A case of Pitt‐hopkins Syndrome with de novo mutation in TCF4: Clinical features and treatment for epilepsy

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.

Pitt-Hopkins Syndrome: Clinical and Molecular Findings of a 5-Year-Old Patient

“…The phenotype of our patient was suggestive for PTHS, being similar to that reported in the literature previously [ 5 , 6 , 7 , 26 ]. We recommend the periodic reevaluation of PTHS patients without genetic confirmation and especially of PTH-like patients or patients where the clinical diagnosis is not precise, with a clinical diagnostic score ≤ 8 [ 1 ], suggesting possible PTHS.…”

“…Currently, the criteria for the clinical diagnosis were redefined in the first consensus statement [ 1 ] due to the fact that the two sets published before were not sufficiently precise [ 1 , 4 ]. As a result, signs and symptoms such as severe intellectual disability, limited or loss of speech, delay in gross motor skills, affected intestinal motility (constipation), dysregulated respiration (intermittent hyperventilation and/or apnea), absence of congenital malformations, distinctive facial appearance including a narrow 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 in the latest criteria for clinical diagnosis (moreover, some of the signs and symptoms have been described and used previously) [ 1 , 2 , 3 , 5 , 6 , 7 , 8 ]. From a clinical point of view, even if the latest criteria for the clinical diagnosis are more specific, the fact that there are some overlapping signs and symptoms between PTHS and Angelman, Mowat-Wilson, Kleefstra, Rett, etc., syndromes, represents a challenge for physicians to recognize and diagnose PTHS [ 1 , 8 ] especially in younger patients where the clinical diagnosis may be extremely difficult in some situations [ 1 ].…”

Regional gene expression patterns are associated with task‐specific brain activation during reward and emotion processing measured with functional MRI

“…This transcription factor is mainly characterized by its regulatory role for the proliferation and differentiation of neuronal and glial progenitor cells (Ross et al, 2003 ). Besides impaired emotion processing, mutations in TCF4 may lead to Pitt‐Hopkins syndrome, characterized by intellectual disabilities as well as altered brain morphology (Kirikae et al, 2021 ; Liu et al, 2018 ). The regulatory role of TCF4 was further demonstrated in schizophrenia by Torshizi et al ( 2019 ) in two independent datasets by means of transcriptional network analysis.…”

Clinical and genetic characterization of 47 Chinese pediatric patients with Pitt–Hopkins syndrome: a retrospective study

“…Estimates from the United Kingdom and the Netherlands, based on the number of known affected individuals, suggest a prevalence range of 1 in 225,000 to 300,000 [ 2 ]. However, limited information is available regarding the prevalence of PTHS in China, and only a few Chinese PTHS cases have been reported [ 10 , 11 ]. Due to the scarcity of data in the international literature and the heterogeneity in clinical presentation, molecular diagnostic criteria, and care practices, a group of international experts has promoted the first international consensus statement on the diagnosis and management of Pitt–Hopkins syndrome [ 2 ].…”