Clinical and genetic characteristic of patients with Pitt–Hopkins syndrome

Background. Pitt–Hopkins syndrome (PHS) is the rare inherited disease, caused by a microdeletion on chromosome 18q21 or heterozygous mutation TCF4 gene and characterized by severe mental retardation, abnormal breathing patterns: hyperventilation, apnea, and unusual facial features. 

Material and method. We examined 9 children, included 4 boys and 5 girls at the age of 1 year 8 months to 12 years with PHS. All children have clinical symptoms characteristic of this syndrome. The diagnosis was confirmed by Array CGH (deletion of genomic material in chromosomal region 18q21) and new generation sequencing.

Results. Microdeletions chromosome 18 (18q21) were identified in 5 patients. The size of the microdeletions varied from 307 Kb to 11.62 Mb. A point mutation was detected in 4 children: two patients had a mutation in the splicing site, 1 — missense and 1 — nonsense-mutation. The clinical picture was analyzed in all children: psychomotor retardation, severe intellectual disability, poor speech, autistic behavior, hypotonia, and specific phenotype. 

Conclusion. Comparative analysis of the clinical picture in patients with PHS, caused by a microdeletion on chromosome 18q21 and point mutation in the TCF4 gene showed that no significant clinical differences were found. The main clinical criteria for suspecting PHS are gross developmental delay, severe delayed psychomotor development, behavioral disorders, and episodes of  hyperventilation with the subsequent apnea.

1. Amiel J., Rio M., de Pontual L., Redon R., Malan V., Boddaert N., 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): 988-93. https://doi.org/10.1086/515582

2. Zollino M., Zweier C., Van Balkom I.D., Sweetser D.A., Alaimo J., Bijlsma E.K., et al. Diagnosis and management in Pitt-Hopkins syndrome: First international consensus statement. Clin. Genet. 2019; 95(4): 462-78. https://doi.org/10.1111/cge.13506

3. Zweier C., Peippo M.M., Hoyer J., Sousa S., Bottani A., Clayton-Smith J., et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am. J. Hum. Genet. 2007; 80(5): 994-1001. https://doi.org/10.1086/515583

4. Brockschmidt A., Todt U., Ryu S., Hoischen A., Landwehr C., Birnbaum S., et al. Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum. Mol. Genet. 2007; 16(12): 1488-94. https://doi.org/10.1093/hmg/ddm099

5. Pitt D., Hopkins I. A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust. Paediatr. J. 1978; 14(3): 182-4. https://doi.org/10.1111/jpc.1978.14.3.182

6. Goodspeed K., Newsom C., Morris M.A., Powell C., Evans P., Golla S. Pitt-Hopkins syndrome: a review of current literature, clinical approach, and 23-patient case series. J. Child Neurol. 2018; 33(3): 233-44. https://doi.org/10.1177/0883073817750490.

7. Rosenfeld J.A., Leppig K., Ballif B.C., Thiese H., Erdie-Lalena C., Bawle E., et al. Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet. Med. 2009; 11(11): 797-805. https://doi.org/10.1097/GIM.0b013e3181bd38a9

8. Kageyama R., Nakanishi S. Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system. Curr. Opin. Genet. Dev. 1997; 7(5): 659-65. https://doi.org/10.1016/s0959-437x(97)80014-7

9. Massari M.E., Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol. Cell. Biol. 2000; 20(2): 429-40. https://doi.org/10.1128/mcb.20.2.429-440.2000

10. Peippo M., Ignatius J. Pitt-Hopkins Syndrome. Mol. Syndromol. 2012; 2(3-5): 171-80. https://doi.org/10.1159/000335287

11. Watkins A., Bissell S., Moss J., Oliver C., Clayton-Smith J., Haye L., et al. Behavioural and psychological characteristics in Pitt-Hopkins syndrome: a comparison with Angelman and Cornelia de Lange syndromes. J. Neurodev. Disord. 2019; 11(1): 24. https://doi.org/10.1186/s11689-019-9282-0

12. Harrison V., Connell L., Hayesmoore J., McParland J., Pike M.G., Blair E. Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am. J. Med. Genet. A. 2011; 155A(11): 2826-31. https://doi.org/10.1002/ajmg.a.34255

13. Zweier C., de Jong E.K., Zweier M., Orrico A., Ousager L.B., Collins A.L., et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 2009; 85(5): 655-66. https://doi.org/10.1016/j.ajhg.2009.10.004

14. Lopes F., Barbosa M., Ameur A., Soares G., de Sá J., Dias A.I., et al. Identification of novel genetic causes of Rett syndrome-like phenotypes. J. Med. Genet. 2016; 53(3): 190-9. https://doi.org/10.1136/jmedgenet-2015-103568

15. de Winter Ch.F., Baas M., Heukelingen J.van, Routledge Sue, Hennekam R.C.M. Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system. Orpha. J. Rare Dis. 2016; 11: 37 DOI: https://doi.org/10.1186/s13023-016-0422-2