Despite the rare occurrence of Pitt-Hopkins syndrome in clinical practice, signs and symptoms have been well-established in previous years [1] [2] [3] [4] [5] [6]:

• Intellectual impairment - Virtually, all patients develop a severe delay in intellectual growth that manifests in early years of life [1] [3] [6]. Furthermore, speech is almost completely absent or severely underdeveloped, whereas drooling (but without eating problems) is a constant finding [3] [6].
• Facial dysmorphism - Enophthalmos, thin eyebrows, a large beaked nose with flared nostrils, broad cup-shaped ears, a fleshy and Cupid's bow appearance of the upper lip, a wide and shallow palate, and widely spaced teeth are prominent signs [1] [2]. Over time, the lower aspect of the face becomes protruded [1].
• Breathing abnormalities - An early onset of respiratory impairment, mainly as diurnal hyperventilation followed by reduced breathing and apnea can ensue and lead to hypoxia or even loss of consciousness [1] [2] [3].
• Growth changes - Despite the fact that a normal birth weight and height are observed, postnatal microcephaly and growth retardation are commonly encountered in these patients [1] [3].

Other notable manifestations are epilepsy (usually appearing in later stages of the disease), nystagmus, constipation, poor activity of the motor system (children start walking around 6 years of age, while head movement and fine motor skills are affected as well), and stereotypic movements of hands and the head [1] [2] [3] [4] [6]. The movements are seen in up to 80% of cases and it is assumed that hand clapping, wringing, swaying, or flapping of the hands are attempts to achieve communication [6]. Many reports describe children who suffer from Pitt-Hopkins syndrome as happy and sociable, with only occasional signs of anxiety and aggression, although they may exhibit excessive sleeping [3] [6].

• Developmental Delay

  From Wikidata Jump to navigation Jump to search rare genetic disorder characterized by developmental delay, epilepsy, distinctive facial features, and possible intermittent hyperventilation followed by apnea Encephalopathy, Severe Epileptic, With Autonomic [wikidata.org]

  delay 55,229,004(-) ATTG/ATTGATTG coding_sequence_variant, frameshift rs1057518864 pathogenic, Anteverted nares, Drooling, Epicanthus, Feeding difficulties in infancy, Global developmental delay, Short nose, Stereotypy 55,350,409(-) C/T genic_upstream_transcript_variant [genecards.org]

  Pitt Hopkins syndrome is a condition characterized by intellectual disability and developmental delay, breathing problems, recurrent seizures (epilepsy), and distinctive facial features. [cityofwarren.org]

  Symptoms Developmental Delay and Intellectual Disability- Individuals with PTHS have moderate to severe intellectual disability. Motor skills including walking are generally quite delayed. Children with PTHS often have a wide-based, unsteady gait. [pediatricbrainfoundation.org]

  Intellectual disability and developmental delay, breathing problems, recurrent seizures (epilepsy), and distinctive facial features characterize the disorder. [secure.ssa.gov]

• Developmental Disorder

  […] convulsions (780.39) 299 Pervasive developmental disorders 315.9 Unspecified delay in development, Developmental disorder NOS, Learning disorder NOS [genedx.com]

  Pitt-Hopkins syndrome (PTHS) is a rare developmental disorder associated with severe mental retardation, facial abnormalities, and intermittent hyperventilation. [ncbi.nlm.nih.gov]

  General symptoms Children with PTHS have delayed motorics development, developmental disorders, and limited or no ability to speak. A small head is common, and around half the children suffer from epilepsy. [mun-h-center.se]

  De Rubeis S, et al. (2014) Yes - 16 Support Large-scale discovery of novel genetic causes of developmental disorders. [gene.sfari.org]

• Pathologist

  […] transcription factor expressed in the central nervous system that heterodimerizes with tissue-specific transcription factors to control nervous system development (PMID: 22460224) Assay Assay and technical information Invitae is a College of American Pathologists [invitae.com]

  […] gastrointestinal tract), an ophthalmologist (a physician who specializes in the diagnosis and treatment of disorders of the eye), a pulmonologist (a physician who specializes in the diagnosis and treatment of disorders of the lungs and breathing issues), a speech pathologist [rarediseases.org]

• Single Transverse Palmar Crease

  Single transverse palmar crease MedGen UID: 96108 •Concept ID: C0424731 • Finding The distal and proximal transverse palmar creases are merged into a single transverse palmar crease. [ncbi.nlm.nih.gov]

• Multiple Congenital Anomalies

  In this article, we describe two sibs, a brother and sister, with severe mental retardation and multiple congenital anomalies including "coarse" facial features, short stature, seizures, hypertrichosis, short great toes, and overbreathing. [ncbi.nlm.nih.gov]

• Macrostomia

  Mental retardation, macrostomia and hyperpnoea syndrome. J Paediatr Child Health 1993; 29 (2) 156-157 3 Van Balkom ID, Quartel S, Hennekam RC. Mental retardation, “coarse” face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome. [doi.org]

  PubMed Google Scholar Singh HA: Mental retardation, macrostomia and hyperpnoea syndrome. J Paediatr Child Health. 1993, 29: 156-157. 10.1111/j.1440-1754.1993.tb00472.x. [ijponline.net]

  Singh HA (1993) Mental retardation, macrostomia and hyperpnoea syndrome. J Paediatr Child Health 29:156–157 [ PubMed ] [ Google Scholar ] 5. [ncbi.nlm.nih.gov]

• Strabismus

  Succinylcholine is best omitted in hypotonic patients and those with strabismus. Opioids should be used at a minimum or avoided because of the risk for apnea and worsening constipation. Nursing in a monitored setting postoperatively is indicated. [anesthesiaexperts.com]

  Other features include decreased reflexes in the upper extremities, constipation, strabismus, and protruding tongue with drooling. [uniprot.org]

  Many have eye symptoms, such as short-sightedness and strabismus. Episodic hyperventilation is common, with periodic panting which can lead to breathing cessation. Constipation and other stomach and bowel problems are common. [mun-h-center.se]

  Eyes and Vision- Vision problems are common in people with PTHS and may include crossed eyes (strabismus), and severe near-sightedness (myopia). [pediatricbrainfoundation.org]

  Breathing problems such as episodes of rapid breathing (hyperventilation), followed by episodes of struggling to breathe or not breathing; • Seizures; • Sleep disturbances; • Eye or vision problems such as nearsightedness (myopia); eye misalignment (strabismus [secure.ssa.gov]

• Esotropia

  Ophthalmologic examination revealed left-sided esotropia and severe myopia. See Fig. 1. [jmhg.springeropen.com]

• Muscle Hypotonia

  hypotonia. 8, 9, 10, 11, 13, 17, 26 TCF4 is a bHLH transcription factor. [doi.org]

• Broad Nasal Bridge

  nasal bridge, down-turned nasal tip and flaring nostrils, typical shape of the mouth, with a tented and M shaped upper lip, and widely spaced teeth. [ncbi.nlm.nih.gov]

  These specific facial features include deep set eyes, myopia, a broad nasal bridge, large mouth, tented upper lip, widely spaced teeth, a wide and shallow palate, and thick ears. [fdna.health]

• Coarse Face

  Cardinal findings in this syndrome are mental retardation, "coarse" face, and an abnormal breathing pattern. [ncbi.nlm.nih.gov]

  " face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome. [genome.jp]

  Mental retardation, “coarse” face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome. Am J Med Genet 1998; 75 (3) 273-276 4 Orrico A, Galli L, Zappella M, et al. Possible case of Pitt-Hopkins syndrome in sibs. [doi.org]

• Beaked Nose

  Pitt-Hopkins syndrome (PHS) is a probably underdiagnosed, syndromic mental retardation disorder, marked by hyperventilation episodes and characteristic dysmorphism (large beaked nose, wide mouth, fleshy lips, and clubbed fingertips). [ncbi.nlm.nih.gov]

  Facial dysmorphism include a beaked nose, flared nostrils, and a wide mouth with a 'cupid's-bow' shaped upper lip. A particular breathing pattern is characteristic of PTHS. [genome.jp]

  Facial dysmorphism - Enophthalmos, thin eyebrows, a large beaked nose with flared nostrils, broad cup-shaped ears, a fleshy and Cupid's bow appearance of the upper lip, a wide and shallow palate, and widely spaced teeth are prominent signs. [symptoma.com]

• Narrow Forehead

  Dysmorphic physical and skeletal features Picture: Wikimedia Commons PTHS can lead to a number of dysmorphic physical and skeletal features including: Narrow forehead. Wide nasal bridge. Cupid’s bow upper lip. Microcephaly. Scoliosis. [rcni.com]

  Examination showed a happy demeanor, microcephaly (head circumference is 45 cm), wide nasal bridge, and tip, narrow forehead, cupid-bow-shaped upper lip, wide mouth, full lips, and small hands. She is hyperactive with severe speech impairment. [jmhg.springeropen.com]

  Narrow forehead MedGen UID: 326956 •Concept ID: C1839758 • Finding Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective). [ncbi.nlm.nih.gov]

  Though PTHS patients often have characteristic facial features such as a narrow forehead, thin lateral eyebrows, wide nasal bridge, ridge, or tip, flared nasal alae, full cheeks, prominent midface, wide mouth, full lips, prominent cupid’s bow upper lip [jtggjournal.com]

  forehead, thin lateral eyebrows, specific nose conformation with a broad nasal bridge, ridge and a bulbous tip with flared nasal alae, full cheeks/prominent midface, and wide mouth/full lips/cupid bow upper lip, etc., were considered suggestive for PTHS [mdpi.com]

• Short Neck

  Short neck MedGen UID: 99267 •Concept ID: C0521525 • Finding Diminished length of the neck. [ncbi.nlm.nih.gov]

• Happy Personality

  Most patients have a happy personality, but they may also become anxious or agitated. The most common signs and symptoms of PTHS are listed below. [forgottendiseases.org]

• Seizure

  […] first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. [ncbi.nlm.nih.gov]

  NOS Recurrent seizures NOS Seizure disorder NOS Excludes: convulsion (convulsive) disorder (780.39) convulsive seizure or fit NOS (780.39) recurrent convulsions (780.39) 299 Pervasive developmental disorders 315.9 Unspecified delay in development, Developmental [genedx.com]

  Further, patients with seizure onset after age two were more likely to achieve seizure freedom. They also found that even in patients with drug-resistant epilepsy, seizures became less frequent as patients aged. [jtggjournal.com]

  Intellectual disability and developmental delay, breathing problems, recurrent seizures (epilepsy), and distinctive facial features characterize the disorder. [secure.ssa.gov]

• Ataxia

  We report on a female patient with PHS showing severe mental retardation with absent speech, pronounced muscular hypotonia, ataxia, distinctive facial features, such as a coarse face, a broad nasal bridge and a wide mouth, and hyperventilation attacks [ncbi.nlm.nih.gov]

  CNTNAP2 View recommended genes panels Clinical Features Top most frequent phenotypes and symptoms related to Pitt-hopkins Syndrome Intellectual disability Seizures Global developmental delay Generalized hypotonia Hearing impairment Microcephaly Scoliosis Ataxia [mendelian.co]

  Floppiness or poor muscle control is a key sign, as well as poor coordination (ataxia). A child with PTHS may be late to roll over, sit up or grab for things. If they’re able to walk, they may be wobbly and need a walker or leg braces for support. [childrens.com]

• Global Developmental Delay

  developmental delay 55,229,004(-) ATTG/ATTGATTG coding_sequence_variant, frameshift rs1057518864 pathogenic, Anteverted nares, Drooling, Epicanthus, Feeding difficulties in infancy, Global developmental delay, Short nose, Stereotypy 55,350,409(-) C/T [genecards.org]

  Affected individuals are described to have global developmental delay, intellectual disability, and characteristic dysmorphic features. [n.neurology.org]

  [From OMIM] All Countries Lebanon United Arab Emirates Subject ID Country Sex Family History Parental Consanguinity HPO Terms Variant Zygosity Mode of Inheritance Reference Remarks 610954.1 United Arab Emirates Male Yes Yes Global developmental delay; [cags.org.ae]

  Pitt-Hopkins syndrome is characterized by distinctive facial features (e.g., deep-set eyes, prominent nose, wide mouth with widely spaced teeth), global developmental delay, and moderate-severe intellectual disability. [ncbi.nlm.nih.gov]

  Global developmental delay and intellectual disabilities are usually apparent in the first year of life. [rcni.com]

• Convulsions

  fits, or seizures NOS Recurrent seizures NOS Seizure disorder NOS Excludes: convulsion (convulsive) disorder (780.39) convulsive seizure or fit NOS (780.39) recurrent convulsions (780.39) 299 Pervasive developmental disorders 315.9 Unspecified delay [genedx.com]

• Generalized Tonic-Clonic Seizure

  At the age of 2 1/3 years, she had her first generalized tonic clonic seizure which recurred frequently and was partially controlled with sodium valproate and clobazam. [jmhg.springeropen.com]

Because of the distinct clinical findings encountered in these patients, the physician plays a key role in raising suspicion. A properly obtained history and a thorough physical examination can showcase relevant attributes. A family history can provide crucial details for recognizing Pitt-Hopkins syndrome in parents and close relatives (given the presumed autosomal dominant pattern of inheritance), further solidifying the diagnosis. The workup should include electroencephalography (EEG) and magnetic resonance imaging (MRI), which can highlight hypoplasia of the frontal lobes, hippocampus, and corpus callosum, ventricular enlargement, and pronounced hyperintensity signaling of white matter in the temporal lobes in many patients [1] [3] [4]. To confirm the condition, however, employment of molecular genetic studies is needed. Whole-exome sequencing and chromosomal analysis are procedures that are able to identify TCF4 mutations of chromosome 18 [3] [5]. Some studies have advocated TCF4 mutation testing in people who are diagnosed with other similar diseases that have no genetic confirmation, such as Angelman syndrome, Rett syndrome, and Mowat-Wilson syndromes, mainly to prevent a missed diagnosis [1].

Treatments & Therapies Currently there is no known cure for Pitt Hopkins Syndrome and treatment is symptomatic. Affected persons often benefit from glasses and assistive communication devices. [pediatricbrainfoundation.org]

Even though the cause of PTHS is known, there are currently no pharmaceutical treatments available for this disorder. [teespring.com]

There are two main types of clinical studies: Clinical trials determine if a new test or treatment for a disease is effective and safe by comparing groups receiving different tests/treatments. [rarediseases.info.nih.gov]

Treatment depends on the specific symptoms and severity in each person and ideally is managed by a team of specialists with knowledge of PTHS. [rareguru.com]

Orofacial/odontological treatment Early contact with dental services for intensified prophylactic care and oral hygiene information is essential in cases of difficulty with managing dental treatment and tooth brushing. [mun-h-center.se]

Studying behaviour and cognition may improve diagnosis and prognosis, allows recognition of comorbidities, and contributes to adequate counselling of families. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press. [ncbi.nlm.nih.gov]

Outlook / Prognosis What can I expect if my child has Pitt-Hopkins syndrome? Children with Pitt-Hopkins syndrome typically need specialized medical care and educational services. Your healthcare provider may recommend: Occupational therapy. [my.clevelandclinic.org]

Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. Infants with Pitt-Hopkins syndrome may have diminished muscle tone (hypotonia) and appear abnormally “floppy.” [rarediseases.org]

Mutations in TCF4 have also been reported for AML cases (0.5%) 4 and were associated with a poor prognosis, 5 suggesting a potential role of TCF4 in the pathogenesis of these myeloid malignancies. [haematologica.org]

Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. [ncbi.nlm.nih.gov]

Neurodevelopmental disorders including Schizophrenia and Autism are chronic and debilitating, with relatively unknown etiology and pathophysiology. [grantome.com]

Codes: ICD-10: Q87.0 ORPHA: 2896 Estimated occurrence 2-3:100,000 live births Etiology Pitt-Hopkins syndrome (PTHS) occurs due to a de novo mutation on gene TCF4, which is on chromosome 18q21.1. [mun-h-center.se]

These characteristics, in addition to the co-association between TCF4 DNA copy number gains and somatic mutations of CD79B and MYD88, suggest that TCF4 may be an important modifier of BCR signaling and contribute to the etiology of ABC-like DLBCL. [bloodjournal.org]

Epidemiology No population-based prevalence or incidence figures for PTHS are available at present. Until 2007, PTHS was rarely reported, but increasing numbers of patients have been published since molecular testing became available. [karger.com]

Neurodevelopmental disorders including Schizophrenia and Autism are chronic and debilitating, with relatively unknown etiology and pathophysiology. [grantome.com]

Investigating the physiological function and regulation of TCF4 and the pathophysiological consequences of its disease-linked mutations is of major interest, because it may provide deeper insight into pathophysiological pathways shared between these enigmatic [jneurosci.org]

Design/Methods: Relevant publications describing the phenotype and genetic pathophysiology of PTHS were collected and frequencies of common characteristics were calculated for comparison to those recorded in the 23 PTHS patients cared for in the Center [n.neurology.org]

Common Pathophysiology in Multiple Mouse Models of Pitt-Hopkins Syndrome. J. Neurosci. 2018, 38, 918–936. [Google Scholar] [CrossRef][Green Version] Li, H.; Zhu, Y.; Morozov, Y.M.; Chen, X.; Page, S.C.; Rannals, M.D.; Maher, B.J.; Rakic, P. [mdpi.com]

The control of these breathing alterations is important to prevent the neurological sequelae linked to chronic cerebral hypoxemia in early ages. [ncbi.nlm.nih.gov]

Prevention How can I prevent Pitt-Hopkins syndrome? Pitt-Hopkins syndrome occurs because of a genetic change. There isn’t anything you can do to prevent this change. [my.clevelandclinic.org]

Some studies have advocated TCF4 mutation testing in people who are diagnosed with other similar diseases that have no genetic confirmation, such as Angelman syndrome, Rett syndrome, and Mowat-Wilson syndromes, mainly to prevent a missed diagnosis. [symptoma.com]

TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer. Int. J. Mol. Sci. 2015, 16, 10411-10425. Show more citation formats [Return to top] [mdpi.com]

Haggarty’s long-term goal is to translate this knowledge into the discovery of novel targeted therapeutics for the treatment and prevention of neuropsychiatric disorders. Learn more about Dr. Haggarty's research. [massgeneral.org]

1. Amiel J, Rio M, Pontual L de, et al. Mutations in TCF4, Encoding a Class I Basic Helix-Loop-Helix Transcription Factor, Are Responsible for Pitt-Hopkins Syndrome, a Severe Epileptic Encephalopathy Associated with Autonomic Dysfunction. Am J Hum Genet. 2007;80(5):988-993.
2. Peippo MM, Simola KO, Valanne LK, et al. Pitt-Hopkins syndrome in two patients and further definition of the phenotype. Clin Dysmorphol. 2006;15(2):47-54.
3. Sweatt JD. Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med. 2013;45(5):e21.
4. Marangi G, Ricciardi S, Orteschi D, et al. Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome. Am J Med Genet A. 2012;158A:1604–1611.
5. Whalen S, Héron D, Gaillon T, et al. Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum Mutat. 2012;33:64–72.
6. Peippo M, Ignatius J. Pitt-Hopkins Syndrome. Mol Syndromol. 2012;2(3-5):171-180.