The assessment of outcomes in rare endocrine conditions

Ali, Salma Rashid (2023) The assessment of outcomes in rare endocrine conditions. PhD thesis, University of Glasgow.

Abstract

Endocrine pathology in children may manifest in infancy or adolescence by either a deficiency or excess of one or more hormones, with a range of metabolic sequelae. Almost all conditions are associated with long-term morbidity, societal and healthcare implications. Optimal patient management requires an awareness of these conditions and specialist expertise within a multidisciplinary setting. However, due to the rarity of some of these conditions, the end result is often substantial variation in patient care.

The focus of this thesis was on the exchange of real-world data and knowledge for rare endocrine conditions through local, regional and international networks including detailed disease registries (I-DSD, I-CAH), facilitating the development of clinical benchmarks, with the overall aim of improving patient care.

Rare disease registries enable pooling of data for research and surveillance and are regarded as essential for networks such as the European Reference Network for Rare Endocrine Conditions (Endo-ERN). It was unclear how many cross-border registries exist for rare endocrine conditions and the extent of involvement of expert centres with these registries. This was investigated by a database search to identify cross-border international endocrine registries. Concurrently, an international survey of 71 Endo-ERN reference centres was performed. Of the 42 conditions with orphacodes covered within Endo-ERN, international registries existed for 33 (78%), with Endo-ERN expert centres aware of 11 (41%) of these registries. Despite awareness of these registries, some experts did not use the registries. The I-DSD/I-CAH registries were amongst the most commonly identified and used registries, thus, providing an ideal platform for the study of core clinical outcomes at an international level.

With the recent global expansion in the number of rare disease registries, it was imperative that a process for quality evaluation of registries was developed, in order to ensure the sustainability of registries in the longer term and the exchange of high quality data for investigating core clinical outcomes. Rare disease registry leaders representing 40 registries were surveyed to ascertain the level of consensus regarding the quality criteria that should be considered essential features of a disease registry. Over 95% of leaders indicated that essential quality criteria should include establishment of a good governance system, procedures for checking data quality and construction of an IT infrastructure complying with Findable, Accessible, Interoperable and Reusable (FAIR) principles. Rare endocrine registries, identified in the database search and Endo-ERN mapping exercise, performed self-evaluation of these quality criteria, with the methodology applicable to all rare disease registries.

The initial mapping exercise of Endo-ERN reference centres highlighted the need to improve the awareness and signposting of existing registries through a simple platform that can be used by the whole endocrine community. Standardised data collection on the conditions covered within Endo-ERN as well as information on the incidence, prevalence and natural history of rare endocrine conditions is also important for networks such as Endo-ERN. Web-based methods of capturing presentation of rare endocrine conditions were explored and the European Registries for Rare Endocrine Conditions (EuRRECa) was developed to achieve this objective. Analysis of data entered by clinicians via the e-Reporting platform (e-REC) within EuRRECa revealed increasing popularity of the platform since its inception in 2018, with a total of 9,715 and 4,243 new cases reported in adults and children, respectively, over this time. Conditions affecting sex development were most commonly encountered in children (40% of all reported conditions), with a median of 0.6 (range 0, 38) cases reported per centre per month. The EuRRECa platform has the potential to provide the infrastructure for future research activity, with the overall aim of improving patient care.

Disorders or differences of sex development (DSD) and congenital adrenal hyperplasia (CAH) were used as models of rare endocrine conditions where there was a paucity of real-world data in large, multi-centre, international cohorts relating to prevalence, morbidity (acute adrenal insufficiency (AI) related adverse events in CAH) and psychosocial outcomes in children with DSD. Provision of optimum healthcare for infants with atypical genitalia requires a clear understanding of the occurrence of this condition. Thus, to study the presentation of DSD at a national level in Scotland, a nationwide study of the prevalence and management of atypical genitalia was performed. A prospective, electronic survey of clinicians within managed clinical networks in Scotland with cross verification of cases at cytogenetic labs was undertaken over a 6 year period. The birth prevalence of term infants with atypical genitalia was 1:1,881 and 1 in 3,318 required specialist input over the first 3 months of life. The birth prevalence of a case of atypical genitalia where sex assignment was delayed beyond birth was estimated at 1 in 11,097 births. The study provided new clinical benchmarks for comparing and improving the delivery of care in centres that manage these rare conditions.

Another study investigated the occurrence of sick day episodes (SDE) and adrenal crises (AC), factors which may influence these outcomes and inter-centre variability for these events in children. Data from 518 children from 34 centres in 18 countries showed that infectious illness was the most frequent precipitating event, reported in 1,105 (72%) of SDE. Interestingly, children from high income countries had significantly higher rates of SDE compared with children from low-middle incomes, 0.75 (0, 13.3) vs 0.11 (0, 12.0), p<0.001. Risk factors for SDE were younger age (1-4 years), adolescence (15-18y), male sex and normal or lower doses of glucocorticoids, all p<0.05. These new clinical benchmarks were used to produce centre-specific reports for I-CAH centres. As these data were increasingly used as benchmarks in CAH care, a need for further research to improve and standardise the definition and management of SDE and AC was highlighted. An international survey of 56 expert centres revealed a good level of consensus on specific aspects that may lead to greater benchmarking of care. Over 60% of centres were in agreement regarding the criteria that should be considered essential for diagnosis of an adrenal crisis and these criteria included hypotension, hyponatraemia, hyperkalaemia and clinical improvement following parenteral glucocorticoids.

To date, there is a paucity of information on health-related quality of life (QoL) outcomes in parents and children with DSD and a lack of instruments available for evaluating these outcomes. The final part of the project explored the use of parent reported outcome (PRO) measures in clinical practice as part of routine healthcare evaluation in parents of children with DSD and other endocrine conditions. The study found that parents of children with DSD had greater concerns regarding their child’s future than parents of children with other endocrine conditions. To further investigate the psychosocial concerns amongst parents of children with DSD and reduce respondent burden, short questionnaires that could be used in routine outpatient settings were developed using previous QoL-DSD data from 132 patients that had completed validated long questionnaires. Initial validation of the short questionnaire was performed in 24 patients. Results showed good agreement between the short and the long questionnaires in 11 out of 12 (92%) scales on the parent self-report and 4 out of 5 (80%) scales on the parent proxy-report. Following further psychometric validation in larger cohort, these QoL tools may be used to establish national and international benchmarks for psychosocial outcomes in parents and young children with DSD and CAH.

The final chapter (Chapter 10) summarises my work for this thesis, highlighting its strengths and limitations as well as providing perspectives into the future directions of this work.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from University of Glasgow via the Gardiner Clinical Lectureship in Child Health, Diurnal Ltd, Neurocrine Biosciences, the EU Health Programme, the Glasgow Children’s Hospital Charity, the Medical Research Council, the Seventh EU Framework Program, and the ESPE Research Unit.
• Subjects: R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Ahmed, Professor Syed Faisal
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83681
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Jun 2023 08:54
• Last Modified: 01 Apr 2026 15:13
• Thesis DOI: 10.5525/gla.thesis.83681
• URI: https://theses.gla.ac.uk/id/eprint/83681

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