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Congenital adrenal hyperplasia (CAH) is one of the commonest forms of primary adrenal insufficiency with an incidence of about 1 in 10,000 to 1 in 15,000. More than 10 years ago, several studies highlighted the suboptimal health status and care provision in adults with CAH that were associated with significant co-morbidities in relatively young adults. The Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) supported by the Society for Endocrinology was formed in 2003 to study the health status of patients with CAH in adulthood. CaHASE has become the landmark global study informing on the health status in adults with CAH. CaHASE was supported by SfE and CET and was a highly successful specialist society led academic collaboration. CaHASE identified that adults with CAH had poor health outcomes and as a result a new modified release formulation of hydrocortisone (development name Chronocort) was developed in the UK, and approved as Efmody by the EMA and MHRA for the treatment of CAH. The CaHASE study underpinned the development of the I-CAH registry and many of the collaborators now input into the I-CAH registry.

Key finding of CaHASE:

  • Only a minority of adults living with CAH in the UK were under specialist endocrine care.
  • Glucocorticoid replacement was generally non-physiological
  • Androgens levels were poorly controlled.
  • Patients had adverse metabolic profiles
  • Increased rates of osteoporosis
  • Impaired fertility
  • Reduced quality of life

Similar findings were reported in an NIH study2 and a French cohort study3 and evidence suggests that poor health outcomes relate to treatment rather than genotype.

The need for CaHASE2:
Recruitment into CaHASE took place from 2003 and 2007. Thus, data from this landmark study reflects the situation in the UK from 15 to 20 years ago. In addition, in the early 2000s, CAH clinical guidelines were widely publicised that suggested changes in the use and dosage of corticosteroid replacement in CAH in all age groups. Thus, there is now a generation of young adults with CAH, who should have presumably been treated differently during childhood and adolescence than the cohorts investigated in the early to mid 2000s. In addition, our recent data in children and young people from the UK demonstrates an increased prevalence of problems with growth and weight gain in CAH children and suggest reduced quality of life during paediatric care. Our recent data implies that problems in health care provision might well persist into adulthood. There is, however, anecdotal evidence that a significant number of UK centres have implemented specialised CAH clinics. However, the number of patients under the care of such specialist centres remains unclear and number of patients looked after in such settings remains also elusive. Several important questions such as corticosteroid replacement, metabolic co-morbidities, blood pressure, bone health as well as psychological health remain unsolved issues in CAH care provision. New therapies including modified release hydrocortisone and CRF antagonists are being developed and introduced into clinical practice and it will be important to assess their impact on management and health care outcomes.

Current unknown questions and the unmet needs in the management of patients with CAH:

  • How should we monitor patients with CAH both biochemically and clinically?
  • Are patients over- or under-treated with mineralocorticoids?
  • Are patients with CAH at risk of hypo- and / or hypertension?
  • Are patients over- or undertreated with glucocorticoids?
  • What are the best strategies to promote bone health in patients living with CAH?
  • Does metabolic risk remain significantly increased?
  • Has quality of life improved in adults with CAH?

The aims and objectives for CaHASE2 will be:

  1. To reassess the clinical management and health status of adults living with CAH in the UK and Ireland, twenty years after the first CaHASE study.
  2. To implement a strategy for prospective continuous recruitment with longitudinal data collection.
  3. To identify specific unmet needs, through standardised, deep clinical phenotyping across all participating centres
  4. To establish a deep-phenotyped cohort that can be approached for interventional clinical studies.

We propose a multi-step process to achieve these goals and establish a longitudinal annual data collection using the I-CAH registry.

1. Assessing current clinical practice of CAH care delivery in the UK and Ireland:
As a first step, we will seek support from the Society for Endocrinology to establish a service evaluation using an anonymous online survey. A dedicated survey will be constructed to assess current management practices across the UK and Ireland. This will include understating the individual clinician’s approach to management, monitoring and therapy change in patients with CAH and has proved valuable in other clinical contexts. This will be distributed to endocrinologists treating patients with CAH utilizing the SfE network contacts and publicity at SfE BES 2022.

2. Establishing a minimum dataset based on assessment of current practice:
After assessing the current practice in the UK and Ireland, we will organise a workshop with additional experts in field to form a broader executive. We will agree on the minimal data set that will be most likely recorded by the participating centres. We envisage that this will include the following parameters in line with published CAH guidelines: 

  • Age
  • Sex
  • Co-morbidities (including medications)
  • Height, weight, BMI
  • Fertility / pregnancy / menstrual irregularity
  • Blood pressure
  • Glucocorticoid +/- mineralocorticoid replacement therapy (dose, timing compliance)
  • Biochemical & hormonal biomarkers (e.g. U&Es, 17-hydroxyprogesterone, androstenedione, testosterone, renin, lipid profiles, HbA1c and blood glucose).
  • Genotype (if available)

3. Longitudinal data collection and analysis:
Patients will be recruited into the portfolio adapted I-CAH registry and the standardized clinical protocol will collect the following data annually and is fully aligned with current gold-standard of clinical care. Currently, 8 UK tertiary Endocrine Centres are already entering CAH cases into the I-CAH registry. We anticipate that the proposed process will increase engagement with systematic data collection:
Data will be analysed after the first completed 12 months cycle, and then annually thereafter to assess the current level of care provision and inform the development of national CAH standards. In addition, we will establish a report that will provide centres with information about their level of care provision in relation to other centres.

4. In-depth phenotyping of the CAH cohort:
Once the longitudinal data collection is established, additional modules for data recording within the I-CAH registry will be developed that will allow for in-depth phenotyping to assess key unsolved problems in individuals with CAH. These modules will allow for additional data collection annually (unless otherwise stated):

  • Genotype (once only)
  • Blood pressure (clinic and 24h ambulatory BP)
  • DXA bone mineral density (3-5 yearly)
  • Testicular US (male patients) (2-3 yearly)
  • Body composition (bioimpedance)
  • QoL and psychological health
  • Approval for biomaterial collection including serum, urine and saliva

Such a multi-step approach will support the easier recruitment to a longitudinal study. We proposed to use the existing I-CAH registry infrastructure to avoid duplication of work and the potential to easily compare our data with international data in future analysis. Furthermore, this will allow also for easier future collaborations with colleagues from Paediatric Endocrinology to compile longitudinal data sets, who are mainly represented by other professional societies such as the British Society for Paediatric Endocrinology and Diabetes (BSPED).

What will CaHASE2 deliver?:

  1. The current status of health care provision in the UK and Ireland for patients with CAH, defining the impact of clinical guideline implementation.
  2. Identify areas of suboptimal clinical management and areas of unmet clinical need that can form the basis for future research and / or defining clinical standards of care.
  3. Service evaluation of any new therapies introduced in the treatment of CAH.
  4. The first assessment of health problems in older adults with CAH.
  5. Development of a deep phenotype longitudinal cohort of patients to define the natural history of CAH as well as a resource for interventional studies.
  6. Implementation of a well characterised CAH cohort to explore effects on disease control of newly and future developed treatment modalities
  7. To use data generated to inform future service models for care of the rare and complex condition.

    This might serve as a template for other rare endocrine disorders for which a more centralised ‘hub and spoke’ model may be more appropriate.

Steering Group

Prof Nils Krone
Prof Jeremy Tomlinson
Prof Aled Rees
Dr Michael O’Reilly
Dr Yasir Elhassan
Dr Lynette James
Sue Elford – patient liason
Dr Sofia Llanaha
Prof Syed Faisal Ahmed

If you wish to have further information about this project please contact [email protected]