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Open access

Nikolaos Kyriakakis, Marilena Giannoudi, Satish S Kumar, Khyatisha Seejore, Georgios K. Dimitriadis, Harpal Randeva, Adam Glaser, Michelle Kwok-Williams, Georgina Gerrard, Carmel Loughrey, Ahmed Al-Qaissi, Ramzi Ajjan, Julie Lynch, and Robert D Murray

Background: Survivors of childhood brain tumours (SCBT) and teenage and young adult cancer survivors have an adverse cardiovascular risk profile, which translates into an increased vascular mortality. Data on cardiovascular risk profile in SCBT are limited and furthermore there are no data in adult-onset brain tumours.

Patients and Methods: Fasting lipids, glucose, insulin, 24-hour blood pressure, and body composition were measured in 36 brain tumours survivors [20 adult-onset (AO); 16 childhood-onset (CO)] and 36 age- and gender-matched controls.

Results: Compared with controls, patients had elevated total cholesterol (5.3±1.1 Vs. 4.6±1.0mmol/l, p=0.007), LDL-C (3.1±0.8 Vs. 2.7±0.9mmol/l, p=0.011), insulin (13.4±13.1 Vs. 7.6±3.3miu/l, p=0.014) and increased insulin resistance (HOMA-IR 2.90±2.84 Vs. 1.66±0.73, p=0.016). Patients showed adverse body composition, with increased total body fat mass (FM) (24.0±12.2 Vs. 15.7±6.6kg, p<0.001) and truncal FM (13.0±6.7 Vs. 8.2±3.7kg, p<0.001). After stratification by timing of onset, CO survivors showed significantly increased LDL-C, insulin, and HOMA-IR compared with controls. Body composition was characterized by increased total body and truncal FM. Truncal fat mass was increased by 84.1% compared with controls. AO survivors showed similar adverse cardiovascular risk profile, with increased total cholesterol and HOMA-IR. Truncal fat mass was increased by 41.0% compared with matched controls (p=0.029). No difference in mean 24hr BP was noted between patients and controls irrespective of timing of cancer diagnosis.

Conclusion: The phenotype of both CO and AO brain tumour survivors is characterized by an adverse metabolic profile and body composition, putatively placing long-term survivors at increased risk of vascular morbidity and mortality.

Open access

Wolfgang Högler, Agnès Linglart, Anna Petryk, Priya S Kishnani, Lothar Seefried, Shona Fang, Cheryl Rockman-Greenberg, Keiichi Ozono, Kathryn Dahir, and Gabriel Ángel Martos-Moreno

Objective

Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children.

Design

Data from children (aged <18 years) with hypophosphatasia were analyzed from the observational Global Hypophosphatasia Registry.

Methods

Anthropometric parameters were evaluated by age group (<2 years and ≥2 years) at assessment. The frequency of hypophosphatasia manifestations was compared between children with short stature (< percentile) and those with normal stature.

Results

This analysis included 215 children (54.4% girls). Short stature presented in 16.1% of children aged <2 years and 20.4% of those aged ≥2 years at assessment. Among those with available data (n = 62), height was below the target height (mean: −0.66 standard deviations). Substantial worsening of growth (mean delta height z score: −1.45; delta weight z score: −0.68) occurred before 2 years of age, while in those aged ≥2 years, anthropometric trajectories were maintained (delta height z score: 0.08; delta weight z score: 0.13). Broad-ranging hypophosphatasia manifestations (beyond dental) were observed in most children.

Conclusions

Short stature was not a consistent characteristic of children with hypophosphatasia, but growth impairment was observed in those aged <2 years, indicating that hypophosphatasia might affect growth plate activity during infancy. In addition, a broad range of clinical manifestations occurred in those above and below the third percentile for height, suggesting that height alone may not accurately reflect hypophosphatasia disease burden and that weight is less affected than longitudinal growth.

Open access

Qiankai Jin, Guoqing Huang, Xiaoqing Tian, Yimeng Shu, Ximisinuer Tusongtuoheti, and Yushan Mao

Objective

The aim of this study was to elaborate the link of thyroid hormones (THs) and metabolic syndrome (MetS) in a Chinese euthyroid employee population with MetS component(s).

Methods

An annual health checkup was performed on employees in 2019. Anthropometric parameters, metabolic parameters, and thyroid function were measured. A questionnaire was used in conjunction with Zhenhai Lianhua Hospital database to receive employees' medication records and thyroid surgical history records.

Results

A total of 5486 eligible employees were included; the prevalence of MetS was generally higher in males than in females (38.9 vs. 30.4%, P < 0.001). Among employees with central obesity, hypertriglyceridemia, hyperglycemia, hypertension, and low high-density lipoprotein cholesterol (HDL-C), the prevalence of MetS was 68.8, 63.6, 68.2, 48.8, and 60.0% in males and 72.6, 63.3, 61.3, 42.3, and 42.3% in females, respectively. Logistic regression analysis showed that thyroid-stimulating hormone and free thyroxine (FT4) quartiles had no significant impact on MetS. Free triiodothyronine/free thyroxine (FT3/FT4) and free triiodothyronine (FT3)) quartiles were positively associated with the increased odds ratio (OR) for MetS and dyslipidemia (hypertriglyceridemia and low HDL-C), regardless of gender. In males, FT3 and FT3/FT4 quartiles were positively associated with the OR for central obesity, whereas FT4 quartiles were negatively associated; both FT3 and FT4 quartiles were positively associated with increased OR of hyperglycemia, while similar results were not observed in females. Interaction analysis indicated no significant effect of gender and TH interactions on risk of MetS.

Conclusion

High FT3 and FT3/FT4 were strongly linked with MetS and dyslipidemia in our study, even in the euthyroid individuals. Tighter control of thyroid function was necessary for those with preexisting MetS component(s).

Open access

Nathalia Gbp Ferreira, Joao Madeira, Peter Gergics, Renata Kertsz, Juliana Moreira Marques, Nicholas Silvestre de Souza Trigueiro, Anna Flavia Figueredo Benedetti, Bruna V Azevedo, Bianca Helena Ventura Fernandes, Debora D Bissegatto, Isabela Peixoto Biscotto, Qing Fang, Qianyi Ma, Asye Bilge Ozel, Jun Li, Sally A Camper, Alexander A L Jorge, Berenice Bilharinho Mendonca, Ivo Jp Arnhold, and Luciani R Carvalho

Context: Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.

Objectives: To conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant.

Design: Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD and ABraOM), in silico prediction of pathogenicity, and gene expression in pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing.

Results: One female patient with deficiencies in GH, TSH, ACTH, LH, and FSH and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wild type CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected.

Conclusion: A homozygous CDH2 allelic variant was found in 1 hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations.

Open access

Julia Herteux, Simon Johannes Geiger, Christina Starchl, Johanna Windisch, Theresa Lerchl, Adelina Tmava-Berisha, Gerit Wünsch, Kathrin Eller, Astrid Fahrleitner-Pammer, and Karin Amrein

Objective

Chronic hypoparathyroidism (HP) is associated with acute and chronic complications, especially those related to hypocalcemia. We aimed to analyze details on hospital admissions and the reported deaths in affected patients.

Design and methods

In a retrospective analysis, we reviewed the medical history of 198 patients diagnosed with chronic HP over a continuous period of up to 17 years at the Medical University Graz.

Results

The mean age in our mostly female cohort (70.2%) was 62.6 ± 18.7 years. The etiology was predominantly postsurgical (84.8%). About 87.4% of patients received standard medication (oral calcium/vitamin D), 15 patients (7.6%) used rhPTH1–84/Natpar® and 10 patients (4.5%) had no/unknown medication. Two hundred and nineteen emergency room (ER) visits and 627 hospitalizations were documented among 149 patients, and 49 patients (24.7%) did not record any hospital admissions. According to symptoms and decreased serum calcium levels, 12% of ER (n = 26) visits and 7% of hospitalizations (n = 44) were likely attributable to HP. A subgroup of 13 patients (6.5%) received kidney transplants prior to the HP diagnosis. In eight of these patients, parathyroidectomy for tertiary renal hyperparathyroidism was the cause of permanent HP. The mortality was 7.8% (n = 12), and the causes of death appeared to be unrelated to HP. Although the awareness for HP was low, calcium levels were documented in 71% (n = 447) of hospitalizations.

Conclusions

Acute symptoms directly related to HP did not represent the primary cause of ER visits. However, comorbidities (e.g. renal/cardiovascular diseases) associated with HP played a key role in hospitalizations and deaths.

Significance statement

Hypoparathyroidism (HP) is the most common complication after anterior neck surgery. Yet, it remains underdiagnosed as well as undertreated, and the burden of disease and long-term complications are usually underestimated. There are few detailed data on emergency room (ER) visits hospitalizations and death in patients with chronic HP, although acute symptoms due to hypo-/hypercalcemia are easily detectable. We show that HP is not the primary cause for presentation but that hypocalcemia is a typical laboratory finding (when ordered) and thus may contribute to subjective symptoms. Patients often present with renal/cardiovascular/oncologic illness for which HP is known to be a contributing factor. A small but very special group (n = 13, 6.5%) are patients after kidney transplantations who showed a high ER hospitalization rate. Surprisingly, HP was never the cause for their frequent hospitalizations but rather the result of chronic kidney disease. The most frequent cause for HP in these patients was parathyroidectomy due to tertiary hyperparathyroidism. The causes of death in 12 patients appeared to be unrelated to HP, but we found a high prevalence of chronic organ damages/comorbidities related to it in this group. Less than 25% documented HP correctly in the discharge letters, which indicates a high potential for improvement.

Open access

Gregory Knowles, Emily Warmington, Lisa M Shepherd, Jonathan M Hazlehurst, Anne de Bray, Helena Gleeson, Wiebke Arlt, and Alessandro Prete

Objective: Patients with primary adrenal insufficiency (PAI) are thought to be particularly vulnerable to COVID-19; however, little is known about its true impact on this group. We assessed morbidity and health promotion attitudes during the pandemic amongst a large cohort of patients with PAI.

Design: Cross-sectional, single-centre study.

Methods: In May 2020, COVID-19 advice on social distancing and sick-day rules was distributed to all patients with PAI registered with a large secondary/tertiary care centre. A semi-structured questionnaire was used to survey patients in early 2021.

Results: Of 207 contacted patients, 162 responded (82/111 with Addison’s disease, AD; 80/96 with congenital adrenal hyperplasia, CAH). Patients with AD were older than those with CAH (median age 51 vs. 39 years; p<0.001) and had more comorbidities (Charlson comorbidity index ≥2 47.6% vs. 10.0%; p<0.001). By the time of the survey, 47 patients (29.0%) had been diagnosed with COVID-19, the second commonest cause of sick-day dosing during the study and the leading trigger of adrenal crises (4/18 cases). Patients with CAH had a higher risk of COVID-19 compared to AD (adjusted odds ratio 2.53 [95% CI 1.07-6.16], p=0.036), were less inclined to have the COVID-19 vaccine (80.0% vs. 96.3%; p=0.001), and were less likely to have undergone hydrocortisone self-injection training (80.0% vs. 91.5%; p=0.044) or wear medical alert jewellery (36.3% vs. 64.6%; p=0.001).

Conclusions: COVID-19 was a principal trigger for adrenal crises and sick-day dosing in patients with PAI. Despite a higher risk of COVID-19, patients with CAH showed less engagement with self-protective attitudes.

Open access

Zuyao Chen, Xiaolin Zhong, Weiqiang Tang, Min Xia, Chang Liu, Yinping Guo, Yan Yi, Qingshan Jiang, Xuyu Zu, and Jing Zhong

Background

Fibroblast growth factor 1 (FGF1) is extensively amplified in many tumors and accelerates tumor invasion and metastasis. However, the role and precise molecular mechanism by which FGF1 participates in thyroid cancer (TC) are still unclear.

Methods

Quantitative real-time polymerase chain reaction- and western blotting were used to detect the mRNA and protein levels of FGF1, high mobility group A (HMGA1), epithelial-to-mesenchymal transition (EMT)-related factors, and FGFs in both TC tissues and cell lines. Immunohistochemistry was conducted to examine the expression of FGF1 and HMGA1. Immunofluorescence staining was used to detect the coexpression of FGF1 and HMGA1. Transwell and wound healing assays were conducted to evaluate the effects of FGF1 on the capacity of invasion and migration in cells.

Results

FGF1 was upregulated in papillary thyroid carcinoma (PTC) tissues and cell lines and was relatively higher in PTC tissues with cervical lymph node metastasis. Furthermore, FGF1 promotes invasion and metastasis through the EMT pathway. Mechanistically, FGF1 promotes EMT through intracellular function independent of FGF receptors. Interestingly, we demonstrated that FGF1 could upregulate HMGA1 in TC cells, and the correlation of FGF1 and HMGA1 was positive in PTC tissues. FGF1 and HMGA1 had obvious colocalization in the nucleus. We further revealed that FGF1 promotes the invasion and migration of TC cells through the upregulation of HMGA1.

Conclusion

Intracellular FGF1 could promote invasion and migration in TC by mediating the expression of HMGA1 independent of FGF receptors, and FGF1 may be an effective therapeutic target in TC.

Open access

Róża Aleksandrowicz and Marek Strączkowski

Skeletal muscle is the main metabolic tissue responsible for glucose homeostasis in the body. It is surrounded by the extracellular matrix (ECM) consisting of three layers: epimysium, perimysium, and endomysium. ECM plays an important role in the muscle, as it provides integrity and scaffolding cells. The observed disturbances in this structure are related to the abnormal remodeling of the ECM (through an increase in the concentration of its components). ECM rearrangement may impair insulin action by increasing the physical barrier to insulin transport and reducing insulin transport into muscle cells as well as by directly inhibiting insulin action through integrin signaling. Thus, improper ECM remodeling may contribute to the development of insulin resistance (IR) and related comorbidities. In turn, IR-associated conditions may further aggravate disturbances of ECM in skeletal muscle. This review describes the major components of the ECM that are necessary for its proper function. Particular attention was also paid to receptors (integrins) involved in the signaling of metabolic pathways. Finally, changes in ECM components in the context of clinical and animal studies are discussed. This article will help the reader to systematize knowledge related to the ECM and to better understand the relationship between ECM remodeling and IR, and its role in the pathogenesis of T2DM. The information in this article presents the concept of the role of ECM and its remodeling in the pathogenesis of IR, which may contribute to developing new therapeutic solutions.

Open access

Lukas Ochsner Ridder, Agnethe Berglund, Kirstine Stochholm, Simon Chang, and Claus H Gravholt

Context

Klinefelter syndrome (KS, 47,XXY) and 47,XYY syndrome are genetic conditions characterized by a supernumerary sex chromosome. The conditions share many traits, but considerable phenotypic differences are seen between the two. Focusing on morbidity, mortality, and socioeconomics, this review highlights similarities and differences.

Methods

Relevant literature was identified through PubMed with the following search terms; 'Klinefelter', '47,XXY', '47,XYY', and 'Jacobs syndrome'. Included journal articles were chosen at the authors’ discretion.

Results

KS and 47,XYY are the most common sex chromosome disorders in males, with an expected prevalence of 152 and 98 per 100,000 newborn males, respectively. Non-diagnosis is extensive, as only about 38% of KS and 18% of 47,XYY are diagnosed. Both conditions are associated with an increased mortality risk and increased risk of a variety of diseases and other health-related problems affecting virtually every organ system. Early diagnosis seems to predict a lesser comorbidity burden. Neurocognitive deficits as well as social and behavioral problems are commonly described. Both syndromes are associated with poor socioeconomicfor example, lower income and educational level and higher rates of crime. Infertility is a hallmark of KS, but fertility seems also reduced in 47,XYY.

Conclusion

Being born as a boy with an extra X or Y chromosome is associated with increased mortality and excess morbidity, partially expressed in a sex chromosome-specific pattern.Both syndromes continue to be greatly underdiagnosed, even thoughearly intervention may improve the overall outcome. Earlier diagnosis to initiate timely counseling and treatment should be emphasized.

Open access

Ja Hye Kim, Yunha Choi, Soojin Hwang, Ji-Hee Yoon, Jieun Lee, Min Jae Kang, Gu-Hwan Kim, Han-Wook Yoo, and Jin-Ho Choi

Objective

This study was performed to investigate the molecular characteristics and frequency of copy number variations (CNVs) of ANOS1 in patients with Kallmann syndrome (KS) or normosmic isolated hypogonadotropic hypogonadism (nIHH) using multiplex ligation-dependent probe amplification (MLPA) analysis and sequencing.

Methods

Among 45 patients from 43 independent families, Sanger sequencing, next-generation sequencing (NGS), or microarray was performed in 24 patients from 23 families, and MLPA was performed in 19 patients who did not show rare sequence variants (n = 18) or ANOS1 amplification by PCR (n = 1).

Results

Seven patients (four patients with KS, one patient with nIHH, one prepubertal boy with anosmia, and one newborn patient) from six families (6/43, 14%) harbored molecular defects in ANOS1 including a nonsense mutation (c.1140G>A (p.W380*)), a frameshift mutation (c.1260del (p.Q421Kfs*61)), a splice site mutation (c.1449+1G>A), an exon 7 deletion, a complete deletion, and 7.9 Mb-sized inversion encompassing ANOS1. The complete deletion of ANOS1 was identified in a neonate with a micropenis and cryptorchidism. Unilateral renal agenesis was found in three patients, whereas only one patient displayed both synkinesia and sensorineural hearing loss. There was no reversal of hypogonadotropic hypogonadism in any patient during 9.1 ± 2.9 years of treatment with testosterone enanthate.

Conclusions

Molecular defects in the ANOS1 gene could be identified in 14% of probands including various types of CNVs (3/43, 7.0%). Comprehensive analysis using sequencing and analysis for CNVs is required to detect molecular defects in ANOS1.