Clinical characteristics.

Pitt-Hopkins syndrome (PTHS) is characterized by significant developmental delays with moderate-to-severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.

Diagnosis/testing.

The diagnosis is suspected on clinical findings and confirmed by identification on molecular genetic testing of a heterozygous pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2).

Management.

Treatment of manifestations: Developmental services for infants (physical, occupational, and speech therapies); individualized education plan for older children with strong consideration for early training in alternative means of communication; behavioral management strategies; possible treatment of abnormal respiratory pattern. Routine management of seizures, myopia, constipation, scoliosis, and ankle instability.

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 clinical genetics professional regarding current information and recommendations.

Genetic counseling.

PTHS is caused by haploinsufficiency of TCF4 resulting from either a pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2). Most affected individuals have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant 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. Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Suggestive Findings

PTHS should be suspected in individuals with developmental delay, moderate-to-severe intellectual disability, behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake.

Developmental delay / intellectual disability / behavioral differences

• Motor milestones are delayed; often with hypotonia.
• Speech is severely limited to absent, with a history of regression in verbal abilities in some.
• Intellectual disability is typically moderate to severe.
• Autism spectrum disorder (ASD) symptoms are also common, though social engagement is generally present.
• Other behavioral characteristics suggestive of PTHS include the following:
  • Love of music
  • Frequent smiling
  • Stereotypic hand movements
  • Hand flapping
  • Spontaneous laughter

Characteristic facial features that become more apparent with age. The craniofacial features are an important aspect for the diagnosis of PTHS, but may be less obvious in infancy. 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 Figures 1, 2, 3, 4, 5).

Figure 1.

Newborn male with Pitt-Hopkins syndrome. Note high nasal root with prominent nasal bridge, depressed nasal tip, and ears with overfolded helix.

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, and wide mouth (more...)

Figure 3.

Boy age 13 years with Pitt-Hopkins syndrome (same individual as in Figures 1 and 2). Note wide nasal ridge and alae, short philtrum, and full lips, with everted lower lip.

Figure 4.

Girl age ten years with Pitt-Hopkins syndrome. Note deep-set eyes and depressed nasal tip.

Figure 5.

Woman age 24 years with Pitt-Hopkins syndrome (same individual as in Figure 4). Note prominent nose with depressed tip, short philtrum, full lips, wide mouth with downturned corners, and well-developed chin.

• Deeply set eyes with prominent supraorbital ridges
• Mildly upslanted palpebral fissures
• Broad nasal root, wide nasal ridge, and wide nasal base with enlarged nostrils
• Overhanging or depressed nasal tip, which may be pointed
• Short philtrum
• Thick vermilion of the lower lip, which is often everted
• In some individuals, wide mouth with downturned corners and exaggerated Cupid's bow or tented vermilion of the 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.
• Mildly cupped ears with overfolded helices

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 developmental history and characteristic facial features) 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; Author, personal observation].

Establishing the Diagnosis

The diagnosis of PTHS is established in a proband with severe intellectual disability and severe speech impairment and confirmed by identification on molecular genetic testing of a heterozygous pathogenic variant in TCF4 or a deletion of the chromosome region in which TCF4 is located (18q21.2) (see Table 1). Rare individuals with a TCF4 pathogenic variant or deletion may lack obvious characteristic facial features, but still manifest intellectual disability and speech impairment.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PTHS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability / developmental delay are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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].

Developmental delay / intellectual disability. Developmental delays are significant and intellectual disability is moderate to severe. Hypotonia can be significant and motor skills are delayed with a mean age of walking of four to six years (range 27 months - 7 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. Most require orthotics to stabilize the ankle.

Speech is significantly delayed in all individuals with PTHS and excessive drooling is common. Most are nonverbal. Some have developed a few words, but subsequently regressed later in life and become entirely nonverbal. Rare individuals can string words into sentences. Receptive language is generally stronger than expressive language, and many individuals with PTHS are able to understand and follow simple commands. The use of augmentative communication devices has been useful for many individuals, though other individuals lack the fine motor skills to make use of these devices.

Self-care skills are also delayed and few are reported to develop consistent dressing or toileting skills.

Behavioral. PTHS is most commonly associated with autism spectrum disorder (ASD) symptoms, characterized by impairments in communication, behavior, and social interactions. The relationship between autism and PTHS remains ambiguous; however, in a study conducted by Van Balkom et al, the Autism Diagnostic Interview Revised (ADI-R) assessed ten participants with confirmed PTHS diagnoses who scored at or above social, behavioral, and communication criteria for ASD (2 participants did not score above the behavioral domain cutoff value). Six out of ten participants were observed to have fixations that prompted repetitive exposure to a specific object, listening to the same song, or viewing the same video repeatedly [Van Balkom et al 2012].

Many individuals with PTHS are described as having a happy disposition [Zweier et al 2008, Marangi et al 2011], though it has been proposed that an anxious disposition with a smiling appearance is a more apt description [Whalen et al 2012]. 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, de Pontual et al 2009]. The onset of puberty can be associated with increased aggression and behavioral issues [Authors, personal observation].

Individuals with PTHS may be shy or anxious in new situations and self-aggression can occur. Disruptions of routine have also been associated with episodes of anxiety. Hand biting and head banging have been commonly reported by families of individuals with PTHS.

Unprovoked laughter may occur. Sleep disturbance in childhood is reported in fewer than half of affected individuals [Whalen et al 2012] and includes difficulty falling asleep, problems sleeping through the night, and night terrors [de Winter et al 2016].

Stereotypic head movements (e.g., head rotation) and stereotypic hand movements (e.g., flapping, clapping, washing movements, hand to mouth, finger crossing) are commonly observed [Takano et al 2010, Marangi et al 2011, Whalen et al 2012]. Three individuals have been reported to have lost the use of hand skills [Zweier et al 2008, Armani et al 2012, Whalen et al 2012].

Individuals with PTHS invariably have a profound affinity for music. Families report that during episodes of anxiety or frustration, music will very often soothe or placate them. Many appear to love playing with water, and exhibit a fascination with running water [Authors, personal observation].

Craniofacial. In addition to the craniofacial features discussed in Diagnosis, cherry red lips have been noted infrequently [Ghosh et al 2012].

Growth. Growth is typically in the normal range for size at birth; slower postnatal growth is noted in about 25%.

Head growth was found to slow postnatally in 26% [de Winter et al 2016], with microcephaly reported in up to 60% [Zweier et al 2008, Goodspeed et al 2018].

The initiation and progression of secondary sexual characteristics appear to be unimpaired in individuals with PTHS [Authors, personal observation].

Respiratory. Episodic hyperventilation often followed by breath-holding/apnea while awake are reported in 40%-60% of individuals [Whalen et al 2012, de Winter et al 2016, Goodspeed et al 2018]. Hyperventilation 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, and in rare cases syncope, and can occur independently of hyperventilation [Whalen et al 2012]. Finger clubbing and chronic hypoxia has been noted in 7%-19% [Whalen et al 2012, Goodspeed et al 2018].

Breathing abnormalities tend to develop between ages three and seven years; few individuals are affected at birth. In one study 30% had symptoms by age 15 years [de Winter et al 2016]. In some children, hyperventilation and/or breath-holding episodes are observed for only a few months or years. However, in most affected individuals breathing abnormalities persist to some degree, though too few adults have been described to make conclusive statements about frequency or severity. Breath-holding/apnea episodes are not typically related to seizure activity [Maini et al 2012]. Treatment can mitigate the severity and frequency of symptoms.

Neurologic. Seizures, reported in 40%-50% of individuals with PTHS, vary in type and severity. Onset of seizures is reported from early infancy to as late as age 18 years [de Pontual et al 2009].

In an internet questionnaire study of 101 families, 37.6% had epilepsy [de Winter et al 2016]. Of those with a history of epilepsy, 23.7% became seizure-free at a mean age of 6.4 years. 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.

The breathing abnormality in PTHS does not appear to be a manifestation of seizure activity [Maini et al 2012], though in this study, 7/38 individuals with seizures had apnea or hyperventilation shortly before their seizures.

In most individuals with seizures, these are well controlled by antiepileptic drugs – valproic acid, levetiracetam, lamotrigine, and carbamazepine being the most common [de Winter et al 2016].

EEG and MRI findings reported in PTHS are limited.

• One study reported EEGs in four individuals with PTHS; no specific patterns other than occipital and central delta waves were found in the younger two individuals. Pseudoperiodic complexes were present during wakefulness over the central and occipital regions, at times admixed with slow spike and wave in the two older individuals [Amiel et al 2007].
• In those individuals who have had a brain MRI, a variety of findings have been reported, though many studies are reported as normal. The most common findings 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, posterior fossa abnormalities, small hippocampi, and moderate hypoplasia of the frontal lobes [Amiel et al 2007, Marangi et al 2011, Whalen et al 2012].

Signs of general autonomic dysfunction have been observed in some individuals or reported by families [Authors, personal observation]. These include:

• High pain tolerance (very common);
• Lack of tears;
• Impaired ability to sweat and dysregulation of body temperature homeostasis.

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, with one individual reported [Peippo et al 2006].

Gastroesophageal reflux is reported in fewer than half of individuals with PTHS [de Winter et al 2016]. In some individuals, reflux is associated with symptoms of impaired swallowing, and videofluoroscopic swallowing studies may be useful.

Musculoskeletal. Minor hand and foot anomalies such as slender or small hands and feet, broad fingertips, clinodactyly, tapered fingers, transverse palmar crease, flat feet with hindfoot valgus deformity, overriding toes, and short metatarsals have been reported. Absent flexion creases of the thumbs may occur with thumb ankylosis. In one individual an absent thumb tendon was found during surgery [Authors, personal observation].

Hands and feet are reported to be cold and cyanosed in some individuals.

Hyperpronation of the ankles is a nearly universal feature.

Clubfeet have been reported in 20% [Whalen et al 2012].

Scoliosis has been noted in about 25% although no information regarding severity is available.

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].

Adult-onset features. Relatively few older teens or adults have been reported with PTHS; thus it is not yet known what, if any, other adult-onset findings may be of concern in PTHS. Several adults have had significant hand tremors. Another had chronic urinary retention requiring intermittent catheterization [Authors, personal observations].

Other. Hodgkin lymphoma has been reported in an individual age 29 years with PTHS [Zweier et al 2007]. While TCF4 has a role in lymphocyte development [Zhuang et al 1996], the lack of other individuals with PTHS reported to have lymphoma suggests that this finding is coincidental.

Genotype-Phenotype Correlations

According to most studies reported, the phenotype associated with PTHS appears to be independent of TCF4 variant type.

Size of deletion. In several studies comparing chromosomal deletions of varying lengths of chromosome 18q21.2 involving TCF4, individuals appeared to have similar phenotypes to each other and single-nucleotide variants in TCF4 [Andrieux et al 2008, Hasi et al 2011, Stavropoulos et al 2010, Giurgea et al 2008]. However, one case suggested that haploinsufficiency of the neighboring genes MBD1 and MBD2 may confer a more severe Rett syndrome-like phenotype [Kato et al 2010].

Mosaicism for chromosome 18q21.1 deletions have been described. 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]. Another individual with mosaic 18q21.2 deletion (185 kb) involving a portion of TCF4 was reported to have dysmorphic features, attention-deficit disorder, anxiety, self-mutilation, and stiff joints [Pham et al 2014]. Two other individuals mosaic for 18q21 deletions including TCF4 have been described with dysmorphic facial features (though not classic for PTHS), severe developmental delay, and microcephaly. One of these individuals had 5%-10% mosaicism and the other about 40% [Rossi et al 2012].

Penetrance

Penetrance of a pathogenic TCF4 allele is complete, though some phenotypic variability is seen among sibs born to a presumably mosaic parent.

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.

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

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 if they have not already been completed:

• Developmental assessment to establish a cognitive baseline and determine the types of services and educational strategies needed. In school-aged children this information is important for the child's individualized education plan (IEP).
• Assessment for the use of nonverbal communication devices and strategies (given that most individuals do not develop useful speech)
• Child behavior specialist to aid with behavioral concerns. Consultation with a child psychiatrist may be warranted if there are significant behavioral issues.
• 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 to establish a neurologic baseline and evaluate for other neurologic issues such as sleep dysfunction or seizures. This should be expedited if there are familial concerns about seizure activity. Consider a baseline polysomnogram to assess for sleep disturbances.
• Ophthalmology evaluation to evaluate for myopia, astigmatism, and/or strabismus
• Gastroenterology evaluation to establish treatment regimen for chronic constipation and other possible GI issues such as gastroesophageal reflux
• Musculoskeletal evaluation by an orthopedist or physiatrist to evaluate ambulatory skills and need for special mobility equipment and/or orthotics to aid in foot position
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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 clinical 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 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 may not be clinical trials for this disorder.

Mode of Inheritance

Pitt-Hopkins syndrome (PTHS) is caused by haploinsufficiency of TCF4 resulting from either a pathogenic variant in TCF4 or a deletion of the chromosome 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 pathogenic variant or deletion.

Risk to Family Members – TCF4 Pathogenic Variant

Parents of a proband

• Most individuals with PTHS reported to date have the disorder as the result of a de novo genetic alteration and both parents are unaffected.
• Molecular genetic testing is recommended for the parents of a proband.
• If the TCF4 pathogenic variant identified in the proband cannot be identified in the leukocyte DNA of either parent, the most likely explanation is that the pathogenic variant is de novo in the proband. Another possible explanation is germline and/or somatic and germline mosaicism in a parent.
• Somatic and (presumed) germline mosaicism has been identified in at least two parents:
  • The unaffected mother of two sibs diagnosed with PTHS [Steinbusch et al 2013]
  • The mother (of an affected child) who had been treated for chronic depression and epilepsy since age 20 years [de Pontual et al 2009]

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

• If the parents have been tested for the TCF4 pathogenic variant identified in the proband and:
  • A parent of the proband has the TCF4 pathogenic variant (even in a mosaic state), the risk to the sibs of inheriting the variant could be as high as 50%. Sibs who inherit a TCF4 pathogenic variant will be affected; phenotypic variability among affected sibs (born to a presumably mosaic parent) has been reported [Steinbusch et al 2013; Author, personal observation].
  • If the TCF4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Parental germline mosaicism for PTHS has been inferred [de Pontual et al 2009, Steinbusch et al 2013].
• If the parents have not been tested for the TCF4 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for PTHS because of the possibility of parental germline mosaicism.

Offspring of a proband. There have been no reports of individuals with PTHS reproducing.

Other family members. Because PTHS typically occurs as a de novo genetic alteration, the risk to other family members is presumed to be low.

Risk to Family Members – Chromosome 18q21.2 Deletion

Parents of a proband

• The chromosome 18q21.2 deletion (whether resulting from an "apparently balanced" chromosome rearrangement or, more commonly, from a simple deletion) has been de novo in almost all affected individuals (reported in the medical literature) whose parents had cytogenetic studies.
• Parents of a proband are typically not affected.
• Rare instances of somatic mosaicism have been detected in a parent of an affected individual. One of these parents had chronic depression and epilepsy from age 20 years; the other was healthy [Steinbusch et al 2013, de Pontual et al 2009].
• Evaluation of the parents by genomic testing that will detect the chromosome 18q21.2 deletion present in the proband may be offered (note: low-level somatic and/or germline mosaicism in a parent can never be entirely ruled out by testing).

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

• If a chromosome 18q21.2 deletion identified in the proband is not identified in one of the parents, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism for the deletion.
• 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.

Other family members. Because PTHS typically occurs as a de novo genetic alteration, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the variant identified in the proband or clinical evidence of the disorder, the variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PTHS-related genetic alteration has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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Author History

Holly H Ardinger, MD; University of Missouri-Kansas City (2012-2018)
Ibrahim Elsharkawi, MD (2018-present)
Kimberly Parkin (2018-present)
Carol J Saunders, PhD; University of Missouri-Kansas City (2012-2018)
Marci Steeves, MS, CGC (2018-present)
David A Sweetser, MD, PhD (2018-present)
Ronald Thibert, DO, MsPH (2018-present)
Holly I Welsh, MS; University of Missouri-Kansas City (2012-2018)
Lael Yonker, MD (2018-present)

Revision History

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