RESUMO
Swyer syndrome is a condition where individuals with a 46XY karyotype, typically associated with males, display complete gonadal dysgenesis and lack testicular differentiation. This results from a mutation in the SRY gene, which is essential for testis development. As a consequence, affected individuals who appear phenotypically female have male chromosomes but do not develop functional testes. As a result, there is an absence of testosterone that leads to lack of masculinization and the presence of female genitalia. This article describes a 20-year-old female from Pakistan who exhibited primary amenorrhea. On examination, she possessed a typical female physique but lacked breast growth and axillary hair. She had scant pubic hair with female-type external genitalia. The pelvic imaging showed a underdeveloped uterus, along with small ovaries and fallopian tubes. Her karyotype came out to be 46XY. The examination and radiological results indicated Swyer syndrome. During laparoscopy, the patient's uterus was found to be infantile, while the fallopian tubes were healthy. Streak gonads were also present, and due to the risk of gonadoblastoma, they were surgically removed. Hormone replacement therapy was started to induce pubertal development and optimize bone mineral accumulation.
Assuntos
Disgenesia Gonadal 46 XY , Neoplasias Ovarianas , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Amenorreia/genética , Amenorreia/complicações , Paquistão , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/diagnóstico , GenótipoRESUMO
Germ cell tumors (GCTs) are associated with pure gonadal dysgenesis or Swyer syndrome. Swyer syndrome usually presents with primary amenorrhea, streak ovaries, and mixed GCT. However, our patient presented with secondary amenorrhea, normal female external genitalia, and a mixed GCT. Constitutional karyotype was suggestive of 46,XY. Management comprised chemotherapy, followed by surgery. Histopathology was suggestive of dysgerminoma complicating a gonadoblastoma. The purpose of reporting this case is its rarity and the importance of diagnosing an XY karyotype, as the incidence of GCTs is higher in these patients.
Assuntos
Disgerminoma , Disgenesia Gonadal 46 XY , Gonadoblastoma , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Amenorreia/complicações , Disgerminoma/diagnóstico , Disgerminoma/terapia , Disgerminoma/patologia , Gonadoblastoma/complicações , Gonadoblastoma/diagnóstico , Gonadoblastoma/patologia , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/complicações , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Embrionárias de Células Germinativas/complicaçõesRESUMO
Complete gonadal dysgenesis with 46,XY karyotype is a clinical condition characterized by the absence of testicular tissue but with the presence of typical Müllerian structures in a phenotypically female individual. The condition presents as primary amenorrhoea or delayed puberty. Eventually, malignant neoplasms may arise. We report a case of a 16-year-old Indian male with Swyer syndrome presenting with primary amenorrhoea and with an earlier diagnosis of a malignant dysgerminoma in the right ovary.
Assuntos
Disgerminoma , Disgenesia Gonadal 46 XY , Neoplasias Ovarianas , Masculino , Feminino , Humanos , Adolescente , Disgerminoma/diagnóstico , Neoplasias Ovarianas/complicações , Amenorreia/diagnóstico , Disgenesia Gonadal 46 XY/complicaçõesRESUMO
BACKGROUND: Gonadal dysgenesis with minifascicular neuropathy (GDMN) is a rare autosomal recessive condition associated with biallelic DHH pathogenic variants. In 46, XY individuals, this disorder is characterized by an association of minifascicular neuropathy (MFN) and gonadal dysgenesis, while in 46, XX subjects only the neuropathic phenotype is present. Very few patients with GDMN have been reported so far. We describe four patients with MFN due to a novel DHH likely pathogenic homozygous variant and the results of nerve ultrasound assessment. METHODS: This retrospective observational study included 4 individuals from 2 unrelated Brazilian families evaluated for severe peripheral neuropathy. Genetic diagnosis was performed with a peripheral neuropathy next-generation sequencing (NGS) panel based on whole exome sequencing focused analysis that included a control SRY probe to confirm genetic sex. Clinical characterization, nerve conduction velocity studies, and high-resolution ultrasound nerve evaluation were performed in all subjects. RESULTS: Molecular analysis disclosed in all subjects the homozygous DHH variant p.(Leu335Pro). Patients had a striking phenotype, with marked trophic changes of extremities, sensory ataxia, and distal anesthesia due to a sensory-motor demyelinating polyneuropathy. One 46, XY phenotypically female individual had gonadal dysgenesis. High-resolution nerve ultrasound showed typical minifascicular formation and increased nerve area in at least one of the nerves assessed in all patients. CONCLUSION: Gonadal dysgenesis with minifascicular neuropathy is a severe autosomal recessive neuropathy characterized by trophic alterations in limbs, sensory ataxia, and distal anesthesia. Nerve ultrasound studies are very suggestive of this condition and may help to avoid invasive nerve biopsies.
Assuntos
Disgenesia Gonadal 46 XY , Disgenesia Gonadal , Doenças do Sistema Nervoso Periférico , Síndrome de Turner , Humanos , Feminino , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/complicações , Disgenesia Gonadal/complicações , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Síndrome de Turner/complicaçõesRESUMO
BACKGROUND AND AIM: Disorders of sexual differentiation (DSD) with karyotype 46,XY include gonadal developmental differences such as complete gonadal dysgenesis, partial gonadal dysgenesis, testicular regression and ovotesticular sexual differentiation disorder, differences in androgen synthesis or action, such as androgen synthesis deficiency, androgen action deficits, LH receptor deficiency, AMH synthesis or action deficits, and other conditions such as severe hypospadias, cloaca estrophy, etc. Methods: A 17 years-old girl came to our attention for hirsutism, clitoral hypertrophy, primary amenorrhea, and bilateral mammary hypoplasia. According to clinical features and anamnesis, the diagnosis of 46, XY DSD was made. For diagnostic purposes, she underwent an extensive genetic analysis, hormone dosage and instrumental examinations. After a clitoridoplasty and hormone replacement treatment, the patient performs appropriate multidisciplinary follow-up and regular psychotherapy. RESULTS: The clinical case reported falls, according to the recent classification developed by the Chicago Consensus, within the scope of DSD with karyotype 46, XY. About 160 cases of patients with 17ß-HSD3 deficiency, diagnosed at a mean age of 12 years, are described in the literature, most of them coming from Western Asia and Europe and only three cases from Eastern Asia. Clinically, about 30% of patients showed virilization, 20% clitoromegaly, ambiguous genitalia, inguinal/labial mass, 16% primary amenorrhea, and 5% absence of mammary development, features that are partly traced in the case described here. CONCLUSIONS: This case underscores the complexity of managing individuals with DSD. Having acquired the concept that irreversible surgery should be avoided, except in cases where failure to do so would determine health risks, the primary objective of the medical decision lies in meeting conditions aimed at harmonious sexual identification, especially regarding sexual activity and fertility, involving a team of experienced professionals (psychologists, pediatricians, surgeons, endocrinologists, radiologists), capable of promptly identifying suggestive clinical signs.
Assuntos
Transtornos do Desenvolvimento Sexual , Disgenesia Gonadal 46 XY , Disgenesia Gonadal , Adolescente , Amenorreia/complicações , Androgênios , Criança , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/genética , Feminino , Disgenesia Gonadal/complicações , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/diagnóstico , Humanos , Masculino , Comportamento SexualRESUMO
BACKGROUND: The aim of the present study is to report a rare occurrence of a successful twin pregnancy in a woman with pure 46,XY gonadal dysgenesis. RESULT(S): A patient with Swyer syndrome (pure 46,XY gonadal dysgenesis) presented with a twin pregnancy after in vitro fertilization. Due to unidentified conditions, the patient developed selective intrauterine growth restriction in one of the fetuses. Twins were born at 33 weeks of pregnancy due to the risk of asphyxia. Nonetheless, the patient did not develop gonadal malignancies before the pregnancy and, despite receiving estrogen, remained amenorrheic. CONCLUSION(S): The aim of this case report is to show the course of twin pregnancy in patients with Swyer syndrome through assisted reproduction. Due to certain disorders in the development of their reproductive organs, such as the less mature uterus, such pregnancies may be associated with an increased risk. The above case report demonstrates the need to systematize methods of pregnancy management in patients with Swyer syndrome, such as: preparation for the pregnancy, assessment of the uterus, medications used, and necessary checkups. Capsule: This case report and review shows clinicians that patients with Swyer syndrome may become pregnant. Twin pregnancies may occur without any major problems through assisted reproduction.
Assuntos
Disgenesia Gonadal 46 XY , Gravidez de Gêmeos , Feminino , Fertilização in vitro , Disgenesia Gonadal 46 XY/complicações , Humanos , Incidência , Gravidez , ÚteroRESUMO
Cryptorchidism, i.e., undescended testis, is one of the most common genital malformations in newborn male babies. The birth rate of cryptorchidism varies from 1.6 to 9.0 %. Etiology of disrupted testicular descent is complex and predisposing causes include genetic, hormonal, environmental, lifestyle and maternal factors. Testicular descent occurs in two major steps and testicular hormones and normal function of hypothalamic-pituitary-testicular axis are important for normal descent. Several gene mutations are associated with syndromic cryptorchidism but they are rarely found in boys with isolated undescended testis. Testicular regression can also cause an empty scrotum. Normal male genital phenotype indicates that the boy has had functioning testis during development. Torsion of the testis can cause testicular regression but in many cases the reason for vanishing testis remains elusive. In this narrative review we discuss genetics of cryptorchidism and testicular regression.
Assuntos
Criptorquidismo , Disgenesia Gonadal 46 XY , Criptorquidismo/genética , Feminino , Disgenesia Gonadal 46 XY/complicações , Humanos , Masculino , Mutação , Testículo/anormalidadesRESUMO
Abstract Swyer syndrome is one of the disorders of sexual differentiation. Previous studies have demonstrated increased sympathetic activity with heart rate variability (HRV) analysis with decreasing estradiol levels. One patient presented a pure 46, XY gonadal dysgenesis with female phenotype. Cardiac autonomic modulation was assessed through HRV analysis while at rest. This research analyzed linear and nonlinear indexes. HRV analysis showed reduced parasympathetic and global modulation with an apparent increase in sympathetic tone and a loss of HR fractal dynamics toward correlated behavior, characterized by low entropy and high determinism of time series.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Doenças Cardiovasculares/complicações , Disgenesia Gonadal 46 XY/complicações , Progestinas/uso terapêutico , Modelos Lineares , Dinâmica não Linear , Terapia de Reposição Hormonal , Estrogênios/uso terapêuticoRESUMO
BACKGROUND: 46XY pure gonadal dysgenesis (Swyer syndrome) is a rare disorder of sexual development. Patients have a 46XY karyotype, though phenotypically they appear female with normal external genitalia and vagina. Although patients exhibit normal Müllerian structures (uterus, fallopian tubes, and vagina), they possess a pair of bilateral undifferentiated gonad streaks. Delayed puberty and primary amenorrhea are the common presentations. There is an increased risk of developing tumors in the gonads and therefore a bilateral gonadectomy is recommended. CASE: A 16-year-old girl who presented with primary amenorrhea was diagnosed with Swyer syndrome. She underwent prophylactic bilateral gonadectomy and salpingectomies. She was discovered to have no gonadal malignancy, conversely dysgerminoma solely within the fallopian tube. SUMMARY AND CONCLUSION: Both bilateral salpingectomies and bilateral gonadectomies should be recommended as the operation of choice in patients with Swyer Syndrome.
Assuntos
Disgerminoma , Disgenesia Gonadal 46 XY , Gonadoblastoma , Neoplasias Ovarianas , Adolescente , Disgerminoma/cirurgia , Tubas Uterinas , Feminino , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/cirurgia , Humanos , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/cirurgiaRESUMO
A disorder of sex development (DSD) is defined as a congenital condition in which development of chromosomal, gonadal, or anatomical sex is atypical. Swyer syndrome is an example of 46,XY DSD with a female phenotype. It usually becomes apparent in adolescence with delayed puberty and amenorrhoea. Spontaneous breast development is very rare. A 15-year-old girl was presented due to primary amenorrhoea with breast development compatible with Tanner stage V. Hormonal tests revealed hypergonadotropic hypogonadism with low level of oestradiol. Pelvic ultrasound and magnetic resonance imaging revealed a small uterus, and no ovaries were found. In the right lower abdomen, a structure of unknown origin was visible. The chromosome analysis revealed a 46,XY karyotype. The patient was qualified for a laparoscopic bilateral gonadectomy. Postoperative histopathological examination revealed gonadoblastoma. We underline the need to consider DSD 46,XY in the presence of primary amenorrhoea, even when pubertal development is present. Germ cell tumors have a tendency to grow and metastasize rapidly. Delayed diagnosis may increase the risk of malignant transformation and cause a poor diagnosis.
Assuntos
Disgenesia Gonadal 46 XY , Gonadoblastoma , Neoplasias Ovarianas , Anormalidades Urogenitais , Adolescente , Amenorreia , Mama/crescimento & desenvolvimento , Feminino , Disgenesia Gonadal 46 XY/complicações , HumanosRESUMO
Complete gonadal dysgenesis (CGD) or Swyer syndrome is characterised by sexual infantilism in a phenotypic female with 46, XY karyotype. Patients with gonadal dysgenesis and Y-chromosome material are at a high risk of developing gonadoblastoma and dysgerminoma. A 16-year-old girl presented with progressive virilisation, poor breast development and primary amenorrhea. On evaluation, she was found to have male-range serum testosterone, large abdominopelvic mass lesion, elevated germ cell tumour markers and 46, XY karyotype. She underwent surgical excision of left gonadal mass and right streak gonad, histopathology of which revealed dysgerminoma and gonadoblastoma, respectively. A diagnosis of virilising germ cell tumour arising in the setting of 46, XY CGD was, therefore, made. This case highlights a rare presentation of 46, XY CGD and the need to consider early prophylactic gonadectomy in patients affected with this rare condition. The presence of dysgerminoma/gonadoblastoma should be suspected if a hitherto phenotypic female with CGD undergoes virilisation.
Assuntos
Disgerminoma/cirurgia , Disgenesia Gonadal 46 XY/cirurgia , Gonadoblastoma/cirurgia , Neoplasias Ovarianas/cirurgia , Adolescente , Disgerminoma/etiologia , Disgerminoma/patologia , Feminino , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/patologia , Gonadoblastoma/etiologia , Gonadoblastoma/patologia , Humanos , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/patologia , Doenças RarasRESUMO
BACKGROUND: Complete 46XY gonadal dysgenesis (Swyer syndrome) is a rare and challenging diagnosis among prepubertal girls, as estrogen insufficiency becomes evident only during adolescence, with nonspecific symptoms such as primary amenorrhea and/or delayed puberty. Unfortunately, girls with Swyer syndrome are at high risk for malignancies in the dysgenetic gonads, which can be prevented only by performing prophylactic bilateral gonadectomy. CASE: We present a 9-year-old patient with Swyer syndrome diagnosed with dysgerminoma in the right gonad and gonadoblastoma in the left gonad after prophylactic bilateral gonadectomy. SUMMARY AND CONCLUSION: Concerning the high risk of early gonadoblastoma and its malignant transformation, we recommend performing prophylactic bilateral gonadectomy at the time of diagnosis, even if the patient is prepubertal.
Assuntos
Disgerminoma/genética , Disgenesia Gonadal 46 XY/complicações , Gonadoblastoma/genética , Neoplasias Ovarianas/genética , Castração , Criança , Disgerminoma/patologia , Disgerminoma/prevenção & controle , Feminino , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/cirurgia , Gonadoblastoma/patologia , Gonadoblastoma/prevenção & controle , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/prevenção & controle , Procedimentos Cirúrgicos ProfiláticosRESUMO
Differences in Sex Development (DSD) encompasses many diagnoses, where the development of chromosomal make-up, gonadal development or anatomical development is atypical. XY, DSD is a classification under the recent international consensus statement, and XY females commonly encapsulate disorders of androgen synthesis and androgen action. Complete Androgen Insensitivity Syndrome (CAIS) is the most common XY, DSD diagnosis, which results in an individual having XY chromosomes, but the person is phenotypically female. This article explores the care and management of children and young people with a DSD and focuses on the diagnosis of CAIS in adolescence. Medical and surgical management is discussed, alongside sexual function, gender identity and the psychological impact of the diagnosis. The involvement of the multidisciplinary team is stressed, together with an emphasis on the investment that is needed in psychological and nursing support for girls with CAIS, and their families.
Assuntos
Síndrome de Resistência a Andrógenos/tratamento farmacológico , Disgenesia Gonadal 46 XY/tratamento farmacológico , Adolescente , Comportamento do Adolescente/psicologia , Síndrome de Resistência a Andrógenos/complicações , Feminino , Identidade de Gênero , Disgenesia Gonadal 46 XY/complicações , Humanos , Masculino , Pediatria/métodos , Desenvolvimento Sexual/efeitos dos fármacos , Desenvolvimento Sexual/fisiologiaRESUMO
BACKGROUND: Swyer syndrome is a rare type of disorder of sex development and typically presents with delayed puberty and primary amenorrhea. We describe an unusual presentation of this condition. CASE: A 17-year-old female patient with typical thelarche and adrenarche presented with primary amenorrhea. Pelvic ultrasound showed normally developed uterus and bilateral ovoid hypoechoic structures suggestive of gonads. Laboratory investigations revealed highly elevated gonadotrophins with estradiol level within a range typical for a female of reproductive age and chromosome analysis showed a 46,XY karyotype. Histopathological examination of the gonadectomy specimens revealed gonadoblastoma and dysgerminoma with no functional ovarian or testicular tissue. SUMMARY AND CONCLUSION: This report reminds us the possibility of diagnosis of Swyer syndrome in the presence of normal pubertal development and normal sex steroid levels considered to be produced by gonadoblastoma.
Assuntos
Amenorreia/diagnóstico , Disgerminoma/diagnóstico , Disgenesia Gonadal 46 XY/patologia , Gonadoblastoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adolescente , Amenorreia/congênito , Amenorreia/patologia , Diagnóstico Diferencial , Disgerminoma/congênito , Disgerminoma/patologia , Feminino , Disgenesia Gonadal 46 XY/complicações , Disgenesia Gonadal 46 XY/diagnóstico , Gonadoblastoma/congênito , Gonadoblastoma/patologia , Humanos , Neoplasias Ovarianas/congênito , Neoplasias Ovarianas/patologiaRESUMO
BACKGROUND: Disorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation. CASE: We present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor. SUMMARY AND CONCLUSION: To our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications.
Assuntos
Disgerminoma/patologia , Tumor do Seio Endodérmico/patologia , Disgenesia Gonadal 46 XY/complicações , Gonadoblastoma/patologia , Neoplasias Ovarianas/patologia , Adolescente , Amenorreia/genética , Disgerminoma/genética , Tumor do Seio Endodérmico/genética , Feminino , Gonadoblastoma/genética , Humanos , Neoplasias Ovarianas/genéticaRESUMO
BACKGROUND: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. PATIENTS AND METHODS: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. RESULTS: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. CONCLUSION: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.
Assuntos
Disgenesia Gonadal 46 XY/genética , Proteínas Hedgehog/genética , Polineuropatias/genética , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Feminino , Disgenesia Gonadal 46 XY/complicações , Humanos , Pessoa de Meia-IdadeAssuntos
Disgenesia Gonadal 46 XY/complicações , Pré-Eclâmpsia/etiologia , Gravidez de Gêmeos , Adulto , Feminino , Humanos , GravidezRESUMO
Patients with Swyer syndrome, which is also known as 46,XY pure gonadal dysgenesis, are at an increased risk of gonadoblastoma and germ cell tumor. Prophylactic gonadectomy is recommended for these patients. We report a case of stage IIA dysgerminoma arising in a streak gonad in a patient with Swyer syndrome, which was not diagnosable preoperatively and intraoperatively. The patient was primarily amenorrheic and identified as female phenotypically. She underwent gonadectomy at 27 years of age. Preoperative image analysis showed a relatively small uterus without adnexal masses. Laparoscopic findings showed bilateral streak gonads. Postoperatively, histopathological examination revealed that the patient had dysgerminoma in her left streak gonad. Preoperative and intraoperative diagnosis of dysgerminoma in normal size ovaries is thought to be difficult. Although it is rare, considering the occurrence of dysgerminoma in streak gonad with extension to the mesosalpinx, prompt prophylactic gonadectomy is strongly recommended for these patients regardless of the size of the ovaries.
Assuntos
Disgerminoma/diagnóstico por imagem , Disgenesia Gonadal 46 XY/complicações , Neoplasias Ovarianas/diagnóstico por imagem , Adulto , Disgerminoma/complicações , Disgerminoma/cirurgia , Feminino , Disgenesia Gonadal 46 XY/diagnóstico por imagem , Humanos , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia. OBJECTIVE: This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition. METHODS: We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal "ambiguous genitalia" or "indeterminate sex." RESULTS: Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions. DISCUSSION: Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial. CONCLUSION: Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques.
Assuntos
Hiperplasia Suprarrenal Congênita/complicações , Tomada de Decisão Clínica , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/epidemiologia , Disgenesia Gonadal 46 XY/complicações , Centros Médicos Acadêmicos , Hiperplasia Suprarrenal Congênita/diagnóstico , Estudos de Coortes , Bases de Dados Factuais , Transtornos do Desenvolvimento Sexual/etiologia , Feminino , Seguimentos , Disgenesia Gonadal 46 XY/diagnóstico , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Medição de Risco , Desenvolvimento Sexual/fisiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co-existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify ß-catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated ß-catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of ß-catenin through the FLNB-MAP3K1-RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain-of-function mutations in MAP3K1.