81 Pitt-Hopkins syndrome

• Published in: Archives of disease in childhood Vol. 106; no. Suppl 2; pp. A34 - A35
• Main Authors: Kondakova, OB, Grebenkin, DI, Zhurkova, NV, Batysheva, TT, Lialina, AA, Khrustaleva, EV, Kanivets, IV
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health 11-10-2021; BMJ Publishing Group LTD
• Subjects: Abstracts; Apnea; Atrophy; Autism; Behavior Disorders; Cerebellum; Children; Chromosome 18; Corpus callosum; Differential diagnosis; Dysplasia; Gene deletion; Hereditary diseases; Hybridization; Hydrocephalus; Hyperventilation; Hypoplasia; Intellectual disabilities; Intellectual Disability; Lager; Magnetic resonance imaging; Missense mutation; Motor Development; Mutation; Myopia; Pediatrics; Phenotypes; Point mutation; Scoliosis; Seizures
• ISSN: 0003-9888; 1468-2044
• DOI: 10.1136/archdischild-2021-europaediatrics.81

Pitt-Hopkins syndrome is rare inherited disease, characterized by mental retardation, moderate to severe, autistic disorders, breathing problems, seizures, apnea, and distinctive facial features. Frequency of disease is between 1: 34 000 – 1: 41 000 in newborn. Pitt-Hopkins syndrome (PTHS) is caused by deletions, duplication (30%), lager deletion (30%), point mutation (40%) in the TCF4 gene located at 18q21.2 and encoding Transcription Factor 4. Variants in TCF4 usually occur de novo in children with severe phenotype, milder phenotypes inherited autosomal dominant We have examined 9 patients (4 boys and 5 girls) with Pitt-Hopkins aged 1 to 12 years.Array-comparative genomic hybridization was performed in 5 children Target areas of the exome were investigated by massive parallel sequencing (NGS) in 4 cases. Validation of the identified variants was carried out by the Sanger method.De novo microdeletions 1 revealed in 5 cases: arr 18q21.2q21.32 (51266708_56293087) ×1, arr 18q21.2 (52691678_52999165) ×1, arr 18q21.2q21.1 (50029734_61654329) ×1, arr 18q21.2q21.31 (51620900_54883094) ×1, arr18q21.2q21.31 (49493248_55403360) ×1. Detected deletions was from 307 Kb to 1162 Mb.We identified 4 different mutations in the TCF4 gene in 4 patients with Pitt-Hopkins syndrome: c.961+2T>C, c.1452+1G>T, c.1634C>G, c.2033G>A.Spectrum of mutations represented by splicing site mutations, nonsense and missense mutations.All children had severe motor development delay and muscle hypotonia. Only one child was able to walk independently. All children had severe mental retardation. Expressive speech represented by vocalizations, individual words. Autistic and behavioral disorders were in 6 children. Severe episodes of hyperventilation followed by apnea observed in one child. Dysmorphic features included coarse face, protruding lower face, deep-set eyes, upslanting palpebral fissures, high, wide nose bridge, wide open mouth, cupid’s bow upper lip – thick, fleshy lips, cup-shaped ears. Three children diagnosed with myopia, scoliosis in one case. Brain MRI (in 4 children) show hypoplasia/dysplasia of the corpus callosum, atrophy/hypoplasia of the cerebellum, Dandy – Walker anomaly, hydrocephalus, small hippocampus size.ConclusionPitt-Hopkins syndrome is important for the differential diagnosis in children with severe mental retardation and behavioral disorders.