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CC BY 4.0 · Glob Med Genet 2024; 11(03): 220-224
DOI: 10.1055/s-0044-1788060
Case Report

46 XX Ovotesticular Disorder of Sex Development with Gonadotropin-Releasing Hormone Receptor, Autosomal Recessive Heterozygous Missense Mutation and Autosomal Dominant Heterozygous Missense Mutation of the PROKR2 Gene: A Case Report

Francesca Peranzoni
1   Department of Pediatric Surgery, Lausanne University Hospital, Lausanne, Switzerland
,
Roberto De Castro
2   Thien Nhan and Friends Association, Italy
,
Emilio Merlini
3   Department of Pediatric Surgery, Hospital of Alexandria, Italy
,
Yen Le Nguyen
4   Department of Pediatric Urology, Vietnam National Hospital of Pediatric 2, Ho Chi Minh City, Vietnam
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Abstract

True hermaphroditism is a disorder of sex development (DSD), accounting for less than 5% of all DSD cases, defined by the simultaneous presence of testicular tissue and ovarian tissue in the same individual. In the reported case, the patient presented two genetic mutations involved in the pathogenic pathway of the DSD condition associated with the clinical features of Kallmann syndrome (KS), a developmental disease that associates hypogonadotropic hypogonadism (HH), due to gonadotropin-releasing hormone deficiency, and anosmia, related to the absence or hypoplasia of the olfactory bulbs. Given the variable degree of hyposmia in KS, the distinction between KS and normosmic idiopathic HH is currently unclear, especially as HH patients do not always undergo detailed olfactory testing. This syndrome is very rare, with an estimated prevalence of 1:80,000 in males and 1:40,000 in females.

This is the only case report concerning a patient with 46 XX true hermaphroditism affected by HH and digenic inheritance of Kallmann syndrome.

Keywords

ovotestis - Kallmann syndrome - disorder of sex development

Patient Consent

The family of the patient gave written informed consent to publish this article.




Publication History

Article published online:
09 July 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 The genetic aspects of primary eunuchoidism. Semantic Scholar. Accessed June 20, 2024 at: https://www.semanticscholar.org/paper/The-genetic-aspects-of-primary-eunuchoidism-Kallmann/9f415d8d9e1a4aab4faff38d21bfa067ee4401ca
    Google Scholar
  • 2 Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature 1989; 338 (6211) 161-164
    CrossrefPubMedGoogle Scholar
  • 3 Schwanzel-Fukuda M, Crossin KL, Pfaff DW, Bouloux PM, Hardelin JP, Petit C. Migration of luteinizing hormone-releasing hormone (LHRH) neurons in early human embryos. J Comp Neurol 1996; 366 (03) 547-557
    CrossrefPubMedGoogle Scholar
  • 4 Hagen C, McNeilly AS. The gonadotrophins and their subunits in foetal pituitary glands and circulation. J Steroid Biochem 1977; 8 (05) 537-544
    CrossrefPubMedGoogle Scholar
  • 5 Sinclair AH, Berta P, Palmer MS. et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990; 346 (6281) 240-244
    CrossrefPubMedGoogle Scholar
  • 6 Huhtaniemi IT, Yamamoto M, Ranta T, Jalkanen J, Jaffe RB. Follicle-stimulating hormone receptors appear earlier in the primate fetal testis than in the ovary. J Clin Endocrinol Metab 1987; 65 (06) 1210-1214
    CrossrefPubMedGoogle Scholar
  • 7 O'Shaughnessy PJ, Baker PJ, Monteiro A, Cassie S, Bhattacharya S, Fowler PA. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester. J Clin Endocrinol Metab 2007; 92 (12) 4792-4801
    CrossrefPubMedGoogle Scholar
  • 8 Tapanainen J, Kellokumpu-Lehtinen P, Pelliniemi L, Huhtaniemi I. Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metab 1981; 52 (01) 98-102
    CrossrefPubMedGoogle Scholar
  • 9 Wilson JD, Griffin JE, Leshin M, George FW. Role of gonadal hormones in development of the sexual phenotypes. Hum Genet 1981; 58 (01) 78-84
    CrossrefPubMedGoogle Scholar
  • 10 Tevosian SG, Albrecht KH, Crispino JD, Fujiwara Y, Eicher EM, Orkin SH. Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 2002; 129 (19) 4627-4634
    CrossrefPubMedGoogle Scholar
  • 11 Agrawal R, Wessely O, Anand A, Singh L, Aggarwal RK. Male-specific expression of Sox9 during gonad development of crocodile and mouse is mediated by alternative splicing of its proline-glutamine-alanine rich domain. FEBS J 2009; 276 (15) 4184-4196
    CrossrefPubMedGoogle Scholar
  • 12 Massa G, de Zegher F, Vanderschueren-Lodeweyckx M. Serum levels of immunoreactive inhibin, FSH, and LH in human infants at preterm and term birth. Biol Neonate 1992; 61 (03) 150-155
    CrossrefPubMedGoogle Scholar
  • 13 Forabosco A, Sforza C. Establishment of ovarian reserve: a quantitative morphometric study of the developing human ovary. Reprod Endocrinol 2007; 88 (03) P675-P683
    Google Scholar
  • 14 Baker TG, Scrimgeour JB. Development of the gonad in normal and anencephalic human fetuses. Reproduction 1980; 60 (01) 193-199
    CrossrefPubMedGoogle Scholar
  • 15 Clements JA, Reyes FI, Winter JS, Faiman C. Studies on human sexual development. III. Fetal pituitary and serum, and amniotic fluid concentrations of LH, CG, and FSH. J Clin Endocrinol Metab 1976; 42 (01) 9-19
    CrossrefPubMedGoogle Scholar
  • 16 Kaplan SL, Grumbach MM. The ontogenesis of human foetal hormones. II. Luteinizing hormone (LH) and follicle stimulating hormone (FSH). Acta Endocrinol (Copenh) 1976; 81 (04) 808-829
    PubMedGoogle Scholar
  • 17 Beck-Peccoz P, Padmanabhan V, Baggiani AM. et al. Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: circulating levels of gonadotropins, their common alpha-subunit and free testosterone, and discrepancy between immunological and biological activities of circulating follicle-stimulating hormone. J Clin Endocrinol Metab 1991; 73 (03) 525-532
    CrossrefPubMedGoogle Scholar
  • 18 Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-to-date review about minipuberty and overview on hypothalamic-pituitary-gonadal axis activation in fetal and neonatal life. Front Endocrinol (Lausanne) 2018; 9: 410
    CrossrefPubMedGoogle Scholar
  • 19 Wang M-H, Baskin LS. Endocrine disruptors, genital development, and hypospadias. J Androl 2008; 29 (05) 499-505
    CrossrefPubMedGoogle Scholar
  • 20 Nassar N, Abeywardana P, Barker A, Bower C. Parental occupational exposure to potential endocrine disrupting chemicals and risk of hypospadias in infants. Occup Environ Med 2010; 67 (09) 585-589
    CrossrefPubMedGoogle Scholar
  • 21 Oanh NTP, Kido T, Honma S. et al. Androgen disruption by dioxin exposure in 5-year-old Vietnamese children: decrease in serum testosterone level. Sci Total Environ 2018; 640-641: 466-474
    CrossrefPubMedGoogle Scholar
  • 22 Dodé C, Hardelin J-P. Kallmann syndrome. Eur J Hum Genet 2009; 17 (02) 139-146
    CrossrefPubMedGoogle Scholar
  • 23 McArdle C. Gonadotropin releasing hormone (GnRH) receptor. In: Enna SJ, Bylund DB. eds. xPharm: The Comprehensive Pharmacology Reference. New York: Elsevier; 2007: 1-12
    Google Scholar
  • 24 GNRHR gonadotropin releasing hormone receptor [Homo sapiens (human)]. Accessed June 20, 2024 at: https://www.ncbi.nlm.nih.gov/gene/2798
    Google Scholar
  • 25 Li M, Bullock CM, Knauer DJ, Ehlert FJ, Zhou QY. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Mol Pharmacol 2001; 59 (04) 692-698
    CrossrefPubMedGoogle Scholar
  • 26 Cheng MY, Bullock CM, Li C. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 2002; 417 (6887) 405-410
    CrossrefPubMedGoogle Scholar
  • 27 Matsumoto S-I, Yamazaki C, Masumoto K-H. et al. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci U S A 2006; 103 (11) 4140-4145
    CrossrefPubMedGoogle Scholar
  • 28 Dodé C, Teixeira L, Levilliers J. et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet 2006; 2 (10) e17-5
    CrossrefPubMedGoogle Scholar
  • 29 Louden ED, Poch A, Kim HG, Ben-Mahmoud A, Kim SH, Layman LC. Genetics of hypogonadotropic hypogonadism-human and mouse genes, inheritance, oligogenicity, and genetic counseling. Mol Cell Endocrinol 2021; 534: 111334
    CrossrefPubMedGoogle Scholar
  • 30 Hardelin J-P, Dodé C. The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. Sex Dev 2008; 2 (4-5): 181-193
    CrossrefPubMedGoogle Scholar
  • 31 de Roux N. Isolated gonadotropic deficiency with and without anosmia: a developmental defect or a neuroendocrine regulation abnormality of the gonadotropic axis. Horm Res 2005; 64 (Suppl. 02) 48-55
    PubMedGoogle Scholar
  • 32 Zhou Q-Y, Cheng MY. Prokineticin 2 and circadian clock output. FEBS J 2005; 272 (22) 5703-5709
    CrossrefPubMedGoogle Scholar
  • 33 Truwit CL, Barkovich AJ, Grumbach MM, Martini JJ. MR imaging of Kallmann syndrome, a genetic disorder of neuronal migration affecting the olfactory and genital systems. AJNR Am J Neuroradiol 1993; 14 (04) 827-838
    PubMedGoogle Scholar
  • 34 Quinton R, Duke VM, de Zoysa PA. et al. The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 1996; 81 (08) 3010-3017
    CrossrefPubMedGoogle Scholar