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].

• 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]

• Eating Problem

  Furthermore, speech is almost completely absent or severely underdeveloped, whereas drooling (but without eating problems) is a constant finding. [symptoma.com]

  Sleeping disturbances and eating problems have not been reported. The authors have personal experience of one adult PTHS patient who takes melatonin occasionally to help to fall asleep. [ncbi.nlm.nih.gov]

• Pallister-Hall Syndrome

  Hall Syndrome’ 125 publications. [doi.org]

  Hall Syndrome' 125 publications. [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]

• 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]

  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]

  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]

  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 - 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]

  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]

  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]

• 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].

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.