Disorders of sex development – biologic, genetic, cultural, societal, and psychologic diversity of the human nature

Several years ago, we commented on ongoing research, debates and controversies addressing disorders of sex development (DSD) [1]. Variants of sexual development pose indeed a challenge for individuals and their families who seek help and assistance and for physicians who attempt to provide advice, medical services and support. Both at an individual and at societal level there is still controversy and-sadly so-uncertainty as what might be the correct and ethically approved way of care for individuals with DSD. Some of the people affected will in adulthood not agree with and not adjust to the gender identity that had been assigned to them at young age: adults who feel that they may have been treated wrongly as children, have advocated strongly to have an individual right to be informed at all ages and then be able to make their informed decision themselves. Legislation in most countries has followed this wish and put forward a clear notion of this. Early surgical procedures on minors with DSD have thus been banned in many countries and for example in the European Union entirely.

Again, we would like to emphasize that history is also a history of medicine and medicine does have history. In other words, what might have been viewed as being correct medical practice decades ago is now sometimes being viewed as harmful, obsolete, or even neglectful and malpractice. This does not mean that physicians treating patients in a certain way many years ago did this purposefully to cause harm to their patients. In addition, and importantly, medicine does not live a life outside society. In other words, what might be considered correct, ethical, and right in one society and in one culture might be viewed wrong in another culture and under other circumstances. It is our duty to discuss medical practice openly and install transparency, listen to everyone and especially to the ones affected. By doing this we shall find the better ways to cope with nature’s challenges and our own failures and fallacies.

In this issue of the Journal of Pediatric Endocrinology and Metabolism, again manuscripts are being published that deal with wider issues of DSD. It once more becomes clear that variants of sexual development trigger emotions, and relate to psychological, biological, genetic, and medical issues. They always have to be viewed with their societal, historical and cultural context. Problems arising from dealing and coping with DSD can only be solved by leading transparent and honest discussions and seeking consent between individuals. Discussions must be based upon respect for one another and each individual. There are now guidelines and consensus statements involving patient advocacy that offer help to solve difficult situations. This short editorial aims to assist in training pediatric endocrinologists and other professionals in their understanding and coping with issues of DSD, and in topics such as human sexuality and fertility in broader terms.

In a fine review article, P. Chakraborty and coworkers report on the Endocrine Society of Bengal (ESB) consensus statement on the diagnostic approach in 46, XY DSD: as they state clearly 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of under androgenization of male genitalia. Such individuals should be approached systematically to reach an etiological diagnosis. However, we lack, at present, a uniform clinical practice guideline on the diagnostic approach in 46, XY DSD from that part of the globe that is Bengal. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests and investigations, which may be necessary in these cases. Hence, a consensus statement on the diagnostic approach to 46, XY DSD which focused on taking a relevant family and medical history performing a clinical examination, and lastly biochemical evaluation, medical imaging, and genetic analysis. This consensus was reached by 34 highly experienced endocrinologists with interest and experience in managing DSD from the geographic area of Bengal. As is standard the consensus was guided by following a systematic review of the existing literature followed by an extensive discussion. Finally, the final draft was approved by all committee members: It was concluded that the diagnostic approach to the individual with 46, XY DSD should be multidisciplinary and should be coordinated by an experienced pediatric endocrinologist. Formal karyotyping, even if Y chromosome material has been detected by other methods, should be performed. Meticulous history taking and complete head-to-toe physical examination should be performed with a focus on examination of the external genitalia, including the location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to age and interpreted according to age-appropriate normative data. Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, may be acceptable alternatives. The authors suggest that all patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may also be used to identify the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation or molecular testing of a candidate gene or next generation sequencing should be performed in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings and of course depending on the available resources [2].

In a paper by Reuben Rohn et al. a slightly different topic albeit distantly related to DSD is addressed: Genital staging is tripartite in nature and is prone to ambiguity because it may be based upon subjective visual cues that may lead to erroneous assessments and medical errors. However, Tanner staging is still the standard for rating sexual maturation (SMR) in boys (pubic hair [PH] and genital [G] development). Measurement of penile growth (penile girth or diameter) may provide an additional tool (in addition to testicular size as assessed by using an orchidometer) to make G staging more valid. Although studies on penile growth (either circumference or width) have been reported, none were longitudinal. Therefore, the objective of this paper was to compare penile development in boys – measured as penile diameter (PD) – to PH stage and testicular volume (TV) and secondarily to G stage on a longitudinal basis. Charts of 61 boys, ages 6–21 years of age, who were seen longitudinally, were reviewed. Each boy had his PD, and TV measured along with his PH and G stage assessed on a quarterly to semi-annual basis. PD increased significantly among PH stages II, III and IV only. PD increased significantly among G stages I, II, III and IV only. PD correlated significantly with TV in all PH stages. However, for G stage correlations were not significant for stages II, III and IV. PH stage was a better predictor of PD than G stage. Measuring PD may indeed be a tool to assess sexual maturation (SMR) in boys with less vagueness and subjectiveness as is encountered with the visual SMR G stage scales [3].

Ivo et al. reported four unusual cases of Congenital Adrenal Hyperplasia (CAH), which represents a group of genetic diseases characterized by impaired cortisol biosynthesis. 95% of CAH cases result from mutations in the CYP21A2 gene encoding for 21-hydroxilase. The TNX-B gene partially overlaps CYP21A2 and encodes for a matrix protein called tenascin-X (TNX). Complete tenascin deficiency causes Enlers–Danlos syndrome (EDS). A mono allelic variant called CAH-X CH-1 was recently described, resulting from a CYP21A2 complete deletion that extends into the TNXB. This haploinsufficiency of TNX may be associated with a mild hypermobility form of EDS, as well as other connective tissue comorbidities such as hernia, cardiac defects, and chronic arthralgia. This manuscript describes four patients heterozygous for a CAH-X CH-1 allele that did not present clinical manifestations of the EDS. This indicates EDS joint hypermobility manifestations may not be present in patients mono allelic for CAH-X CH-1. Carriers of these TNXA/TNXB chimeras should be evaluated for clinical manifestations related to connective tissue hypermobility, cardiac abnormalities and other EDS features, allowing for better clinical surveillance management. This paper adds an important clinical aspect of the heterogeneity of CAH [4].

In another article within this issue of our journal, Oroz and colleagues present to date smallest known dislocated microduplication of Xq27.1 harboring the SOX3 gene, which is associated with XX male phenotype. Approximately 90% of “XX males” are positive for SRY (Sex determining region Y). However, there are isolated cases in which sex reversal was attributed to other genes in male-determining pathway such as SOX9 (SRY-box transcription factor 9) and SOX3 (SRY-box transcription factor 3). Here a 1.3-old patient with 46, XX karyotype, male phenotypic gender and cryptorchidism, but without other congenital anomalies was reported. Microarray analysis revealed de novo 273 kb duplication in the Xq27.1 region that contains SOX3. Fluorescence in situ hybridization with probes specific to SOX3 confirmed a unique genomic location of this duplication, which was dislocated proximal to the centromere of the X chromosome. This rare genetic condition was described in yet a few other isolated cases that had associated SOX3 genetic rearrangements and DSD. Microarray and genome-wide-sequencing represents an important part in routine diagnostics, as well as in delineation of other sex-determination-pathway genes in sex reversal disorders [5].

In summary, DSD and variants of sexual development still pose a challenge for individuals and their families who seek help and assistance and importantly also for physicians who attempt to provide learned advice, medical services and support. Both at an individual and a societal level there is still controversy and research on DSD should incorporate a multidisciplinary approach beyond medicine and include ethical, societal, legal, genetic, biochemical and medical and psychological dimensions.