DNA ligase IV deficiency identified in a patient with hypergonadotropic hypogonadism: a case report

Deniz Yasar; Abdullah Sezer; Caner Aytekin; Gülin Karacan Küçükali; Beyhan Özkaya Dönmez; Aslıhan Araslı Yılmaz; İclal Okur; Behiye Sarıkaya Özdemir; Erdal Kurnaz; Melikşah Keskin; Şenay Savaş Erdeve

doi:10.1515/jpem-2024-0510

Article

DNA ligase IV deficiency identified in a patient with hypergonadotropic hypogonadism: a case report

Deniz Yasar , Abdullah Sezer , Caner Aytekin , Gülin Karacan Küçükali , Beyhan Özkaya Dönmez , Aslıhan Araslı Yılmaz , İclal Okur , Behiye Sarıkaya Özdemir , Erdal Kurnaz , Melikşah Keskin and Şenay Savaş Erdeve

Published/Copyright: February 17, 2025

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 4

Abstract

Objectives

DNA ligase IV (LIG4) deficiency is a rare autosomal recessive disorder associated with impaired DNA damage-response mechanisms. LIG4 deficiency exhibits a broad clinical spectrum, including microcephaly, facial abnormalities, sensitivity to ionizing radiation, ranging from severe combined immunodeficiency to normal immune function, progressive bone marrow failure, and predisposition to malignancy.

Case presentation

We report an 18-year-old girl of consanguineous Turkish parents, first evaluated at 13 years old for growth retardation and short stature. She was born preterm at 32 weeks with dysmorphic facial features, lissencephaly, intellectual disability, and without immunodeficiency. Although diagnosed with growth hormone deficiency, she did not receive appropriate hormone therapy due to special circumstances. At the age of 15, she presented with primary amenorrhea. Further evaluation revealed hypergonadotropic hypogonadism due to gonadal failure. Genetic analysis revealed a homozygous c.2440C>T (p.Arg814Ter) mutation in the LIG4 gene. Following genetic counseling, her parents opted for prenatal diagnosis in a subsequent pregnancy, resulting in the birth of another child with the same condition.

Conclusions

LIG4 syndrome should be considered in the differential diagnosis of cases with growth retardation, microcephaly, and gonadal failure. In the literature, there are limited cases reported with gonadal failure in LIG4 syndrome. Here, we emphasize this aspect to highlight its significance.

Keywords: DNA ligase IV; hypergonadotropic hypogonadism; microcephaly; growth retardation

Corresponding author: Deniz Yasar, General Pediatrics, Etlik City Hospital, Ankara Etlik Şehir Hastanesi, Varlık, Halil Sezai Erkut Cd. No:5, 06170 Yenimahalle, Ankara, Türkiye, E-mail: denizyasar94@gmail.com

Research ethics: The local Institutional Review Board deemed the study exempt from review.
Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. The conception and design of the work were developed by D.Y., A.S., C.A., and Ş.S.E. The investigation of the genetic aspects was conducted by A.S., while the immunological aspects of the cases were explained by C.A. Data acquisition and analysis were performed by D.Y., A.S., G.K.K., B.Ö.D., A.A.Y., İ.O., and B.S.Ö. The interpretation of the data was carried out by D.Y., A.S., C.A., E.K., M.K., and Ş.S.E. The drafting and revision of the work for important intellectual content were managed by D.Y., A.S., C.A., and Ş.S.E.
Use of Large Language Models, AI and Machine Learning Tools: Language improvement support was provided by ChatGPT. However, all text was written and approved by the authors, who take full responsibility for the content.
Conflict of interest: All authors state no conflict of interest.
Research funding: None declared.
Data availability: The detailed patient data used in this study are stored in our institution’s data repository. While these data are not directly accessible in an open format, interested parties may request access by contacting the authors under special circumstances.

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Received: 2024-10-24

Accepted: 2025-01-31

Published Online: 2025-02-17

Published in Print: 2025-04-28

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Articles in the same Issue

https://doi.org/10.1515/jpem-2024-0510

Keywords for this article

DNA ligase IV; hypergonadotropic hypogonadism; microcephaly; growth retardation