Clinical case of Wieacker–Wolff syndrome in a 5-year girl

Wieacker–Wolff syndrome (WWS) (OMIM 314580, 301041) is rare, slowly progressive, X-linked hereditary disorder. It is characterized by fetal akinesia, which results in congenital multiplex arthrogryposis, spasticity, and development delay. WWS is caused by the point mutations or extended deletions in the ZC4H2 gene, located on the long arm of the X chromosome (Xq11.2). Currently, about 100 cases have been described.

We present the case of WWS 5-year girl. DNA diagnostic was performed using full exome sequencing and confirmed by Sanger sequencing. Determination of non-random X-chromosome inactivation was performed by methyl-sensitive PCR of GAAA-repeat RP2 gene. 

The main clinical symptoms in our case are stiffness of large and small joints, specific facial phenotype, spasticity and lack of independent walking. We revealed  heterozygous mutation с.22_23delAT (p.Met8fs) in ZC4H2 gene. Non-random inactivation of the X chromosome was detected (XCI = 96.1%).

Conclusions. Clinical symptoms of the disease, the nature of the detected mutation and the literature data indicate to the presence of an X-linked dominant pattern of inheritance of WWS in our patient. We described the case referred to the group of ZC4H2-associated rare disorders.

Contribution:
Kondakova O.B. — concept, writing text, editing text;
Kuzenkova L.M. — concept, editing text;
Lyalina A.A. — writing text; editing text;
Nezhelskaya A.A. — writing text; editing text;
Davydova Yu.I. — design of demonstrating materials, writing text;
Grebenkin D.I. — design of demonstrating materials, writing text;
Zhanin I.S. — writing text, editing text;
Alekseeva E.A. — conducting laboratory molecular genetic diagnostics, editing text;
Kanivets I.V. — conducting laboratory molecular genetic diagnostics, editing text;
Pushkov A.A. — writing text, editing text.
All co-authors are responsible for the integrity of all parts of the manuscript and approval of its final version.

Acknowledgements. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: April 15, 2023
Accepted: May 22, 2023
Published: June 30, 2023

1. Zanzottera C., Milani D., Alfei E., Rizzo A., D’Arrigo S., Esposito S., et al. ZC4H2 deletions can cause severe phenotype in female carriers. Am. J. Med. Genet. A. 2017; 173(5): 1358–63. https://doi.org/10.1002/ajmg.a.38155

2. Piccolo G., d’Annunzio G., Amadori E., Riva A., Borgia P., Tortora D., et al. Neuromuscular and neuroendocrinological features associated with ZC4H2-related arthrogryposis multiplex congenita in a Sicilian family: A case report. Front. Neurol. 2021; 12: 704747. https://doi.org/10.3389/fneur.2021.704747

3. May M., Hwang K.S., Miles J., Williams C., Niranjan T., Kahler S.G., et al. ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons. Hum. Mol. Genet. 2015; 24(17): 4848–61. https://doi.org/10.1093/hmg/ddv208

4. Kondo D., Noguchi A., Takahashi I., Kubota H., Yano T., Sato Y., et al. A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings. Brain Dev. 2018; 40(9): 760–7. https://doi.org/10.1016/j.braindev.2018.05.003

5. Wang D., Hu D., Guo Z., Hu R., Wang Q., Liu Y., et al. A novel de novo nonsense mutation in ZC4H2 causes Wieacker–Wolff Syndrome. Mol. Genet. Genomic. Med. 2020; 8(2): e1100. https://doi.org/10.1002/mgg3.1100

6. Frints S.G.M., Hennig F., Colombo R., Jacquemont S., Terhal P., Zimmerman H.H., et al. Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita. Hum. Mutat. 2019; 40(12): 2270–85. https://doi.org/10.1002/humu.23841

7. Godfrey N.D., Dowlatshahi S., Martin M.M., Rothkopf D.M. Wieacker-Wolff syndrome with associated cleft palate in a female case. Am. J. Med. Genet. A. 2018; 176(1): 167–70. https://doi.org/10.1002/ajmg.a.38527

8. Sun J.J., Cai Q., Xu M., Liu Y.N., Li W.R., Li J., et al. Loss of protein function causing severe phenotypes of female-restricted Wieacker Wolff syndrome due to a novel nonsense mutation in the ZC4H2 gene. Genes (Basel). 2022; 13(9): 1558. https://doi.org/10.3390/genes13091558

9. Hirata H., Nanda I., van Riesen A., McMichael G., Hu H., Hambrock M., et al. ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity. Am. J. Hum. Genet. 2013; 92(5): 681–95. https://doi.org/10.1016/j.ajhg.2013.03.021

10. Nagara S., Fukaya S., Muramatsu Y., Kaname T., Tanaka T. A case report of rare ZC4H2-associated disorders associated with three large hernias. Pediatr. Int. 2020; 62(8): 985–6. https://doi.org/10.1111/ped.14211

11. Godfrey D., Torres A., Heidary G., Zahoor H., Lee A., Berry G., et al. A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker–Wolff syndrome. Ophthalmic. Genet. 2021; 42(5): 612–4. https://doi.org/10.1080/13816810.2021.1923040

12. Chistyakov D.A., Savost’yanov K.V., Turakulov R.I., Shcherbacheva L.N., Mamaeva G.G., Balabolkin M.I., et al. Antioxidant protection genes and predisposition to diabetes mellitus. Sakharnyy diabet. 2000; (3): 2–7. https://www.elibrary.ru/qilnjh (in Russian)

13. Okubo Y., Endo W., Inui T., Suzuki-Muromoto S., Miyabayashi T., Togashi N., et al. A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation. Brain Dev. 2018; 40(4): 334–8. https://doi.org/10.1016/j.braindev.2017.11.011

14. Online Mendelian Inheritance in Man. Wieacker–Wolff syndrome, female-restricted; WRWFFR. Available in: https://www.omim.org/entry/301041?search=ZC4H2&highlight=zc4h2

15. Comlekoglu T., Kumar V., King K., Al Saif H., Li R., Couser N. Ophthalmic abnormalities in Wieacker–Wolff syndrome. J. AAPOS. 2022; 26(2): 91–3. https://doi.org/10.1016/j.jaapos.2021.10.010

16. Savost’yanov K.V. Modern Algorithms of Genetic Diagnosis of Rare Hereditary Diseases in Russian Patients [Sovremennye algoritmy geneticheskoy diagnostiki redkikh nasledstvennykh bolezney u rossiyskikh patsientov]. Moscow: Poligrafist i izdatel’; 2022. (in Russian)

17. Brunet T., Jech R., Brugger M., Kovacs R., Alhaddad B., Leszinski G., et al. De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. Clin. Genet. 2021; 100(1): 14–28. https://doi.org/10.1111/cge.13946