No Association between T222P/LGR8 Mutation and Cryptorchidism in the Moroccan Population

Houate, Brahim El; Rafiey, Hassan; Imken, Laila; Sibai, H.; Chafik, Abdelaziz; Boulouiz, Redouane; Chadli, Elbakkay; Hassar, M; McElreavey, Ken; Barakat, Abdelhamid

doi:10.1159/000151596

Cited by 23 publications

(17 citation statements)

References 25 publications

(26 reference statements)

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“…The chromosome complement was determined by examining 40–50 metaphases from each patient. The SRY, NR5A1, GATA4, FOG2, INSL3, LGR8 and MAP3K1 genes were sequenced as previously described [20–25] in all patients with DSD until the genetic diagnosis was determined (except in case 24, for which the brother, case 16, had been sequenced). In the patients with anorchia, the complete open reading frames of SRY, NR5A1, INSL3, MAMLD1 and the T222P variant for LGR8 were sequenced as previously described [20–25].…”

Section: Methodsmentioning

confidence: 99%

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

et al. 2016

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BackgroundFamilies with 46,XY Disorders of Sex Development (DSD) have been reported, but they are considered to be exceptionally rare, with the exception of the familial forms of disorders affecting androgen synthesis or action. The families of some patients with anorchia may include individuals with 46,XY gonadal dysgenesis. We therefore analysed a large series of patients with 46,XY DSD or anorchia for the occurrence in their family of one of these phenotypes and/or ovarian insufficiency and/or infertility and/or cryptorchidism.MethodsA retrospective study chart review was performed for 114 patients with 46,XY DSD and 26 patients with 46,XY bilateral anorchia examined at a single institution over a 33 year period.ResultsOf the 140 patients, 25 probands with DSD belonged to 21 families and 7 with anorchia belonged to 7 families. Familial forms represent 22% (25/114) of the 46,XY DSD and 27% (7/26) of the anorchia cases. No case had disorders affecting androgen synthesis or action or 5 α-reductase deficiency. The presenting symptom was genital ambiguity (n = 12), hypospadias (n = 11) or discordance between 46,XY karyotyping performed in utero to exclude trisomy and female external genitalia (n = 2) or anorchia (n = 7). Other familial affected individuals presented with DSD and/or premature menopause (4 families) or male infertility (4 families) and/or cryptorchidism. In four families mutations were identified in the genes SRY, NR5A1, GATA4 and FOG2/ZFPM2. Surgery discovered dysgerminoma or gonadoblastoma in two cases with gonadal dysgenesis.ConclusionsThis study reveals a surprisingly high frequency of familial forms of 46,XY DSD and anorchia when premature menopause or male factor infertility are included. It also demonstrates the variability of the expression of the phenotype within the families. It highlights the need to the physician to take a full family history including fertility status. This could be important to identify familial cases, understand modes of transmission of the phenotype and eventually understand the genetic factors that are involved.

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Section: Methodsmentioning

confidence: 99%

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

et al. 2016

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“…The distribution of this variant shows marked geographic differences, and it is mainly present in the Mediterranean area due to a "founder effect". [37][38][39][40] Given that this variant has been reported also in controls with normal testis descent (1-2%), it cannot be considered a clear-cut cause of cryptorchidism and should not be included in the list of causative genetic alterations of this disease. In Italy it seems to confer a mild risk to cryptorchidism but its diagnostic role is greatly limited by the fact that 1.7% of controls are carrier of this variant.…”

Section: Varicocelementioning

confidence: 99%

Male infertility: Pathogenesis and clinical diagnosis

Krausz¹

2011

Best Practice & Research Clinical Endocrinology & Metab

413

315

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“…, 2003). However, a very recent Moroccan study has found this mutation also in non‐cryptorchid controls, suggesting that the phenotype is dependent on the genetic and/or environmental background (El Houate et al. , 2008).…”

Section: Pathophysiological Conditions With Abnormal Insl3 Levelsmentioning

confidence: 99%

Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders

Bay

Andersson

2010

International Journal of Andrology

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Knockout of the gene encoding insulin-like factor 3 (INSL3) results in cryptorchidism in mice due to disruption of the transabdominal phase of testicular descent. This finding was essential for understanding the complete course of testis descensus, and wound up years of speculations regarding the endocrine regulation of this process. INSL3 is, along with testosterone, a major secretory product of testicular Leydig cells. In addition to its crucial function in testicular descent, INSL3 is suggested to play a paracrine role in germ cell survival and an endocrine role in bone metabolism. INSL3 is produced in human prenatal and neonatal, and in adult Leydig cells to various extents, and is in a developmental context regulated like testosterone, with production during second trimester, an early postnatal peak and increasing secretion during puberty, resulting in high adult serum levels. INSL3 production is entirely dependent on the state of Leydig cell differentiation, and is stimulated by the long-term trophic effects mediated by luteinizing hormone (LH). Once differentiated, Leydig cells apparently express INSL3 in a constitutive manner, and the hormone is thereby insensitive to the acute, steroidogenic effects of LH, which for example is an important factor in the regulation of testosterone. Clinically, serum INSL3 levels can turn out to be a usable tool to monitor basal Leydig cell function in patients with various disorders affecting Leydig cell function. According to animal studies, foetal INSL3 production is, directly or indirectly, sensitive to oestrogenic or anti-androgenic compounds. This provides important insight into the mechanism by which maternal exposure to endocrine disrupters can result in cryptorchidism in the next generation. Conclusively, INSL3 is an interesting testicular hormone with potential clinical value as a marker for Leydig cell function. It should be considered on a par with testosterone in the evaluation of testicular function and the consequences of Leydig cell dysfunction.

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No Association between T222P/LGR8 Mutation and Cryptorchidism in the Moroccan Population

Cited by 23 publications

References 25 publications

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

Familial forms of disorders of sex development may be common if infertility is considered a comorbidity

Male infertility: Pathogenesis and clinical diagnosis

Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders

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