LHCGR Inactivating Variants: Single Center Experience and Systematic Review of Phenotype-Genotype of 46, XY and 46, XX Patients

Authors

• Rohit Barnabas
• Swati Jadhav
• Anurag Ranjan Lila
• Sirisha Kusuma Boddu
• Saba Samad Memon
• Sneha Arya
• Samiksha Chandrashekhar Hegishte
• Manjiri Karlekar
• Virendra A Patil
• Vijaya Sarathi
• Nalini S Shah
• Tushar Bandgar

Language

English

Publication Date

10-1-2024

Journal

Endocrine Connections

DOI

10.1530/EC-24-0246

PMID

39162678

PMCID

PMC11466245

PubMedCentral® Posted Date

10-4-2024

PubMedCentral® Full Text Version

Post-print

Abstract

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 three 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 center, 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 human chorionic gonadotropin (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 luteinizing hormone (LH) (97.6%, 41/42) and low (< 1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone 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 actions for LH and hCG.

Keywords

hypogonadism, Leydig cell hypoplasia, LHCGR

Published Open-Access

yes

Recommended Citation

Barnabas, Rohit; Jadhav, Swati; Lila, Anurag Ranjan; et al., "LHCGR Inactivating Variants: Single Center Experience and Systematic Review of Phenotype-Genotype of 46, XY and 46, XX Patients" (2024). Faculty, Staff and Student Publications. 4415.
https://digitalcommons.library.tmc.edu/uthmed_docs/4415