Sex Reversal Syndrome (SRS): A case of SRY-Positive 46,XX Testicular Disorder / Journal of the ASEAN Federation of Endocrine Societies

@#We report a case of an SRY-positive 46,XX Indian male who presented with small testis and phallus, poor beard and mustache development and gynecomastia at the age of 24 years. He was biochemically found to have hypergonadotropic hypogonadism. He had 46,XX karyotype and Quantitative Fluorescence-PCR (QF-PCR) identified the SRY gene on the X chromosome. SRY-positive 46 XX male SRS cases usually present as phenotypically male since birth but develop features of hypogonadism, poor testicular development, and infertility after puberty. Infertility, hypogonadism, external genital development, and psychological distress are the major concerns during the management of the patients. Testosterone therapy for hypogonadism, artificial reproductive technologies for fertility, surgical repair of hypospadias/cryptorchidism/under-virilized genitalia and psychological and genetic counseling are helpful for proper management of the patients.

Clinical and molecular genetic characterizations of 7 children with X-linked adrenal hypoplasia congenita / 中华实用儿科临床杂志

Objective To analyze the clinical and molecular genetic characterizations of X-linked adrenal dysplasia congenita(AHC) onset in infant.Methods Seven children (from 7 families) with X-linked AHC who were admitted to the Department of Endocrinology,Genetics and Metabolism,Children's Hospital Affiliated to Zhengzhou University,from July 2012 to June 2017 were selected.All patients were screened for dosage-sensitive-sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene1 (DAX1/NR0B1) mutations.The clinical manifestation and laboratory examination were analyzed,their clinical characterizations were summarized.Results Seven patients were all male,the onset age of the patients were from after birth to 7 months old,and 4 patients (4 families) had a family history of X-linked recessive inheritance.The clinical manifestations were skin pigmentation [100.0％ (7/7 cases)],vomiting [71.4％ (5/7 cases)],no weight gain [57.1％ (4/7 cases)] and poor spirit [28.6％ (2/7 cases)].Laboratory tests showed that hyperkalemia and hyponatremia,increased coricotrophin,normal or decreased cortisol,17α-hydroxyprogesterone,progesterone,aldosterone and dehydroepiandrosterone.Testosterone levels increased in 5 patients.The abnormalities of adrenal glands imaging could be seen in 2 patients.Two patients were misdiagnosed as congenital adrenal cortical hyperplasia.Then the definitive diagnosis were made by genetic test.DAX1/ NR0B1 gene mutations were found in all patients.Five patients were novel mutations (c.114_126del,c.872G ＞ A,c.56delG,c.884T ＞ G,c.1217delG).Conclusions The clinical manifestations of X-linked AHC with infant onset include pigmentation,poor spirit and growth retardation,which should be differentiated from congenital adrenal cortical hyperplasia.Hormone levels such as elevated blood 17α-hydroxyprogesterone and family history are the main identification points,and AHC cannot be excluded when testosterone level increases.Five novel mutations are found in this study,which enrich the gene database.

Masculinization of South American catfish (Rhamdia quelen) through dietary administration of 17α-methyltestosterone / Masculinización del pez Liso (Rhamdia quelen) mediante suministro dietario de 17α-metiltestosterona / Masculinização do Jundiá (Rhamdia quelen) através da administração dietética de 17α-metiltestosterona

Abstract Background: Production of monosex cultures of females is desirable in commercial aquaculture of certain species due to their higher growth rate. Ideally, females should be free of exogenous hormones. The initial step to produce hormone-free all-female offspring is masculinization of normal females to create sex reversed animals, called neomales, which are then be bred with normal females obtaining all-female offspring. Objective: To masculinize Rhamdia quelen fry by adding 17α-methyltestosterone (MT) hormone to the feed. Methods: Larvae of R. quelen were fed diets supplemented with 60, 80, or 100 mg MT/kg feed for 21 days. A control group was fed the same diet free of MT. At 150 days post-hatching, 30 fish of each treatment group were euthanized to evaluate gonadal changes using histological techniques. Results: MT significantly affected the differentiation of female gonads in the 60 and 80 mg MT/kg feed groups. Sex reversal was observed in all MT treatment groups, with 50, 40, and 20% neomales produced with 60, 80, and 100 mg MT/kg feed, respectively. Intersex gonads were observed only in the masculinization treatment groups. Inhibitory effects on gonadal development of females and males were observed at the highest MT doses. Conclusion: Dietary administration of MT effectively masculinizes R. quelen fry; however, the lowest dose of 60 mg/kg feed is recommended, since higher doses have inhibitory effects on gonadal development in both sexes.

Resumen Antecedentes: Debido a su mayor tasa de crecimiento, la producción de peces femeninos monosexo es deseable en acuicultura comercial de determinadas especies. Idealmente, las hembras deben estar libres de hormonas exógenas. El paso inicial para generar descendencia femenina libre de hormonas es la masculinización de hembras genéticas para producir animales sexualmente revertidos, llamados neomachos, los cuales se aparean luego con hembras genéticas para producir descendencia femenina. Objetivo: Masculinizar larvas de Rhamdia quelen con 17α-metiltestosterona (MT) incorporada en el alimento. Métodos: Larvas de R. quelen fueron alimentadas con dietas suplementadas con 60, 80 y 100 mg de MT/kg de alimento durante 21 días. Un grupo control recibió la misma dieta, sin MT. A los 150 días pos-eclosión, 30 peces de cada tratamiento fueron eutanasiados para evaluación gonadal mediante técnicas histológicas. Resultados: La MT afectó significativamente la diferenciación de las gónadas femeninas en las dosis de 60 y 80 mg MT/kg de alimento. El cambio de sexo se observó en los tratamientos con las dosis de 60, 80 y 100 mg MT/kg alimento, con 50, 40 y 20% de neomachos, respectivamente. En los tratamientos de masculinización se observaron gónadas intersexuales. En las dosis más altas de MT se observó inhibición del desarrollo gonadal de hembras y machos. Conclusiones: El suministro dietario de MT masculinizó las larvas de R. quelen. Se recomienda usar 60 mg/kg, ya que dosis mayores tienen efectos inhibidores en el desarrollo gonadal para ambos sexos.

Resumo Antecedentes: O cultivo monossexo feminino é desejável na aquicultura comercial de determinadas espécies devido à maior taxa de crescimento. Idealmente, as fêmeas devem ser livres de hormônios exógenos. O passo inicial para gerar descendências femininas livres destes hormônios é a masculinização de fêmeas normais para produzir animais revertidos sexualmente, os chamados neomachos. Os neomachos podem então ser cruzados com fêmeas normais para a produção de descendências femininas. Objetivo: Masculinizar larvas de R. quelen utilizando o hormônio 17α-metiltestosterona (MT) incorporado no alimento. Métodos: Larvas de R. quelen foram alimentadas com dietas suplementadas com MT nas doses de 60, 80 ou 100 mg/kg de alimento durante 21 dias. Um grupo controle foi alimentado com dieta similar livre de MT. Aos 150 dias pós-eclosão, 30 peixes de cada grupo de tratamento foram eutanasiados para avaliação gonadal através de técnicas histológicas. Resultados: O uso de MT afetou significativamente a diferenciação das gônadas femininas nas doses 60 e 80 mg/kg de alimento. A reversão sexual foi observada em todos os grupos tratados com MT, gerando 50, 40 e 20% de neomachos nas doses 60, 80 e 100 mg MT/kg de alimento, respectivamente. Gônadas intersexuais foram observadas somente nos tratamentos masculinizantes. Nas maiores doses de MT, efeitos inibitórios de desenvolvimento gonadal foram observados em fêmeas e machos. Conclusão: A administração dietética de MT efetivamente masculinizou larvas de R. quelen. No entanto, a dose mais baixa de 60 mg/kg de alimento é recomendada devido aos efeitos inibitórios das doses mais elevadas de MT no desenvolvimento gonadal de ambos os sexos.

Síndrome PAGOD y anomalías vasculares: ¿es un defecto de la angiogénesis embrionaria? Un nuevo caso y revisión / PAGOD syndrome and vascular anomalies: is a defect embryonic angiogenesis? A case report and review

El Síndrome PAGOD es un acrónimo de hipoplasia de pulmón y arterias pulmonares, agonadismo, onfalocele / defecto diafragmático y dextrocardia. Se describe una serie de 21 pacientes, en la cual, 90,5 % presentó un cariotipo 46,XY y solo dos casos 46,XX; el 66,6 % exhibió un fenotipo femenino y 28,6 % genitales ambiguos. La ocurrencia de dos paciente 46,XX excluye al cromosoma Y como portador del defecto genético y plantea la posibilidad de una herencia recesiva ligada al cromosoma X, sin descartar que los casos observados en hermanos puedan deberse a mutaciones en otros genes como STRA6, VEGFA, VEGFB, VEGFC, transcritos de empalmes alternativos de VEGFA, HIF1, HIF2, entre otros. Las malformaciones congénitas observadas en los pacientes fueron: genitales y gónadas 85,7 %, diafragma y pared 66,6 %, cardíaco 80,9 %, pulmonar 71,4 %, vascular 80,9 % y abdomen 42,8 %. La revisión de los pacientes ha demostrado un alto grado de variabilidad en la expresividad de malformaciones de órganos, aparatos o sistemas. Las malformaciones vasculares representan un componente importante y característico del síndrome PAGOD y cuya base morfogenética del síndrome pueda deberse a un defecto de la angiogénesis embrionaria temprana con repercusión en la organogénesis de aparatos y sistemas. Dentro de los genes relacionados con el remodelamiento vascular durante la embriogénesis, regeneración tisular y carcinogénesis está el Factor de Crecimiento del Endotelio Vascular D (VEGFD), localizado en Xp22.31, con expresión en pulmón, corazón, intestino delgado, pulmón fetal, útero, mamas, tejido neural y neuroblastoma, el cual representa un fuerte candidato para su análisis molecular como una de las posibles causa del síndrome.

PAGOD Syndrome is an acronym for lung and pulmonary arteries hypoplasia, agonadism, omphalocele / diaphragmatic defect and dextrocardia. A series of 21 patients is described, where 90.5% had a 46,XY karyotype and only two cases 46,XX; 66.6% exhibited a female phenotype and 28.6% ambiguous genitalia. The occurrence of two patients 46,XX excludes the Y chromosome as a carrier of the genetic defect and raises the possibility of a recessive X-linked inheritance, without ruling out that the observed cases in siblings may be due to mutations in other genes as Stra6, VEGFA, VEGFB, VEGFC, and alternative splicing of transcripts VEGFA, HIF1, HIF2, among others. Congenital malformations were observed in patients’ genitals and gonads 85.7%, 66.6% in diaphragm and abdominal wall , heart 80.9%, 71.4% lungs, blood vessels 80.9% and 42.8% in abdomen. The review of patients has demonstrated a high degree of variability in the expression of malformations of organs and organ systems. Vascular malformations represent an important and characteristic component of PAGOD syndrome and whose base morphogenetic syndrome may be due to a defect in early embryonic angiogenesis with impact on organogenesis and system development. Among genes related to vascular remodeling during embryogenesis, tissue regeneration and carcinogenesis, the Endothelial Growth Factor D Vascular (VEGFD), located in the Xp22.31 region, with expression in lung, heart, small intestine, uterus, breast, neuroblastoma and neural tissue, represents a strong candidate for molecular analysis as a cause of the syndrome.

Efficacy of Basella alba and Tribulus terrestris extracts for production of monosex Nile tilapia, Oreochromis niloticus.

The present study was aimed to evaluate the efficacy of Basella alba and Tribulus terrestris for induction of masculinisation in Nile tilpia. B. alba leaves and T. terrestris seeds were extracted with water, ethanol, methanol, dichloromethane, hexane and successive methanol and mixed sex juveniles of Nile tilapia were subjected to dietary treatment with the extracts at the concentration of 0.5, 1.0 and 1.5 gm/kg feed. Treatment with both the plants showed no adverse effect on general fish health. There was no significant interaction effects (P>0.05) of solvent and concentration, and solvent and plant material for percentage of males. But, significant interaction effect (P<0.05) of concentration and plant material was observed for percentage of males. Also, there was significant interaction effect (P<0.05) of solvent, concentration and plant material for percentage of males. For dietary administration of B. alba leaves, the highest percentage of males (83.2±0.7) was obtained by treatment with ethanol extract at the concentration of 1.0 gm/kg feed. For all the solvents, the highest percentage of males was observed at the concentration of 1.0 gm/kg. But, in treatment with T. terrestris seeds, the highest percentage of males (88.9±1.1) was obtained with ethanol extract at the concentration of 1.5 gm/kg feed, which was also the highest percentage of males for all the treatment categories.

Phenotypic Variability in Congenital Lipoid Adrenal Hyperplasia.

Background: Congenital lipoid adrenal hyperplasia presents with adrenal insufficiency and sex reversal in 46XY genetic males. Case characteristics: Two patients (46 XY karyotype), one having ambiguous genitalia and other having female external genitalia, presented with adrenal crisis at 6 months and 4 weeks of age, respectively. Observation: Steroidogenic Acute Regulatory Protein gene sequencing revealed homozygous mutations in both patients. Outcome: Treatment with hydrocortisone and fludrocortisone resulted in marked improvement . Message: Congenital lipoid adrenal hyperplasia should be considered in infants having female or ambiguous genitalia, and presenting with adrenal insufficiency.

Relationship of congenital urogenital abnormalities and chromosomal abnormalities: a report of 200cases / 中华全科医师杂志

A total of 200 outpatients with congenital urogenital abnormalities were recruited.Peripheral blood from each patient had mixed lymphocyte culture and chromosome karyotype was analyzed.Among them,22 (11％) cases showed abnormal chromosomal karyotypes.The aberrations included abnormal chromosome number (n =13),abnormal chromosome structure (n =8) and sex reversal syndrome (n =1).Chromosomal aberrations are important causative factors of congenital urogenital abnormalities.

Effects of methyltestosterone, tamoxifen, genistein and Basella alba extract on masculinization of guppy (Poecilia reticulata).

The effects of different anti-estrogenic chemicals were evaluated in guppy, Poecilia reticulata on sex differentiation and survival. New-born fry of the fish were fed diets containing genistein (1 gm kg-1), tamoxifen (100 mg kg-1), methanol extract of Basella alba (1 gm kg-1) and 17α-methyltestosterone (60 mg kg-1) for 30 days. The treated groups showed no significant difference (P>0.05) in survival percentage while a significant increase (P<0.05) in percentage of males were observed in all the treatment groups compared to that in control. Control fish showed the lowest percentage (44.49%) of males while 17α-methyltestosterone treatment provided maximum (81.90%) males, followed by tamoxifen (80.09%), genistein (70.59%) and B. alba (63.55%). Intersex fish with male like colouration and gonopodium development, but female gonad structure was observed in all the treated groups. The nonsteroidal compounds evaluated in this study showed potential for affecting sex ratios although their potency was lower compared to 17α-methyltestosterone. Further studies are needed to determine an optimum treatment regime with these agents for induction of 100% sex reversal in guppy.

The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

Male sex determination in humans is controlled by the SRY gene, which encodes a transcriptional regulator containing a conserved high mobility group box domain (HMG-box) required for DNA binding. Mutations in the SRY HMG-box affect protein function, causing sex reversal phenotypes. In the present study, we describe a 19-year-old female presenting 46,XY karyotype with hypogonadism and primary amenorrhea that led to the diagnosis of 46,XY complete gonadal dysgenesis. The novel p.E89K missense mutation in the SRY HMG-box was identified as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. According to the three-dimensional structure of the human SRY HMG-box, the substitution of the conserved glutamic acid residue by the basic lysine at position 89 introduces an extra positive charge adjacent to and between the positively charged residues R86 and K92, important for stabilizing the HMG-box helix 2 with DNA. Thus, we propose that an electrostatic repulsion caused by the proximity of these positive charges could destabilize the tip of helix 2, abrogating DNA interaction.

A novel mutation of SRY gene identified in a 46,XY complete gonadal dysgenesis patient / 中华内分泌代谢杂志

The clinical and genetic characteristics in a patient with 46,XY complete gonadal dysgenesis was investigated. Clinical features and laboratory data were collected from the patient and the family. The exon of SRY gene was amplified by PCR and sequenced. The patient presented with primary amenorrhea, nonambiguous female external genitalia, slight breast development, and no axillary hair or pubic hair. The female internal reproductive organs consisted of uterus and streaks of ovarian tissue. Howerver, the chromosome karyotype was 46,XY. A missense mutation of A66T in SRY gene was identified, which was not previously reported. The novel SRY mutation caused the sex reversal in this 46,XY female patient.

A Case of a 46,XX Male with SRY Gene

46,XX male is a rare sex constitution characterized by the development of bilateral testis in persons who lack a Y chromosome. Manifestations of 46,XX males are usually hypogonadism, gynecomastia, azoospermia, and hyalinations of seminiferous tubules. The incidence of XX male reversal is approximately 1 in 20,000 male neonates. The SRYgene is located at the short arm of the Y chromosome(Yp11.31) and codes for testis determining factor in humans. Here, the patient, who presented with a normal male phenotype, was referred for azoospermia. Conventional cytogenetic analysis showed a 46,XX karyotype. Quantitative fluorescent polymerase chain reaction(QF-PCR) and Multiplex PCR studies identified SRY gene. And, Fluorescence In Situ Hybridization(FISH) confirmed the SRY gene on the distal short arm of chromosome X. We identified the SRY gene on the distal short arm of chromosome X by molecular cytogenetic and molecular analyses. Therefore, molecular-cytogenetics and molecular studies were proved to be clinically useful adjunctive tool to conventional prenatal cytogenetic analysis.

46,XX male sex reversal syndrome:a case report / 中华泌尿外科杂志

Objective To investigate the manifestations and genetic mechanisms of male sex reversal syndrome. Methods A 22 year old male patient with 46,XX karyotype was systemically examined and a Y specific sequence tagged site (STS),sY14,was chosen to detect sex determining region of Y (SRY) gene by polymerase chain reaction (PCR). Results This patient shows primary and secondary male sex characters while gonads are hypoplastic and malfunctional.The patent has 46,XX karyotype and SRY gene.Therefore,the patient is diagnosed as 46,XX male sex reversal syndrome. Conclusions Translocation of SRY can bring about 46,XX male sex reversal syndrome,whereas gonads of the patients are hypoplastic and malfunctional because of the absence of other genes on Y chromosome.SRY gene plays an important role in sex determination.

46,XX male sex reversal syndrome and its treatment recommendation (report of 4 cases) / 中华泌尿外科杂志

Objective To analyze the clinical,endocrinal and genetic features of 46,XX male syndrome. Methods Retrospectively collect and analyze the clinical data of 4 cases of 46,XX male sex reversal syndrome. Results Four patients were all sociopsychologically males.Among them,2 cases had cryptorchidism,3 hypospadia and 1 severe chordee with short urethra.Neither ovary nor uterus was detected through B ultrasonography or surgical exploration.Assessment of serum sex hormone suggested hypergonadotropic hypogonadism.Genetic detection indicated 46,XX karyotype as normal female's type. Conclusions 46,XX male has nearly normal male phenotype otherwise with testes dysgenesis and most are infertile.The target of treatment is to correct the urinogenital malformation and to compensate hormone defect with androgen.