Novel homozygous inactivating mutation in the luteinizing hormone receptor gene (LHCGR) associated with 46, XY DSD in a Moroccan family
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Achwak Alla
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Farel Elilie Mawa Ongoth
Abstract
Objectives
We present the first cases of two male brothers with Leydig cell hypoplasia secondary to a novel mutation in the LHCGR gene that has never been described before.
Case presentation
We report the case of two brothers with Leydig cell hypoplasia (LCH) type II caused by novel homozygous inactivating mutation of the LHCGR gene, located in exon 10 in c 947 position. The two patients presented at 11 years 7 months and 1 year 6 months, respectively, with abnormal sexual development, micropenis and cryptorchidism. Genetic analysis revealed a homozygous deletion of approximately 4 bp encompassing exon 10 of the LHR gene in the two brothers indicating autosomal recessive inheritance. An hCG stimulation test induced testosterone secretion within the normal range. Subsequently, a treatment with enanthate of testosterone was started, with an increase in the length of the penis.
Conclusions
Leydig cell hypoplasia is a rare form of disorder of sex development. We report the occurrence of a new mutation of the LHCGR gene in two Moroccan brothers in whom the clinical features and the molecular diagnosis were correlated.
Acknowledgments
We would like to thank our patients and their family for their participation in this research study.
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Research funding: None declared.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The local Institutional Review Board deemed the study exempt from review.
References
1. Fendereski, K, Carey, J, Timme, K, Hayes, K, Robnett, J, Schaeffer, A. 46 XY undervirulized male DSD: reporting a patient with prenatally diagnosed disorder/difference of sex development (DSD) with heterozygous LHCGR mutations. [Internet]. Urol Case Reports 2022;41:101971. https://doi.org/10.1016/j.eucr.2021.101971.Suche in Google Scholar
2. Potorac, I, Trehan, A, Szymańska, K, Fudvoye, J, Thiry, A, Huhtaniemi, I, et al.. Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46, XY disorder of sex development. Eur J Endocrinol 2019;181:K11–20. https://doi.org/10.1530/eje-19-0170.Suche in Google Scholar
3. Martens, JWM, Verhoef-Post, M, Abelin, N, Ezabella, M, Toledo, SPA, Brunner, HG, et al.. A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: correlation between receptor activity and phenotype. [Internet]. Mol Endocrinol 1998;12:775–84.10.1210/mend.12.6.0124Suche in Google Scholar
4. Simoni, M, Gromoll, J, Nieschlag, E. The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. [Internet]. Endocr Rev 1997;18:739–73.10.1210/edrv.18.6.0320Suche in Google Scholar
5. Sherman, GB, Heilman, F, Hoss, AJ, Bunick, D, Lund, LA. Messenger RNAs encoding the subunits of Guinea pig (Cavia porcellus) luteinizing hormone (gpLH) and putative chorionic gonadotropin (gpCG) are transcribed from a single-copy gpLH/CG gene. Available from: http://www.endocrinology.org [Accessed 29 Nov 2021].10.1677/jme.0.0260267Suche in Google Scholar
6. Ascoli, M, Fanelli, F, Segaloff, DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. [Internet]. Endocr Rev 2002;23:141–74.10.1210/edrv.23.2.0462Suche in Google Scholar
7. Gromoll, J, Eiholzer, U, Nieschlag, E, Simoni, M. Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH. [Internet]. J Clin Endocrinol Metab 2000;85:2281–6.10.1210/jcem.85.6.6636Suche in Google Scholar
8. Zhang, FP, Kero, J, Huhtaniemi, I. The unique exon 10 of the human luteinizing hormone receptor is necessary for expression of the receptor protein at the plasma membrane in the human luteinizing hormone receptor, but deleterious when inserted into the human follicle-stimulating hormone re. Mol Cell Endocrinol 1998;142:165–74. https://doi.org/10.1016/s0303-7207(98)00108-7.Suche in Google Scholar
9. Segaloff, DL. Diseases associated with mutations of the human lutropin receptor. Prog Mol Biol Transl Sci [Internet] 2009;89:97–114.10.1016/S1877-1173(09)89004-2Suche in Google Scholar
10. Richter-Unruh, A, Martens, JWM, Verhoef-Post, M, Wessels, HT, Kors, WA, Sinnecker, GHG, et al.. Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene. Clin Endocrinol 2002;56:103–12. https://doi.org/10.1046/j.0300-0664.2001.01437.x.Suche in Google Scholar PubMed
11. Bruysters, M, Christin-Maitre, S, Verhoef-Post, M, Sultan, C, Auger, J, Faugeron, I, et al.. A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister. Available from: http://humrep.oxfordjournals.org/ [Accessed 29 Nov 2021].10.1093/humrep/den180Suche in Google Scholar PubMed PubMed Central
12. Latronico, A, Anasti, J, Arnhold, I, Rapaport, R, Mendonca, B, Bloise, W, et al.. Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. Obstet Gynecol Surv 1996;51:416–9. https://doi.org/10.1097/00006254-199607000-00017.Suche in Google Scholar
13. Laue, LL, Wu, S-M, Kudo, M, Bourdony, CJ, Cutler, GB, Hsueh, AJW, et al.. Compound heterozygous mutations of the luteinizing hormone receptor gene in leydig cell hypoplasia. Mol Endocrinol 1996;10:987–97. 10.1210/mend.10.8.8843415.10.1210/mend.10.8.8843415Suche in Google Scholar PubMed
14. Misrahi, M, Meduri, G, Pissard, S, Bouvattier, C, Beau, I, Loosfelt, H, et al.. Comparison of immunocytochemical and molecular features with the phenotype in a case of incomplete male pseudohermaphroditism associated with a mutation of the luteinizing hormone receptor*. J Clin Endocrinol Metab 1997;82:2159–65. https://doi.org/10.1210/jc.82.7.2159.Suche in Google Scholar
15. Kossack, N, Troppmann, B, Richter-Unruh, A, Kleinau, G, Gromoll, J. Aberrant transcription of the LHCGR gene caused by a mutation in exon 6A leads to Leydig cell hypoplasia type II; 2013. Available from: https://doi.org/10.1016/j.mce.2012.11.018 [Accessed 29 Nov 2021].Suche in Google Scholar PubMed
16. Newton, CL, Anderson, RC, Katz, AA, Millar, RP. Loss-of-function mutations in the human luteinizing hormone receptor predominantly cause intracellular retention. Endocrinology 2016;157:4364–77. 10.1210/en.2016-1104.10.1210/en.2016-1104Suche in Google Scholar PubMed
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
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- Novel homozygous inactivating mutation in the luteinizing hormone receptor gene (LHCGR) associated with 46, XY DSD in a Moroccan family
Artikel in diesem Heft
- Frontmatter
- Review Article
- Effects and dose-response relationships of exercise intervention on weight loss in overweight and obese children: a meta-regression and system review
- Original Articles
- Diabetic ketoacidosis in children with new-onset type 1 diabetes mellitus: demographics, risk factors and outcome: an 11 year review in Hong Kong
- Incidence tendency, etiological classification and outcome of congenital hypothyroidism in Guangzhou, China: an 11-year retrospective population-based study
- Metabolically healthy obesity in a paediatric obesity clinic
- Universal salt iodization potentially contributes to health equity: socio-economic status of children does not affect iodine status
- Association between clinical variations and copy number variations in cases with Turner syndrome
- The mediating function of obesity on endocrine-disrupting chemicals and insulin resistance in children
- Relationship between prolactin level and puberty in girls with early breast development
- Pattern of presentation of paediatric endocrine disorders in a Nigerian tertiary institution: an 11-year survey
- Case Reports
- Novel non-stop variant of the NR0B1 gene in two siblings with adrenal hypoplasia congenita
- Identification of two novel ACAT1 variant associated with beta-ketothiolase deficiency in a 9-month-old boy
- Craniosynostosis in a patient with Fanconi–Bickel syndrome: a case report
- Severe loss of adipose tissue in a Vietnamese lipodystrophy patient caused by LMNA p.G465D mutation: a first clinical characterization and two-year follow-up
- The response to growth hormone treatment in a child with short stature, growth hormone deficiency and autosomal dominant cutis laxa type 3 – case report
- Novel homozygous inactivating mutation in the luteinizing hormone receptor gene (LHCGR) associated with 46, XY DSD in a Moroccan family
