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

Abstract

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.

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development

“…Our study and others (Camats et al, 2012;Swartz et al 2017) have suggested that neither the mutation in NR5A1 nor its reduction in SF1 activity is a good indicator of a patient's phenotype or clinical outcome. Inherited mutations in DSD tend to be rare as fertility is often affected; however, familial cases of NR5A1 including those shown here are shifting this paradigm (Brauner et al, 2016).…”

“…) have suggested that neither the mutation in NR5A1 nor its reduction in SF1 activity is a good indicator of a patient's phenotype or clinical outcome. Inherited mutations in DSD tend to be rare as fertility is often affected; however, familial cases of NR5A1 including those shown here are shifting this paradigm (Brauner et al., ). Our studies suggest that oligogenecity may be a contributing factor in the variable expressivity and incomplete penetrance is often observed with NR5A1 variants in DSD patients.…”

Baseline Characteristics of Infants With Atypical Genital Development: Phenotypes, Diagnoses, and Sex of Rearing

“…Our study identified a family history of DSD in 15% of the 92 subjects and a family history of hypospadias in 10% of those with 46,XY DSD, consistent with the limited available data. Brauner et al [11] reported that 22% of those with 46,XY DSDs had a family history of DSD. However, it is important to note they had included infertility as positive family history for a DSD [11].…”

“…Brauner et al [11] reported that 22% of those with 46,XY DSDs had a family history of DSD. However, it is important to note they had included infertility as positive family history for a DSD [11]. Also, they had included all those with DSDs but not specifically ambiguous genitalia.…”

Papel do gene DHX37 na etiologia dos distúrbios do desenvolvimento sexual 46,XY associados a anormalidades do desenvolvimento gonadal

“…Famílias portadoras de anormalidades do desenvolvimento testicular são raras, e constituem modelos de estudos fundamentais para a compreensão do modo de transmissão dessas doenças bem como na identificação de novos fatores genéticos envolvidos na sua etiologia (64).…”