Pitt-Hopkins syndrome

Inspired by a patient

Liu Y, Guo Y, Liu P, Li F, Yang C, Song J, Hu J, Xin D, Chen Z. A case of

Pitt-hopkins Syndrome with de novo mutation in TCF4: Clinical features and

treatment for epilepsy. Int J Dev Neurosci. 2018 Jun;67:51-54.

Abstract

Pitt-Hopkins syndrome (PTHS), belonging to the group of 18q-syndromes, is a rare genetic disorder caused by mutations in TCF4. PTHS is characterized by distinctive facial appearance, intermittent hyperventilation, intellectual disability and developmental delay. Although patients with PTHS generally have various systemic symptoms, most of them with a TCF4 mutation manifest the central nervous system (CNS) disorders. We described the first Chinese case with Pitt-Hopkins syndrome based on clinical presentations and genetic findings. In addition to the typical features of PTHS, the girl also had paroxysms of tachypnea followed by cyanosis and recurrent seizures. Comprehensive medical examinations were performed including metabolic screening, hepatic and renal function evaluation, abdominal and cardiac ultrasounds. The presence of epileptic discharges in electroencephalography and abnormal brain magnetic resonance imaging were found. High-throughput sequencing was used to detect genetic mutations associated with CNS disorders. Sanger sequencing was used to confirm the mutations in the patient. The c.2182C＞T (p.Arg728Ter) mutation was a de novo nonsense mutation at exon 18 in the TCF4 gene of the patient. In conclusion, we have identified a de novo nonsense mutation of TCF4 carried by a Chinese girl with PTHS. The patient underwent anti-epileptic therapy (sodium valproate, levetiracetam, clonazepam), resulting in a reduction of the seizures.

Motojima T, Fujii K, Ohashi H, Arakawa H. Catathrenia in Pitt-Hopkins syndrome associated with 18q interstitial deletion. Pediatr Int. 2018 Apr 6. doi:10.1111/ped.13514. [Epub ahead of print]

From the article.  No abstract.

Herein we report a case of catathrenia in a Japanese girl with Pitt–Hopkins syndrome with an interstitial 8.6 Mb deletion that included TCF4 and MBD2, as well as 26 other genes. Catathrenia is a phenotype of sleep disorder, consisting of breath holding and expiratory groaning during sleep. Given that sleep disturbance has not been well described in Pitt–Hopkins syndrome, the present report of catathrenia could be valuable to explain its etiology.

Pitt–Hopkins syndrome is known to encompass sleep disturbance as well as breathing abnormality.3 Whalen et al. showed that 42% of patients with TCF4 molecular abnormalities had sleep disturbance, compared with 18% as reported in previous studies.3 Details of sleep disturbance in Pitt–Hopkins syndrome have not been investigated, and catathrenia may represent a form of parasomnia in this syndrome.

On polysomnography in a patient with Pitt–Hopkins syndrome, physiological organization of rapid eye movement (REM) and non‐REM structures associated with central apnea was noted for a short duration during the EEG arousal period.4 TCF4, responsible for Pitt–Hopkins syndrome, defectively interacts with the ASCL1‐PHOX‐RET pathway, which alters the development of the noradrenergic system.5

Breathing abnormality in Pitt–Hopkins syndrome may be tightly linked to sleep disturbance. Although there is no concrete evidence that respiratory rhythm abnormality is involved in this subtype of parasomnia, catathrenia as seen in the present case may be one of the significant features explaining the complicated pathogenesis of this syndrome.

Sweetser DA, Elsharkawi I, Yonker L, Steeves M, Parkin K, Thibert R. Pitt-Hopkins Syndrome. 2012 Aug 30 [updated 2018 Apr 12]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Excerpt

CLINICAL CHARACTERISTICS:

Pitt-Hopkins syndrome (PTHS) is characterized by significant global 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.

Marangi G, Zollino M. Pitt-Hopkins Syndrome and Differential Diagnosis: A Molecular and Clinical Challenge. J Pediatr Genet. 2015 Sep;4(3):168-76. 

Abstract

Pitt-Hopkins syndrome is an emerging neurodevelopmental disorder caused by haploinsufficiency of the TCF4 gene on chromosome 18q21. It is characterized by severe intellectual disability, seizures, microcephaly, constipation and a distinctive facial gestalt. Although the overlapping phenotype of microcephaly, epilepsy, absent speech and constipation represents a challenge for the differential diagnosis with Angelman syndrome, Rett syndrome and Mowat-Wilson syndrome, distinctive of Pitt-Hopkins syndrome are breathing abnormalities, that can occur as either hyperventilation episodes or apnea crises, and a typical facial dysmorphism, including bitemporal narrowing, squared forehead, deep-set eyes, peculiar nose conformation, with broad 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. The occurrence of these signs in variable association of uncoordinated movements, microcephaly of postnatal onset, eye abnormalities, constipation, epilepsy and subtle brain abnormalities is highly predictive of a TCF4 mutation, making it possible to plan a genetic test of choice among severe encephalopathies. Angelman syndrome represents the nosological condition closest to Pitt-Hopkins syndrome.