Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development

STUDY QUESTION What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)? SUMMARY ANSWER An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases. WHAT IS KNOWN ALREADY Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear. STUDY, DESIGN, SIZE, DURATION This study was a retrospective review of investigations performed on 122 boys. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1–11). Details of phenotype, endocrine and genetic investigations were obtained from case records. MAIN RESULTS AND THE ROLE OF CHANCE An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1–10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5–11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5–11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1–9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations. LIMITATIONS, REASONS FOR CAUTION A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel. WIDER IMPLICATIONS OF THE FINDINGS The lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD

Progressive osseous heteroplasia: A case report with an unexpected trigger

Progressive osseous heteroplasia (POH) is a rare genetic disorder characterised by progressive heterotopic ossification (HO) within the skin and subcutaneous tissues. The condition is caused by heterozygous inactivating mutations of the GNAS gene and usually presents in infancy. We describe the case of a white male ex-preterm who was first referred because of subcutaneous calcium deposits along the right arm after extravasation of parenteral nutrition. As these lesions progressed, a skin biopsy was undertaken which revealed intramembranous ossification. Genetic testing revealed a constitutional, de novo, heterozygous, nonsense variant in the GNAS gene that has not previously been described, but which is consistent with patient's clinical diagnosis of POH. No endocrine abnormalities or other signs congruent with overlapping conditions were detected. To the best of our knowledge, this is the first case describing an inflammatory trigger in POH. Trials with intravenous bisphosphonate and glucocorticoid as well as with topical sodium thiosulphate were attempted without clinical improvement. Excision of the calcifications and physiotherapy seem to have provided a partial improvement on mobility of the elbow. This case widens the spectrum of phenotypes seen in GNAS mutation disorders and suggests that alternative anti-inflammatory treatments may be effective. Mutations in GNAS should be considered in cases of significant progressive calcium deposition after extravasation injury

Evaluation of DSD training schools organized by cost action BM1303 "DSDnet"

Abstract Background The Differences of Sex Development network (DSDnet) aims to establish interactive relationships between clinicians, scientists, support groups and people with a difference of sex development (DSD) to improve the overall care for people affected by such condition. DSDnet has hosted three Training Schools (TSs) in Ghent, Bologna and Budapest between 2015 and 2017 with the primary purpose of providing multidisciplinary training to young professionals and encouraging ongoing activity in the field of DSD. The aim of our study was to evaluate the success and long-term effect effectiveness of these three TSs. Methods and results Eighty-seven trainees (70 women, 17 men) attended one of three TSs. The distribution of trainees according to their professional field was: 47 (54.0%) from Pediatrics/Endocrinology, 13 (14.9%) from Biology/Genetics, 12 (13.8%) from Psychology/Psychiatry and 15 (17.2%) from Surgical Professions. All trainees were asked to complete an evaluation form on the last day of the TS to gain feedback on how to improve the next one. A further survey was sent at the end of 2017 to provide information about the overall long-term impact of the TSs. Seventy-eight (89.7%) trainees completed evaluation forms at the end of the respective TSs. Replies to the subsequent survey were received from 76 (87.4%) of trainees. A total of 72/76 (94.7%) responders reported that they continue to be active in the field of DSD. The vast majority (64/68, 94.1%) reported that the TSs had enlarged their professional networks. Among the 76 respondent trainees, 11.8% (n = 9) had applied for a research grant and 10.5% (n = 8) had received a fellowship related to DSD since their TS attendance. Conclusions According to our results, the majority of TS participants continue to be active in the field of DSD and have enlarged their professional networks following participation at the TS. These findings indicate the need of this type of educational program and justify ongoing efforts to provide postgraduate multidisciplinary training in rare diseases such as DSD

Addressing gaps in care of people with conditions affecting sex development and maturation

Differences of sex development are conditions with discrepancies between chromosomal, gonadal and phenotypic sex. In congenital hypogonadotropic hypogonadism, a lack of gonadotropin activity results primarily in the absence of pubertal development with prenatal sex development being (almost) unaffected in most patients. To expedite progress in the care of people affected by differences of sex development and congenital hypogonadotropic hypogonadism, the European Union has funded a number of scientific networks. Two Actions of the Cooperation of Science and Technology (COST) programmes - DSDnet (BM1303) and GnRH Network (BM1105) - provided the framework for ground-breaking research and allowed the development of position papers on diagnostic procedures and special laboratory analyses as well as clinical management. Both Actions developed educational programmes to increase expertise and promote interest in this area of science and medicine. In this Perspective article, we discuss the success of the COST Actions DSDnet and GnRH Network and the European Reference Network for Rare Endocrine Conditions (Endo-ERN), and provide recommendations for future research

Gonadectomy in conditions affecting sex development: a registry-based cohort study

Objectives To determine trends in clinical practice for individuals with DSD requiring gonadectomy. Design Retrospective cohort study. Methods Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. Results Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p &lt; 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Serum anti-Müllerian hormone in the prediction of response to hCG stimulation in children with DSD

The relationship between serum anti-Müllerian hormone (AMH) and the testosterone response to hCG stimulation test is unclear. Children who had hCG stimulation tests in one tertiary centre between 2001-2018 were included (n,138). Serum testosterone (T) was measured before (D1) and after 3 days (D4) of hCG stimulation. Sixty-one of these children also had prolonged hCG stimulation for 2 more weeks and serum T measured after 21 days (D22). All children had a serum AMH measured on D1. Of the 138 children, D4 T was normal in 104 (75%). AMH was low in 24/138 (17%) children and 16 (67%) of these had a low D4 testosterone. Median AMH in those who had a normal vs low D4 T was 850 pmol/l (24, 2280) and 54 pmol/l (0.4, 1664), respectively (p&lt;0.0001). An AMH &gt;5th centile was associated with a low D4 testosterone in 18/118 (13%, p&lt;0.0001). Of the 61 children who had prolonged hCG stimulation, D22 T was normal in 39 (64%). AMH was low in 10/61(16%) children and 9 (90%) of these had a low D22 testosterone. Median AMH in children who responded and did not respond by D22 was 639 pmol/l (107, 2280) and 261 pmol/l (15, 1034) (p&lt;0.0001). A normal AMH may provide valuable information on overall testicular function. However, a low AMH does not necessarily predict a sub-optimal testosterone response to hCG stimulation. [Abstract copyright: © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].