46,XY disorders of sex development (DSD).
ABSTRACT The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. Mutations in genes present in X, Y or autosomal chromosomes can cause abnormalities of testis determination or disorders of sex differentiation leading to 46,XY DSD. Detailed clinical phenotypes allow the identification of new factors that can alter the expression or function of mutated proteins helping to understand new undisclosed biochemical pathways. In this review we present an update on 46,XY DSD aetiology, diagnosis and treatment based on extensive review of the literature and our three decades of experience with these patients.
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ABSTRACT: The phytoestrogen (plant estrogen) genistein, present in soy products, is of interest because in utero exposure to genistein can cause hypospadias in our mouse model and maternal consumption of soy is prevalent in human populations. Another compound of interest is the fungicide vinclozolin, which also causes hypospadias in the mouse and rat and can occur concurrently with genistein in the diet as a residue on exposed foods. A study in the United Kingdom found no relationship between a maternal organic vegetarian diet and hypospadias frequency, but women who consumed nonorganic vegetarian diets had a greater percentage of sons with hypospadias. Because nonorganic diets can include residues of pesticides such as vinclozolin, we sought to assess the interaction of realistic daily exposures to genistein and vinclozolin and their effects on the incidence of hypospadias. Pregnant mice were fed a soy-free diet and orally gavaged from gestational days 13 to 17 with 0.17 mg/kg/day of genistein, 10 mg/kg/day of vinclozolin, or genistein and vinclozolin together at the same doses, all in 100 microL of corn oil. The controls received the corn oil vehicle. The male fetuses were examined at gestational day 19 for hypospadias, both macroscopically and histologically. We identified no hypospadias in the corn oil group. The incidence of hypospadias was 25% with genistein alone, 42% with vinclozolin alone, and 41% with genistein and vinclozolin together. These findings support the idea that exposure to these compounds during gestation could contribute to the development of hypospadias.Urology 10/2007; 70(3):618-21. · 2.42 Impact Factor
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ABSTRACT: The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch--Sry in the case of mammals--is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.PLoS Biology 07/2006; 4(6):e187. · 12.69 Impact Factor
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ABSTRACT: A collaborative study, supported by the Biomed2 Programme of the European Community, was initiated to optimise the aetiological diagnosis in genetic or gonadal males with intersex disorders, a total of 67 patients with external sexual ambiguity, testicular tissue and/or a XY karyotype. In patients with gonadal dysgenesis or true hermaphroditism, the incidence of vaginal development was 100%, a uterus was present in 60%; uni or bilateral cryptorchidism was seen in nearly all cases of testicular dysgenesis (99%) but in only 57% of true hermaphrodites. Mean serum levels of anti-mullerian hormone and of serum testosterone response to chorionic gonadotropin stimulation were significantly decreased in both conditions, by comparison with patients with unexplained male pseudohermaphroditism or partial androgen insensitivity (PAIS). Mutations in the androgen receptor, 90% within exons 2-8, were detected in patients with PAIS. Clinically, a vaginal pouch was present in 90%, cryptorchidism in 36%. In 52% of cases, no diagnosis could be reached, despite an exhaustive clinical and laboratory work-up, including routine sequencing of exons 2-8 of the androgen receptor. By comparison with PAIS, unexplained male pseudohermaphroditism was characterised by a lower incidence of vaginal pouch (55%) and cryptorchidism (22%) but a high incidence of prematurity/intrauterine growth retardation (30%) or mild malformations (14%). Conclusion: reaching an aetiological diagnosis in cases of male intersex is difficult because of the variability of individual cases. Hormonal tests may help to discriminate between partial androgen insensitivity and gonadal dysgenesis/true hermaphroditism but are of less use for differentiating from unexplained male pseudohermaphroditism. Sequencing of exons 2-8 of the androgen receptor after study of testosterone precursors following human chorionic gonadotrophin stimulation is recommended when gonadal dysgenesis and true hermaphroditism can be excluded.European Journal of Pediatrics 02/2002; 161(1):49-59. · 1.91 Impact Factor
This is an Accepted Work that has been peer-reviewed and approved for publication in the
Clinical Endocrinology, but has yet to undergo copy-editing and proof correction.
See http://www.blackwell-synergy.com/loi/cen for details.
Please cite this article as a “Postprint”; doi: 10.1111/j.1365-2265.2008.03392.x
46,XY disorders of sex development
Berenice Bilharinho Mendonca1, MD; Sorahia Domenice1, MD; Ivo J P Arnhold1,
MD; Elaine M F Costa1, MD.
1Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e
Genetica Molecular, LIM 42, Hospital da Clinicas da Faculdade de Medicina da
Universidade de Sao Paulo, São Paulo, Brazil
Berenice B Mendonca, M. D.
Hospital das Clínicas, FMUSP, Divisão de Endocrinologia
Caixa Postal 3671, São Paulo, 01060-970, Brasil.
E-mail: firstname.lastname@example.org; email@example.com; firstname.lastname@example.org;
The term disorders of sex development (DSD) includes congenital conditions in
which development of chromosomal, gonadal or anatomical sex is atypical.
Mutations in genes present in X, Y or autosomal chromosomes can cause
abnormalities of testis determination or disorders of sex differentiation leading to
46,XY DSD. Detailed clinical phenotypes allow the identification of new factors that
can alter the expression or function of mutated proteins helping to understand new
undisclosed biochemical pathways. In this review we present an update on 46,XY
DSD aetiology, diagnosis and treatment based on extensive review of the literature
and our three decades of experience with these patients.
Male phenotypic development can be viewed as a 2-step process: 1) testis
formation from the primitive gonad (sex determination) and 2) internal and external
genitalia differentiation due to factors secreted by the testis (sex differentiation).
The first step is very complex and involves interplay of several transcription
factors.1,2,3 (Fig 1). The second step, male sex differentiation, is a more
straightforward process (Fig 2).
The term disorders of sex development (DSD) includes congenital conditions
in which development of chromosomal, gonadal or anatomical sex is atypical. The
terms “male pseudohermaphroditism”, “intersex”, “sex reversal”, that previously
described the disorders of sex development, were potentially derogatory to the
patients and the consensus on the management of intersex disorders
recommended a new nomenclature that will be followed in this review.4, 5
The 46,XY disorders of sex development (46,XY DSD) are characterized by
ambiguous or female external genitalia, caused by incomplete intrauterine
masculinisation, and the presence or absence of Mullerian structures. Complete
absence of virilization results in normal female external genitalia and these patients
generally seek medical attention at pubertal age, due to the absence of breast
development and/or primary amenorrhoea. A classification of 46,XY DSD based on
the disorder’s aetiology is proposed in Table 1.
46,XY DSD DUE TO ABNORMALITIES OF GONADAL DEVELOPMENT
Total absence of gonadal tissue or gonadal streak has rarely been described in
46,XY subjects with female external and internal genitalia indicating the absence of
testicular determination. The origin of this disorder remains to be determined. A
defect in genes essential for bipotential gonad development is likely the cause of
46,XY DSD DUE TO GONADAL DYSGENESIS
Complete and partial 46,XY gonadal dysgenesis
46,XY gonadal dysgenesis consist of a variety of clinical conditions in which the
fetal gonad development is abnormal and encompasses both complete and a
partial forms. The complete form is characterized by female external and internal
genitalia, lack of secondary sexual characteristics, normal or tall stature without
somatic stigmata of Turner syndrome and the presence of bilateral dysgenetic
gonads. The partial form of this syndrome is characterized by impaired testicular
development that results in patients with ambiguous external genitalia with or
without Mullerian structures. Similar phenotypes can also result from a 45,X/46,XY
46,XY gonadal dysgenesis is a heterogeneous disorder that results from
SRY deletions or point mutations, dosage sensitive sex (DSS) locus duplication on
X chromosome or mutations in autosomal genes. Mutations in SRY were found in
less than 20% of the patients with complete 46,XY gonadal dysgenesis. To date,
more than 53 mutations have been identified within the SRY, and most of them (43
mutations), are located in the HMG box. Most of the mutations described in SRY
are predominantly de novo mutations. However, some cases of fertile fathers and
their XY affected children, sharing the same altered SRY sequence, have been
reported.6, 7 In few of these cases, the father’s somatic mosaicism for the normal
and mutant SRY have been demonstrated.
A recent study describes a remarkable family pedigree across four
generations with multiple affected family members, of both sexes, with variable
degrees of gonadal dysgenesis. The phenotypic mode of inheritance was strongly
suggestive of X-linkage.8 In this report, a fertile woman had a 46,XY karyotype in
peripheral lymphocytes, mosaicism in cultured skin fibroblasts (80% 46,XY and
20% 45,X) and a predominantly 46,XY karyotype in the ovary (93% 46,XY and 6%
45,X). She gave birth to a 46,XY daughter with complete gonadal dysgenesis. The
range of phenotypes observed in this unique family suggests a new mechanism
which predisposes to chromosomal mosaicism.8
Embryonic testicular regression syndrome (ETRS)
ETRS has been considered part of the clinical spectrum of partial 46,XY gonadal
dysgenesis. Most of the patients present ambiguous genitalia or severe micropenis
associated with complete regression of testicular tissue in one or both sides. The
dysgenetic testes showed disorganized seminiferous tubules and ovarian stroma
with occasional primitive sex cords devoid of germ cells; primordial follicles are
sometimes observed in the streak gonad in the first years of life9. Familial cases
have been reported with variable degrees of sexual ambiguity, but the nature of the
underlying defect is still unknown. Recently, a novel heterozygous missense
mutation (V355M) in SF1 gene was found in one boy with a micropenis and
testicular regression syndrome.10