Clinical characteristics.

Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia.

Diagnosis/testing.

The diagnosis of PTHS is established in a proband with suggestive findings and one of the following identified by molecular genetic testing: (1) a heterozygous TCF4 pathogenic variant or small intragenic deletions or indels (~70% of affected individuals) or (2) a heterozygous deletion of chromosome 18q21.2 involving TCF4 (~30% of affected individuals).

Management.

Treatment of manifestations: Developmental services for infants (physical, occupational, and speech therapies); education tailored to the needs of older children with strong consideration for early training in alternative means of communication; behavioral management strategies; possible treatment of abnormal respiratory pattern; treatment of seizures per neurologist; feeding therapy (for poor weight and persistent feeding issues); physical medicine and rehabilitation, physical therapy, occupational therapy, orthopedics (for treatment of scoliosis if needed); management of bowel dysfunction (gastroesophageal reflux, aspiration risk, constipation as needed) per gastroenterologist; pulmonary medicine (for treatment of respiratory dysregulation as needed).

Surveillance: Ongoing routinely scheduled assessments of development and communication as well as with other specialists providing supportive care to tailor services to individual needs. For older children, develop a plan for transition from pediatric to adult care.

Genetic counseling.

PTHS is an autosomal dominant disorder typically caused by a de novo genetic alteration. Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a mosaic parent or, in one family to date, an affected non-mosaic parent. Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

PTHS should be suspected in a proband with the following clinical and imaging findings and family history.

Clinical findings

• Developmental delay / intellectual disability
  • Delayed motor milestones, often associated with hypotonia
  • Severely limited-to-absent speech, with regression in verbal abilities in some individuals
  • Intellectual disability, typically moderate to severe
• Neurobehavioral/psychiatric manifestations
  • Autistic features or autism spectrum disorder (ASD); however, social engagement is generally present.
  • Anxiety
  • Other. Love of music, frequent smiling and spontaneous laughter, stereotypic hand movements including hand wringing and flapping, bruxism
• Characteristic facial features. An important aspect of PTHS, characteristic facial features may be less obvious in infancy. In an infant with developmental concerns, the wide nose with a distinctive wide nasal ridge and wide nasal root may be the earliest clue to PTHS (see Figures 1, 2, 3, 4, and 5).
  • Narrow forehead (bitemporal narrowing)
  • Thin lateral eyebrows
  • Wide nasal bridge/ridge/tip
  • Flared nasal alae
  • Full cheeks and prominent midface
  • Wide mouth, thick vermilion of the upper and lower lips, exaggerated Cupid's bow
  • Thickened/overfolded helices
• Autonomic dysfunction
  • Respiratory dysregulation
    • Apnea can be seen in neonates or in the first months of life; it often must be distinguished from seizure activity, which can also occur.
    • Hyperventilation triggered by excitement or anxiety is common.
    • Breathing abnormalities 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: Absence of a breathing abnormality in a child should not eliminate consideration of the diagnosis of PTHS.
  • Other
    • Intestinal dysmotility with constipation
    • High pain tolerance to external stimuli, with visceral hyperalgesia
    • Cool extremities
    • Decreased sweating with heat intolerance

Figure 1.

Newborn male with Pitt-Hopkins syndrome. Note wide nasal root with prominent nasal bridge, flared nasal alae, depressed nasal tip, ears with overfolded helix, and full everted vermilion of the lower lip.

Figure 2.

Boy age seven years 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, deeply set eyes, prominent nasal bridge with depressed nasal tip, flared nasal (more...)

Figure 3.

Boy age 13 years with Pitt-Hopkins syndrome (same individual as in Figures 1 and 2). Note thin lateral eyebrows, wide nasal ridge and alae, short philtrum, and thick vermilion of the upper and lower lips, with everted vermilion of the lower lip and widely (more...)

Figure 4.

Girl age ten years with Pitt-Hopkins syndrome. Note deeply set eyes, thin lateral eyebrows, wide nasal ridge, depressed nasal tip, thick and everted vermilion of the lower lip, widely spaced teeth, and prominent chin.

Figure 5.

Woman age 24 years with Pitt-Hopkins syndrome (same individual as in Figure 4). Note narrow forehead, prominent nose with depressed tip, short philtrum, thick vermilion of the upper and lower lips, wide mouth with downturned corners, and prominent chin. (more...)

Brain MRI. Although many brain MRIs are reported as normal, the most common findings when noted include white matter abnormalities such as hypoplasia/agenesis of the corpus callosum and white matter hyperintensity in the temporal poles, as well as ventricular dilatation, widened sulci, posterior fossa abnormalities, small hippocampi, and moderate hypoplasia of the frontal lobes [Amiel et al 2007, Marangi et al 2011, Whalen et al 2012].

Family history. Because PTHS is typically caused by a de novo genetic alteration, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of PTHS is established in a proband with suggestive findings and one of the following identified by molecular genetic testing [Whalen et al 2012] (see Table 1):

• A heterozygous TCF4 pathogenic (or likely pathogenic) variant or small intragenic deletions or indels (~70% of affected individuals)
• A heterozygous deletion of chromosome 18q21.2 involving TCF4 (~30% of affected individuals)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous TCF4 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis [CMA], exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not.

For individuals with suggestive findings, testing approaches to consider include the following:

• CMA, which can detect TCF4 partial- and whole-gene deletions as well as contiguous gene deletions involving TCF4, can be performed before or after single-gene testing and/or multigene panel testing.
• Single-gene testing. Directed sequence analysis of TCF4 may be considered initially to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes TCF4 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

A karyotype should be considered when a diagnosis of PTHS is strongly suspected and results of molecular genetic testing are normal, as balanced chromosomal rearrangements disrupting TCF4 without a deletion have been detected in individuals with features of PTHS [Kalscheuer et al 2008, Marangi et al 2011, Schluth-Bolard et al 2013, Zollino et al [2019].

Comprehensive genomic testing is another approach to consider. Exome sequencing is most commonly used; genome sequencing is increasingly being used. To date, the majority of TCF4 pathogenic variants reported (e.g., missense, nonsense) are within the coding region or splice site variants in the sequences adjacent to the coding regions and are likely to be identified on exome sequencing. However, exome sequencing can miss deletions involving one or two exons. Such deletions are more likely to be detected with CMA or whole-genome sequencing. To date, no deep intronic splice variants causing PTHS have been described. This may change over time with the increasing use of genome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia (see Table 2).

Developmental delay / intellectual disability. Children with PTHS typically present in the first year of life with hypotonia and global developmental delay.

Hypotonia is noted in most infants and young children. Poor balance often causes difficulty with learning to walk. Fine motor skill acquisition is also delayed and variably achieved.

Motor milestones are delayed in all individuals, most of whom are not ambulatory until after age three years [Goodspeed et al 2018]. The mean age of walking is four to six years (range: 27 months to 7 years); some individuals may walk only with assistance, and a minority do not achieve independent ambulation [Whalen et al 2012]. Those who walk independently often have a wide-based, unsteady gait. Most individuals require orthotics to stabilize the ankle.

Speech and language. Speech is significantly delayed in practically all individuals. Because most individuals are nonverbal, important means of communication include interpretation of body language and use of gestures or leading behaviors. Although some individuals develop a few words, later in life they regress, becoming nonverbal. Rare individuals can combine words into sentences.

Receptive language is generally stronger than expressive language; many individuals understand and follow simple commands. The use of augmentative communication devices and alternate forms of communication including signs often improve communication, thus helping to reduce frustrations and behaviors and to improve learning (see Management). Although all individuals with PTHS have significant intellectual disability, poor communication skills may result in underestimation of cognitive abilities.

Self-care skills are also delayed; few individuals develop consistent dressing or toileting skills.

Neurobehavioral/psychiatric manifestations include features of autism spectrum disorder (ASD) such as impairments in communication, behavior, and social interactions.

Some individuals meet diagnostic criteria for ASD. Eight of ten participants scored at or above the social, behavioral, and communication criteria for ASD using the Autism Diagnostic Interview Revised (ADI-R) [Van Balkom et al 2012]. All participants had repetitive hand or finger movements and high scores for self-absorption. Six of the ten had fixations that prompted repetitive exposure to a specific object, listening to the same song, or viewing the same video repeatedly. Many individuals love water play (with a fascination with running water), spinning objects, and lights [D Sweetser, personal observation].

By contrast, most individuals with PTHS often seek attention and enjoy being with people. Most individuals generally have an easygoing, happy temperament [Marangi et al 2011, Goodspeed et al 2018], frequently smiling and seemingly content. Unprovoked laughter may occur. However, they commonly exhibit periods of behaviors that may be set off by anxiety, frustration, or pain [D Sweetser, personal experience]. Given the frequent underlying anxiety, Whalen et al [2012] proposed that an anxious disposition with a smiling appearance is a more apt description.

Individuals may be shy or anxious in new situations (such as disruptions of routines) and can show self-aggression such as hand biting and head banging, pinching, or hitting themselves [de Winter et al 2016].

Many individuals have outbursts of aggression or bouts of shouting associated with frustration or unanticipated changes in routine [Andrieux et al 2008, Giurgea et al 2008, de Pontual et al 2009]. The onset of puberty can also be associated with increased aggression and behavioral issues [D Sweetser, personal observation].

Stereotypic head movements (e.g., head rotation) and hand movements (e.g., flapping, clapping, washing movements, hand to mouth, finger crossing) are common [Takano et al 2010, Marangi et al 2011, Whalen et al 2012]. Although three individuals were reported to have lost hand skills [Armani et al 2012, Whalen et al 2012], this is not generally seen.

Individuals with PTHS invariably have a profound affinity for music. Families report that during episodes of anxiety or frustration, music is often soothing.

Respiratory dysregulation is common [Zweier et al 2007, de Winter et al 2016, Goodspeed et al 2018]. Breathing abnormalities tend to develop between ages three and seven years. Although rare, neonatal presentation occurs [Tas et al 2022]. In one study, 30% of individuals with PTHS exhibited symptoms by age 15 years [de Winter et al 2016].

Breath-holding episodes of varying severity and independent of hyperventilation may occur. Breath-holding/apnea episodes are not typically related to seizure activity and generally do not occur during sleep [Maini et al 2012].

Apnea from birth to age three months, not associated with prematurity or seizures, is seen in about 6% of infants [D Sweetser, personal observation].

Subtle breathing pauses are common. Overt breath-holding with hypoxia and cyanosis can be seen, and in rare cases syncope may occur [Whalen et al 2012]. Chronic hypoxia presumably underlies the clubbing seen later in life in some individuals. Note: Parents/caregivers may need to be queried directly about breath-holding (which typically is not serious enough to seek medical attention) [Takano et al 2011; D Sweetser, personal observation].

In some children, hyperventilation and/or breath-holding episodes are observed for only a few months or years; however, in most individuals breathing abnormalities persist to some degree. It is difficult to make conclusive statements about frequency or severity of such episodes in adults, as to date too few adults with PTHS have been described.

Chronic hypoxemia and associated finger clubbing has been reported in 7%-19% of individuals [Whalen et al 2012, Goodspeed et al 2018]. While the etiology of digital clubbing is not well elucidated, it may be related to cumulative periods of hypoxemia. Detailed studies of pulmonary function, including diffusing capacity, are not possible given behavioral barriers.

Disorders of sleep-related breathing, such as obstructive apnea, hypoxemia, and hypoventilation, can have significant long-term effects on health, behavior, and development. Children with developmental disorders may be more susceptible to the deleterious effects of these disorders than neurotypical children [Menzies et al 2022].

Episodic hyperventilation, usually in the context of heightened emotion such as anxiety or excitement, occurs in 40-60% of individuals [Giurgea et al 2008, Whalen et al 2012, Steinbusch et al 2013, de Winter et al 2016, Goodspeed et al 2018]. Rare children manifest repeated episodes of hyperventilation immediately followed by apnea and syncope.

Other signs of general autonomic dysfunction observed in some individuals or reported by families include the following [Zollino et al 2019]:

• Dilated pupils with sluggish response to light
• Decreased distal circulation
• Urinary retention
• High external pain tolerance with visceral hyperesthesia
• Dysregulation of body temperature

Gastrointestinal. Feeding issues related to hypotonia can present in the first months of life with poor feeding and poor coordination of suck and swallow resulting in poor weight gain. Most of these issues resolve with age.

Constipation, which is common (75%), often starts in infancy, may be severe, and generally is lifelong.

Dysmotility of the gastrointestinal tract and autonomic dysfunction resulting in gastroparesis and chronic intestinal pseudo-obstruction are thought to contribute to frequent and significant abdominal pain. Constipation or intestinal dysmotility is a common source of pain. Effective control of constipation and improving gastrointestinal motility may lessen such spells [Comisi et al 2023], as can institution of pain management [Reaney & Collins 2024] (see Table 5).

Visceral hyperalgesia can be a cause of abdominal pain [Reaney & Collins 2024], which contrasts with individuals with PTHS having a higher tolerance in general for cutaneous pain. Due to impaired communication, it can be difficult to determine the cause of unexplained crying episodes, though an intestinal cause should be suspected.

Aerophagia (i.e., excessive air swallowing) can be caused by dysregulated breathing, leading to abdominal bloating. While aerophagia is generally benign, it can cause abdominal pain; rarely, it has been associated with colonic volvulus and/or bowel perforation [Zollino et al 2019, Koppen et al 2023]. Fatal gastrointestinal complications have been reported in which aerophagia may have been a contributing factor [Koppen et al 2023].

Malrotation, reported in up to 16% of individuals [Goodspeed et al 2018], can predispose to the serious complication of intestinal volvulus.

Gastroesophageal reflux disease (GERD), reported in fewer than half of individuals with PTHS [de Winter et al 2016], can be associated with manifestations of impaired swallowing but often improves with age.

Bruxism is also common [de Winter et al 2016, Zollino et al 2019].

Excessive drooling is seen in most individuals with PTHS [de Winter et al 2016]. Drooling can decrease in early childhood in some children due to improved oral motor coordination; however, it can continue even into adulthood, indicating sialorrhea as a possible cause. Drooling can also be a manifestation of GERD.

Eyes. Myopia, strabismus, and/or astigmatism are common.

Myopia can be severe (>6 diopters) and evident before age two years [Giurgea et al 2008, Stavropoulos et al 2010]. Retinal detachment has not been reported. Most individuals can tolerate glasses to correct their myopia.

Cerebral visual impairment has been diagnosed in about 14% of individuals [D Sweetser, personal observation].

Seizures vary in type and severity. Onset ranges from early infancy to as late as age 18 years [de Pontual et al 2009].

In an internet-based questionnaire involving 101 families, 37.6% reported epilepsy [de Winter et al 2016]. The majority (51.4%) had involuntary motor movements or tonic-clonic seizures often with absence seizures, 16.2% had only absence seizures, and the rest could not accurately describe their family member's seizures. Since this was a questionnaire study, it is unclear whether "absence" events were true absence seizures or focal-onset seizures with no motor component. Of those with a history of epilepsy, 23.7% became seizure-free at a mean age of 6.4 years.

In a study of 38 individuals with PTHS, Maini et al [2012] reported that the breathing abnormality observed did not appear to be a manifestation of seizure activity; however, seven individuals with seizures had apnea or hyperventilation shortly before their seizures.

Although seizures are usually well controlled with standard anti-seizure medications, presumed sudden unexplained death in epilepsy has been observed [D Sweetser, personal observation].

EEG findings in four individuals reported no specific patterns other than occipital and central delta waves in the two younger individuals. Pseudo-/quasiperiodic complexes present during wakefulness over the central and occipital regions were at times admixed with slow spike and wave in the two older individuals [Amiel et al 2007].

Of 11 EEGs in individuals with PTHS with seizures, the most common EEG findings were generalized background slowing in six individuals, focal spikes and discharges in three, and focal slowing in two [D Sweetser, personal observation].

Genital abnormalities. Small penis or cryptorchidism in males and abnormal clitoris or labia in females have been noted in 30% of individuals. Rare instances of absent vagina or uterus and ovaries have been noted [Whalen et al 2012, Zollino et al 2019].

Sleep disturbances, reported in 33%-43% of individuals, can include difficulties with sleep initiation and maintenance, circadian disorders, sleep-disordered breathing, and sleep-related movement disorders [Whalen et al 2012, de Winter et al 2016, Gandhi et al 2021].

Some infants with PTHS have been described as quiet and "unusually good," with excessive sleeping [Giurgea et al 2008].

Musculoskeletal. Hyperpronation of the ankles with flat feet is nearly universal.

Mild-to-moderate scoliosis has been noted in about 20% [Goodspeed et al 2018].

Minor hand and foot anomalies such as slender or small hands and feet, broad fingertips, clinodactyly, tapered fingers, transverse palmar crease, prominent heels, overriding toes, and short metatarsals have been reported [Goodspeed et al 2018]. Absent interphalangeal flexion creases of the thumbs with limited or absent voluntary thumb flexion generally without thumb ankylosis has been observed in about 9% of individuals [D Sweetser, personal observation]. A thumb tendon was not found in one individual during attempted surgical correction [D Sweetser, personal observation].

Many affected individuals have prominent pads (i.e., persistent fetal pads) on fingertips and/or toes [Lehalle et al 2011, Goodspeed et al 2018].

Other

• Growth is typically in the normal range for size at birth; slower postnatal growth with short stature has been noted in 26%-38% of individuals [Peippo & Ignatius 2012, Goodspeed et al 2018].
• Head growth slowed postnatally in 26% of individuals [de Winter et al 2016], with microcephaly reported in up to 60% [Zweier et al 2008, Goodspeed et al 2018].
• Hearing loss (type not specified) was reported in 10% of individuals [de Winter et al 2016].
• Hands and feet are reported to be cold and cyanosed in some individuals.
• Supernumerary nipples have been observed in at least 10 individuals [Rosenfeld et al 2009, Takano et al 2010, Marangi et al 2011].
• In addition to the craniofacial features (see Figures 1, 2, 3, 4, and 5), cherry-red lips have been noted infrequently [Ghosh et al 2012].
• The initiation and progression of secondary sexual characteristics appear to be unaffected [D Sweetser, personal observation].

Adult-onset features. Relatively few older teens or adults have been reported; thus, it is not yet known what, if any, other adult-onset findings may be of concern. Several adults have had significant hand tremors. Several had chronic urinary retention requiring intermittent catheterization. One 34-year-old had bipolar disorder [D Sweetser, personal observations].

Other. Hodgkin lymphoma was reported in a 29-year-old [Zweier et al 2007]. While TCF4 has a role in lymphocyte development [Zhuang et al 1996], the lack of other reports of individuals with PTHS with lymphoma suggests that this might be a coincidental finding.

Genotype-Phenotype Correlations

TCF4 single-nucleotide variants

• PTHS is associated with TCF4 pathogenic variants in exons 7-19. Individuals with nonsense or frameshift pathogenic variants in exons 7 and 8 (which encode the nuclear localization signal) generally have an "incomplete PTHS phenotype" with less distinctive facial features and moderate-to-severe intellectual disability. In contrast, individuals with pathogenic variants in exons 9-19 have classic PTHS features [Bedeschi et al 2017, Zollino et al 2019].
• Milder nonsyndromic intellectual disability (see Genetically Related Disorders) is associated with deletions and pathogenic variants in exons 1-6.
• Milder intellectual disability in association with preserved language but with typical facial features has been observed with certain presumably leaky splice site variants or in-frame deletions [D Sweetser, personal observation].

18q21.2 contiguous gene deletions

• The phenotypes of individuals with an 18q21.2 contiguous gene deletion up to 12 Mb involving TCF4 and individuals with a TCF4 single-nucleotide variant appear to be similar [Andrieux et al 2008, Giurgea et al 2008, Stavropoulos et al 2010, Hasi et al 2011, Zollino et al 2019]. Two reported individuals with mosaicism for chromosome 18q21.2 deletions (11.9 Mb and 7.5 Mb in size) had the typical PTHS phenotype [Giurgea et al 2008, Stavropoulos et al 2010].
• The phenotypes of individuals with deletions larger than 12 Mb involving TCF4 tend to have features less typical of PTHS and may more accurately be considered to have 18q deletion syndrome [Zollino et al 2019] (see Genetically Related Disorders).

Prevalence

Overall prevalence of PTHS is unknown. However, based on a lower relative detection rate as compared to Williams syndrome and Smith-Magenis syndrome deletions, one laboratory estimated that the frequency of chromosome 18q21 deletions associated with PTHS is between 1:34,000 and 1:41,000 [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 1:11,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PTHS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for PTHS. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There are clinical trials for this disorder.

Mode of Inheritance

Pitt-Hopkins syndrome (PTHS) is an autosomal dominant disorder typically caused by a de novo genetic alteration (a pathogenic variant in TCF4, a heterozygous deletion of 18q21.2 involving TCF4, or, rarely, a balanced chromosome rearrangement disrupting TCF4 without a deletion).

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with PTHS whose parents have undergone molecular genetic/cytogenetic testing have the disorder as the result of a de novo genetic alternation.
• Rarely, individuals diagnosed with PTHS have the disorder as the result of a genetic alteration inherited from a parent. Sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism has been reported [Steinbusch et al 2013; D Sweetser, personal observation]. Transmission of a PTHS-related genetic alteration from an affected non-mosaic mother to her affected child has been reported in one family to date [Li et al 2019].
• Genetic testing capable of identifying the genetic alteration identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo genetic alteration.
  • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism.* Mosaicism has been reported in several parents with an overall frequency of 2% to 3% [Zollino et al 2019], including an unaffected mother of two sibs diagnosed with PTHS [Steinbusch et al 2013] and a mother (of an affected child) who had been treated for chronic depression and epilepsy since age 20 years [de Pontual et al 2009].
    * Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ (gonadal) cells only.

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

• If the PTHS-related genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is estimated to be up to 2% because of the possibility of parental gonadal mosaicism [Zollino et al 2019]. Parental gonadal mosaicism has been inferred in several families [de Pontual et al 2009, Steinbusch et al 2013, Zollino et al 2019, Tang et al 2023].
• If a parent of the proband has the genetic alteration (even in a mosaic state), the risk to the sibs of inheriting the genetic alteration may be as high as 50%.
• Sibs who inherit a genetic alteration will be affected; phenotypic variability among affected sibs (born to a presumably mosaic parent) has been reported [Steinbusch et al 2013; D Sweetser, personal observation].
• If the parents have not been tested for the genetic alteration but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for PTHS because of the possibility of parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with PTHS has a 50% chance of inheriting the PTHS-related genetic alteration; however, individuals with PTHS typically do not reproduce.
• Transmission of a PTHS-related genetic alteration from an affected non-mosaic mother to her affected child has been reported in one family to date [Li et al 2019]; other than this report, there are no data on fertility in PTHS [Zollino et al 2019].

Other family members. Given that almost all probands with PTHS reported to date have the disorder as the result of a genetic alteration that occurred de novo in the proband or in a mosaic parent, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TCF4 encodes transcription factor 4 (TCF4), a member of the class I basic helix-loop-helix (bHLH) family of transcription factors that regulate multiple processes including cellular differentiation, 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]. TCF4 plays important roles in neocortical development, and disruption of its regulatory network contributes to the neurodevelopmental manifestations of Pitt-Hopkins syndrome (PTHS). Expression of TCF4 has also been demonstrated in human enteric ganglion cells of the myenteric plexus and Paneth cells [de Pontual et al 2009] that may underlie the gastrointestinal dysmotility observed in PTHS.

Mechanism of disease causation. The similar phenotype observed in individuals with truncating and missense pathogenic variants or deletions of TCF4 support haploinsufficiency as the molecular mechanism [Whalen et al 2012, Sweatt 2013].

TCF4-specific laboratory technical considerations. Pathogenic variants in exons 1-6 are associated with intellectual disability of varying severity with minimal to no facial or physical features of PTHS (see Genetically Related Disorders). PTHS is associated with pathogenic variants in exons 7-19. Most PTHS-related pathogenic variants are private. Missense variants are largely confined to exon 18 and several recurrent exon 18 variants have been reported. Exon 18 encodes the bHLH domain critical for dimerization and DNA binding. Most pathogenic variants outside this exon are nonsense or frameshift variants. Several splice site variants between exons 9 and 19 have been described [de Pontual et al 2009, Zweier et al 2008]. For ClinGen variant interpretation guidelines, see ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 4.0.0.

Author Notes

The authors are all providers in the Massachusetts General Hospital Pitt Hopkins Clinic.

Dr David A Sweetser

Chief of Medical Genetics and Metabolism
MGH Site Director Undiagnosed Diseases Network
Co-Director Harvard Affiliated Hospitals NORD Rare Disease Center of Excellence
Associate Professor of Pediatrics Harvard Medical School
Department of Pediatrics and Center for Genomic Medicine
Massachusetts General Hospital
Boston, Massachusetts

Dr Sweetser is a biochemical and medical genetics clinician-researcher with a focus on understanding and diagnosing rare and undiagnosed diseases. He has a clinical and research focus on rare neurodevelopmental disorders.

Dr Sweetser is actively involved in clinical and basic science research regarding individuals with Pitt-Hopkins syndrome (PTHS). He would be happy to communicate with persons who have any questions regarding diagnosis of PTHS or other considerations.

Contact Dr Sweetser to inquire about review of TCF4 variants of uncertain significance.

Web pages:

• www.massgeneral.org/doctors/17525/david-sweetser
• www.massgeneral.org/children/genetics

Kevin S Gipson, MD, MS

Division of Pediatric Pulmonology and Sleep Medicine
MassGeneral for Children
Boston, Massachusetts

Dr Gipson is a pediatric pulmonologist and sleep medicine physician who specializes in the care of infants, children, and adolescents with complex respiratory and sleep disorders.

Web page: https://www.massgeneral.org/doctors/20627/kevin-gipson

Claire Zar-Kessler, MD, MPH

Medical Director, Pediatric Neurogastroenterology Program
Instructor, Harvard Medical School
Division of Pediatric Gastroenterology and Nutrition
MassGeneral for Children
Boston, Massachusetts

Dr Zar-Kessler is a pediatric gastroenterologist who specializes in the care of difficult-to-manage gastrointestinal problems and is involved in research studying the evaluation and management of gastrointestinal motility diseases and the overlap with psychiatric disorders.

Web page: https://www.massgeneral.org/doctors/19701/claire-zar-kessler

Acknowledgments

The Massachusetts General Hospital Pitt Hopkins Clinic would like to acknowledge the generous support of Walter Herlihy and Nancy LeGendre and the many families we have seen in our multidisciplinary clinic that have broadened our understanding of PTHS.

Author History

Holly H Ardinger, MD; University of Missouri-Kansas City (2012-2018)
Ibrahim Elsharkawi, MD; Washington University (2018-2025)
Kevin S Gipson, MD, MS (2025-present)
Kimberly Parkin; Massachusetts General Hospital (2018-2025)
Carol J Saunders, PhD; University of Missouri-Kansas City (2012-2018)
Marci Steeves, MS, CGC; MassGeneral Hospital for Children (2018-2025)
David A Sweetser, MD, PhD (2018-present)
Ronald Thibert, DO, MsPH; Massachusetts General Hospital (2018-2025)
Holly I Welsh, MS; University of Missouri-Kansas City (2012-2018)
Lael Yonker, MD; MassGeneral Hospital for Children (2018-2025)
Claire Zar-Kessler, MD, MPH (2025-present)

Revision History

• 22 May 2025 (bp) Comprehensive update posted live
• 12 April 2018 (ha) Comprehensive update posted live
• 30 August 2012 (me) Review posted live
• 4 May 2012 (hha) Original submission

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