Genetic Analysis for the Diagnosis of Disorders of Sexual Development in Indonesia

Disorders of sex development (DSD) is defined by congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical, while in clinical practice this term means any abnormality of the external genitalia. DSD patients have been managed by a multidisciplinary gender team in our center as collaboration between Dr. Kariadi province referral hospital and Faculty of Medicine Diponegoro University. Diagnosis should be established by specific physical examination hormonal, chromosomal and DNA studies; and imaging for most of the cases depending on indication.Since 2004 the involvement of molecular and cytogenetic analysis so far can diagnosed many of the DSD cases. Most of the genetically proven cases were Congenital Adrenal hyperplasia, Androgen Insensitivity syndrome and sex chromosomal DSD that lead abnormal gonadal development. Many of them remain undiagnosed, further testing such as advanced DNA study should be carried out in collaboration with other center in overseas.The novel genes were found in some cases that contributed for the management of DSD. Information for medical professionals, patients, family members and community about the availability and necessity of DSD diagnosis should be delivered to improve DSD management and patient quality of life.

Download Full-text

Differences in sex development

10.1093/med/9780199682874.003.0114 ◽

2021 ◽

pp. 1313-1320

Author(s):

Dan Wood

Keyword(s):

Sexual Development ◽

Functional Outcomes ◽

External Genitalia ◽

Disorders Of Sexual Development ◽

Diagnosis And Management ◽

Sex Development ◽

Complex Group

Disorders of sexual development are a complex group of conditions with anomalies of the internal and external genitalia due to abnormal chromosomal and hormonal influences during development. Diagnosis and management, including timing of intervention, and both long-term cosmetic and functional outcomes are discussed in this chapter.

Download Full-text

The Investigation of Quality of Life in 87 Chinese Patients with Disorders of Sex Development

BioMed Research International ◽

10.1155/2015/342420 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Chunqing Wang ◽

Qinjie Tian

Keyword(s):

Quality Of Life ◽

Social Relationship ◽

Disorders Of Sex Development ◽

Androgen Insensitivity Syndrome ◽

Chinese Patients ◽

Sexual Life ◽

Process Of Care ◽

Sex Development ◽

The Difference

Objective. In the process of care for disorders of sex development (DSD), clinical decisions should focus on the long-term quality of life (QOL). We sought to investigate the QOL of patients with DSD in China.Design. Case-control study was carried out.Patients.90 patients of DSD participated in the study. Finally, 87 patients were analyzed including Turner’s syndrome (23), Noonan syndrome (2), androgen insensitivity syndrome (22), testicular regression syndrome (2), congenital adrenal hyperplasia (16), and pure gonadal dysgenesis (22).Measurements. The WHOQOL-BREF questionnaire was chosen for the present investigation. Four domain scores were analyzed independently including physical, psychological, and social relationship and environmental domains.Results. The average age of the DSD group is 22.34 ± 4.97 years, and only 13.79% patients ever had sexual life. The scores of psychological and environmental domains were lower than that of the physical and social relationship domains, but the difference was not significant (P>0.05). Compared with the Chinese urban population, the QOL scores of DSD patients in China were not significantly lower.Conclusions. With proper treatment, including the follow-up and psychological support, the QOL of DSD patients cannot be significantly reduced. For DSD patients, more attention should be paid to the potential psychological and sexual problems.

Download Full-text

Disorders of Sex Development of Adrenal Origin

Frontiers in Endocrinology ◽

10.3389/fendo.2021.770782 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gabriela P. Finkielstain ◽

Ana Vieites ◽

Ignacio Bergadá ◽

Rodolfo A. Rey

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Special Focus ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Trophic Effect ◽

Salt Wasting ◽

Sex Development ◽

21 Hydroxylase Deficiency

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

Download Full-text

Disorders of sex development: a study of 194 cases

Endocrine Connections ◽

10.1530/ec-18-0022 ◽

2018 ◽

Vol 7 (2) ◽

pp. 364-371 ◽

Cited By ~ 9

Author(s):

R Walia ◽

M Singla ◽

K Vaiphei ◽

S Kumar ◽

A Bhansali

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Sex Chromosome ◽

Tertiary Care ◽

Disorders Of Sex Development ◽

Androgen Insensitivity Syndrome ◽

North India ◽

Care Hospital ◽

Adrenal Hyperplasia ◽

Androgen Insensitivity ◽

Sex Development

Objective To study the clinical proﬁle and the management of patients with disorders of sex development (DSD). Design and setting Retrospective study from a tertiary care hospital of North India. Methods and patients One hundred ninety-four patients of DSD registered in the Endocrine clinic of Postgraduate Institute of Medical Education and Research, Chandigarh between 1995 and 2014 were included. Results One hundred and two patients (52.5%) had 46,XY DSD and seventy-four patients (38.1%) had 46,XX DSD. Sex chromosome DSD was identified in seven (3.6%) patients. Of 102 patients with 46,XY DSD, 32 (31.4%) had androgen insensitivity syndrome and 26 (25.5%) had androgen biosynthetic defect. Of the 74 patients with 46,XX DSD, 52 (70.27%) had congenital adrenal hyperplasia (CAH) and eight (10.8%) had ovotesticular DSD. Five patients with sex chromosome DSD had mixed gonadal dysgenesis. Excluding CAH, majority of the patients (90%) presented in the post-pubertal period. One-fourth of the patients with simple virilising CAH were reared as males because of strong male gender identity and behaviour and firm insistence by the parents. Corrective surgeries were performed in twenty patients (20%) of 46,XY DSD without hormonal evaluation prior to the presentation. Conclusion Congenital adrenal hyperplasia is the most common DSD in the present series. Most common XY DSD is androgen insensitivity syndrome, while CAH is the most common XX DSD. Delayed diagnosis is a common feature, and corrective surgeries are performed without seeking a definite diagnosis.

Download Full-text

Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00144 ◽

2019 ◽

Vol 104 (12) ◽

pp. 6385-6390 ◽

Cited By ~ 3

Author(s):

Rafael Loch Batista ◽

Katsumi Yamaguchi ◽

Andresa di Santi Rodrigues ◽

Mirian Yumie Nishi ◽

John L Goodier ◽

...

Keyword(s):

Disorders Of Sex Development ◽

External Genitalia ◽

Androgen Insensitivity Syndrome ◽

Gonadal Hormones ◽

Mobile Dna ◽

Laboratory Findings ◽

Cultured Fibroblasts ◽

Androgen Insensitivity ◽

Sex Development ◽

Partial Androgen Insensitivity Syndrome

Abstract Context Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition usually caused by pathogenic allelic variants in the androgen receptor (AR) gene. The phenotype depends on the AR variant, ranging from severe undervirilization (complete AIS) to several degrees of external genitalia undervirilization. Although 90% of those with complete AIS will have AR mutations, this will only be true for 40% of those with partial AIS (PAIS). Objective To identify the genetic etiology of AIS in a large multigenerational family with the PAIS phenotype. Participants Nine affected individuals with clinical and laboratory findings consistent with PAIS and a normal exonic AR sequencing Settings Endocrine clinic and genetic institute from two academic referral centers Design Analysis of whole exons of the AR gene, including splicing regions, was performed, followed by sequencing of the 5′untranslated region (UTR) of the AR gene. Detailed phenotyping was performed at the initial diagnosis and long-term follow-up, and circulating levels of steroid gonadal hormones were measured in all affected individuals. AR expression was measured using RT-PCR and cultured fibroblasts. Results All 46,XY family members with PAIS had inherited, in hemizygosity, a complex defect (∼1100 bp) in the 5′UTR region of the AR surrounded by a duplicated 18-bp sequence (target site duplication). This sequence is 99.7% similar to an active, long, interspersed element present on the X chromosome (AC002980; Xq22.2), which was inserted in the 5′UTR of the AR gene, severely reducing AR expression and leading to PAIS. Conclusion The molecular diagnosis of PAIS remains challenging. The genomic effect of retrotransposon mobilization should be considered a possible molecular cause of AIS and other AR diseases.

Download Full-text

SRY and NR5A1 gene mutation in Algerian children and adolescents with DSD and testicular dysgenesis

African Health Sciences ◽

10.4314/ahs.v21i3.61 ◽

2021 ◽

Vol 21 (3) ◽

pp. 1491-1497

Author(s):

Naouel Kherouatou-Chaoui ◽

Djalila Chellat-Rezgoune ◽

Mohamed Larbi Rezgoune ◽

Ken Mc Elreavey ◽

Laaldja Souhem Touabti ◽

...

Keyword(s):

Mutational Analysis ◽

Direct Sequencing ◽

Point Mutations ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Gonadal Development ◽

Genetic Alterations ◽

Peripheral Blood Lymphocytes ◽

Blood Leukocytes ◽

Sex Development

Background: In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and internal genitalia. Variants in transcription factors such as SRY, NR5A1 and SOX9, can cause changes in gonadal development often associated with ambiguity of the external genitalia. Objectives: This study has been conducted to determine the frequency, types and associated genetic alterations in patients with DSD in the Algerian population. Methods: Thirty patients were included. Based on their clinical presentation, thirteen patients presented with ambiguous external genitalia, thirteen patients presented with hypospadias and four patients presented with bilateral undescended tes- tes. Karyotype analysis was performed on peripheral blood lymphocytes using standard R-banding. DNA was isolated from blood leukocytes for PCR reaction and mutational analysis of SRY and NR5A1 was done by direct sequencing. Results: Most patients with ambiguous genitalia had a 46,XY karyotype. One patient had a deletion of SRY, otherwise no point mutations in SRY or NR5A1 genes were identified. However, a single NR5A1 polymorphism (p.Gly146Ala) in patient with 46,XX DSD has been detected. Conclusions: The absence of mutations in these genes suggests that there are others genes playing an important role in sex development and differentiation. Keywords: DSD; consanguinity; karyotyping; SRY; NR5A1; sequencing.

Download Full-text

Síndrome da Insensibilidade Androgênica: perfil clínico e epidemiológico de uma série de casos

Revista de Ciências Médicas e Biológicas ◽

10.9771/cmbio.v11i2.6672 ◽

2012 ◽

Vol 11 (2) ◽

pp. 129

Author(s):

Bianca Costa Mota ◽

Caio Rapôso Leão ◽

Luciana Mattos Barros Oliveira ◽

Maria Betânia Toralles

Keyword(s):

Sexual Development ◽

Average Length ◽

Positive Family History ◽

External Genitalia ◽

Ambiguous Genitalia ◽

Androgen Insensitivity Syndrome ◽

Font Size ◽

Disorders Of Sexual Development ◽

Common Location ◽

Epidemiological Profile

Introdução: Os Distúrbios do Desenvolvimento Sexual (DDS) resultam de uma interação anormal de fatores genéticos e hormonais implicados no desenvolvimento embrionário da determinação e diferenciação sexual. Os indivíduos com cariótipo 46, XY que apresentaram virilização deficiente da genitália externa são classificados como tendo um quadro sindrômico de Distúrbio do Desenvolvimento Sexual (46, XY DDS), incluindo entre esses a Síndrome da Insensibilidade Androgênica (AIS). Vários genes já foram reconhecidos por sua participação na formação das gônadas e genitálias (interna e externa) entre eles o gene do Receptor de Andrógenos (AR). Objetivo: Analisar os aspectos sócio-epidemiológicos e clínicos de indivíduos com diagnóstico sindrômico de 46, XY Distúrbio do Desenvolvimento Sexual (46,XY DDS) matriculados no Ambulatório de Genética (C-HUPES-UFBA). Metodologia: 13 pacientes com 46, XY DDS e suspeita diagnóstica de AIS, foram selecionados para se traçar o perfil clínico e epidemiológico. Resultados: Entre os pacientes estudados, 07 foram diagnosticados como PAIS e 06 como CAIS, tendo como o sexo de criação, respectivamente, o masculino e o feminino; a média de idade na primeira consulta foi de 06 anos. Cerca de 38% apresentavam história familiar positiva. O motivo de encaminhamento mais frequente foi hipospádia e genitália ambígua. A média do comprimento do falus foi de 2,77 cm. A localização mais comum das gônadas foi na bolsa escrotal. Apenas dois pacientes apresentaram mais de um orifício perineal. Dois pacientes fizeram tratamento medicamentoso e dez foram submetidos à cirurgia corretiva da genitália. Conclusão: Na população estudada o diagnóstico foi mais tardio, isso requer ações sócio-educativas nessa região para incentivar o rápido encaminhamento dos pacientes para diagnóstico e tratamento precoce. Abstract Introduction: Disorders of Sexual Development (DSD) result from an abnormal interaction of genetic and hormonal factors involved in determining embryonic development and sexual differentiation. Individuals with 46, XY karyotype who presented deficient virilization of the external genitalia are classified as having a syndrome of Sexual Development Disorder (46, XY DSD), including those between Androgen Insensitivity Syndrome (AIS). Several genes have been recognized for their participation in the formation of gonads and genitalia (internal and external) including the gene Androgen Receptor (AR). Objective: The aim of this study is to analyze the socio-epidemiological and clinical syndromic diagnosis of individuals with 46, XY disorders of sexual development (46, XY DSD) enrolled in the Genetics Clinic (C-HUPES-UFBA). Methods: we selected 13 patients with clinical diagnosis of AIS and traced the clinical and epidemiological profile. Results: Among the patients studied, 07 were diagnosed as CAIS and 06 as PAIS, and with the sex of rearing, respectively, the male and female and the average age at diagnosis was 06 years. About 38% had a positive family history. The most common reason for referral was hypospadias and ambiguous genitalia. The average length of falus was 2.77 cm. The most common location was the gonads in the scrotum. Only two patients had more than one hole perineal. Two patients received drug treatment and ten underwent corrective surgery of the genitalia. Conclusion: In this study population were diagnosed later, this requires social and educational actions in the region to encourage the rapid referral of patients for early diagnosis and treatment.

Download Full-text

Chromosomal Disorders of Sex Development

10.1093/med/9780199329007.003.0023 ◽

2018 ◽

Author(s):

R. J McKinlay Gardner ◽

David J Amor

Keyword(s):

Sexual Development ◽

De Novo ◽

Chromosome Abnormality ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Sequential Process ◽

Chromosomal Disorders ◽

Sex Development ◽

Development Proceeds

Chromosomal sex is, for the most part, congruently XX female and XY male. The XX and XY embryo are built on a fundamentally similar outline plan, and only as development proceeds do certain modifications evolve. If at any point in this sequential process some genetic instruction is faulty, inappropriate, or cannot be acted on, the direction of anatomical sexual development may proceed imperfectly or completely incongruently. This chapter reviews the conditions of ambiguous/incomplete/indeterminate development of the internal and external genitalia, where the basis of this is a chromosome abnormality, usually of the X or the Y chromosome. The key role of the SRY male-determining gene in a number of these conditions is noted. The de novo or familial origin of these disorders is discussed, with particular reference to possible risks of recurrence.

Download Full-text

Rare cases of disorders of sex development (DSD) in adolescents with female phenotype

International Journal of Adolescent Medicine and Health ◽

10.1515/ijamh.2012.027 ◽

2012 ◽

Vol 24 (2) ◽

Cited By ~ 2

Author(s):

Jenara Kristesashvili ◽

Mariam Chipashvili ◽

Teimuraz Jorbenadze ◽

Donald E. Greydanus

Keyword(s):

Turner Syndrome ◽

Physiological Stress ◽

Disorders Of Sex Development ◽

Androgen Insensitivity Syndrome ◽

Point Of View ◽

Androgen Insensitivity ◽

Female Phenotype ◽

Sex Development

Abstract Background: Disorders of sex development (DSD) belong to uncommon pathologies; in addition, there are especially rare forms, such are ovotesticular disorders (OT), Turner syndrome and early malignisation of intraabdominal located gonads in the cases of androgen insensitivity syndrome. Objective: In this article we present four rare cases of DSD in female phenotype adolescents: two cases of ovotesticular DSD with 46,XX and 46,XY karyotypes; one familial case of androgen insensitivity syndrome (AIS) with early malignancy (19-year-old) of intra-abdominally-located testicle in older siblings, and a case of spontaneous menstruation in a patient with Turner syndrome and mosaic karyotype 45,X/47,XXX. Rare cases of DSD are connected with diagnostic and management difficulties and so description of each such case and collection of data in this field is very important from a scientific, as well as a practical, point of view. Determination of prognosis and adequate management of each individual patient are also essential. Study of this issue is especially sensitive in the case of adolescent patients in order to avoid physiological stress, to reduce health risks and to improve quality of life.

Download Full-text