RESUMO
BACKGROUND: The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series. METHODS: We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of 3 patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described. RESULTS: Three 46,XY patients(age 6-18 years) from our centre, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n=70, 56 raised as females) presented with pubertal delay (n=41) or atypical genitalia(n=17). Sinnecker score ≥3 (suggesting antenatal hCG inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/ml) in 77.4% (24/31), whereas puberty/postpubertal age, high LH (97.6%, 41/42) and low (<1.0 ng/ml) basal testosterone (94.9%, 37/39) was observed in most. FSH was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs. 0/5, p=0.033). 46,XX patients (n=18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2-38). CONCLUSION: In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential action for LH and hCG.