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Open access

V Jain, L A Metherell, A David, R Sharma, P K Sharma, A J L Clark, and L F Chan

Background

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Mutations in the ACTH receptor/melanocortin 2 receptor (MC2R), the MC2R accessory protein (MRAP) or the STAR protein (STAR) cause FGD types 1, 2 and 3, respectively, accounting for ∼50% of all cases.

Patient and methods

We report a neonate of Indian origin, who was diagnosed with FGD in the first few days of life. He presented with hypoglycaemic seizures and was noted to have generalised intense hyperpigmentation and normal male genitalia. Biochemical investigations revealed hypocortisolaemia (cortisol 0.223 μg/dl; NR 1–23 μg/dl) and elevated plasma ACTH (170 pg/ml). Serum electrolytes, aldosterone and plasma renin activity were normal. Peak cortisol following a standard synacthen test was 0.018 μg/dl. He responded to hydrocortisone treatment and continues on replacement. Patient DNA was analysed by direct sequencing. The effect of the novel mutation was assessed by an in vitro splicing assay using wild type and mutant heterologous minigenes.

Results

A novel homozygous mutation c.106+2_3dupTA was found in the MRAP gene. Both parents were heterozygous for the mutation. In an in vitro splicing assay, the mutation resulted in the skipping of exon 3.

Conclusion

We have identified a novel MRAP mutation where disruption of the intron 3 splice-site results in a prematurely terminated translation product. This protein (if produced) would lack the transmembrane domain that is essential for MC2R interaction. We predict that this would cause complete lack of ACTH response thus explaining the early presentation in this case.

Open access

Feng Sun, Jun-Xiu Zhang, Chang-Yi Yang, Guan-Qi Gao, Wen-Bin Zhu, Bing Han, Le-Le Zhang, Yue-Yue Wan, Xiao-Ping Ye, Yu-Ru Ma, Man-Man Zhang, Liu Yang, Qian-Yue Zhang, Wei Liu, Cui-Cui Guo, Gang Chen, Shuang-Xia Zhao, Ke-Yi Song, and Huai-Dong Song

Objective

Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited.

Design and methods

One hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees.

Results

Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands.

Conclusions

Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.

Open access

Peter Bang, Joachim Woelfle, Valerie Perrot, Caroline Sert, and Michel Polak

Objective

The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS).

Design

Ongoing, open-label, observational registry (NCT00903110).

Methods

Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008–2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs).

Results

Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years’ treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common.

Conclusions

In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.

Open access

Wiebke Arlt, Stephanie E Baldeweg, Simon H S Pearce, and Helen L Simpson

We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient glucocorticoid supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high fever, we suggest oral stress dose cover with 20 mg hydrocortisone every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.

Open access

Jens Bollerslev, Lars Rejnmark, Alexandra Zahn, Ansgar Heck, Natasha M Appelman-Dijkstra, Luis Cardoso, Fadil M Hannan, Filomena Cetani, Tanja Sikjaer, Anna Maria Formenti, Sigridur Björnsdottir, Camilla Schalin-Jäntti, Zhanna Belaya, Fraser Gibb, Bruno Lapauw, Karin Amrein, Corinna Wicke, Corinna Grasemann, Michael Krebs, Eeva Ryhänen, Özer Makay, Salvatore Minisola, Sébastien Gaujoux, Jean-Philippe Bertocchio, Zaki Hassan-Smith, Agnès Linglart, Elizabeth M Winter, Martina Kollmann, Hans-Georg Zmierczak, Elena Tsourdi, Stefan Pilz, Heide Siggelkow, Neil Gittoes, Claudio Marcocci, Peter Kamenický, and the 2021 PARAT Working Group

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders in 2019 were discussed during two virtual workshops in 2021 and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosis of familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represents areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborn children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed at a broader clinical audience and were developed with the focus on endocrinologists in training.

Open access

Margaret C S Boguszewski, Cesar L Boguszewski, Wassim Chemaililly, Laurie E Cohen, Judith Gebauer, Claire Higham, Andrew R Hoffman, Michel Polak, Kevin C J Yuen, Nathalie Alos, Zoltan Antal, Martin Bidlingmaier, Beverley M K Biller, George Brabant, Catherine S Y Choong, Stefano Cianfarani, Peter E Clayton, Regis Coutant, Adriane A Cardoso-Demartini, Alberto Fernandez, Adda Grimberg, Kolbeinn Guðmundsson, Jaime Guevara-Aguirre, Ken K Y Ho, Reiko Horikawa, Andrea M Isidori, Jens Otto Lunde Jørgensen, Peter Kamenicky, Niki Karavitaki, John J Kopchick, Maya Lodish, Xiaoping Luo, Ann I McCormack, Lillian Meacham, Shlomo Melmed, Sogol Mostoufi Moab, Hermann L Müller, Sebastian J C M M Neggers, Manoel H Aguiar Oliveira, Keiichi Ozono, Patricia A Pennisi, Vera Popovic, Sally Radovick, Lars Savendahl, Philippe Touraine, Hanneke M van Santen, and Gudmundur Johannsson

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Open access

Armand Valsesia, Pierre Chatelain, Adam Stevens, Valentina A Peterkova, Alicia Belgorosky, Mohamad Maghnie, Franco Antoniazzi, Ekaterina Koledova, Jerome Wojcik, Pierre Farmer, Benoit Destenaves, Peter Clayton, and the PREDICT Investigator group

Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years −3.3 cm; −0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage.

Open access

S Fjalldal, C Follin, D Svärd, L Rylander, S Gabery, Å Petersén, D van Westen, P C Sundgren, I M Björkman-Burtscher, J Lätt, B Ekman, A Johanson, and E M Erfurth

Context

Patients with craniopharyngioma (CP) and hypothalamic lesions (HL) have cognitive deficits. Which neural pathways are affected is unknown.

Objective

To determine whether there is a relationship between microstructural white matter (WM) alterations detected with diffusion tensor imaging (DTI) and cognition in adults with childhood-onset CP.

Design

A cross-sectional study with a median follow-up time of 22 (6–49) years after operation.

Setting

The South Medical Region of Sweden (2.5 million inhabitants).

Participants

Included were 41 patients (24 women, ≥17 years) surgically treated for childhood-onset CP between 1958–2010 and 32 controls with similar age and gender distributions. HL was found in 23 patients.

Main outcome measures

Subjects performed cognitive tests and magnetic resonance imaging, and images were analyzed using DTI of uncinate fasciculus, fornix, cingulum, hippocampus and hypothalamus as well as hippocampal volumetry.

Results

Right uncinate fasciculus was significantly altered (P ≤ 0.01). Microstructural WM alterations in left ventral cingulum were significantly associated with worse performance in visual episodic memory, explaining approximately 50% of the variation. Alterations in dorsal cingulum were associated with worse performance in immediate, delayed recall and recognition, explaining 26–38% of the variation, and with visuospatial ability and executive function, explaining 19–29%. Patients who had smaller hippocampal volume had worse general knowledge (P = 0.028), and microstructural WM alterations in hippocampus were associated with a decline in general knowledge and episodic visual memory.

Conclusions

A structure to function relationship is suggested between microstructural WM alterations in cingulum and in hippocampus with cognitive deficits in CP.

Open access

Adam Stevens, Philip Murray, Jerome Wojcik, John Raelson, Ekaterina Koledova, Pierre Chatelain, Peter Clayton, and The PREDICT Investigator Group

Objective

Single-nucleotide polymorphisms (SNPs) associated with the response to recombinant human growth hormone (r-hGH) have previously been identified in growth hormone deficiency (GHD) and Turner syndrome (TS) children in the PREDICT long-term follow-up (LTFU) study (Nbib699855). Here, we describe the PREDICT validation (VAL) study (Nbib1419249), which aimed to confirm these genetic associations.

Design and methods

Children with GHD (n = 293) or TS (n = 132) were recruited retrospectively from 29 sites in nine countries. All children had completed 1 year of r-hGH therapy. 48 SNPs previously identified as associated with first year growth response to r-hGH were genotyped. Regression analysis was used to assess the association between genotype and growth response using clinical/auxological variables as covariates. Further analysis was undertaken using random forest classification.

Results

The children were younger, and the growth response was higher in VAL study. Direct genotype analysis did not replicate what was found in the LTFU study. However, using exploratory regression models with covariates, a consistent relationship with growth response in both VAL and LTFU was shown for four genes – SOS1 and INPPL1 in GHD and ESR1 and PTPN1 in TS. The random forest analysis demonstrated that only clinical covariates were important in the prediction of growth response in mild GHD (>4 to <10 μg/L on GH stimulation test), however, in severe GHD (≤4 μg/L) several SNPs contributed (in IGF2, GRB10, FOS, IGFBP3 and GHRHR).

Conclusions

The PREDICT validation study supports, in an independent cohort, the association of four of 48 genetic markers with growth response to r-hGH treatment in both pre-pubertal GHD and TS children after controlling for clinical/auxological covariates. However, the contribution of these SNPs in a prediction model of first-year response is not sufficient for routine clinical use.

Open access

Christopher J Child, Alan G Zimmermann, Whitney W Woodmansee, Daniel M Green, Jian J Li, Heike Jung, Eva Marie Erfurth, and Leslie L Robison

Objective

GH and IGFs have mitogenic properties, causing speculation that GH treatment could increase risk of malignancy. While studies in GH-treated childhood cancer survivors have suggested a slight increase in second neoplasms, studies in GH-treated adults have been equivocal.

Design

Incidence of de novo and second cancers was evaluated in 6840 GH-treated and 940 non GH-treated adult patients in the Hypopituitary Control and Complications Study pharmacoepidemiological database.

Methods

Evident cancer cases were evaluated in the main analysis, with sensitivity analyses including probable and possible cancers. Standardized incidence ratios (SIRs) for cancers were calculated using Surveillance, Epidemiology and End Results for the USA and GLOBOCAN for all other countries.

Results

During the mean follow-up of 3.7 years/GH-treated patient, 142 evident cancer cases were identified, giving an overall SIR of 0.88 (95% confidence interval (CI) 0.74–1.04); 95% CIs included the value of 1.0 for each country examined. The SIR for GH-treated patients from the USA (71 cases) was 0.94 (95% CI 0.73–1.18), and for non GH-treated patients from the USA (27 cases) was 1.16 (95% CI 0.76–1.69). For GH-treated patients from the USA aged <35 years, the SIR (six cases) was 3.79 (1.39–8.26), with SIR not elevated for all other age categories; SIR for patients from the USA with childhood onset (CO) GH deficiency (GHD) was 2.74 (95% CI 1.18–5.41). The SIR for colorectal cancer in GH-treated patients (11 cases) was 0.60 (95% CI 0.30–1.08).

Conclusions

With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs were found for subgroups in the USA cohort defined by age <35 years or CO GHD.