ESPE Abstracts

Objective: to assess diagnostic usefulness and accuracy of different tools in patients with Kallmann syndrome and ichthyosis due to X-chromosome microdeletion.Materials: сongenital hypogonadotropic hypogonadism due to KAL1 pathological variants manifest with micropenis, cryptorchidism, delay of puberty, and not associated with disorder of sex development. This condition can be associated with ichthyosis due to deletion of X chromosome region with genes KAL1 and STS (steroid sulphatase gene).We report the clinical cases of 2, XY siblings with Kallmann syndrome associated with ichthyosis and different clinical features of the disease. The ichthyosis was diagnosed at birth in both of them. One boy was born with micropenis and bilateral cryptorchidism. At the age of 7 months, his height SDS was 0.28 SD, LH 0.001 IU/ml, FSH 0.4 IU/ml, AMH 0.58 ng/ml, testosterone 1.6 nmol/l. Uterus was absent on ultrasound. During hCG stimulation test (5000 IU) level of testosterone increased to 1.82 nmol/l. After 12 months of topic androgens use the length of penis increased up to 2.5 cm. Because of micropenis, unpalpable bilateral testes, inadequate testosterone level after hCG test, next generation sequencing (NGS) was performed to analyse 38 genes associated with disorders of sex development. It revealed the variant with uncertain significance in gene MAMLD1. His elder brother (patient 2) was admitted to the endocrinological department at the age of 12 due to hypoplasia of both testes combined with ichthyosis. His height SDS was 0.87 SD. Tanner stage 1. Penis length ~ 5.1 cm, both testes were in scrotum. D=S=0.45 ml (by ultrasound). Bone age was 11-12 years. LH 0.06 IU/ml. FSH 0.84 IU/ml, AMH 23.7 ng/ml, inhibin B 11 pg/ml.Due to ichthyosis, testes hypoplasia and younger brother with micropenis and bilateral cryptorchidism chromosomal microarray analyses were performed in both boys. Microdeletions in Xp22.3 region from position 6533602 to position 8791660 were identified in both sibs. This region include KAL1 (OMIM 308700) and STS genes (OMIM 308100).The patients were diagnosed with contiguous gene syndrome.Conclusion: Congenital hypogonadotropic hypogonadism can be misdiagnosed with sex disorders due common features, such as to combination of micropenis and bilateral cryptorchidism. The majority of cases can be diagnosed with NGS.However, the results of NGS with the variants with uncertain significance must be carefully interpreted together with clinical features. Clinical features analysis can help the clinicians to choose the best diagnostic tool, to diagnosis the disease and initiate the therapy timely.