Contexts of care for people with differences of sex development: Diversity is still missing in the laboratory routine.

The 2006 Chicago consensus statement of management of disorders/difference of sex development (DSD) has achieved advantages in clinical care and diagnosis for patients and families affect by DSD. This article provides a brief overview of contexts of care for physicians, and points out specific challenges in clinical practice that have arisen from the transformations of the sex/gender system in recent years. We focus on the impact of diagnosis and laboratory measurements. Both laboratory measurements and hormonal therapies still depend on the binary system. One problem is the lack of reference intervals for the different forms of DSD, which means that diversity is often neglected. In the following, we will give a brief insight into this complex topic.

Assessing the health-related management of people with differences of sex development.

PURPOSE: Health care requirements and perception of people with differences of sex development (DSD) have changed enormously since the "Chicago Consensus Conference" in 2005. Therefore, new standards of care and evaluation of care have to be developed. METHODS: We summarize the social and legal approach to care for DSD during the last two decades and report the main results of European research activities. RESULTS: The last two decades were accompanied by legal and societal discussion regarding how to deal with a nonbinary concept of sex. This leads to the necessity to assess health care requirements for individuals with DSD in an objective manner. We briefly review the results of the recently funded European research projects dealing with health-related issues in DSD like EU COST Action DSD, I-DSD, and dsd-LIFE, and address the compilation of quality indicators that will be needed to benchmark health care provision and health care-related outcomes. CONCLUSIONS: The benchmarking process has to be implemented among health care providers for individuals with DSD within the European Reference Networks for Rare Conditions.

Gonadectomy in Complete Androgen Insensitivity Syndrome: Why and When?

Prophylactic gonadectomy has been recommended in complete androgen insensitivity syndrome (CAIS) because of an increased risk for the development of malignant germ cell tumors in the intra-abdominal gonads. No reliable screening parameters are available to detect early (pre-)malignant changes. Because the tumor risk before puberty is very low, the timing of gonadectomy has been postponed to allow spontaneous puberty and involvement of the patients in important decisions affecting their body and health. Gonadectomy after puberty is still discussed controversially. There are difficulties in determining the absolute malignancy risk for individuals with CAIS, difficulties with hormone therapy, and lack of studies supporting different protocols. In contrast, endogenous hormone profiles show very specific features that influence bone health, psychosocial well-being, and many other aspects which still have to be investigated. For women with CAIS who wish to keep their gonads, we propose a biannual screening program which has to be evaluated in a prospective multi-center trial.

Pubertal Development in17Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency
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BACKGROUND: 17ß-hydroxysteroid dehydrogenase (17ß-HSD) type 3 deficiency is an autosomal recessive disorder with diminished testosterone synthesis and consequently underandrogenisation. 46,XY patients with 17ß-HSD type 3 deficiency are often assigned a female sex at birth but have a high virilisation potential at the time of puberty. METHODS: We studied four 46,XY patients with 17ß-HSD type 3 deficiency at puberty with regard to the underlying mutations, the hormone values, and the clinical findings. RESULTS: Three patients were initially assigned a female sex and 1 was assigned a male sex. All had relevant mutations in the HSD17B3 gene. The 2 patients with deleterious mutations had lower testosterone values at the time of puberty than the patients with possible residual activity of 17ß-HSD type 3. One of the latter patients changed to male gender. CONCLUSION: All 4 patients with 17ß-HSD type 3 deficiency synthesized relevant amounts (>0.7 µg/L) of testosterone at puberty, which lead to variable androgenisation. In patients with presumable residual activity of the mutated enzyme, testosterone values in the male reference range can be achieved, thereby inducing male pubertal development. These patients should possibly be assigned a male sex. Any surgical intervention should be avoided until the patients are old enough to consider their options of medical and surgical intervention.
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Novel Insights into 46,XY Disorders of Sex Development due to NR5A1 Gene Mutation.

The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD.

Management of disorders of sex development.

The medical term disorders of sex development (DSDs) is used to describe individuals with an atypical composition of chromosomal, gonadal and phenotypic sex, which leads to differences in the development of the urogenital tract and reproductive system. A variety of genetic factors have been identified that affect sex development during gonadal differentiation or in specific disorders associated with altered androgen biosynthesis or action. The diagnosis of DSDs in individuals and the subsequent management of patients and their families requires a targeted and structured approach, involving a multidisciplinary team with effective communication between the disciplines. This approach includes distinct clinical, imaging, laboratory and genetic evaluations of patients with DSDs. Although treatment of patients with DSDs can include endocrine and surgical options, many patients have concerns that arise from past incorrect treatments that were founded on the traditional binary concept of the sexes. To dispel these concerns, it is necessary to create centres of expertise for DSDs that include physicians, surgeons, psychologists and specialists in diagnostic procedures to manage patients and their families. Additionally, the inclusion of trained peer support in the multidisciplinary DSD team seems to be integral to the supportive management of patients with DSDs. Most importantly, dealing with DSDs requires acceptance of the fact that deviation from the traditional definitions of gender is not necessarily pathologic.