ESPE Abstracts

Introduction: LIG4 syndrome, a rare autosomal recessive disorder, arises from mutations in the DNA ligase IV (LIG4) gene on chromosome 13q33–q34. It disrupts DNA damage response and the repair of double-strand DNA breaks crucial for T and B lymphocyte receptor production. This syndrome manifests various clinical features such as microcephaly, atypical facial characteristics, growth delays, skin issues, genital abnormalities (micropenis/cryptorchidism), amenorrhea, CNS defects, speech delays, radiosensitivity, combined immunodeficiency, pancytopenia, susceptibility to malignancies, bone abnormalities, and hypothyroidism. We present a case of a patient with a homozygous LIG4 mutation, identified during an investigation for short stature and hypergonadotropic hypogonadism.

Case: 12 years 4 months girl, followed up at the neurology clinic due to lissencephaly&developmental delay, was evaluated for short stature. Physical examination revealed a distinctively high forehead, long face, arched eyebrows, low hairline at the nape, malar hypoplasia, narrow/downward-slanting palpebral fissures, hypotelorism, bulbous nasal tip, prominent anterior teeth, webbed neck, and widely spaced nipples. No signs of puberty were present. The bone age was 10 years. In the biochemical tests, FSH level was 80.92 IU/L, LH was14.59 IU/L, E2 was <12 pg/mL, AMH was <0.001 ng/mL, and IGF-1 was 210 g/mL[-0.69 standard deviations (SD)]. While calcium and phosphorus metabolism tests were normal, the patient had a BMD z-score of -2.2 SD and a BMD of 0.779 g/cm². In pelvic ultrasonography, the uterus and ovaries were found to be prepubertal size. The karyotype was 46,XX, but the patient exhibited an insufficient response to growth hormone stimulation tests. Genetic analysis revealed no mutations in the NBS1 gene (Nijmegen Breakage Syndrome). The DEB test was found to be normal according to IFAR scales. In all exome analyses, a homozygous mutation was detected in the LIG4 gene [NM_206937.1c.2440C>T(p.Arg814Ter)(rs104894419)]. At the last visit, the patient's chronological age was 17 years and 10 months, with normal hematological parameters. She is using oral contraceptives and experiencing regular menstrual cycles. Due to the diagnosis of LIG4 syndrome, the patient was placed under multidisciplinary surveillance for malignancy, immunodeficiency, CNS defects, and endocrinological issues.

Conclusion: When hematological issues, short stature, gonadal abnormalities, and central nervous system defects are observed together, DNA repair mechanism-related problems should be considered. In cases with short stature and hypergonadotropic hypogonadism, where Turner Syndrome has been ruled out but additional clinical and laboratory findings are present, LIG4 syndrome should be considered in the differential diagnosis.