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Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia

Sinéad M McGlacken-Byrne, Jasmina Kallefullah Mohammad, Niamh Conlon, Diliara Gubaeva, Julie Siersbæk, Anders Jørgen Schou, Huseyin Demirbilek, Antonia Dastamani, Jayne A L Houghton, Klaus Brusgaard, Maria Melikyan, Henrik Christesen, Sarah E Flanagan, Nuala P Murphy, and Pratik Shah

Objective

The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY).

Design

We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995–2020).

Methods

Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis.

Results

A total of 34 patients (70.6% female, n  = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n  = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2–6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0–13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%).

Conclusions

We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

Free access

Comment on long-term male fertility after treatment with radioactive iodine for DTC

Nayana Tara Vasireddy, Krishna Shantilal Mori, Adlyne Reena Asirvatham, and Shriraam Mahadevan

Restricted access

Effect of obstructive sleep apnea on glucose metabolism

Han-Chow E Koh, Stephan van Vliet, Chao Cao, Bruce W Patterson, Dominic N Reeds, Richard Laforest, Robert J Gropler, Yo-El S Ju, and Bettina Mittendorfer

Background

Obstructive sleep apnea (OSA) is prevalent in people with obesity and is a major risk factor for type 2 diabetes (T2D). The effect of OSA on metabolic function and the precise mechanisms (insulin resistance, β-cell dysfunction, or both) responsible for the increased T2D risk in people with OSA are unknown.

Design and methods

We used a two-stage hyperinsulinemic–euglycemic clamp procedure in conjunction with stable isotopically labeled glucose and palmitate tracer infusions and 18F-fluorodeoxyglucose injection and positron emission tomography to quantify multi-organ insulin action and oral and intravenous tolerance tests to evaluate glucose-stimulated insulin secretion in fifteen people with obesity and OSA and thirteen people with obesity without OSA.

Results

OSA was associated with marked insulin resistance of adipose tissue triglyceride lipolysis and glucose uptake into both skeletal muscles and adipose tissue, whereas there was no significant difference between the OSA and control groups in insulin action on endogenous glucose production, basal insulin secretion, and glucose-stimulated insulin secretion during both intravenous and oral glucose tolerance tests.

Conclusions

These data demonstrate that OSA is a key determinant of insulin sensitivity in people with obesity and underscore the importance of taking OSA status into account when evaluating metabolic function in people with obesity. These findings may also have important clinical implications because disease progression and the risk of diabetes-related complications vary by T2D subtype (i.e. severe insulin resistance vs insulin deficiency). People with OSA may benefit most from the targeted treatment of peripheral insulin resistance and early screening for complications associated with peripheral insulin resistance.

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An impressive response with larotrectinib in a patient with a papillary thyroid carcinoma harboring an SQSTM1-NTRK1 fusion

Sophie Bargas, Anne Mc Leer, Julie Mondet, Olivier Chabre, and Mathieu Laramas

NTRK

rearrangements represent a very rare genomic abnormality among all cancers but can be detected in thyroid cancer with a non-negligible frequency of 2%. Dramatic clinical responses to therapies targeting NTRK chimeric proteins are now well described in the literature. SQSTM1-NTRK1fusions have not yet been described in a full clinical case report. We report a patient with a papillary thyroid carcinoma harboring this unique rearrangement, with an impressive clinical and radiologic response to larotrectinib, a highly specific inhibitor.

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Inflammatory biomarkers in the evaluation of pediatric endogenous Cushing syndrome

Rachel Wurth, Megan Rescigno, Chelsi Flippo, Constantine A Stratakis, and Christina Tatsi

Objective

Inflammatory biomarkers, such as absolute neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), platelet (PLT)-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), are associated with the progression and development of several disorders. Although patients with Cushing syndrome (CS) have immunosuppression with altered leucocyte counts, the profile of the inflammatory biomarkers in these patients has not been extensively studied.

Design

We compared a panel of inflammatory biomarkers in patients with active endogenous CS (n of complete blood count (CBC) reports = 319) and eucortisolemic subjects of similar age, gender and BMI (n of CBC reports = 93). Patients were divided into two age groups (6–12 years at the time of CBC and >12 years at the time of CBC) based on age differences in normal reference ranges.

Results

Patients with CS had higher NLR vs controls (6–12 years: 2.47 (1.86, 3.32) vs 1.35 (1.11, 2.27), P  < 0.0001; >12 years: 3.00 (2.23–4.17) vs 1.80 (1.23–2.31), P  < 0.0001). Similarly, absolute neutrophil and lymphocyte counts, MLR and PLR differed between patients with CS and controls. The inflammatory biomarkers correlated with indices of cortisol secretion, such as midnight serum cortisol, 24-h urinary free cortisol and morning cortisol. On receiver operating characteristic analysis, NLR showed high area under the curve (AUC) (6–12 years: cutoff of 1.72 had AUC: 0.77, >12 years: cutoff of 2.35 had AUC: 0.81).

Conclusions

We conclude that multiple inflammatory biomarkers differed between patients with CS and controls suggesting substantial effects of hypercortisolemia on the immune system.

Open access

Oral 11β-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial

R A Ajjan, E M A Hensor, F Del Galdo, K Shams, A Abbas, R J Fairclough, L Webber, L Pegg, A Freeman, A E Taylor, W Arlt, A W Morgan, A A Tahrani, P M Stewart, D A Russell, and A Tiganescu

Background

Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.

Objectives

Efficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.

Design

Investigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.

Methods

Single-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.

Results

Exploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: −3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69–104%). Wound diameter was 34% (7–63%) smaller with AZD4017 at day 2, and 48% (12–85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.

Conclusion

A phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.

Significance statement

Stress hormone activation by the enzyme 11β-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11β-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11β-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11β-HSD type 1 as a novel therapeutic target forchronic wounds.

Restricted access

Parathyroid hormone in situ measurement in patients with hyperparathyroidism: single-centre experience of 179 patients

Carine Richa, Hazar Haidar, Margot Dupeux, Jean-François Papon, Benoit Lambert, Sylvie Salenave, Mohammed Bouyacoub, Jacques Young, Philippe Chanson, Séverine Trabado, and Luigi Maione

Context

The measurement of parathyroid hormone(PTH) in situ (PTHis) by fine-needle aspiration (FNA) has been proposed as a tool to preoperatively help localize parathyroid glands detected on ultrasound. However, the accuracy of PTHis is highly variable according to the few available studies.

Aim

We aimed to develop and validate the PTHis procedure and assessed the performance of PTHis in a large series of patients with hyperparathyroidism and/or undetermined cervical lesions.

Patients and methods

The technique set-up consisted of PTHis measurement in thyroid samples from patients with thyroid nodules and patients with high circulating PTH levels (tertiary hyperparathyroidism). Consecutive patients were recruited at one tertiary referral centre from 2017 to 2020 and submitted to ultrasound-guided FNA-PTHis determination.

Results

During the method set-up, we obtained undetectable PTHis levels in all non-parathyroid tissues after sample dilutions. PTHis was higher in patients with hyperparathyroidism (n = 145; 1817 ± 3739 ng/L; range: <4.6–31 140) than in those with thyroid or undetermined cervical lesions (n= 34; <4.6 ng/mL; P  < 0.0001). When evaluating PTHis performance in histologically proven samples (158 lesions from 121 patients), PTHis was detectable in 85/97 parathyroid lesions (87%; range: 22–31;140 ng/L) and undetectable in all non-parathyroid lesions (n = 61; P  < 0.0001). The specificity and positive predictive value were 100%, and the sensitivity was 87.6%. False-negative lesions (n= 12) were smaller (9.4 ± 5.9 mm) and more often consisted of hyperplasias (75%) than true-positive lesions (16.1 ± 8.4 mm and 33%, P = 0.009 and P = 0.0089, respectively). The method was safe and well tolerated. Four educational cases are also provided.

Conclusions

PTHis determination is a safe and well-tolerated procedure that enhances the specificity of ultrasound-detected lesions. If accurately set-up, it confirms the parathyroid origin of uncharacterized cervical lesions.

Open access

Prenatal exposure to glucocorticoids and the prevalence of overweight or obesity in childhood

Kristina Laugesen, Henrik Toft Sørensen, Jens Otto L Jorgensen, and Irene Petersen

Objective

Prenatal exposure to excess cortisol can affect postnatal metabolic health by epigenetic mechanisms. We aimed to investigate if prenatal exposure to pharmacological glucocorticoids increases the risk of overweight/obesity in childhood.

Design

A nationwide population registry-based cohort study.

Methods

We identified 383 877 children born in Denmark (2007–2012), who underwent routine anthropometric evaluation at 5–8 years of age. Prenatal exposure to glucocorticoids was divided into systemic and topical glucocorticoids, cumulative systemic dose, and use by trimester. The comparison cohort included children without exposure, born to maternal never-users. Negative control exposures were used to investigate confounding from an underlying disease or unmeasured characteristics. Such exposures included children without glucocorticoid exposure born to maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of glucocorticoids, or paternal users of glucocorticoids during the pregnancy of their partner. We estimated sex-stratified adjusted prevalence ratios (aPR) of overweight/obesity at 5–8 years of age, as epigenetic modifications have shown to be sex-specific.

Results

In the study, 21 246 (11%) boys and 27 851 (15%) girls were overweight/obese at 5–8 years of age. Overall, neither systemic nor topical glucocorticoids were associated with overweight/obesity. In boys, high-dose systemic glucocorticoids was associated with higher prevalence of overweight/obesity vs the comparison cohort (aPR: 1.41 (95% CI: 1.07–1.86), prevalence: 16% vs 11%). Negative control exposures indicated robustness to confounding.

Conclusion

Overweight/obesity might be an adverse effect of prenatal exposure to high-dose systemic glucocorticoids in boys. We found no association for neither prenatal exposure to lower doses of systemic nor topical glucocorticoids. These results merit clinical attention.

Free access

Response to comment on long-term male fertility after treatment with radioactive iodine for DTC

Marloes Nies, Eus G J M Arts, Astrid E P Cantineau, and Thera P Links

Open access

Serum 25-hydroxy vitamin D and the risk of low muscle mass in young and middle-aged Korean adults

Yejin Kim, Yoosoo Chang, Seungho Ryu, In Young Cho, Min-Jung Kwon, Sarah H Wild, and Christopher D Byrne

Objective

Despite the known benefit of vitamin D in reducing sarcopenia risk in older adults, its effect against muscle loss in the young population is unknown. We aimed to examine the association of serum 25-hydroxy vitamin D [25(OH)D] level and its changes over time with the risk of incident low muscle mass (LMM) in young and middle-aged adults.

Design

This study is a cohort study.

Methods

The study included Korean adults (median age: 36.9 years) without LMM at baseline followed up for a median of 3.9 years (maximum: 7.3 years). LMM was defined as the appendicular skeletal muscle (ASM) mass by body weight (ASM/weight) of 1 s.d. below the sex-specific mean for the young reference group. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs.

Results

Of the 192,908 individuals without LMM at baseline, 19,526 developed LMM. After adjusting for potential confounders, the multivariable-adjusted HRs (95% CIs) for incident LMM comparing 25(OH)D levels of 25–<50, 50–<75, and ≥75 nmol/L to 25(OH)D <25 nmol/L were 0.93 (0.90–0.97), 0.85 (0.81–0.89), and 0.77 (0.71–0.83), respectively. The inverse association of 25(OH)D with incident LMM was consistently observed in young (aged <40 years) and older individuals (aged ≥40 years). Individuals with increased 25(OH)D levels (<50–≥50 nmol/L) or persistently adequate 25(OH)D levels (≥50 nmol/L) between baseline and follow-up visit had a lower risk of incident LMM than those with persistently low 25(OH)D levels.

Conclusions

Maintaining sufficient serum 25(OH)D could prevent unfavourable changes in muscle mass in both young and middle-aged Korean adults.