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].

• 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]

• 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]

• Beaked Nose

  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]

  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 - 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]

• Coarse Face

  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]

  " 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]

• Narrow Forehead

  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]

  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]

  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]

  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]

  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]

• 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]

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].

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]

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]

Mowat–Wilson syndrome is seen in early infancy and is characterized by distinctive facial abnormalities.[12] Treatment[edit] Currently there is no specific treatment for this condition. It is based on symptomatology. [en.wikipedia.org]

[…] and treatment of disorders of the 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 [rarediseases.org]

No data are available on effective treatment options for breathing abnormalities of Pitt-Hopkins syndrome. [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]

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]

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]

Point mutations in ZBTB18 and HNRNPU were implicated etiologies. [jmhg.springeropen.com]

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]

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]

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]

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]

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.