Experience of health care at a reference centre as reported by patients and parents of children with rare conditions

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

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: 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.<p></p> Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.<p></p> Design, Setting, and Patients: 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.<p></p> Results: 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.<p></p> Conclusions: 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.<p></p&gt

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: 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.<p></p> Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.<p></p> Design, Setting, and Patients: 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.<p></p> Results: 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.<p></p> Conclusions: 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.<p></p&gt

Society for Endocrinology UK guidance on the initial evaluation of a suspected difference or disorder of sex development (DSD) (Revised 2021)

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

Characterisation of the androgen dependent phenotype

The effects of androgens reach far and wide and can be physiological as well as pathological. They are not limited to males and involve almost every system in the human body. Their influence on reproductive development and behaviours is well studied, but more recently, attention has turned to the wider reaching consequences of androgen exposure. Disorders of sex development (DSD) are rare conditions in which individuals may be deficient in, or resistant to, the effects of androgens. The long-term health and quality of life for these individuals is not well reported, but where there are reports, there are descriptions of increased depressive like behaviours, anxiety and poor social functioning. Lack of androgens has been linked to poorer neurocognitive outcomes in some studies and there is a concern that more aggressive hormone replacement should be considered in early life for those individuals lacking in androgens. These disorders can be difficult to study for many reasons. Firstly, they are rare conditions. Secondly, adults with DSD do not tend to visit hospital regularly and can therefore be challenging to engage in research. Thirdly, studying the effects of early life exposure to steroid hormones and relating these to later life behaviours is incredibly complex. Animal models have been used for many years to study the hormonal environment. For my first study, I used a model of rodent neonatal androgen blockade by treating pups with the anti-androgen flutamide for the first five days of life. The animals were studied again in adolescence (6 weeks of age) and early adulthood (10 weeks of age). There were no significant differences found in testosterone, dihydrotestosterone and androstenedione levels in either age group, demonstrating that the androgen blockade was transient. The anogenital index (AGI) was significantly shorter in the treated animals when compared to controls at 6 weeks of age and 10 weeks of age. Phallus length was significantly shorter in treated males when compared to the healthy males at 6 weeks of age and at 10 weeks of age. Phallus weight was significantly lower in the treated animals at 10 weeks of age when compared to the healthy animals. This work demonstrated that my rodent model of neonatal androgen blockade was an effective one. My next study used the same rodent model and aimed to link the perinatal hormonal environment with in vivo brain chemistry using a painless, non-invasive technique known as Magnetic Resonance Spectroscopy. Using a mixed effects model, I analysed the effects of sex, gender, treatment with flutamide and age on the metabolite pattern of the rodent brain. Ɣ-aminobutyric acid (GABA), glucose, glutamine, glutamate, phosphocholine and myo-inositol all changed over time. The combined peaks of glutamate and glutamine also demonstrated a significant change over time. GABA, glutamate, phosphocholine and myo-inositol showed significant sex differences as did the combined peaks of glycerophosphocholine and phosphocholine, N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) and glutamate and glutamine. Aspartate, GABA and myo-inositol were all significantly changed by treatment of the animals with flutamide and GABA and myo-inositol levels in treated males were similar to control females at both 6 and 10 weeks. My final study using the rodent model of androgen blockade looked at the histological changes in the brain. Brains were sectioned and stained for neuronal cell counts and microglial cell counts, and PCR for the Androgen Receptor (AR) was performed. I demonstrated significant, sexually dimorphic changes in neuronal cell counts, microglial cell counts and androgen receptor expression in two clearly defined areas in the rodent brain. In summary, my rodent work demonstrated a link between the neonatal hormonal environment and the sexually dimorphic chemistry and histology of the in vivo brain, and supports the hypothesis that the microglial cell plays a critical role in brain masculinisation. To include a translational aspect to this thesis I extended my work to a population of undermasculinised boys, who were attending hospital for an hCG stimulation test as part of their investigations for 46 XY DSD. The hCG stimulation test is a valuable method for assessing androgen production but there is a need to explore its utility in assessing androgen responsiveness and long-term prognosis. I aimed to assess the effects of the hCG test on the in vivo brain chemistry using MRS, and the peripheral transcriptome using microarray. I reliably demonstrated metabolites in the brains of healthy male infants, healthy female infants and affected male infants. Healthy male infants had significantly lower levels of N-acetylaspartate than affected males in the hypothalamus and lower levels of the phosphocholines in the frontal cortex. In my transcriptomic study of DSD patients, I demonstrated the existence of an androgen responsive group of small RNAs that are measurable in peripheral mononuclear blood cells, and that change over the short duration of an hCG stimulation test, raising the prospect of combining the biochemical assessment of testosterone production with an objective molecular assessment of androgen sufficiency. In summary, in this thesis I have successfully linked the early hormonal environment with later life in vivo brain chemistry, confirmed by histological studies. I have also identified a novel marker, which could potentially be used as an assessment of androgen sufficiency in the future

Advances in neuroimaging

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

Parsing the Heterogeneity of Brain Metabolic Disturbances in Autism Spectrum Disorder

BackgroundDespite 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 (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ.MethodsWe 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.ResultsEffects 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.ConclusionsResults 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

Early Androgen Blockade Influences Longer-Term Brain Metabolism As Assessed By Magnetic Resonance Spectroscopy

Background: Magnetic resonance spectroscopy (MRS) can provide a non-invasive, functional insight into brain metabolism and alterations may predict long-term neurocognitive impairment. A sexually dimorphic pattern of spectroscopy has been reported in humans but there is a need to investigate this further in rodents. Methods: Male and female Sprague Dawley rats (n=32, 16) were treated on postnatal days 1-5 with an antiandrogen (flutamide, 50mg/kg) or corn oil SC and scanned at 6wks and 10wks of age using a small animal 7T MRI scanner. Water-suppressed hydrogen MR spectra were acquired from a voxel placed in the frontal cortex using PRESS sequence and metabolites measured using the LC Model software. Serum testosterone (T) was measured by GCMS. Results were analysed with a repeated measures nested general linear model. Full width at half maximum (FWHM) of the water peak was used as a marker of reliability and was within the optimal range (12-18Hz). Results: Male anogenital distance (AGD) was significantly reduced in the treatment group when compared to controls at both 6 and 10 weeks (p=0.003, p=0.02) and this remained significant when corrected for weight (p=0.001, p=0.02). Phallus length was reduced in the treatment group at both ages (p=0.05, p=0.001). Serum T was higher in the control and treated males at 10 weeks (median 1.9ng/ml, 2.05ng/ml) when compared to the same animals at 6 weeks (0.56ng/ml, 0.61ng/ml, p<0.001). T levels were <0.1ng/ml in all female animals. T levels showed a positive correlation with AGD (p<0.001). On MR spectral analysis, glucose, glutamine, phosphocholine and myo-inositol levels were higher in the treated males compared to control males (p=0.05, p=0.03, p=0.01, p=0.01); these levels were similar to those in age-matched female controls (ns). N-acetylaspartylglutamate(NAAG) levels were lower in older animals from all groups (p=0.05) and glutamine, glutamate and GABA also declined over time (ns). Phosphocholine and myo-inositol increased with age (p=0.05, p=0.01). T levels showed a negative correlation with glutamate (p=0.01) and female animals tended to have higher glutamate levels (ns). Conclusions: MRS based assessment shows that brain metabolites have an age and sex dependency. In addition to undermasculinisation of the male external genitalia, early postnatal androgen blockade alters the pattern of these metabolites. The functional effects of these alterations need further study. - See more at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.NP.15.SUN-0680#sthash.KIrgKFSu.dpu

Early Androgen Blockade Influences Longer-Term Brain Metabolism As Assessed By Magnetic Resonance Spectroscopy

Background: Magnetic resonance spectroscopy (MRS) can provide a non-invasive, functional insight into brain metabolism and alterations may predict long-term neurocognitive impairment. A sexually dimorphic pattern of spectroscopy has been reported in humans but there is a need to investigate this further in rodents. Methods: Male and female Sprague Dawley rats (n=32, 16) were treated on postnatal days 1-5 with an antiandrogen (flutamide, 50mg/kg) or corn oil SC and scanned at 6wks and 10wks of age using a small animal 7T MRI scanner. Water-suppressed hydrogen MR spectra were acquired from a voxel placed in the frontal cortex using PRESS sequence and metabolites measured using the LC Model software. Serum testosterone (T) was measured by GCMS. Results were analysed with a repeated measures nested general linear model. Full width at half maximum (FWHM) of the water peak was used as a marker of reliability and was within the optimal range (12-18Hz). Results: Male anogenital distance (AGD) was significantly reduced in the treatment group when compared to controls at both 6 and 10 weeks (p=0.003, p=0.02) and this remained significant when corrected for weight (p=0.001, p=0.02). Phallus length was reduced in the treatment group at both ages (p=0.05, p=0.001). Serum T was higher in the control and treated males at 10 weeks (median 1.9ng/ml, 2.05ng/ml) when compared to the same animals at 6 weeks (0.56ng/ml, 0.61ng/ml, p<0.001). T levels were <0.1ng/ml in all female animals. T levels showed a positive correlation with AGD (p<0.001). On MR spectral analysis, glucose, glutamine, phosphocholine and myo-inositol levels were higher in the treated males compared to control males (p=0.05, p=0.03, p=0.01, p=0.01); these levels were similar to those in age-matched female controls (ns). N-acetylaspartylglutamate(NAAG) levels were lower in older animals from all groups (p=0.05) and glutamine, glutamate and GABA also declined over time (ns). Phosphocholine and myo-inositol increased with age (p=0.05, p=0.01). T levels showed a negative correlation with glutamate (p=0.01) and female animals tended to have higher glutamate levels (ns). Conclusions: MRS based assessment shows that brain metabolites have an age and sex dependency. In addition to undermasculinisation of the male external genitalia, early postnatal androgen blockade alters the pattern of these metabolites. The functional effects of these alterations need further study. - See more at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.NP.15.SUN-0680#sthash.KIrgKFSu.dpu