The Pitt-Hopkins Syndrome: Report of 5 Patients and Literature Comparison

Yıl 2021, Cilt: 5 Sayı: 3, 317 - 325, 31.12.2021

Gültekin Kutluk , Elif Naz Kadem , Nadide Cemre Randa , Ayşe Öz

https://doi.org/10.30565/medalanya.891840

Cited By: 2

Öz

Pitt-Hopkins syndrome (PTHS) is characterized by developmental delay, intellectual disability and behavioral changes, distinctive facial gestalt, and breathing abnormalities. PTHS is caused by deletions or pathological variants in the TCF4 gene located at 18q21.2. In this report, we aimed to describe the clinical and genetic findings of patients diagnosed with PTHS and compare our patients with the literature. Patients who were followed up with severe intellectual disability and a variable association of features previously described as characteristic of the PTHS phenotype in the pediatric neurology clinic of Antalya Training and Research Hospital were screened for TCF4 mutations using next-generation sequencing (NGS)-based tests, between 2017 and 2020. A genetic mutation associated with PTHS was detected in five patients. This paper emphasis on mutational and clinical spectrum of PTHS and its significant part in the differential diagnosis of severe mental retardation

Anahtar Kelimeler

Angelman syndrome, breath-holding episode, intellectual disability, Pitt-Hopkins syndrome, TCF4

Pitt-Hopkins Sendromu: 5 Vaka Sunumu ve Literatür Karşılaştırması

Öz

Pitt-Hopkins sendromu (PTHS) gelişimsel gecikme, mental retardasyon ve davranış değişiklikleri, belirgin yüz görünümü ve solunum anormallikleri ile karakterizedir. PTHS, 18q21.2'de bulunan TCF4 genindeki delesyonlardan veya varyantlardan kaynaklanır. Bu yazıda PTHS tanısı alan hastaların klinik ve genetik bulgularını tanımlamayı ve bulgularımızı literatür ile karşılaştırmayı amaçladık. Antalya Eğitim ve Araştırma Hastanesi pediatrik nöroloji kliniğinde 2017 ve 2020 arasında takip edilen, ağır mental retardasyon ve daha önce PTHS fenotipinin karakteristiği olarak tanımlanan özellikleri taşıyan hastalar, yeni nesil dizileme (NGS) tabanlı testler ile TCF4 mutasyonları açısından tarandı. 5 hastada PTHS ile ilişkili bir genetik mutasyon tespit edildi. Bu yazıda, PTHS'nin mutasyonel ve klinik spektrumuna ve ciddi zihinsel geriliğin ayırıcı tanısındaki önemli kısmına vurgulandı.

Anahtar Kelimeler

Angelman sendromu, nefes tutma nöbetleri, Pitt-hopkins sendromu, TCF4, zeka geriliği

Kaynakça

• 1. Goodspeed K, Newsom C, Morris MA, 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. doi:10.1177/0883073817750490.
• 2. Tripon F, Bogliș A, Micheu C, Streață I, Bănescu C. Pitt-hopkins syndrome: Clinical and molecular findings of a 5-year-old patient. Genes(Basel). 2020;11(6):596. doi:10.3390/genes11060596.
• 3. Zweier C, Sticht H, Bijlsma EK, et al. Further delineation of Pitt-Hopkins syndrome: Phenotypic and genotypic description of 16 n.ovel patients. J Med Genet. 2008;45(11):738-44. doi: 10.1136/jmg.2008.060129.
• 4. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi: 10.1038/gim.2015.30.
• 5. Robinson JT, Thorvaldsdóttir H, Wenger AM, Zehir A, Mesirov JP. Variant review with the integrative genomics viewer. Cancer Res. 2017;77(21):e31-34. doi:10.1158/0008-5472.CAN-17-0337.
• 6. Peippo M, Ignatius J. Pitt-Hopkins syndrome. Mol Syndromol. 2012;2(3-5):171-80. doi: 10.1159/000335287.
• 7. Kim H, Berens NC, Ochandarena NE, Philpot BD. Region and Cell Type Distribution of TCF4 in the Postnatal Mouse Brain. Front Neuroanat. 2020;14:42. doi:10.3389/fnana.2020.00042.
• 8. Laan LAEM, Vein AA. Angelman syndrome: Is there a characteristic EEG? Brain Dev. 2005;27(5):80-7. doi:10.1016/j.braindev.2003.09.013
• 9. Marangi G, Zollino M. Pitt–Hopkins Syndrome and Differential Diagnosis: A Molecular and Clinical Challenge. J Pediatr Genet. 2015;4(03):168-76. doi:10.1055/s-0035-1564570.
• 10. 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(1):64-72. doi:10.1002/humu.21639.
• 11. Takano K, Lyons M, Moyes C, Jones J, Schwartz CE. Two percent of patients suspected of having Angelman syndrome have TCF4 mutations. Clin Genet. 2010;78(3):282-8. doi:10.1111/j.1399-0004.2010.01380.x.
• 12. Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35(11):1978-80. doi:10.1093/bioinformatics/bty897
• 13. Hamdan FF, Srour M, Capo-Chichi JM, et al. De Novo Mutations in Moderate or Severe Intellectual Disability. PLoS Genet. 2014;10(10):e1004772. doi: 10.1371/journal.pgen.1004772.
• 14. Zweier C, Peippo MM, Hoyer 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. doi:10.1086/515583.
• 15. Mary L, Piton A, Schaefer E, et al. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: Lessons from large-scale sequencing approaches in diagnosis. Eur J Hum Genet. 2018;26(7):996-1006. doi:10.1038/s41431-018-0096-4.
• 16. Zweier C, Sticht H, Bijlsma EK, et al. Further delineation of Pitt-Hopkins syndrome: Phenotypic and genotypic description of 16 novel patients. J Med Genet. 2008;45(11):738-44. doi: 10.1136/jmg.2008.060129.
• 17. Ahmet A. [Systematic Reviews and Meta-Analyses]. Acta Med. Alanya 2018;2(2):62-63. DOI: 10.30565/medalanya.439541