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].

• Pallister-Hall Syndrome

  Hall Syndrome’ 125 publications. [doi.org]

  Hall Syndrome' 125 publications. [ncbi.nlm.nih.gov]

• Hypoxemia

  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]

• 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]

• Hypopigmented Skin

  Other abnormalities were hypopigmented skin macules in one and high-grade myopia in the other. Both had unusual frontal slow-and-sharp-wave discharges on electroencephalography. [ncbi.nlm.nih.gov]

  Hypopigmented skin macules have occasionally been reported. Individuals with Pitt–Hopkins syndrome typically have a happy, excitable demeanor with frequent smiling and laughter. Genetics[edit] The condition was first described in 1978 by D. [en.wikipedia.org]

• Hypertrichosis

  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]

• Enophthalmos

  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]

• Small Eyes

  Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. [ncbi.nlm.nih.gov]

• Muscle Hypotonia

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

• 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]

• Coarse Face

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

  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]

  Journal Ital J Pediatr 36:12 (2010) DOI:10.1186/1824-7288-36-12 Reference PMID:9475596 Authors Van Balkom ID, Quartel S, Hennekam RC Title Mental retardation, "coarse" face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome. [genome.jp]

  PubMed View Article Google Scholar Van Balkom ID, Quartel S, Hennekam RC: Mental retardation, "coarse" face, and hyperbreathing: confirmation of the Pitt-Hopkins syndrome. [ijponline.net]

• 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 PHS. [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]

  Typical facial dysmorphisms include a broad and beaked nose, flared nostrils, a wide mouth with a "Cupid's bow" shaped upper lip, cupped ears, broad helices, a broad palate and clubbed fingertips (due to chronic hypossiemia). [ijponline.net]

• 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]

• Areflexia

  This article reports a boy who presented with developmental delay, facial dysmorphism, microcephaly, hypotonia, and areflexia. He was initially diagnosed with Charcot Marie Tooth disease type 1A based on family history and genetic testing. [ncbi.nlm.nih.gov]

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].

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

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

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]

Subsequent in vivo studies of potential novel treatments for PTHS can also be undertaken in both the types of mouse lines. [doi.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]

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]

This advancement for a single-gene disorder might proceed much more quickly than would be achievable by studying the more complex learning, memory and autism disorders of unknown etiology. [doi.org]

Neurodevelopmental disorders including Schizophrenia and Autism are chronic and debilitating, with relatively unknown etiology and pathophysiology. [grantome.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. [ncbi.nlm.nih.gov]

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]

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]

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]

Once tests are complete, a plan will be created for your child that may include: Medication to prevent seizures, ease breathing and constipation. Diet to better manage constipation and other gastrointestinal issues. [childrens.com]

Safe School Helpline Penn-Trafford School District is implementing a Safe School Helpline to help prevent threats and dangers to the school community. [pths.penntrafford.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]

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.