Patient journeys are instruments developed by EURORDIS, The Voice of Rare Disease Patients in Europe, to collect patients’ experiences; they may identify gaps and areas deserving improvement, as well as elements positively considered by affected persons. As with other patient-reported experiences, they can complete the clinical evaluation and management of a specific disease, improving the often long diagnostic delay, therapy, patient education and access to knowledgeable multidisciplinary teams. This review discusses the utility of such patient-reported experience measures and summarises the experiences of patients with acromegaly, Addison’s disease and congenital adrenal hyperplasia from different European countries. Despite rare endocrine diseases being varied and presenting differently, feelings of not having been taken seriously by health professionals, family and friends was a common patient complaint. Empathy and a positive patient-centred environment tend to improve clinical practice by creating a trustworthy and understanding atmosphere, where individual patient needs are considered. Offering access to adequate patient information on their disease, treatments and outcome helps to adapt to living with a chronic disease and what to expect in the future, contemplating the impact of a disease on patients’ everyday life, not only clinical outcome but also social, financial, educational, family and leisure issues is desirable; this facilitates more realistic expectancies for patients and can even lead to a reduction in health costs. Patient empowerment with patient-centred approaches to these complex or chronic diseases should be contemplated more and more, not only for the benefit of those affected but also for the entire health system.
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Susan M Webb, Jette Kristensen, Anna Nordenström, Diana Vitali, Vincent Amodru, Lenja Katharina Wiehe, and Matt Bolz-Johnson
Manon Engels, Paul N Span, Rod T Mitchell, Joop J T M Heuvel, Monica A Marijnissen-van Zanten, Antonius E van Herwaarden, Christina A Hulsbergen-van de Kaa, Egbert Oosterwijk, Nike M Stikkelbroeck, Lee B Smith, Fred C G J Sweep, and Hedi L Claahsen-van der Grinten
Testicular adrenal rest tumours (TARTs) are benign adrenal-like testicular tumours that frequently occur in male patients with congenital adrenal hyperplasia. Recently, GATA transcription factors have been linked to the development of TARTs in mice. The aim of our study was to determine GATA expression in human TARTs and other steroidogenic tissues. We determined GATA expression in TARTs (n = 16), Leydig cell tumours (LCTs; n = 7), adrenal (foetal (n = 6) + adult (n = 10)) and testis (foetal (n = 13) + adult (n = 8)). We found testis-like GATA4, and adrenal-like GATA3 and GATA6 gene expressions by qPCR in human TARTs, indicating mixed testicular and adrenal characteristics of TARTs. Currently, no marker is available to discriminate TARTs from LCTs, leading to misdiagnosis and incorrect treatment. GATA3 and GATA6 mRNAs exhibited excellent discriminative power (area under the curve of 0.908 and 0.816, respectively), while immunohistochemistry did not. GATA genes contain several CREB-binding sites and incubation with 0.1 mM dibutyryl cAMP for 4 h stimulated GATA3, GATA4 and GATA6 expressions in a human foetal testis cell line (hs181.tes). Incubation of adrenocortical cells (H295RA) with ACTH, however, did not induce GATA expression in vitro. Although ACTH did not dysregulate GATA expression in the only human ACTH-sensitive in vitro model available, our results do suggest that aberrant expression of GATA transcription factors in human TARTs might be involved in TART formation.
Mirjana Kocova, Vesna Janevska, and Violeta Anastasovska
Testicular adrenal rest tumors (TARTs) are found in 30–94% of adult males with congenital adrenal hyperplasia (CAH). We sought to explore TART appearance through yearly ultrasound examination of testes in young boys with CAH, and its association with metabolic control and genetic mutations.
Twenty-five boys with 21-hydroxylase deficiency in the age group 4–18 years diagnosed during the period 2001–2016 were included in the study. ACTH, 17-hydroxyprogesterone, androstenedione and testosterone were measured at 4-month intervals. Growth and BMI were assessed at the time of evaluation. PCR/ACRS method was used for CYP21A2 gene analysis. Testicular ultrasound examination was performed yearly.
TARTs were detected by ultrasound in 8 children at the age of 6–16 years (13.2 years average). Five had salt-wasting form, two had simple virilizing form and one had non-classic form of CAH. Significant differences in the17OHP and androstenedione levels were detected between the boys, adherent and non-adherent to therapy. Inadequate metabolic control was not different in boys with and without TART (11/17 and 5/8 respectively). No significant difference was detected in the distribution of genetic mutations or adherence to therapy between patients with and without TARTs. One patient had a mutation not reported thus far in TART and another developed leukemia.
TART is not rare in young boys with CAH, irrespective of the specific mutation or metabolic control. Ultrasound screening helps timely diagnosis and adjustment of therapy.
Ewa Stogowska, Karol Adam Kamiński, Bartosz Ziółko, and Irina Kowalska
The subject of vocal changes accompanying pathological conditions, although still not well explored, seems to be promising. The discovery of laryngeal receptors for sex hormones and thyroid hormones can strongly support the hypothesis of changes in voice due to various endocrinopathies. On the other hand, the impairment of the proper function of the vocal apparatus can also be caused in the process of the microvasculature complications of diabetes mellitus. This review was a comprehensive summary of the accessible literature concerning the influence of selected endocrinopathies on subjective and objective voice parameters. We analysed a total number of 16 English-language research papers from the PubMed database, released between 2008 and 2021, describing vocal changes in reproductive disorders such as polycystic ovary syndrome and congenital adrenal hyperplasia, thyroid disorders in shape of hypo- or hyperthyroidism and type 2 diabetes mellitus. The vast majority of the analysed articles proved some changes in voice in all mentioned conditions, although the detailed affected vocal parameters frequently differed between research. We assume that the main cause of the observed conflicting results might stem from non-homogeneous methodology designs of the analysed studies.
Anne Bachelot, Magaly Vialon, Amandine Baptiste, Isabelle Tejedor, Caroline Elie, Michel Polak, Philippe Touraine, and the CRMERC study group
Health-related quality of life (QoL) in adult patients with congenital adrenal hyperplasia (CAH) has been variously reported. However, there is no study evaluating the impact of transition on quality of life.
Adult patients with classic or non-classic CAH diagnosed during childhood CAH, born between 1970 and 1990, were recruited from the registers of Pediatric departments belonging to the French reference center for endocrine rare disease. Primary end point was the QoL (WHOQOL-BREF).
Seventy-three patients were included in the study, among them 59/73 were transferred to adult endocrinologist by their pediatricians for transition. WHOQOL-BREF scores were similar between patients with or without transition to specialist adult services, except for environment dimension score, which was slightly higher in CAH patients without transition. However, CAH patients with a regular follow-up had a better physical health, psychological health and environment score and item global QoL than the group without regular follow-up after transition.
Regular medical follow-up in adulthood is associated with the transition between pediatric and adult care and is associated with better QoL in adults with CAH.
Stefan Riedl, Friedrich-Wilhelm Röhl, Walter Bonfig, Jürgen Brämswig, Annette Richter-Unruh, Susanne Fricke-Otto, Markus Bettendorf, Felix Riepe, Gernot Kriegshäuser, Eckhard Schönau, Gertrud Even, Berthold Hauffa, Helmuth-Günther Dörr, Reinhard W Holl, Klaus Mohnike, and the AQUAPE CAH Study Group
Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80–90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.
Qiuli Liu, Lin-ang Wang, Jian Su, Dali Tong, Weihua Lan, Luofu Wang, Gaolei Liu, Jun Zhang, Victor Wei Zhang, Dianzheng Zhang, Rongrong Chen, Qingyi Zhu, and Jun Jiang
Congenital adrenal hyperplasia (CAH) is one of the most prevalent, and potentially severe, genetic inborn errors of steroid synthesis directly affecting metabolism. Most patients are diagnosed and treated at an early age. There have been very limited reports of adults with CAH-associated adrenal myelolipomas. We aimed to analyze two families with CAH-associated giant adrenal myelolipomas caused by defects in CYP21A2 and CYP17A1 genes. A total of 14 individuals from two unrelated families were identified with either CYP21A2 or CYP17A1 mutations. Of note, five patients were found with adrenal myelolipomas. Total DNA isolated from the peripheral blood of the two probands was screened for potential mutations in the following susceptibility genes of CAH: CYP21A2, CYP11B1, CYP17A1, HSD17B3, HSD3B2, ARMC5, and STAR using target capture-based deep sequencing; and Sanger sequencing was conducted for the family members to detect the potential mutations. The following results were obtained. In family 1, molecular genetics sequencing revealed a compound heterozygous mutation (c.293-13C>G/c.518T>A, p.I173N) in CYP12A2 in the patient and his brother. In family 2, all three female patients with adrenal myelolipomas were found to have a compound heterozygous mutation (c.1118A>T, p.H373L/c.1459_1467del9, p.D487_F489del) in CYP17A1. To avoid giant CAH-associated adrenal myelolipomas in adults, it is important to identify CAH early so that appropriate treatment can be initiated to interrupt the chronic adrenal hyperstimulation resulting from increased ACTH. Genetic testing and counseling could be useful in CAH.
Bruno Donadille, Muriel Houang, Irène Netchine, Jean-Pierre Siffroi, and Sophie Christin-Maitre
Human 3 beta-hydroxysteroid dehydrogenase deficiency (3b-HSD) is a very rare form of congenital adrenal hyperplasia resulting from HSD3B2 gene mutations. The estimated prevalence is less than 1/1,000,000 at birth. It leads to steroidogenesis impairment in both adrenals and gonads. Few data are available concerning adult testicular function in such patients. We had the opportunity to study gonadal axis and testicular function in a 46,XY adult patient, carrying a HSD3B2 mutation. He presented at birth a neonatal salt-wasting syndrome. He had a micropenis, a perineal hypospadias and two intrascrotal testes. HSD3B2 gene sequencing revealed a 687del27 homozygous mutation. The patient achieved normal puberty at the age of 15 years. Transition from the paediatric department occurred at the age of 19 years. His hormonal profile under hydrocortisone and fludrocortisone treatments revealed normal serum levels of 17OH-pregnenolone, as well as SDHEA, ACTH, total testosterone, inhibin B and AMH. Pelvic ultrasound identified two scrotal testes of 21 mL each, without any testicular adrenal rest tumours. His adult spermatic characteristics were normal, according to WHO 2010 criteria, with a sperm concentration of 57.6 million/mL (N > 15), 21% of typical forms (N > 4%). Sperm vitality was subnormal (41%; N > 58%). This patient, in contrast to previous reports, presents subnormal sperm parameters and therefore potential male fertility in a 24-years-old patient with severe 3b-HSD deficiency. This case should improve counselling about fertility of male patients carrying HSD3B2 mutation.
Henrik Falhammar, Hedi Claahsen-van der Grinten, Nicole Reisch, Jolanta Slowikowska-Hilczer, Anna Nordenström, Robert Roehle, Claire Bouvattier, Baudewijntje P C Kreukels, Birgit Köhler, and on behalf of the dsd-LIFE group
The knowledge about health status in adults with disorder of sex development (DSD) is scarce.
Design and methods
A cross-sectional observational study in 14 European tertiary centers recruited 1040 participants (717 females, 311 males, 12 others) with DSD. Mean age was 32.4 ± 13.6 year (range 16–75). The cohort was divided into: Turner (n = 301), Klinefelter (n = 224), XY-DSD (n = 222), XX-DSD (excluding congenital adrenal hyperplasia (CAH) and 46,XX males) (n = 21), 46,XX-CAH (n = 226) and 45,X/46,XY (n = 45). Perceived and objective health statuses were measured and compared to European control data.
In DSD, fair to very good general health was reported by 91.4% and only 8.6% reported (very) bad general health (controls 94.0% and 6.0%, P < 0.0001). Longstanding health issues other than DSD and feeling limited in daily life were reported in 51.0% and 38.6%, respectively (controls 24.5% and 13.8%, P < 0.0001 both). Any disorder except DSD was present in 84.3% (controls 24.6%, P < 0.0001). Males reported worse health than females. In the subgroup analysis, Klinefelter and 46,XX-DSD patients reported bad general health in 15.7% and 16.7%, respectively (Turner 3.2% and CAH 7.4%). Comorbidities were prevalent in all DSD subgroups but Klinefelter and Turner were most affected. Early diagnosis of DSD and a healthy lifestyle were associated with less comorbidities.
Overall, general health appeared to be good but a number of medical problems were reported, especially in Klinefelter and Turner. Early diagnosis of DSD and a healthy lifestyle seemed to be important. Lifelong follow-up at specialized centers is necessary.
Ingeborg Brønstad, Lars Breivik, Paal Methlie, Anette S B Wolff, Eirik Bratland, Ingrid Nermoen, Kristian Løvås, and Eystein S Husebye
In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with CAH, of which p.L388R and p.E140K were associated with salt wasting (SW), p.P45L with simple virilising (SV) and p.V211M+p.V281L with SV to non-classical (NC) phenotypes. We aimed to characterise the novel variants functionally utilising a newly designed in vitro assay of 21OH enzyme activity and structural simulations and compare the results with clinical phenotypes. CYP21A2 mutations and variants were expressed in vitro. Enzyme activity was assayed by assessing the conversion of 17-hydroxyprogesterone to 11-deoxycortisol by liquid chromatography tandem mass spectroscopy. PyMOL 1.3 was used for structural simulations, and PolyPhen2 and PROVEAN for predicting the severity of the mutants. The CYP21A2 mutants, p.L388R and p.E140K, exhibited 1.1 and 11.3% of wt 21OH enzyme activity, respectively, in vitro. We could not detect any functional deficiency of the p.P45L variant in vitro; although prediction tools suggest p.P45L to be pathogenic. p.V211M displayed enzyme activity equivalent to the wt in vitro, which was supported by in silico analyses. We found good correlations between phenotype and the in vitro enzyme activities of the SW mutants, but not for the SV p.P45L variant. p.V211M might have a synergistic effect together with p.V281L, explaining a phenotype between SV and NC CAH.