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Pubertal abnormalitiesPrecocious and delayed
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Girls who do not have Turner syndrome but have deletions in a portion of the Xq region only may also have premature ovarian insufficiency.18 Girls with XY gonadal dysgenesis (previously called Swyer syndrome) or mixed gonadal dysgenesis (45X/46XY) will present with ovarian insufficiency but also have risk for dysgerminoma or gonadoblastoma (see Chapter 7). Another group of girls with ovarian insufficiency can be 16% of those with fragile X heterozygote permutation carrier status, particularly if the affected X was of paternal origin. Galactosemia may lead to ovarian failure in 70%–80% of affected girls. Other rare forms of hypergonadotropic hypogonadism, including mutations in the FSH-β subunit or FSH receptor, or type 1 blepharophimosis-ptosis-epicanthus inversus syndrome due to an autosomal mutation in chromosome 3, can also occur.
Sex Chromosome Anomalies
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
L. Hamerton John, A. Evans Jane
46,XY females with gonadal dysgenesis also have a significantly increased risk of developing tumors in the streak gonads, particularly gonadoblastomas, dysgerminomas, and juvenile granulosa cell tumors. Hamerton (38) reviewed the clinical findings in 20 patients with 46,XY gonadal dysgenesis and reported eight to have some form of gonadal malignancy, most frequently a gonadoblastoma. More recently, Radakovic (181) performed bilateral gonadectomies on 20 patients with 46,XY gonadal dysgenesis, and found 11 with gonadoblastomas or other streak gonad tumors. Based on the high frequency of gonadoblastomas in 46,XY females, the presence of a gonadoblastoma susceptibility gene (GBY) on the Y chromosome has been postulated (182,183). Molecular analysis of the Y chromosome in patients with XY gonadal dysgenesis and gonadal tumors found various deletions, missense mutations, or nucleotide substitutions in SRY in four of six patients (184,185). However, as deletions or mutations of SRY are known to be one of the etiological factors in XY gonadal dysgenesis, it is probable that the association between SRY and a high frequency of gonadoblastoma and other germ cell tumors is indirect. A more promising candidate for GBY may lie in a 4 Mb region in the proximal part of Yq that Salo et al. (186) identified as a region of overlap in two patients with gonadoblastoma who were carrying small marker chromosomes. While the precise molecular basis for their increased risk of gonadal tumors remains unknown, patients with XY gonadal dysgenesis obviously require detailed counseling and should be offered preventative gonadectomy.
Normal and abnormal development of the genitalia
Published in David M. Luesley, Mark D. Kilby, Obstetrics & Gynaecology, 2016
Rebecca Deans, Sarah M Creighton
Other forms of XY gonadal dysgenesis that can lead to DSD conditions are less well understood. Partial gonadal dysgenesis with some testicular function, and mixed gonadal dysgenesis (a unilateral testis and a contralateral streak gonad) are conditions that usually present with variable degrees of genital masculinisation or ambiguity. Regression of each Müllerian duct depends on the local concentration of AMH produced by the fetal gonad on each side, and unilateral uterine development can occur if one gonad is more dysgenetic and hence produces less AMH than the contralateral gonad (see Chapter 69, Karyotypic abnormalities).
Twin gestation in a Swyer syndrome patient with superimposed pre-eclampsia
Published in Journal of Obstetrics and Gynaecology, 2018
Jaimin S. Shah, Oscar A. Viteri, Monica Longo, Mazen Abdallah, Baha Sibai
Forty six XY, gonadal dysgenesis, was first described by Gim Swyer in 1955, when he reported a patient with a female phenotype, primary amenorrhoea and sexual infantilism. This rare syndrome, with an incidence of 1 in 80,000 individuals, can be expressed in a complete or incomplete fashion (Kalra et al. 2016). The majority of patients have a mutation in the sex determining region of the Y chromosome (SRY) or a defect in another testis determining factor, such as the steroidogenic factor-1 gene (Creatsas et al. 2011).
Unexpected diagnosis of stage IIA dysgerminoma in streak gonad in a patient with Swyer syndrome: a case report
Published in Gynecological Endocrinology, 2018
Namiko Yada-Hashimoto, Hiroko Komura, Shigenori Nagata, Chiaki Kubo, Masami Fujita, Shoji Kamiura
These patients often have streak gonads and present with primary amenorrhea. Patients with XY gonadal dysgenesis are at an increased risk of gonadoblastoma. Though gonadoblastomas are benign tumors of the ovary, its association with dysgerminoma is observed in 50% of cases [2]. The prevalence of gonadoblastoma and germ cell tumor in patients with Y chromosome material is estimated to be higher than 30% [3,4]. Prophylactic gonadectomy is recommended for these patients, typically at adolescence [2,5].
Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective
Published in Systems Biology in Reproductive Medicine, 2019
MR Nagaraja, Satya Prakash Gubbala, C. R. Wilma Delphine Silvia, Ramars Amanchy
46,XY DSD are clinically typified by ambiguous or female external genitalia, caused by incomplete intrauterine masculinization and the presence or absence of mullerian structures (Mendonca 2009). Hence, these were categorized as defects of testis determination, defects in androgen synthesis or its action and other causes that include maternal exposure of endocrine disruptors (e.g., vinclozolin) (Vilela et al. 2007), syndromic associations of male genital development, defects in antimullerian hormone (AMH)/mullerian inhibiting substance (MIS) synthesis or its AMH receptor (AMHR), isolated hypospadias (chromosome X open reading frame 6 gene (CXORF6) mutation (Ogata et al. 2009). Gonadal dysgenesis (GD) is characterized by incomplete or defective formation of the gonads due to either structural or numerical anomalies of sex chromosome or mutations in the genes involved in the gonadal development (McCann-Crosby et al. 2014). 46,XY gonadal dysgenesis can be evaluated by presence of streak gonads and estimating the levels of circulating AMH and sex steroids which aid to score the severity (complete/partial). Mutations in sex-determining region Y gene (SRY) (<20% of cases) and NR5A1 (also known as SF1) accounted for complete and partial 46,XY gonadal dysgenesis, respectively. In addition, mutations in genes involved in gonadal determination, e.g., underexpression of Wilms tumor 1 gene (WT1), NR5A1, SRY-box 9 gene (SOX9), double sex and mab-3-related transcription factor 1 gene (DMRT1), DMRT2; overexpression of DAX1, Wnt family member 4 gene (WNT4) cause 46,XY gonadal dysgenesis associated syndromic phenotype. Defects in dihydrotestosterone (DHT) synthesis or androgen action on the target tissues share common dysmorphic features. The former is referred as steroid 5α-reductase type 2 (5α-RD2) deficiency and the latter as partial AIS (PAIS). Estimation of serum testosterone (T) to androstenedione (Δ4) (T/Δ4 < 0.8) facilitates biochemical diagnosis of a rare disorder of 17β-hydroxysteroid dehydrogenase 3 deficiency; similarly, serum T/DHT ratio (>30) for 5α-RD2 deficiency. Hormonal analysis may help to make an accurate diagnosis in proband(s) with classical disorders but may have a low conclusive value in the patients at their early stage of development or if there is partial defect. The mist of these differentials could be cleared by mutational analysis of candidate gene(s) and thus would aid in treatment modality of the disorder.