Mutational Analysis of Compound Heterozygous Mutation P.q6x/p.h232r in Srd5a2 Causing 46,xy Disorder of Sex Development

Background: Over 100 mutations in the SRD5A2 gene have been identified in subjects with 46,XY disorder of sex development (DSD). Exploration of SRD5A2 mutations and elucidation of the molecular mechanisms behind their effects should reveal the functions of the domains of the 5α-reductase 2 enzyme and identify the cause of 46,XY DSD. Previously, we reported a novel compound heterozygous p.Q6X/p.H232R mutation of the SRD5A2 gene in a case with 46,XY DSD. Whether the compound heterozygous p.Q6X/p.H232R mutation in this gene causes 46,XY DSD requires further exploration. Results: To clarify the cause of 46,XY DSD in the affected family focused on here, SRD5A2 sequencing was performed. Heterozygous p.H232R mutation was identified in the proband’s father, so we concluded that this mutation originated from the paternal side of the family and did not cause 46,XY DSD. Meanwhile, heterozygous p.Q6X mutation was identified in the proband’s mother, maternal uncle, and maternal grandfather, indicating that this mutation originated from maternal side of the family and did not cause 46,XY DSD. To clarify the effect of the p.H232R mutation in SRD5A2 on dihydrotestosterone (DHT) production, p.H232R mutant SRD5A2 plasmids were transfected into HEK293 cells. LC-MS indicated that DHT production decreased compared with that in cells transfected with wild-type SRD5A2.Conclusions: Our findings confirmed that the compound heterozygous p.Q6X/p.H232R mutation in the SRD5A2 gene is the cause of 46,XY DSD. p.H232R mutation reduced DHT production while attenuating the catalytic efficiency of the 5α-reductase 2 enzyme.

Disorder of Sex Development, Mosaic Genetic Disorder 45x, 46xy: A Case Report

Background. Disorder of sex development (DSD) is a congenital disorder associated with interference in chromosomes, gonads, or sexes anatomically. Individual affected with DSD can be recognized since birth due to external genital ambiguity. Sexual chromosome DSD occurred because sexual chromosome numeric or structural disorder. Mosaic karyotype 45X/46XY is among the rare sexual chromosome DSD with incidence less than 1:15,000 live births. DSD individuals are susceptible to stigmatization. This can cause stress, negative emotion, and social isolation. Therefore, DSD individual management should be done as optimal as possible. Case Presentation: Twelve years old girl complaining a bump arose from anterior side of her genital resembles male genital since 4 years prior to admission without micturition and defecation complains. Patient has not experienced menarche. On external genital examination, we found the normal female external genital such as mons pubis, pubic hair, labia majora, labia minora, hymen, perineum, but without clitoris which in this case it is replaced by a glans of penis, arising from anterior commissure of labia majora area, with an urethral estuary. Before the management is done, patient underwent multidiscipline consultations and further examinations. Subsequently, it was approved that the joint conference formation consisting obstetric and gynecology, urologist, and pediatric endocrinologist to determine the optimal management for the patient. Conclusion: In this case, diagnosis was made with history taking, clinical examination, and supporting investigation such as ultrasound imaging and could be followed by biochemistry test, voiding cystourethrography or genitogram to determine next management. Counseling should be done in detail towards the family to know what action is best for the patient. Multidiscipline team was required to get the optimum result either in medical, ethical, or religious point of view. Surgery in this case was considered followed by long term therapy afterwards.

Up-to-Date Clinical and Biochemical Workup of the Child and the Adolescent with a Suspected Disorder of Sex Development

Background: The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes. Summary: In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation. Key Message: We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels – especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins – and karyotyping.

Psychological Problem in Pediatric Disorder of Sex Development Patient and Relatives

Disorder of sexual development (DSD) is one of challenging disorder that has tobe done clinically and physiologically. The patients and relatives may experiencevarious psychosocial problems that have an impact on their live. The aim of thisstudy is to look at psychological problem in children with DSD and their relatives.A systematic search was conducted in PubMed for articles representinginformation on psychological problem to the patient and their relatives. Relevantdata were extracted and narratively reviewed. The result of this review can beused as basic data in the development of counselling program for the patientsand their relatives.

Tinjauan Deskriptif: Karakteristik Faktor-Faktor Health Seeking Behavior pada Pasien Disorder of Sex Development

Angka kejadian DSD 1:4, 500-5.500. Walalupun angka kejadian DSD masih rendah namun menurut penelitian banyak pasien terdiagnosis DSD ketika umur >2 tahun bahkan ada yang terdiagnosis ketika dewasa. Terdapat pasien yang mengalami late diagnose disebabkan oleh kurangnya Health Seeking Behavior. Penelitian ini bertujuan untuk mengidentifikasi faktor internal dan eksternal Health Seeking Behavior pasien DSD di RSUP Dr. Mohammad Hoesin Palembang pada tahun 2013-2017. Penelitian ini merupakan penelitian deskriptif dengan pendekatan cross sectional menggunakan data primer dan sekunder. Sampel diambil dengan menggunakan metode total sampling dari seluruh data rekam medik yang memenuhi kriterian inklusi. Dari 120 data pasien yang diperoleh, didapatkan 61 sampel pasien DSD di RSUP Dr. Mohammad Hoesin Palembang pada tahun 2013-2017. Pasien terdiagnosis paling banyak saat umur >6 - ≥12 tahun sebanyak 22 pasien (36,1%). Pasien dengan jenis kelamin laki-laki lebih banyak yaitu ditemukan 54 pasien (88,5%). Orang tua pasien yang mengantar anaknya paling banyak berumur 26-35 tahun untuk umur Ibu (52,5%) dan 36-45 tahun untuk umur Ayah (39,3%). Pendidikan terakhir orang tua pasien DSD merupakan tamat SMA (78,7%). Status ekonomi orang tua pasien DSD yang datang ke RSMH paling banyak ditemukan golongan kelas atas (50,8%) dan pasien terbanyak berasal dari Palembang (23%). Pasien DSD di RSUP Dr. Mohammad Hoesin Palembang masih banyak tergolong late diagnose ditinjau dari beberapa faktor Health Seeking Behavior.

Cytogenetic and molecular characterization of an SRY-negative 46, XX ovotesticular DSD

Introduction: Ovotesticular disorder of sex development is a rare condition by the concomitant presence of testicular and ovarian tissue, and usually presents genital ambiguity. Are chromosomally heterogeneous, and cytogenetic analyses is relevant. Objective: report on a patient from Manaus, Amazonas state with ovotesticular disorder of sex differentiation 46, XX and SRY-negative. Case report: Patient of 19 years, first child of non-consanguineous parents. At birth, the patient was diagnosed with genital ambiguity and, without early diagnosis, he was registered as being of the male sex. The patient underwent surgery to correct bilateral cryptorchidism, orchiopexy and colpectomy. During puberty, he developed female and male sexual characteristics. Endocrinological (normal total testosterone and estradiol as high follicle-stimulating hormone and luteinizing hormone), histopathological (right gonad, ovarian follicles and left gonads, atrophic testicles), karyotype (46, XX) and molecular (SRY-negative). Diagnosis of ovotesticular disorder of sex development was established. The patient chose to remain male and underwent bilateral mastectomy, vaginal colpectomy and bilateral gonadectomy. Currently, the patient receives hormonal replacement therapy, follow-up with a multi-professional approach and awaits masculinizing genitoplasty. Discussion: In diagnostic research, cytogenetic and molecular analysis are primary tools. For OT-DSD individuals with 46, XX, the female sex is suggested as the best sex option. Unlike the reported cases, the patient chose the male sex, since the sex at registration of birth was important in his choice. Conclusion: Cytogenetic and molecular analyses allowed us to assist in the etiological diagnosis of the patient with OT-DSD from Manaus. However, molecular analyses are necessary to elucidate the genes involved in the sexual determination of this patient.

46, XY DSD (Disorder of Sex Development) : Diagnosis dan Tatalaksananya.

Disorder of Sex Development (DSD) is a congenital disorder that occurs in the development of chromosomes, gonads, and internal or external genital organ. DSD of 46 XY is a condition where the children with XY genotype is not able to have complete virilization of external genital. Determination phase is an initial phase of reproductive system development. Disruption of this phase may potentially lead to DSD. Optimal care for children with Disorder of Sex Development requires a multidisciplinary team starting since neonatal period. Family and pregnancy history, complete physical examination and assessment of genital organ are the first step of ensuring the diagnose. Management of children with DSD are focusing on gender determination, hormone support therapy and surgical management. On the other hand, Children with XY genotype should be raised as a boy however if there is no responsive evidence in administration of androgen the children should be raised as a girl. Subsequent to prescribe the gender of the children, surgical management is a required treatment for removing unnecessary genital afterward. Keywords: Disorders of Sex Development, DSD, 46 XY DSD