Ingrid Nermoen

Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.

Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl ester lipase (CEL) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL protein were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells.

Subjective health status in men and women with congenital adrenal hyperplasia: A population-based survey in Norway

BACKGROUND Patients with classical congenital adrenal hyperplasia (CAH) require life-long corticosteroid therapy, with uncertain health outcome. Investigations of subjective health status in unselected populations of adult patients are needed. OBJECTIVE To identify all adult Norwegian patients with CAH and obtain population-based data on subjective and psychological health status, working ability and fertility. PATIENTS, METHODS AND DESIGN: Classical CAH patients were identified through search in electronic diagnosis registries at all the university hospitals in Norway. The diagnosis was verified by scrutiny of medical records. The patients were invited to a questionnaire survey including medical history, and the Short Form-36 (SF-36) and Quality of Life Scale questionnaires. The questionnaire responses and fertility data were compared with normative data. RESULTS We identified 104 adult patients (101 alive) with classical CAH (63% female), yielding overall incidence at 1/20,000 live births (1/16,000 in females). Seventy-two (72%) responded; median age 38 years (range 18-72). All the SF-36 scales were significantly impaired, most pronounced for general health and vitality perception. Working disability was reported by 19% of the patients, compared with 10% in the general population. The female patients were often single, and the CAH women had only 21% of the expected number of children compared with the general population. CONCLUSION In this population-based survey of patients with classical CAH, we found that subjective health status and working ability were impaired, and that fertility was reduced in females. There is a need for improvement of the medical treatment and the general care of this patient group.

High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21‐hydroxylase deficiency

Background  Increased frequencies of adrenal tumours and testicular adrenal rest tumours (TART) have been reported in patients with 21‐hydroxylase deficiency (21OHD).

Genetic, anthropometric and metabolic features of adult Norwegian patients with 21-hydroxylase deficiency

OBJECTIVE The aim of this study was to determine the genetic, anthropometric and metabolic features in an unselected population of adult Norwegian patients with 21-hydroxylase deficiency (21OHD). PATIENTS, METHODS AND DESIGN: Sixty-four 21OHD patients participated (23 men and 41 women; median age 38.5 years; range 19-72 years) in a cross-sectional study including DNA sequencing of CYP21A2, anthropometric measurements including dual X-ray absorptiometry scanning and biochemical analyses. The results were compared with reference cohorts from the general population. RESULTS We identified four novel and plausibly disease-causing CYP21A2 mutations. Gene deletions/conversions (42.1% of alleles), the splice mutation I2 splice (23.0%) and point mutation I172 N (22.2%) were common. The genotype corresponded to clinical phenotype in 92% of the patients. The prevalence of osteopenia was 48% in males and 34% in females. Both men and women had normal BMI but markedly increased fat mass compared with the normal population. Diastolic blood pressure was higher than normal. Thirty-nine per cent of the women had testosterone levels above the normal range; 13% of the men had testosterone levels below normal. Reduced final height was more pronounced in men (median -11.2 cm, -1.77 SDS) than in women (-6.3 cm, -1.07 SDS). CONCLUSIONS In this population-based survey of 21OHD, we identified four novel mutations and high concordance between genotype and phenotype. The patients had increased fat mass, increased diastolic blood pressure, reduced final height and high frequency of osteopenia among males. These results show unfavourable metabolic features in 21OHD patients indicating a need for improvement of treatment and follow-up.

Six months of diazoxide treatment at bedtime in newly diagnosed subjects with type 1 diabetes does not influence parameters of β-cell function and autoimmunity, but improves glycemic control.

OBJECTIVE Continuous β-cell rest with diazoxide preserves residual endogenous insulin production in type 1 diabetes. However, side effects have hampered therapeutic usefulness. In a double-blind study, we tested whether lower, intermittent dosing of diazoxide had beneficial effects on insulin production, metabolic control, and autoimmunity markers in the absence of side effects. RESEARCH DESIGN AND METHODS Forty-one newly diagnosed type 1 diabetic patients were randomized to 6 months of treatment with placebo or 100 mg diazoxide at bedtime. A1C, C-peptide (fasting and glucagon stimulated), and FoxP3+ regulatory T-cells (Tregs) were measured. Patients were followed for 6 months after intervention. RESULTS Of six dropouts, three were due to perceived side effects; one subject in the diazoxide group experienced rash, another dizziness, and one in the placebo group sleep disturbance. Adverse effects in others were absent. Diazoxide treatment reduced A1C from 8.6% at baseline to 6.0% at 6 months and 6.5% at 12 months. Corresponding A1C value in the placebo arm were 8.3, 7.3, and 7.5% (P < 0.05 for stronger reduction in the diazoxide group). Fasting and stimulated C-peptide decreased during 12 months similarly in both arms (mean −0.30 and −0.18 nmol/l in the diazoxide arm and −0.08 and −0.09 nmol/l in the placebo arm). The proportion of Tregs was similar in both arms and remained stable during intervention but was significantly lower compared with nondiabetic subjects. CONCLUSIONS Six months of low-dose diazoxide was without side effects and did not measurably affect insulin production but was associated with improved metabolic control.

Two Adults with Adrenal Myelolipoma and 21-Hydroxylase Deficiency

We present incidentally discovered adrenal myelolipomas in two adult males with untreated congenital adrenal hyperplasia (CAH). The patients had simple virilizing form of CAH due to mutations in the CYP21 gene coding for 21-hydroxylase; one was heterozygous for the I172N mutation and the other compound heterozygous for the I172N and I2splice mutations. The masses were not removed since myelolipomas are considered benign tumors, and the tumor size did not increase during four- and nine-year observation periods. An adrenal myelolipoma is an important exception to the rule that large tumours should be removed. Untreated CAH with prolonged excessive ACTH stimulation might contribute to the growth of adrenal masses. CAH should be considered as a differential diagnosis of patients with adrenal masses or adrenal myelolipomas.

Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia

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.

Clues for early detection of autoimmune Addison's disease - myths and realities

Early detection of autoimmune Addisons disease (AAD) is important as delay in diagnosis may result in a life‐threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well‐described, but methodical investigations are scarce.

Klassisk medfødt binyrebarkhyperplasi

Congenital adrenal hyperplasia is attributed to inherited enzyme defects in the adrenal cortex. The classical form results in reduced production of cortisol and aldosterone, accompanied by an increase in production of adrenal cortical androgens. This causes virilisation in girls, adrenocortical failure and early puberty in both sexes. This article describes the genetics, clinical picture, diagnostics and treatment.

The usage of fasting glucose and glycated hemoglobin for the identification of unknown type 2 diabetes in high risk patients with morbid obesity

Abstract Background: In spite of increased vigilance of undiagnosed type 2 diabetes (DM2), the prevalence of unknown DM2 in subjects with morbid obesity is not known. Aim: To assess the prevalence of undiagnosed DM2 and compare the performance of glycated A1c (HbA1c) and fasting glucose (FG) for the diagnosis of DM2 and prediabetes (preDM) in patients with morbid obesity. Patients and methods: We measured fasting glucose and HbA1c in 537 consecutive patients with morbid obesity without previously known DM2. Results: A total of 49 (9%) patients with morbid obesity had unknown DM2 out of which 16 (33%) fulfilled both the criteria for HbA1c and FG. Out of 284 (53%) subjects with preDM, 133 (47%) fulfilled both the criteria for HbA1c and FG. Measurements of agreement for FG and HbA1c were moderate for DM2 (κ = 0.461, p < .001) and fair for preDM (κ = 0.317, p < .001). Areas under the curve for FG and HbA1c in predicting unknown DM2 were 0.970 (95% CI 0.942, 0.998) and 0.894 (95% CI 0.837, 0.951) respectively. The optimal thresholds to identify unknown DM2 were FG ≥6.6 mmol/L and HbA1c ≥ 6.1% (43 mmol/mol). Conclusions: The prevalence of DM2 remains high and both FG and HbA1c identify patients with unknown DM2. FG was slightly superior to HbA1c in predicting and separating patients with unknown DM2 from patients without DM2. We suggest that an FG ≥6.6 mmol/L or an HbA1c ≥6.1% (43 mmol/mol) may be used as primary cut points for the identification of unknown DM2 among patients with morbid obesity.