Primary ciliary dyskinesia in a child with type II Simpson -Golabi - Bemel syndrome due to OFD1 gene mutation

Primary ciliary dyskinesia (PCD) is an orphan disease associated with mutations in several genes. It is a ciliopathy, an abnormality of the cilia and flagella. Ciliopathies include the extremely rare Simpson - Golabi - Bemel syndrome (SSGB) type II.

The aim of this article is to familiarize the reader with the possibility of simultaneous presence of type II SSGB and PCD in a patient with bronchiectasis (BE).

Results. The first clinical observation in the Russian literature is presented withhistory, physical examination, including clinical and morphologic examination, results of additional investigations and initiation of therapy. The case describes a 15-year-old patient with BE and other lesions typical of PCD confirmed on the basis of structural changes in the cilia of the respiratory epithelium of the trachea detected by transmission electron microscopy. The patient had a pathogenic mutation of the OFD1 gene responsible for the development of both type II SSGB and PCD.

Conclusion. Several variants of ciliopathies may occur in one patient, and PCD may present as a syndrome.

1. Simpson J.L., Landey S., New M., German J. A previously unrecognized X-linked syndrome of dysmorphia. Birth Defects Orig. Artic. Ser. 1975; 11 (2): 18-24.

2. Golabi M., Rosen L. A new X-linked mental retardation-overgrowth syndrome. Am. J. Med. Genet. 1984; 17 (1): 345-358. DOI: 10.1002/ajmg.1320170128.

3. Behmel A., Plochl E., Rosenkranz W. A new X-linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syndrome? Hum. Genet. 1984; 67 (4): 409-413. DOI: 10.1007/BF00291401.

4. Neri G., Marini R., Cappa M. et al. Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. Am. J. Med. Genet. 1988; 30 (1-2): 287-299. DOI: 10.1002/ajmg.1320300130.

5. de Conciliis L., Marchitiello A., Wapenaar M.C. et al. Characterization of Cxorf5 (71-7A), a novel human cDNA mapping to Xp22 and encoding a protein containing coiled-coil alpha-helical domains. Genomics. 1998; 51 (2): 243-250. DOI: 10.1006/geno.1998.5348.

6. Ferrante M.I., Zullo A., Barra A. et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat. Genet. 2006; 38 (1): 112-117. DOI: 10.1038/ng1684.

7. Ferrante M.I., Romio L., Castro S. et al. Convergent extension movements and ciliary function are mediated by ofd1, a zebrafish orthologue of the human oral-facial-digital type 1 syndrome gene. Hum. Mol. Genet. 2009; 18 (2): 289-303. DOI: 10.1093/hmg/ddn356.

8. Coene K.L., Roepman R., Doherty D. et al. OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded leb-ercilin. Am. J. Hum. Genet. 2009; 85 (4): 465-481. DOI: 10.1016/j.ajhg.2009.09.002.

9. Webb T.R., Parfitt D.A., Gardner J.C. et al. Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). Hum. Mol. Genet. 2012; 21 (16): 3647-3654. DOI: 10.1093/hmg/dds194.

10. Field M., Scheffer I.E., Gill D. et al. Expanding the molecular basis and phenotypic spectrum of X-linked Joubert syndrome associated with OFD1 mutations. Eur. J. Hum. Genet. 2012; 20 (7): 806-809. DOI: 10.1038/ejhg.2012.9.

11. Thauvin-Robinet C., Thomas S., Sinico M. et al. OFD1 mutations in males: phenotypic spectrum and ciliary basal body docking impairment. Clin. Genet. 2013; 84 (1): 86-90. DOI: 10.1111/cge.12013.

12. Hannah W.B., DeBrosse S., Kinghorn B. et al. The expanding phenotype of OFD1-related disorders: hemizygous loss-of-function variants in three patients with primary ciliary dyskinesia. Mol. Genet. Genomic Med. 2019; 7 (9): e911. DOI: 10.1002/mgg3.911.

13. Knowles M.R., Daniels L.A., Davis S.D. et al. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am. J. Respir. Crit. Care Med. 2013; 188 (8): 913-922. DOI: 10.1164/rccm.201301-0059CI.

14. Budny B., Chen W., Omran H. et al. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum. Genet. 2006; 120 (2): 171-178. DOI: 10.1007/s00439-006-0210-5.

15. Ryzhkova O.P., Kardymon O.L., Prohorchuk E.B. et al. [Guidelines for the interpretation of massive parallel sequencing variants (update 2018, version 2)]. Meditsinskayagenetika. 2019; 18 (2): 3-23. DOI: 10.25557/2073-7998.2019.02.3-23 (in Russian).

16. Behan L., Dimitrov B.D., Kuehni C.E. et al. PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia. Eur. Respir. J. 2016; 47 (4): 1103-1112. DOI: 10.1183/13993003.01551-2015.

17. Shoemark A., Boon M., Brochhausen C. et al. International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria). Eur. Respir. J. 2020; 55 (4): 1900725. DOI: 10.1183/13993003.00725-2019.

18. Frolov P.A., Zhestkova M.A., Ovsyannikov D.Yu. et al. [Predictors of severe course and evaluation of the effectiveness of a stepwise complex conservative therapy of bronchiectasis not associated with cystic fibrosis in children]. Pediatriya. Zhurnalimeni G.N.Speranskogo. 2022; 101 (4): 29-36. DOI: 10.24110/0031-403X-2022-101-4-29-36 (in Russian).

19. Leigh M.W. Primary ciliary dyskinesia. In: Wilmott R.W., Boat T.F., Bush A. et al. Kendig and Chernick’s disorders of the respiratory tract in children. 8th Edn. Elsevier Inc.; 2012: 995-1002. Available at: https://www.uk.elsevierhealth.com/kendig-and-chernicks-disorders-of-the-respiratory-tract-in-children-e-book-9781455740505.html

20. Bukowy-Bieryllo Z., Rabiasz A., Dabrowski M. et al. Truncating mutations in exons 20 and 21 of OFD1 can cause primary ciliary dyskinesia without associated syndromic symptoms. J. Med. Genet. 2019; 56 (11): 769-777. DOI: 10.1136/jmedgenet-2018-105918.