Gonadal Dysgenesis Without Adrenal Insufficiency in a 46, XY Patient Heterozygous for the Nonsense C16X Mutation: A Case of SF1 Haploinsufficiency

Mallet, Delphine; Bretones, Patricia; Michel-Calemard, Laurence; Dijoud, Frédérique; Dávid, M; Morel, Yves

doi:10.1210/jc.2004-0670

Cited by 102 publications

(66 citation statements)

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“…Case Report M-A Burckhardt and others Histology of HSD3B2 deficiency 173:5 K8 Table 4 (8,9,12,13,14,16,23,24,25,26,27,28,29,30,31,32,33,34,35,36). For spermatogenesis and thus fertility, the few data available suggest that it varies between different androgen biosynthetic defects as well as between individuals carrying defects in the same gene.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

Burckhardt

Udhane

Marti

et al. 2015

European Journal of Endocrinology

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Context: 3b-hydroxysteroid dehydrogenase deficiency (3bHSD) is a rare disorder of sexual development and steroidogenesis. There are two isozymes of 3bHSD, HSD3B1 and HSD3B2. Human mutations are known for the HSD3B2 gene which is expressed in the gonads and the adrenals. Little is known about testis histology, fertility and malignancy risk. Objective: To describe the molecular genetics, the steroid biochemistry, the (immuno-)histochemistry and the clinical implications of a loss-of-function HSD3B2 mutation. Methods: Biochemical, genetic and immunohistochemical investigations on human biomaterials. Results: A 46,XY boy presented at birth with severe undervirilization of the external genitalia. Steroid profiling showed low steroid production for mineralocorticoids, glucocorticoids and sex steroids with typical precursor metabolites for HSD3B2 deficiency. The genetic analysis of the HSD3B2 gene revealed a homozygous c.687del27 deletion. At pubertal age, he showed some virilization of the external genitalia and some sex steroid metabolites appeared likely through conversion of precursors secreted by the testis and converted by unaffected HSD3B1 in peripheral tissues. However, he also developed enlarged breasts through production of estrogens in the periphery. Testis histology in late puberty revealed primarily a Sertoli-cell-only pattern and only few tubules with arrested spermatogenesis, presence of few Leydig cells in stroma, but no neoplastic changes. Conclusions: The testis with HSD3B2 deficiency due to the c.687del27 deletion does not express the defective protein. This patient is unlikely to be fertile and his risk for gonadal malignancy is low. Further studies are needed to obtain firm knowledge on malignancy risk for gonads harboring defects of androgen biosynthesis.

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Section: European Journal Of Endocrinologymentioning

confidence: 99%

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

Burckhardt

Udhane

Marti

et al. 2015

European Journal of Endocrinology

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“…The clinical presentation of patients affected by NR5A1 mutations is very diverse, ranging in 46,XY individuals from phenotypically females with complete gonadal dysgenesis with or without adrenal failure (5)(6)(7)(8)(9)(10) to males with penoscrotal hypospadias (8,11,12) or bilateral anorchia (13). In 46,XX women, NR5A1 mutations have been associated with premature ovarian failure (3).…”

Section: Introductionmentioning

confidence: 99%

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Cools

Hoebeke

Wolffenbuttel

et al. 2012

European Journal of Endocrinology

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Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9TOA, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function. Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

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“…Although the first three cases (8)(9)(10) presented with adrenal insufficiency, the others had normal adrenal function (11)(12)(13)(14)(15). Moreover, these individuals displayed varying degrees of gonadal dysfunction, with apparently normal ovarian function in a genotypically female patient (10).…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency

Reuter¹,

Goji²,

Bingham³

et al. 2007

eur j endocrinol

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Objective: Steroidogenic factor 1 (SF1), officially designated NR5A1, is a nuclear receptor that plays key roles in endocrine development and function. Previous reports of human SF1 mutations revealed a spectrum of phenotypes affecting adrenal function and/or gonadal development and sex differentiation. We present the clinical phenotype and functional effects of a novel SF1 mutation. Patient: The patient is a 22-year-old 46, XY Japanese patient who presented with dysgenetic testes, atrophic vasa deferentia and epididymides, lack of Mü llerian structures, and clitoromegaly. Endocrine studies revealed normal adrenal function. Results: Analysis of the SF1 gene revealed compound heterozygosity for a previously described p.G146A polymorphism and a novel missense mutation (p.R84C) in the accessory DNA-binding domain. The father carried the p.G146A polymorphism and the mother had the p.R84C mutation; both were clinically and reproductively normal. Functional studies demonstrated that the p.R84C SF1 had normal nuclear localization but decreased DNA-binding affinity and transcriptional activity compared with wild-type SF1; it did not exhibit any dominant negative activity. Conclusions: These results describe the human phenotype that results from compound heterozygosity of the p.G146A polymorphism and a novel p.R84C mutation of SF1, thereby extending the spectrum of human SF1 mutations that impair testis development and sex differentiation in a sex-limited manner while preserving normal adrenal function. 157 233-238 European Journal of Endocrinology

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Gonadal Dysgenesis Without Adrenal Insufficiency in a 46, XY Patient Heterozygous for the Nonsense C16X Mutation: A Case of SF1 Haploinsufficiency

Cited by 102 publications

References 0 publications

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency

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