Disorders of sex development (DSD): an overview of recent scientific advances

Abstract Developments in biotechnology have radically altered clinical and research themes in the small field of disorders of sex development, as in other rare medical conditions. In the age of genetics, an increasing number of DSDs have been identified. Aided by larger populations of people with DSD diagnoses attending specialist centres, these discoveries are enabling medical doctors and scientists to map out the long-term clinical presentations of a number of conditions. In terms of benefits to patients, the new discoveries have paid dividends in two specific ways. First of all, even though knowledge may remain incomplete, our understanding of the risk of malignancy in retained gonads has improved significantly. Consequently, care providers are in a stronger position than they have ever been to advise patients in their decision-making processes around removing or retaining their gonads. Second, more scientific understanding has led to improved fertility outcomes for women who have a uterus, as in Turner’s Syndrome, Congenital adrenal hyperplasia and Swyer’s Syndrome

Hormone replacement treatment choices in complete androgen insensitivity syndrome: an audit of an adult clinic

OBJECTIVE: To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. DESIGN: Retrospective review. PATIENTS: Women with CAIS identified from our database. RESULTS: The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1-53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. CONCLUSIONS: In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone

Swyer syndrome.

PURPOSE OF REVIEW: This review focuses on the pathogenesis, diagnosis, management and long-term outcomes of disorders of sex development, specifically women with Swyer syndrome (46,XY complete gonadal dysgenesis). RECENT FINDINGS: Recent discoveries have broadened our understanding of the complex pathways involved in normal and abnormal sex development. In 46,XY gonadal dysgenesis, lack of testis development may be triggered by sex determining region Y, NR5A1, DHH or testis-determining gene loss-of-function mutations, DAX1 or WNT4 duplication or MAP3K1 gain-of-function mutations. The diagnosis and management of patients with Swyer syndrome is complex, and optimal care requires an experienced multidisciplinary team. Early diagnosis is vital because of the significant risk of germ cell tumour, and bilateral gonadectomy should be performed. Furthermore, early sex hormone treatment is necessary to induce and maintain typical pubertal development and to achieve optimal bone mineral accumulation. Pregnancy is possible via ova donation, and outcomes are similar to women with 46,XX ovarian failure. SUMMARY: Further pathogenic gene mutations are likely to be identified, and the function, interaction and phenotypic effects of new and existing mutations will be further defined. Patients require long-term follow-up in specialist centres

Clastic polygonal networks around Lyot crater, Mars: Possible formation mechanisms from morphometric analysis

Polygonal networks of patterned ground are a common feature in cold-climate environments. They can form through the thermal contraction of ice-cemented sediment (i.e. formed from fractures), or the freezing and thawing of ground ice (i.e. formed by patterns of clasts, or ground deformation). The characteristics of these landforms provide information about environmental conditions. Analogous polygonal forms have been observed on Mars leading to inferences about environmental conditions. We have identified clastic polygonal features located around Lyot crater, Mars (50°N, 30°E). These polygons are unusually large ( > 100 m diameter) compared to terrestrial clastic polygons, and contain very large clasts, some of which are up to 15 metres in diameter. The polygons are distributed in a wide arc around the eastern side of Lyot crater, at a consistent distance from the crater rim. Using high-resolution imaging data, we digitised these features to extract morphological information. These data are compared to existing terrestrial and Martian polygon data to look for similarities and differences and to inform hypotheses concerning possible formation mechanisms. Our results show the clastic polygons do not have any morphometric features that indicate they are similar to terrestrial sorted, clastic polygons formed by freeze-thaw processes. They are too large, do not show the expected variation in form with slope, and have clasts that do not scale in size with polygon diameter. However, the clastic networks are similar in network morphology to thermal contraction cracks, and there is a potential direct Martian analogue in a sub-type of thermal contraction polygons located in Utopia Planitia. Based upon our observations, we reject the hypothesis that polygons located around Lyot formed as freeze-thaw polygons and instead an alternative mechanism is put forward: they result from the infilling of earlier thermal contraction cracks by wind-blown material, which then became compressed and/or cemented resulting in a resistant fill. Erosion then leads to preservation of these polygons in positive relief, while later weathering results in the fracturing of the fill material to form angular clasts. These results suggest that there was an extensive area of ice-rich terrain, the extent of which is linked to ejecta from Lyot crater

Next generation sequencing reveals novel genetic variants (SRY, DMRT1, NR5A1, DHH, DHX37) in adults with 46,XY DSD

Context: The genetic basis of human sex development is slowly being elucidated and more than 40 different genetic causes of differences (or disorders) of sex development (DSD) have now been reported. However, reaching a specific diagnosis using traditional approaches can be difficult, especially in adults where limited biochemical data may be available. / Objective: We used a targeted next-generation sequencing approach to analyze known and candidate genes for DSD in individuals with no specific molecular diagnosis. / Partcipants and Design: We studied 52 adult 46,XY women attending a single-center adult service, who were part of a larger cohort of 400 individuals. Classic conditions such as17β-hydroxysteroid dehydrogenase deficiency type 3, 5α-reductase deficiency type 2 and androgen insensitivity syndrome were excluded. The study cohort had broad working diagnoses of complete gonadal dysgenesis (CGD) (n=27) and partially-virilised 46,XY DSD (pvDSD) (n=25), a group that included partial gonadal dysgenesis (PGD) and those with a broad ”partial androgen insensitivity syndrome” label. Targetted sequencing of 168 genes was undertaken. / Results: Overall a likely genetic cause was found in 16/52 (30.8%) individuals (22.2% CGD; 40.0% pvDSD). Pathogenic variants were found in SRY (n=3), DMRT1 (n=1), NR5A1/SF-1 (n=1) and DHH (n=1) in the CGD group, and in NR5A1 (n=5), DHH (n=1) and DHX37 (n=4) in the pvDSD group. / Conclusions: Reaching a specific diagnosis can have clinical implications and provides insight into the role of these proteins in sex development. Next-generation sequencing approaches are invaluable, especially in adult populations or where diagnostic biochemistry is not possible

Change Actions: Models of Generalised Differentiation

Cai et al. have recently proposed change structures as a semantic framework for incremental computation. We generalise change structures to arbitrary cartesian categories and propose the notion of change action model as a categorical model for (higher-order) generalised differentiation. Change action models naturally arise from many geometric and computational settings, such as (generalised) cartesian differential categories, group models of discrete calculus, and Kleene algebra of regular expressions. We show how to build canonical change action models on arbitrary cartesian categories, reminiscent of the F\`aa di Bruno construction

A mHealth patient passport for adult Cystic Fibrosis patients

Life expectancy for some Cystic Fibrosis (CF) patients is rising and new complications and procedures are predicted. Subsequently there is need for education and management interventions that can benefit CF adults. This paper proposes a CF patient passport to record basic medical information through a smartphone application (app), giving the patient access to their own data. It is anticipated that such an app will be beneficial to patients when travelling abroad and between CF centres. This app is designed by a CF multidisciplinary team to be a lightweight reflection of a current patient file. The passport app is created using PhoneGap so that is can be deployed for both Android and iOS devices. The app is introduced to seven participants as part of a stress test. The app is found to be usable and accessible. The app is now being prepared for a pilot study with adult CF patients

IVF for premature ovarian failure: first reported births using oocytes donated from a twin sister

BACKGROUND: Premature ovarian failure (POF) remains a clinically challenging entity because in vitro fertilisation (IVF) with donor oocytes is currently the only treatment known to be effective. METHODS: A 33 year-old nulligravid patient with a normal karyotype was diagnosed with POF; she had a history of failed fertility treatments and had an elevated serum FSH (42 mIU/ml). Oocytes donated by her dizygotic twin sister were used for IVF. The donor had already completed a successful pregnancy herself and subsequently produced a total of 10 oocytes after a combined FSH/LH superovulation regime. These eggs were fertilised with sperm from the recipient\u27s husband via intracytoplasmic injection and two fresh embryos were transferred to the recipient on day three. RESULTS: A healthy twin pregnancy resulted from IVF; two boys were delivered by caesarean section at 39 weeks\u27 gestation. Additionally, four embryos were cryopreserved for the recipient\u27s future use. The sister-donor achieved another natural pregnancy six months after oocyte retrieval, resulting in a healthy singleton delivery. CONCLUSION: POF is believed to affect approximately 1% of reproductive age females, and POF patients with a sister who can be an oocyte donor for IVF are rare. Most such IVF patients will conceive from treatment using oocytes from an anonymous oocyte donor. This is the first report of births following sister-donor oocyte IVF in Ireland. Indeed, while sister-donor IVF has been successfully undertaken by IVF units elsewhere, this is the only known case where oocyte donation involved twin sisters. As with all types of donor gamete therapy, pre-treatment counselling is important in the circumstance of sister oocyte donation

Bone and body composition analyzed by Dual-energy X-ray Absorptiometry (DXA) in clinical and nutritional evaluation of young patients with Cystic Fibrosis: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>the improved general therapy has led to reduced morbidity and mortality from Cystic Fibrosis (CF), and bone status may have a potentially greater clinical impact.</p> <p>We investigated the correlation between the severity of the clinical condition, bone status and body composition parameters, in a group of children and young adults with CF.</p> <p>Methods</p> <p>we measured lumbar spine bone density and total body composition by dual energy x-ray absorptiometry (DXA) in 82 consecutive CF patients (42 males; median age: 13 years - range: 5-30). Eighty-two healthy subjects, matched for age, gender, height and pubertal stage were recruited as a control group.</p> <p>Results</p> <p>37 patients (45.1%) had a normal bone mineral density (BMD). A BMD reduction were observed in 45 (54.8%) patients. Lumbar spine Z score was positively related to Body Mass Index (BMI) and a higher Shwachman-Kulczycki score, and negatively related to Crispin-Norman score. A positive and significant correlation was also observed between lumbar spine Z score and total body composition.</p> <p>Conclusion</p> <p>a significant BMD reduction can be present early in CF children and adolescents. A careful follow up of bone status is required starting in childhood.</p