Karijn J. Pijnenburg-Kleizen

Canisius-Wilhelmina Ziekenhuis

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Hedi L. Claahsen‐van der Grinten

Radboud University Nijmegen

Fred C.G.J. Sweep

Radboud University Medical Center

Paul N. Span

Radboud University Nijmegen

Christiaan F. Mooij

Emma Kinderziekenhuis

Nils Krone

University of Sheffield

Barto J. Otten

Radboud University Nijmegen

Antonius E. van Herwaarden

Radboud University Nijmegen

Manon Engels

Radboud University Medical Center

Agustini Utari

Diponegoro University

Wiebke Arlt

University of Birmingham

Cooperative Institutions

Radboud University Nijmegen

Radboud University Medical Center

Inserm

University Medical Center

Université Paris Cité

Radboud Institute for Molecular Life Sciences

Boston Children's Hospital

Sorbonne Paris Cité

Royal Hospital for Children

Karolinska Institutet

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Free cortisol and free 21-deoxycortisol in the clinical evaluation of congenital adrenal hyperplasia

The Journal of Clinical Endocrinology & Metabolism (2024)

Bas P H Adriaansen Agustini Utari André J. Olthaar Rob C.B.M. van der Steen Karijn J. Pijnenburg-Kleizen

Some patients with classic congenital adrenal hyperplasia (CAH) survive without glucocorticoid treatment. Increased precursor concentrations in these patients might lead to higher free (biological active) cortisol concentrations by influencing the cortisol-protein binding. In 21-hydroxylase deficiency (21OHD), the most common CAH form, accumulated 21-deoxycortisol (21DF) may further increase glucocorticoid activity. Both mechanisms could explain the low occurrence of symptoms in some untreated classic CAH patients. Develop and validate an LC-MS/MS method for free cortisol and free 21DF to quantify these steroids in untreated patients with classic CAH (n=29), non-classic CAH (NCCAH, n=5), other forms of adrenal insufficiency (AI, n=3), and controls (n=11) before and 60 minutes after Synacthen® administration. Unstimulated total cortisol concentrations of untreated classic CAH patients (median 109 nmol/L) were lower than in untreated NCCAH patients (249 nmol/L, p=0.010) and controls (202 nmol/L, p=0.016), but free cortisol concentrations were similar. Basal free 21DF concentrations were high in 21OHD patients (median 5.32 nmol/L) and undetectable in AI patients and controls (<0.19 nmol/L). After Synacthen® administration, free 21DF concentrations increased in 21OHD patients, while free cortisol concentrations did not change. Free cortisol concentrations in classic CAH patients were similar to those in controls and NCCAH patients, indicating comparable cortisol availability. Additionally, 21OHD patients produce high concentrations of 21DF, possibly explaining the low occurrence of symptoms in some classic 21OHD patients. Free cortisol and 21DF levels should be considered in evaluating adrenal insufficiency in patients with CAH.

Basal (medicine)

10.1210/clinem/dgae591

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[Multiple endocrine neoplasia type 2B].

PubMed (2015)

Karijn J. Pijnenburg-Kleizen Hanneke M. van Santen David A. Koolen Hedi L. Claahsen‐van der Grinten

Multiple endocrine neoplasia type 2b (MEN2B) is a rare syndrome characterised by the occurrence of medullary thyroid carcinoma at a young age in all patients, and phaeochromocytoma at a later age in half of the patients. Once a medullary thyroid carcinoma causes symptoms, it has usually already metastasised to the lymph nodes and curative treatment is seldom possible at that stage.We present two patients who had phenotypical characteristics of the MEN2B syndrome from a young age: mucosal neuromas, ptosis, a marfanoid habitus, gastrointestinal problems and crying without tears. When the diagnosis was made, at the ages of 15 and 10 years respectively, both patients had already developed metastatic medullary thyroid carcinoma.Early recognition of the phenotype of MEN2B syndrome is crucial in order to be able to perform a prophylactic or curative thyroidectomy. The mucosal neuromas, which are usually present from infancy, are a particularly important characteristic.

Neuroma

Medullary carcinoma

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Absence of Clinically Relevant Growth Acceleration in Untreated Children with Non-Classical Congenital Adrenal Hyperplasia

Hormone Research in Paediatrics (2012)

Karijn J. Pijnenburg-Kleizen George F. Borm Barto J. Otten D Schött Erica L. van den Akker

Background/Aims: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. Methods: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS-THSDS). Bone maturation was expressed as bone age acceleration (BAc = bone age – calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. Results: In symptomatic patients (n = 17), HSDS-THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02–0.10). Mean BAc was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BAc was found. Conclusions: In untreated NC-CAH children, growth acceleration is small and generally not visible on their growth charts. BAc is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account.

10.1159/000337217

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Adrenal Steroid Metabolites Accumulating in Congenital Adrenal Hyperplasia Lead to Transactivation of the Glucocorticoid Receptor

Endocrinology (2015)

Karijn J. Pijnenburg-Kleizen Manon Engels Christiaan F. Mooij Aliesha Griffin Nils Krone

Patients with congenital adrenal hyperplasia (CAH) are often clinically less severely affected by cortisol deficiency than anticipated from their enzymatic defect. We hypothesize that adrenal steroid hormone precursors that accumulate in untreated or poorly controlled CAH have glucocorticoid activity and partially compensate for cortisol deficiency. We studied the in vitro effects of 17-hydroxyprogesterone (17OHP), progesterone (P), 21-deoxycortisol (21DF), and androstenedione (Δ4) on the human glucocorticoid receptor (hGR). Competitive binding assays were performed in HeLa cells. Nuclear translocation of the hGR was studied by transfection of COS-7 cells with a GFP-tagged hGR and fluorescence microscopy. Transactivation assays were performed in COS-7 cells and in HEK 293 cells after cotransfection with hGR and luciferase reporter vectors using a dual luciferase assay. 17OHP, P, and 21DF are able to bind to the hGR with binding affinities of 24–43% compared with cortisol. Δ4 has a low binding affinity. Incubation with 21DF led to complete nuclear translocation of the hGR, whereas treatment with 17OHP or P resulted in partial nuclear translocation. 21DF transactivated the hGR with an EC50 approximately 6 times the EC50 of cortisol. 17OHP and P transactivated the hGR with EC50s of more than 100 times the EC50 of cortisol. No hGR transactivation was detected after incubation with Δ4. 21DF, 17OHP, and P are able to bind, translocate, and transactivate the hGR in vitro and thus may have glucocorticoid activity. 21DF might have a clinically relevant agonistic effect on the hGR and could potentially partially compensate the cortisol deficiency in CAH patients.

Adrenal disorder

Steroid hormone

10.1210/en.2015-1087

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Long-term follow-up of children with classic congenital adrenal hyperplasia: suggestions for age dependent treatment in childhood and puberty

Journal of Pediatric Endocrinology and Metabolism (2019)

Karijn J. Pijnenburg-Kleizen Chris M.G. Thomas Barto J. Otten Nel Roeleveld Hedi L. Claahsen‐van der Grinten

Background In congenital adrenal hyperplasia (CAH), achieving the balance between overtreatment and undertreatment remains challenging. Final height (FH) can serve as a long-term outcome measure. We aimed to identify age-dependent factors that influence FH in CAH patients, resulting in age-specific treatment goals. Methods We retrospectively evaluated longitudinal data of 39 pediatric CAH patients born between 1980 and 1997 from the Radboudumc CAH database. We analyzed height and bone age (BA) at diagnosis or 4 years of age, at the start of puberty and at FH. Height data were corrected for parental height and secular trend. Hydrocortisone (HC) use and salivary steroid concentrations were studied longitudinally throughout childhood and puberty. Results Median FH standard deviation scores (SDSs) corrected for target height SDSs (THSDSs) was -1.63. Median height SDS corrected for THSDS (HSDS-THSDS) decreased from diagnosis/age 4 years to FH in both salt wasting (SW) CAH and simple virilizing (SV) CAH, and in both male and female patients. However, when height was corrected for BA, no height loss occurred from diagnosis/age 4 years to FH in any of the subgroups, while a height gain was seen in SV males. In the combined model analyzing both HC dose and salivary steroid concentrations, in childhood the androstenedione (A) concentration was negatively associated with FH, while in puberty the HC dose was negatively associated with FH. Conclusions In CAH, loss of growth potential already occurs in early childhood. In prepubertal children, exposure to elevated androgens is associated with decreased FH. In puberty, the growth suppressing effects of HC outweigh the negative effects of elevated androgens. Therefore, we suggest different treatment approaches in prepubertal and pubertal patients.

10.1515/jpem-2019-0006

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Adrenal Steroid Precursors Accumulating in Congenital Adrenal Hyperplasia lead to Transactivation of the Glucocorticoid Receptor

54th ESPE Meeting (ESPE 2015) (2015)

Karijn J. Pijnenburg-Kleizen Manon Engels Christiaan F. Mooij Aliesha Griffin Nils Krone

Steroid hormone

ACTH receptor

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Salivary morning androstenedione and 17α-OH progesterone levels in childhood and puberty in patients with classic congenital adrenal hyperplasia

Clinical Chemistry and Laboratory Medicine (CCLM) (2014)

Monique J.M. de Groot Karijn J. Pijnenburg-Kleizen Chris M.G. Thomas Fred C.G.J. Sweep Nike Stikkelbroeck

Abstract Treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be monitored by salivary androstenedione (A-dione) and 17α-hydroxyprogesterone (17OHP) levels. There are no objective criteria for setting relevant target values or data on changes of 17OHP and A-dione during monitoring. We evaluated A-dione and 17OHP levels in nearly 2000 salivary samples collected during long-term treatment of 84 paediatric patients with classic 21-hydroxylase deficiency. A-dione and 17OHP levels and its ratio 17OHP/A-dione remained constant from 4 to 11 years with no sex-related differences. During puberty, A-dione and 17OHP levels both increased, starting at earlier age in girls than in boys. The ratio 17OHP/A-dione declined. Normalised A-dione concomitant with elevated 17OHP [1.43 nmol/L (0.46–4.41) during prepuberty; 2.36 nmol/L (0.63–8.89) for boys and 1.99 nmol/L (0.32–6.98) for girls during puberty] could be obtained with overall median glucocorticoid doses of 11–15 mg/m Normalised A-dione consistent with 17OHP three times URL during prepuberty and normalised A-dione consistent with 4–6 times URL during puberty could be obtained by moderate glucocorticoid dosages. A constant 17OHP/A-dione ratio during prepuberty suggested absence of adrenarche. During puberty, a higher percentage of samples met the criteria for undertreatment, especially of boys.

Prepuberty

Adrenarche

Hydroxyprogesterone

21-Hydroxylase

10.1515/cclm-2014-0375

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Citations (17)

Elevated Concentrations of Adrenal Steroid Precursors with Glucocorticoid Activity Might Prevent Addisonian Crisis in Untreated Patients with Classic Congenital Adrenal Hyperplasia

57th Annual ESPE (2018)

Manon Engels Karijn J. Pijnenburg-Kleizen Agustini Utari Sultana MH Faradz J.J.T.M. Heuvel

Adrenal crisis

Fludrocortisone