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Background Whilst diagnostic pathways for children with rare conditions have shown marked improvement, concerns remain about the care children with rare conditions receive at the level of the health care provider. There is, therefore, a need to improve our understanding of the health care received and explore the development of benchmarks that can be regularly monitored. Methods Patients and parents with rare conditions at a tertiary children’s hospital were approached to complete a questionnaire-based survey that enquired on their experience of clinical care. The survey explored six key themes: diagnosis; provision of information; availability of support; satisfaction with healthcare team; awareness and support for life-limiting conditions; and participation in research. Results 130 questionnaires were completed on behalf of 134 patients between 2018 and 2020. Of these, 114 (85%) had received a formal diagnosis, 5 (4%) had a suspected diagnosis and 15 (11%) were undiagnosed. Of the 114 who had received a diagnosis, 24 (20%) were diagnosed within 6 months of developing symptoms, and 22 (20%) within 1–3 years. Seventy patients (53%) reported that they were given little or no information around the time of diagnosis, whilst 81 (63%) felt they were currently well supported, mostly from family members, followed by friends, hospital services, school, other community based healthcare services and lastly, primary care. Of the 127 who were asked, 88 (69%) reported a consistent team of healthcare professionals taking overall responsibility for their care, 86 (67%) felt part of the team, 74 (58%) were satisfied with the level of knowledge of the professionals, and 86 (68%) knew who to contact regarding their condition. Of the 91 who were asked, 23 (25%) were aware their child had a life limiting condition, but only 4 (17%) were receiving specialist support for this. Of 17 who were asked about research, 4 (24%) were actively participating in research, whilst the remainder were all willing to participate in future research. Conclusions The survey provides a unique insight into the experience of patients and parents within a specialist centre and the benchmarks that it has revealed can be used for future improvement in services.

Provision of optimum healthcare for infants with atypical genitalia requires a clear understanding of the occurrence of this condition. The objective of this study was to determine the prevalence of atypical genitalia and its initial management. A prospective, electronic survey of clinicians within managed clinical networks in Scotland was undertaken between 2013 and 2019. Notification from clinicians was sought for term neonates requiring specialist input for atypical genitalia. Additional information was also sought from the 4 regional genetics laboratories that provided details for neonates who had an urgent karyotype performed for atypical genitalia or sex determination. In total, the study identified 171 term infants who required some investigation for atypical genitalia in the neonatal period, providing a birth prevalence of 1:1,881 term births. Of the 171 infants, 97 (57%) had specialist input over the first 3 months of life, providing a birth prevalence of 1:3,318 term births that received specialist input for atypical genitalia. A total of 92 of these 97 cases had complete 3-month follow-up data, 62 (67%) presented within 24 h of birth, and age at presentation ranged from birth to 28 days. Age at sex assignment ranged from birth to 14 days, and in 63 cases (68%), sex assignment occurred at birth. Thus, the birth prevalence of a case of atypical genitalia where sex assignment was reported to be delayed beyond birth was estimated at 1:11,097 births. In 1 case sex was re-assigned at 3 months. Atypical genitalia requiring specialist input within the first month of life are rare in term newborns, and in only a third of these cases, sex assignment is delayed beyond birth. This study provides new clinical benchmarks for comparing and improving the delivery of care in centres that manage these conditions.

Despite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all60, most20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ.We acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ.Effects of ASD and its severity included reduced levels of multiple metabolites in white matter and the perisylvian cortex and elevated levels in the posterior cingulate, consistent with white matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas.Results support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.

Context:\ud The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases.\ud Objective:\ud To report the range of associated conditions identified in the international DSD (I-DSD) Registry.\ud Design, Setting, and Patients:\ud Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician.\ud Results:\ud Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations.\ud Conclusions:\ud Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.

Background With the proliferation of rare disease registries, there is a need for registries to undergo an assessment of their quality against agreed standards to ensure their long-term sustainability and acceptability.This study was performed to evaluate the I-DSD and I-CAH Registries and identify their strengths and weaknesses. Methods The design and operational aspects of the registries were evaluated against published quality indicators. Additional criteria included the level of activity, international acceptability of the registries and their use for research. Results The design of the I-DSD and I-CAH Registries provides them with the ability to perform multiple studies and meet the standards for data elements, data sources and eligibility criteria. The registries follow the standards for data security, governance, ethical and legal issues, sustainability and communication of activities. The data have a high degree of validity, consistency and accuracy and the completeness is maximal for specific conditions such as androgen insensitivity syndrome and congenital adrenal hyperplasia. In terms of research output, the external validity is strong but the wide variety of cases needs further review. The internal validity of data was condition specific and highest for conditions such as congenital adrenal hyperplasia. The shift of the registry from a European registry to an international registry and the creation of a discrete but linked CAH registry increased the number of users and stakeholders as well as the international acceptability of both registries. Conclusions The I-DSD and I-CAH registries comply with the standards set by expert organisations. Recent modifications in their operation have allowed the registries to increase their user acceptability.

Item does not contain fulltext Context: It is well established that boys are heavier than girls at birth. Although the cause of birth weight (BW) difference is unknown, it has been proposed that it could be generated from prenatal androgen action. Objective: The aim of the current study was to determine the BW of children with disorders of sex development (DSD) of different etiologies and to evaluate the effects of androgen action on BW. Methods: Data regarding diagnosis, BW, gestational age, karyotype, and concomitant conditions were collected from the International Disorders of Sex Development (I-DSD) Registry (www.i-dsd). BW standard deviation score was calculated according to gestational age. Cases were evaluated according to disorder classification in I-DSD (i.e., disorders of gonadal development, androgen excess, androgen synthesis, androgen action, nonspecific disorder of undermasculinization groups, and Leydig cell defect). Results: A total of 533 cases were available; 400 (75%) cases were 46,XY, and 133 (25%) cases were 46,XX. Eighty cases (15%) were born small for gestational age (SGA). Frequency of SGA was higher in the 46,XY group (17.8%) than in the 46,XX (6.7%) group (P = 0.001). Mean BW standard deviation scores of cases with androgen excess and androgen deficiency [in disorders of gonadal development, androgen synthesis, and Leydig cell defect groups and androgen receptor gene (AR) mutation-positive cases in disorders of androgen action groups] were similar to normal children with the same karyotype. SGA birth frequency was higher in the AR mutation-negative cases in disorders of androgen action group and in the nonspecific disorders of the undermasculinization group. Conclusions: BW dimorphism is unlikely to be explained by fetal androgen action per se. 46,XY DSDs due to nonspecific disorders of undermasculinization are more frequently associated with fetal growth restriction, SGA, and concomitant conditions.

Background: Although a karyotype represents the first objective evidence of investigating a case of suspected disorder of sex development (DSD), the factors that influence the clinician’s decision to initiate investigations are unclear. Methods: Cases of suspected DSD in Scotland were identified through the Scottish Genital Anomaly Network (SGAN) Register. The timing as well as other factors that influence the decision to perform a karyotype were subsequently studied. Results: Out of the 572 cases on the register, 383 (67%) were classified as having a non-specific disorder of under-masculinisation. In 463 (81%) cases, the sex of rearing was male, in 71 (12%) female, and in 38 (7%) cases data regarding sex of rearing were unavailable. A karyotype was reported to have been performed in 153/572 (27%) cases. Infants in Scotland with suspected DSD are more likely to have a karyotype performed in the presence of a low external masculinisation score, bilateral impalpable testes, proximal hypospadias, or associated malformations. Discussion: These data represent the first attempt at benchmarking the decision to check a karyotype and investigate infants with suspected DSD. Whilst this decision may be related to the complexity of the genital anomaly, there are other factors that may influence this decision, and these require further exploration through more rigorous systems for data collection.

Infants rarely present with truly ambiguous genitalia and such children should be evaluated by experts who work within a multidisciplinary team that is dedicated for evaluation and management of children and adults with suspected and confirmed disorders of sex development. The paediatric endocrinologist who is a vital and often the central member of this clinical team not only needs to lead the clinical evaluation of the infant systematically but also needs to be sensitive to the needs of the infant, the parents and the rest of the team. A thorough knowledge of the underlying pathophysiology and the strengths and weaknesses of the investigative tools that are available for reaching a diagnosis is crucial.

Disorders of sex development (DSD) are a rare group of conditions which require further research. Effective research into understanding the aetiology, as well as long-term outcome of these rare conditions, requires multicentre collaboration often across national boundaries. The EU-funded EuroDSD programme (www.eurodsd.eu) is one such collaboration involving clinical centres and clinical and genetic experts across Europe. At the heart of the EuroDSD collaboration is a European DSD registry and a targeted virtual research environment (VRE) that supports the sharing of DSD data. Security, ethics and information governance are cornerstones of this infrastructure. This paper describes the infrastructure that has been developed, the inherent challenges in security, availability and dependability that must be overcome for the enterprise to succeed and provides a sample of the data that are stored in the registry along with a summary analysis of the current data sets.

Background:\ud Urinary steroid metabolite ratios may improve the diagnostic yield of potential disorders of steroid hormone synthesis.\ud \ud Objectives:\ud To investigate the range of ratios and their predictive value in children with suspected disorders of steroid synthesis.\ud \ud Design and methods:\ud Twelve ratios were calculated on steroid metabolite data analysed by gas chromatography–mass spectrometry in urine samples collected between 2008–2010 from 93 children. Urine samples were also analysed in 252 children with no known endocrine concerns.\ud \ud Results:\ud Of the 252 controls, 115 (46%) were male with a median age of 10 yr (range 1 month,18.5 years). Of the 93 cases, 38 (41%) were male with a median age of 6.5 yr (1 day,18.5 yrs). Of these, 41 (44%) had at least one ratio greater than the 95% percentile for controls. The most frequently abnormal ratio, found in 18/93 (19%) cases was (THS/(THE + THF + 5αTHF)) suggestive of 11β-hydroxylase deficiency. Over this period, 8 (9%) children were subsequently diagnosed with a steroid hormone disorder; 4 with 21-hydroxylase deficiency, 2 with11β-hydroxylase deficiency and 2 with 5α-reductase deficiency. All except one of these children had at least 1 raised ratio.\ud \ud Conclusions:\ud Urinary steroid metabolite ratios in suspected disorders of hormone synthesis often exceed the reference range for normal children. The predictive value of steroid metabolite ratios in identifying a genetic abnormality may be condition specific and needs further study to improve its clinical utility.

BACKGROUND AND OBJECTIVE: It is unclear whether the proportion of infants with a disorder of sex development who are raised as male or female has changed over time. The temporal trends in sex assignment of affected cases entered in the International Disorder of Sex Development (I-DSD) Registry were studied. METHODS: Cases of disorders of sex development reported as partial androgen insensitivity syndrome (PAIS; n = 118), disorder of gonadal development (DGD; n = 232), and disorder of androgen synthesis (DAS; n = 104) were divided into those who were born before 1990, 1990–1999, and after 1999. External appearance of the genitalia was described by the external masculinization score. RESULTS: The median (5th–95th percentile) external masculinization scores of those infants with PAIS, DGD, and DAS who were raised as boys were 6 (2–9), 6 (3–9), and 6 (1–12), respectively, and were significantly higher than in those raised as girls (2 [0–6], 2 [0–7], and 0 [0–5], respectively); this difference was maintained in the 3 temporal birth cohorts (P < .01). Of the 118 cases in the pre-1990 cohort, 41 (35%) were raised as boys; of the 148 cases in the 1990–1999 cohort, 60 (41%) were raised as boys; and of the 188 cases in the post-1999 cohort, 128 (68%) were raised as boys. CONCLUSIONS: Although there is an association between the external appearance of the genitalia and the choice of sex assignment, there are clear temporal trends in this practice pointing toward an increased likelihood of affected infants being raised as boys. The impact of this change in practice on long-term health outcomes requires additional focus.

Over the last 20 years there have been great advances in the field of neuroimaging. However, information is still lacking for patients with a disorder of sex development (DSD) due to the rarity of these conditions. In this chapter the authors will review newly emerging techniques with a focus on the connectivity of the brain, describe sexually dimorphic brain structures and functions, and summarise what is known about the neuroanatomy and neurochemistry of individuals with a DSD. Sexual dimorphism exists in all aspects of neuroanatomy, neurochemistry and neurofunction, but the major challenge is to evaluate the relationship between these differences and relate them to the genetic and hormonal environment of the individual. Further imaging studies of normal gender differences are needed before the implications of neuroimaging findings for individuals with a DSD can be determined. Future directions for study include the association between gender-specific brain connectivity patterns and gender-related differences of various brain diseases.

The birth of a new baby is one of the greatest wonders of nature. The first question that is usually posed by the new parent is 'is it a boy or a girl?'; without this information the parents cannot even formulate the second question, which is usually 'is he/she alright?'. It is no wonder that the birth of a child with an abnormality of genital development where the sex of rearing is uncertain at birth, presents difficult clinical and ethical issues. However, the recognition of genital ambiguity may depend on the expertise of the observer. The prevalence of genital anomalies at birth may be as high as 1 in 300 births (1), the prevalence of complex anomalies that may lead to true genital ambiguity may be as low as 1 in 5000 births (2). Rather than treating every affected child as a medical emergency, it is paramount that such a child is first assessed by an expert with adequate knowledge about the range of variation in the physical appearance of genitalia, the underlying pathophysiology of disorders of sex development, and the strengths and weaknesses of the tests that can be performed in early infancy. This expert should be able to ensure that the parents’ needs for information are comprehensively addressed, while appropriate investigations are performed in a timely fashion. This expert also needs to have immediate access to the multidisciplinary team that is essential for the management of such a child. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Background Calculation of a urinary steroid metabolite ratio (uSMR) may be a useful method of improving diagnostic yield when investigating disorders of steroid hormone synthesis. Objective and hypothesis: To investigate the range of uSMR in children with suspected disorders of steroid hormone synthesis. Population/Methods Ten ratios were calculated on steroid metabolite data analysed by GC-MS in urine samples collected between 2008–2010 from 219 children who were undergoing investigations. To obtain reference data, urine samples were also analysed in 89 children with no background of endocrine concerns and who had a urine sample collected at presentation to the hospital with an acute illness. Results Of the 89 reference children, 36(40%) were male and median age at time of the test was 3 yrs(range,1month-11yrs). Of the 219 endocrine patients, 64(29%) were boys. In 129(59%) cases, a urine sample was collected to investigate early or exaggerated signs of adrenarche. Median age at test was 7.4yrs(1day-18yrs). Median and ranges of 2 steroid ratios used in the diagnosis of 21-hydroxylase deficiency are demonstrated in the Table. Abbreviations: 17HP: 17-hydroxypregnanolone, PT: pregnanetriolone, THE: tetrahydrocortisone, THF: tetrahydrocortisol. Conclusions These novel data show that reference ranges for urinary steroid metabolite data need to be age matched. Most children with suspected disorders of steroid synthesis have a ratio which is within the reference range and the identification of outliers will lead to better targeting of genetic analyses.

Background By providing a non-invasive, functional insight, Magnetic Resonance Spectroscopy (MRS) has the potential to provide objective longitudinal data on mammalian brain development. Aim To assess the sexual dimorphism in rodent brain chemistry and development using in vivo MRS. Methods 26(19 male) Sprague-Dawley rats were scanned at 6wks and 20(16 male) at 10wks using a 7TMRI scanner. Testosterone concentrations were measured by ELISA. Metabolites were expressed as a ratio to creatine and full width at half-maximum (FWHM) of the water peak was used as a guide to the reliability of the ratios. Results Median weight in 6wk males (M6) and females (F6), 10wk males (M10) and females (F10) was 197g(range,142–230), 131g (121–135), 316g(274–365) and 206g(191–210) respectively. Median anogenital distance (AGD) in M6, F6, M10, F10 was 2.46cm (1.89–2.9), 1.17cm(1.04–1.19), 3.25cm(2.8–3.6) and 1.33cm(1.07–1.60). Median serum testosterone in M6 and M10 were 1.33ng/ml (0.23–5.45) and 3.36ng/ml(1.75–8.26). 14 metabolites were identified in the occipitofrontal cortex. FWHM range was within the optimal range at 12–38Hz. In M6, myo-inositol ratios showed a positive association with circulating testosterone (p = 0.04), and AGD was correlated with phosphocreatine (p = 0.033) and glutamate (p = 0.045). There was a difference between M6 and F6 in 3 metabolite ratios: phosphocholine (p = 0.014), lactate (p = 0.046) and NAA (p = 0.005). In addition, in males, there was an increase from 6wks to 10wks in 3 metabolite ratios: taurine (p = 0.025), myo-inositol (p = 0.012) and phosphocholine (p = 0.005). Conclusions MRS is a reliable tool for studying the brain in maturing rats and may be a useful tool for studying the link between longitudinal changes in sex steroids and brain development.

Background Calculation of a urinary steroid metabolite ratio (uSMR) may be a useful method of improving diagnostic yield when investigating disorders of steroid hormone synthesis. Objective and hypothesis To determine the range of uSMR and the relationship between the uSMR and the diagnostic outcome in abnormal cases. Population/methods Ten ratios were calculated on steroid metabolite data previously analysed by GC-MS in urine samples from 544 patients under 18 years collected between 2008-2010. Results Out of 544 patients, 337 (62%) were female, 189 (35%) were male and in 18 (3%) the sex was not documented. Indications for performing the test included adrenarche or XX virlisation in 239 (44%) cases and XY DSD in 68 (13%) cases. Median age at test was 7.4 years (r, 1 day,18 years) with 11%, 4%, 3%, 3%, 7%, 16%, 40%, 6%, 6% and 4% of tests performed in the following age bands, Conclusions Applying simplified diagnostic ratios to urinary steroid profile data results in a yield of about 20% cases being abnormal. There is a need to improve the sensitivity and specificity of the uSMR and the reference ranges for these ratios.

Effective research into understanding the aetiology of disorders of sex development (DSDs), as well as long-term outcome of these rare conditions, requires multicentre collaboration often across national boundaries. The EU funded EuroDSD programme (www.eurodsd.eu) is one such collaboration and at the heart of this programme is a DSD register that supports the sharing of DSD data. This register has attracted much interest and has evolved into an international register, now funded by the MRC. At last review (November 2011) there were 1000 cases on the register, and users from 36 centres in 22 countries across 6 continents. The United Kingdom has the largest number of cases on the register (n=247) followed by The Netherlands (n=179). The age of presentation ranges from The register has continued to grow and develop into an international research environment within which professionals can develop new DSD related studies.

It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations.