to evaluate for myopia, astigmatism, and/or strabismus
  • Gastroenterology evaluation to establish treatment regimen for chronic constipation
  • Musculoskeletal evaluation to evaluate ambulatory skills and need for special mobility equipment and/or orthotics to aid in foot position
  • Medical genetics consultation

Treatment of Manifestations

  • Developmental. Early infant developmental services (physical, occupational, speech therapies):
    • Infant feeding assessment to address early hypotonia as needed
    • Special education services to address delays with focus on life skills
    • Behavioral modification for self-injurious behavior or anxiety
  • Pulmonary. 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 patient
  • Ophthalmologic. Eyeglasses or surgery as needed for amblyopia
  • Gastrointestinal. In most patients, regular use of high-fiber diet and/or laxative regimen to address constipation
  • Musculoskeletal: Orthotics for abnormal foot position to aid in ambulation. Orthopedic treatment of scoliosis as indicated.
  • Other. Standard care for other medical issues

Surveillance

Appropriate surveillance includes:

  • Ongoing developmental assessments to tailor educational services to an individual’s strengths
  • Regular follow up with an ophthalmologist to monitor for high myopia and strabismus
  • Periodic reevaluation with medical geneticist and/or genetic counselor to review the most current information and recommendations for individuals with PTHS

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pitt-Hopkins syndrome (PTHS) is caused by haploinsufficiency of TCF4 resulting from either a mutation in TCF4 or a deletion of the chromosomal region in which TCF4 is located (18q21.2). Most individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo mutation or deletion.

Risk to Family Members — TCF4 Mutation

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents:
    • If a proband’s parent has a TCF4 mutation (even in a mosaic state), the risk to sibs of being similarly affected could be as high as 50%.
    • Because PTHS typically occurs de novo, the risk to the sibs of a proband is most likely low.
  • Somatic mosaicism in two mothers has been reported; germline mosaicism has been inferred [de Pontual et al 2009, Steinbusch et al 2013]. Therefore, although the risk to sibs of a proband is low, the risk is higher than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband. There have been no reports of individuals with PTHS reproducing. However, each child of an individual with PTHS would have a 50% chance of being affected.

Risk to Family Members — 18q21.2 Deletion

Parents of a proband

  • The 18q21.2 deletion (whether resulting from an ‘apparently balanced’ chromosome rearrangement or, more commonly, from a simple deletion) has been de novo in all affected individuals (reported in the medical literature) whose parents had cytogenetic studies.
  • Parents of a proband are typically not affected.
  • If an 18q21.2 deletion is identified in a proband, both parents could be offered testing. However, low levels of somatic mosaicism can never be entirely ruled out.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

  • Because PTHS typically occurs as a de novo deletion, the risk to the sibs of a proband is most likely low.
  • If a proband’s parent has a chromosome 18q21.2 deletion (even in a mosaic state), the risk for sibs to be similarly affected could be as high as 50%.

Offspring of a proband. There have been no reports of individuals with PTHS reproducing. However, each child of an individual with PTHS would have a 50% chance of being affected.

Other family members. Because PTHS typically occurs as a de novo mutation, other family members of a proband are not at increased risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Routine ultrasound examination. PTHS is not typically associated with structural anomalies which could be identified by ultrasound.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Chromosome 18 Registry and Research Society
    7155 Oakridge Drive
    San Antonio TX 78229
    Phone: 210-657-4968
    Email: Office@Chromosome18.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TCF418q21​.2Transcription factor 4TransCription Factor 4 (TCF4) @ LOVDTCF4

Data 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)

602272TRANSCRIPTION FACTOR 4; TCF4
610954PITT-HOPKINS SYNDROME; PTHS

Normal 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.

References

Literature Cited

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  2. Andrieux J, Lepretre F, Cuisset JM, Goldenberg A, Delobel B, Manouvrier-Hanu S, Holder-Espinasse M. Deletion 18q21.2q21.32 involving TCF4 in a boy diagnosed by CGH-array. Eur J Med Genet. 2008;51:172–7. [PubMed: 18222743]
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  4. Aronheim A, Shiran R, Rosen A, Walker MD. The E2A gene product contains two separable and functionally distinct transcription activation domains. Proc Natl Acad Sci U S A. 1993;90:8063–7. [PMC free article: PMC47288] [PubMed: 8367464]
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Chapter Notes

Revision History

  • 30 August 2012 (me) Review posted live
  • 4 May 2012 (hha) Original submission
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