MOWAT-WİLSON SENDROMU: ONİKİ YENİ OLGUNUN FENOTİPİK VE MOLEKÜLER KARAKTERİZASYONU

Öz

Amaç: Mowat-Wilson sendromu (MOWS); tanınabilir yüz özellikleri, orta-ağır zihinsel yetersizlik ve korpus kallozum anomalileri, oküler tutulum, genital anomaliler, konjenital kalp defektleri ve Hirschsprung hastalığı gibi multisistemik bulgularla karakterize nadir bir malformasyon sendromudur. Etiyolojide ZEB2 genindeki patojenik varyantlar rol oynamakta olup, neredeyse bütün vakalar sporadik olarak de novo varyantlardan kaynaklanmaktadır. Hastalığın düşük prevalansının yanı sıra etkilenmiş olgularda gözlenen geniş klinik spektrum tanı sürecini zorlaştırabilmektedir. Bu çalışmada yeni bir MOWS kohortu tanımlayarak bu hastalığın klinik ve moleküler spektrumunu genişletmeyi amaçladık. Gereç ve Yöntem: Çalışmaya MOWS klinik tanısı almış 12 olgu dahil edildi. Normal karyotip sonuçlarının elde edilmesinin ardından ZEB2 geni Sanger dizi analizi yöntemiyle incelendi. Bulgular: Doğum ve tekrarlayan klinik değerlendirmelerde alınan antropometrik ölçümlerin ulusal ve MOWS’a özgü büyüme eğrileriyle büyük ölçüde uyumlu olduğu gözlendi. Tüm hastalarda orta ila ağır zihinsel yetersizlik ve karakteristik yüz görünümü mevcuttu. Hastalığın iyi bilinen bulgularına ek olarak; persistan sol süperior vena kava, koanal stenoz, şal skrotum ve atipik oküler anomaliler gibi çok nadir veya daha önce MOWS spektrumunda tanımlanmamış bulgular izlendi. Pigmentasyon bozukluklarının literatür verisine kıyasla belirgin şekilde daha yüksek sıklıkta olduğu gözlendi. İki hastada, CHARGE ve Aicardi sendromları ile örtüşen atipik klinik bulguların varlığı dikkat çekiciydi. Hastalarda, ZEB2 geninde beşi daha önce tanımlanmamış olmak üzere 12 heterozigot varyant tespit edildi. Sonuç: On iki hastanın derin fenotipleme verileri, daha önce MOWS ile klinik ilişkisi net şekilde ortaya konulmamış veya hastalık spektrumunda çok nadir olduğu düşünülen klinik bulguların tanımlanmasını sağladı. Ayrıca, bu çalışma kapsamında ilk kez bildirilen patojenik ZEB2 varyantları ile hastalığın moleküler spektrumu da genişletilmiş oldu.

Anahtar Kelimeler

• Mowat-Wilson sendromu
• ZEB2
• zihinsel ye tersizlik
• CHARGE sendromu
• Aicardi sendromu

MOWAT-WILSON SYNDROME: DEEP PHENOTYPING AND MOLECULAR CHARACTERISATION OF TWELVE NEW INDIVIDUALS

Öz

Objective: Mowat-Wilson syndrome (MOWS) is a rare multisystem malformation syndrome characterised by distinctive facial features, moderate to severe intellectual disability, and variable findings including callosal anomalies, ocular features, genital anomalies, congenital heart defects, and Hirschsprung’s disease. Pathogenic variants in the ZEB2 gene are implicated in the aetiology, with nearly all cases arising sporadically due to de novo variants. In addition to its low prevalence, the broad clinical spectrum observed among patients can make the diagnostic process challenging. This study aims to expand the clinical and molecular spectrum of MOWS by elucidating the characteristics of a new cohort. Material and Methods: Twelve patients with a clinical diagnosis of MOWS were included in the study. Following obtaining normal karyotype results, molecular analysis of ZEB2 was performed using Sanger sequencing. Results: Anthropometric measurements at birth and subsequent visits largely aligned with the national and MOWS growth charts, respectively. All patients exhibited moderate to severe intellectual disability and shared a characteristic facial gestalt. In addition to the well-described features, very rare or previously undescribed abnormalities comprising persistent left superior vena cava, choanal stenosis, shawl scrotum, and ocular anomalies were observed. Skin pigmentation defects were noted at significantly higher frequencies than those previously reported. Two patients displayed atypical features overlapping with CHARGE and Aicardi syndromes. We identified 12 heterozygous variants in ZEB2, five of which were novel. Conclusion: Deep phenotyping data of 12 patients enabled the identification of previously uncertain clinical associations and underrepresented features. The novel pathogenic variants identified here expand the molecular spectrum of ZEB2.

Anahtar Kelimeler

• Mowat-Wilson syndrome
• ZEB2
• intellectual disabili ty
• CHARGE syndrome
• Aicardi syndrome

Kaynakça

1. Mowat DR, Wilson MJ, Goossens M. Mowat-Wilson syndrome. J Med Genet 2003;40(5):305-10. [CrossRef] google scholar
2. Wakamatsu N, Yamada Y, Yamada K, Ono T, Nomura N, Taniguchi H, et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet 2001;27(4):369-70. [CrossRef] google scholar
3. Cacheux V, Dastot-Le Moal F, Kaariainen H, Bondurand N, Rintala R, Boissier B, et al. Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease. Hum Mol Genet 2001;10(14):1503-10. [CrossRef] google scholar
4. Ivanovski I, Djuric O, Caraffi SG, Santodirocco D, Pollazzon M, Rosato S, et al. Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care. Genet Med 2018;20(9):965-75. [CrossRef] google scholar
5. McGaughran J, Sinnott S, Dastot-Le Moal F, Wilson M, Mowat D, Sutton B, et al. Recurrence of Mowat-Wilson syndrome in siblings with the same proven mutation. Am J Med Genet A 2005;137A(3):302-4. [CrossRef] google scholar
6. Zweier C, Thiel CT, Dufke A, Crow YJ, Meinecke P, Suri M, et al. Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet 2005;48(2):97-111. [CrossRef] google scholar
7. Cecconi M, Forzano F, Garavelli L, Pantaleoni C, Grasso M, Dagna Bricarelli F, et al. Recurrence of Mowat-Wilson syndrome in siblings with a novel mutation in the ZEB2 gene. Am J Med Genet A 2008;146A(23):3095-9. [CrossRef] google scholar
8. Ohtsuka M, Oguni H, Ito Y, Nakayama T, Matsuo M, Osawa M, et al. Mowat-Wilson syndrome affecting 3 siblings. J Child Neurol 2008;23(3):274-8. [CrossRef] google scholar

9. Adam MP, Schelley S, Gallagher R, Brady AN, Barr K, Blumberg B, et al. Clinical features and management issues in Mowat-Wilson syndrome. Am J Med Genet A 2006;140(24):2730-41. [CrossRef] google scholar
10. Mowat DR, Wilson MJ. Mowat-Wilson syndrome. In: Cassidy SB, Allanson JE, editors. Management of Genetic Syndromes. New York: John Wiley & Sons; 2021.p.597-609. [CrossRef] google scholar
11. Ishihara N, Yamada K, Yamada Y, Miura K, Kato J, Kuwabara N, et al. Clinical and molecular analysis of Mowat-Wilson syndrome associated with ZFHX1B mutations and deletions at 2q22-q24.1. J Med Genet 2004;41(5):387-93. [CrossRef] google scholar
12. Yamada Y, Nomura N, Yamada K, Matsuo M, Suzuki Y, Sameshima K, et al. The spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations. Am J Med Genet A 2014;164A(8):1899-908. [CrossRef] google scholar
13. Wilson M, Mowat D, Dastot-Le Moal F, Cacheux V, Kaariainen H, Cass D, et al. Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B. Am J Med Genet A 2003;119A(3):257-65. [CrossRef] google scholar
14. Wenger TL, Harr M, Ricciardi S, Bhoj E, Santani A, Adam MP, et al. CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases. Am J Med Genet A 2014;164A(10):2557-66. [CrossRef] google scholar
15. Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, et al Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature Am J Med Genet A 2009;149A(3):417-26 [CrossRef] google scholar
16. Jakubiak A, Szczaluba K, Badura-Stronka M, Kutkowska-Kazmierczak A, Jakubiuk-Tomaszuk A, Chilarska T, et al Clinical characteristics of Polish patients with molecularly confirmed Mowat-Wilson syndrome J Appl Genet 2021;62(3):477-85 [CrossRef] google scholar
17. Kilic E, Cetinkaya A, Utine GE, Boduroğlu K A diagnosis to consider in intellectual disability: Mowat-Wilson syndrome J Child Neurol 2016;31(7):913-7 [CrossRef] google scholar
18. Mowat D, Croaker G, Cass D, Kerr B, Chaitow J, Ades L, et al Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23 J Med Genet 1998;35(8):617-23 [CrossRef] google scholar
19. Coyle D, Puri P Hirschsprung’s disease in children with Mowat-Wilson syndrome Pediatr Surg Int 2015;31(8):711-7 [CrossRef] google scholar
20. Verstappen G, van Grunsven LA, Michiels C, Van de Putte T, Souopgui J, Van Damme J, et al . Atypical Mowat-Wilson patient confirms the importance of the novel association between ZFHX1B/SIP1 and NuRD corepressor complex Hum Mol Genet 2008;17(8):1175-83 [CrossRef] google scholar
21. Seuntjens E, Nityanandam A, Miquelajauregui A, Debruyn J, Stryjewska A, Goebbels S, et al Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors Nat Neurosci 2009;12(11):1373-80 [CrossRef] google scholar
22. Weng Q, Chen Y, Wang H, Xu X, Yang B, He Q, et al Dual-mode modulation of Smad signaling by Smad-interacting protein Sip1 is required for myelination in the central nervous system Neuron 2012;73(4):713-28 [CrossRef] google scholar
23. McKinsey GL, Lindtner S, Trzcinski B, Visel A, Pennacchio LA, Huylebroeck D, et al Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons Neuron 2013;77(1):83-98 [CrossRef] google scholar
24. Letunic I, Khedkar S, Bork P SMART: recent updates, new developments and status in 2020 Nucleic Acids Res 2021;49(D1):D458-60 [CrossRef] google scholar
25. Ghoumid J, Drevillon L, Alavi-Naini SM, Bondurand N, Rio M, Briand-Suleau A, et al ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome Hum Mol Genet 2013;22(13):2652-61 [CrossRef] google scholar
26. Zweier C, Horn D, Kraus C, Rauch A Atypical ZFHX1B mutation associated with a mild Mowat-Wilson syndrome phenotype Am J Med Genet A 2006;140(8):869-72 [CrossRef] google scholar
27. Kuroda Y, Naruto T, Kurosawa K Subtle phenotypes of Mowat-Wilson syndrome in a patient with a novel ZEB2 C-ZF domain variant Am J Med Genet A 2024;194(12):e63822 [CrossRef] google scholar
28. Neyzi O, Bundak R, Gokcay G, Gunoz H, Furman A, Darendeliler F, et al Reference Values for Weight, Height, Head Circumference, and Body Mass Index in Turkish Children J Clin Res Pediatr Endocrinol 2015;7(4):280-93 [CrossRef] google scholar
29. Ivanovski I, Djuric O, Broccoli S, Caraffi SG, Accorsi P, Adam MP, et al Mowat-Wilson syndrome: growth charts Orphanet J Rare Dis 2020;15(1):151 [CrossRef] google scholar
30. Garavelli L, Ivanovski I, Caraffi SG, Santodirocco D, Pollazzon M, Cordelli DM, et al Neuroimaging findings in Mowat-Wilson syndrome: a study of54 patients . Genet Med 2017;19(6):691-700 [CrossRef] google scholar
31. Evans E, Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M. The behavioral phenotype ofMowat-Wilson syndrome. Am J Med Genet A 2012;158(2):358-66. [CrossRef] google scholar
32. Tanteles GA, Christophidou-Anastasiadou V. Ocular phenotype of Mowat-Wilson syndrome in the first reported Cypriot patients: an under-recognized association. Clin Dysmorphol 2014;23(1):20-3. [CrossRef] google scholar
33. Kiraz A, Aldemir O, Karabulut Y, Turan C, Dundar M. A new finding in a patient with Mowat Wilson syndrome: peripupillary atrophy and gingival hypertrophy. Genet Couns 2013;24(1):61. google scholar
34. Ho S, Luk HM, Chung BHY, Fung JLF, Mak HHY, Lo IF. Mowat-Wilson syndrome in a Chinese population: A case series. Am J Med Genet A 2020;182(6):1336-41. [CrossRef] google scholar