👤 Mashael Al-Qahtani

BACKGROUND Defects in androgen synthesis, such as 17-beta-hydroxysteroid dehydrogenase type 3 (17-ß-HSD3) deficiency, can lead to ambiguous genitalia in people with karyotype 46,XY due to impaired testosterone and dihydrotestosterone production. This condition may be initially diagnosed as androgen insensitivity syndrome (AIS), an X-linked disorder characterized by female external genitalia, absence of Mullerian structures, inguinal testes, and primary amenorrhea in adolescence. This report describes the case of a 13-year-old phenotypic female with 46,XY karyotype and a history of virilization due to 17-ß-HSD3 deficiency, previously diagnosed with AIS. CASE REPORT We report the case of a 13-year-old phenotypic female who was initially diagnosed with AIS during early childhood at a rural hospital. Several years later, she presented to a pediatric endocrinology clinic with progressive signs of virilization, including hirsutism, deepening of the voice, and severe facial acne. Laboratory evaluation, including a human chorionic gonadotropin (hCG) stimulation test, revealed a markedly low testosterone-to-androstenedione (T/AND) ratio of 0.1, strongly suggestive of 17ß-HSD3 deficiency. Whole-exome sequencing identified a homozygous missense variant of uncertain significance in exon 4 of the HSD17B3 gene. As the patient had been raised as a female, the parents chose to maintain her female gender assignment. Subsequently, the patient underwent bilateral orchiectomy along with clitoroplasty and labioplasty at another medical center. CONCLUSIONS Genetic and hormonal testing play a crucial role in differentiating among various types of disorders of sex development, thereby reducing the risk of diagnostic uncertainty. Early referral to a pediatric endocrinologist is essential to ensure accurate diagnosis and appropriate management of affected individuals. Show less

There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes ( Show less

Specific genetic anomalies or non-genetic factors could lead to epilepsy, but in various cases the underlying cause is unknown. Novel technologies, such as array comparative genomic hybridization, may reveal the copy number variants (CNVs), established as significant risk factor for epilepsy. This study carried out a high-density whole genome array- comparative genomic hybridization analysis with blood DNA samples from a cohort of twenty epilepsy patients to search for CNVs associated with epilepsy. Microdeletion of 14q31.1 was observed in four patients including two from the same family with loss of the NRXN3 gene; microdeletion of 15q12 in one patient with loss of the GABRG3 gene, and microduplication of 20q13.33 in three patients with loss of the gene group CHRNA4, KCNQ2, EEF1A2 and PPDPF were also found. These CNV findings were confirmed by real-time quantitative polymerase chain reaction. We have described, for the first time, numerous potential CNVs/genes implicated in epilepsy in the Saudi population. The study presents a better description of the genetic variations in epilepsy, and would eventually enable us to provide a foundation for understanding the critical genome regions which might be involved in the development of epilepsy. Show less