Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association最新文献

Aim: Despite the high sensitivity of neonatal screening in detecting the classical form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, one of the unclear issues is identifying asymptomatic children with late onset forms. The aim of this nationwide study was to analyse the association between genotype and screened level of 17-hydroxyprogesterone in patients with the late onset form of 21-hydroxylase deficiency and to quantify false negativity.

Methods: In the Czech Republic, 1,866,129 neonates were screened (2006-2022). Among this cohort, 159 patients were confirmed to suffer from 21-hydroxylase deficiency, employing the 17-hydroxyprogesterone birthweight/gestational age-adjusted cut-off limits, and followed by the genetic confirmation. The screening prevalence was 1:11,737. Another 57 patients who were false negative in neonatal screening were added to this cohort based on later diagnosis by clinical suspicion. To our knowledge, such a huge nationwide cohort of false negative patients has not been documented before.

Results: Overall, 57 patients escaped from neonatal screening in the monitored period. All false negative patients had milder forms. Only one patient had simple virilising form and 56 patients had the late onset form. The probability of false negativity in the late onset form was 76.7%. The difference in 17-hydroxyprogesterone screening values was statistically significant (p<0.001) between severe forms (median 478.8 nmol/L) and milder (36.2 nmol/L) forms. Interestingly, the higher proportion of females with milder forms was statistically significant compared with the general population.

Conclusions: A negative neonatal screening result does not exclude milder forms of 21-hydroxylase deficiency during the differential diagnostic procedure of children with precocious pseudopuberty.

Maturity-onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While glucokinase (GCK)-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY, such as hepatocyte nuclear factor-1-alpha (HNF1A)-MODY (formerly MODY-3) and HNF4A (formerly MODY-1), usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports.

Introduction: This study aimed to examine the correlation between the growth response in prepubertal children with idiopathic growth hormone (GH) deficiency after 1 year of treatment with GH to the initial clinical and biochemical parameters. Additionally, the secretion dynamics of GH was also studied by analyzing the GH stimulation test profiles in relation to the GH treatment response.

Methods: This retrospective study included 84 prepubertal children (47 males and 37 females) with a definitive diagnosis of GH deficiency. The GH secretory indexes GH_max, GH secretion rate, and GH secretion volume were analyzed in relation to the response to recombinant human growth hormone (rhGH) treatment as defined by the index of responsiveness (IoR). Correlation and regression models were used to identify the best clinical and biochemical predictors to rhGH treatment. ResultsIoR was negatively correlated with the age (r=-0.607, p<0.01) and positively with the distance of child's height from its midparental height (MPH) r=0.466 (p<0.01) and pretreatment growth velocity (r=0.247, p<0.05). GH secretory indexes were correlated, and the highest association was observed between GH_max and GH secretion volume (r=0.883, p<0.01). Among the GH secretory indexes, GH_max was the best predictor of IoR (β coef. = -0.514, p<0.001) followed by the GH secretion volume (β coef. = -0.47, p<0.001) and GH secretion rate (β coef. = -0.367 p<0.001).

Conclusions: The age and the distance of child's height from its MPH are major predictors of GH treatment response in children with idiopathic GH deficiency. The calculation of the other GH secretory indexes GHSR and GHSV are not better predictors of response to GH than GH_max. The combination of clinical and biochemical indexes may improve the pretreatment assessment of response to rhGH treatment.

Purpose:   Familial hypercholesterolemia (FH) is a genetic disorder associated with extremely high levels of low-density lipoprotein cholesterol (LDL-C) and increased incidence of cardiovascular disease. We aimed to evaluate the efficacy and long-term outcomes of lipoprotein apheresis (LA) in the treatment of FH.

Methods:   Cardiovascular events that occurred before and after LA treatment were evaluated by reviewing previous medical records of patients with FH.

Results:   Thirteen patients (female/male: 8/5) were included in this study. The mean Dutch score was 20±4. All patients were treated with a combination of statin and ezetimibe. Before the onset of LA, 8 patients had a history of coronary artery disease, and the median age at onset of cardiovascular disease (CVD) in these patients was 24 years. At the initiation of LA, the median age was 22 years and the mean LDL-C level was 410±130 mg/dL. The mean duration of LA treatment was 13.9±6.9 years. The mean LDL-C levels before and after the latest three LA treatments were 267±63.4 and 71.5±23.4 mg/dL, respectively. The mean reduction in LDL-C levels after LA was 73±8.2%. De novo cardiovascular events occurred in 10 patients during LA treatment; six of these patients had a known history of CVD before LA. Eight of these patients underwent invasive procedures for therapeutic purposes and the total number of procedures was 12.

Conclusion:   LA is an effective method of reducing LDL-C levels and an additional treatment option that may slow disease progression in patients with FH who are at high risk of cardiovascular events.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by a glucocorticoid excess. If inadequately treated, hypercortisolism can lead to increased morbidity and mortality. Surgical removal of the underlying tumor is the first-line treatment but is sometimes not feasible or even contraindicated. Additionally, in cases with severe CS, rapid control of hypercortisolism may be required. In these scenarios, steroidogenesis inhibitors represent a therapeutic alternative to surgery. Over the last years, the knowledge of the broad therapeutic effects of steroidogenesis inhibitors per se and the number of available drugs have increased. However, large comparative studies are still lacking. Accordingly, the decision on which drug to be used in a certain patient or clinical setting may be difficult. This review aims to summarize the main characteristics of steroidogenesis inhibitors.

The genetic landscape of corticotroph tumours of the pituitary gland has dramatically changed over the last 10 years. Somatic changes in the USP8 gene account for the most common genetic defect in corticotrophinomas, especially in females, while variants in TP53 or ATRX are associated with a subset of aggressive tumours. Germline defects have also been identified in patients with Cushing's disease: some are well-established (MEN1, CDKN1B, DICER1), while others are rare and could represent coincidences. In this review, we summarise the current knowledge on the genetic drivers of corticotroph tumorigenesis, their molecular consequences, and their impact on the clinical presentation and prognosis.

Food-dependent Cushing's syndrome (FDCS) is a rare presentation of hypercortisolism from adrenal origin, mostly observed in primary bilateral macronodular adrenal hyperplasia (PBMAH) but also in some cases of unilateral adrenocortical adenoma. FDCS is mediated by the aberrant expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in adrenocortical cells. GIP, secreted by duodenal K cells after food intake, binds to its ectopic adrenal receptor, and stimulates cortisol synthesis following meals. FDCS was first described more than 35 years ago, and its genetic cause in PBMAH has been recently elucidated: KDM1A inactivation by germline heterozygous pathogenic variants is constantly associated with a loss-of-heterozygosity of the short arm of chromosome 1, containing the KDM1A locus. This causes biallelic inactivation of KDM1A, resulting in the GIPR overexpression in the adrenal cortex. These new insights allow us to propose the KDM1A genetic screening to all PBMAH patients with signs of FDCS (low fasting cortisol that increases after a mixed meal or oral glucose load) and to all first-degree relatives of KDM1A variant carriers. Given that KDM1A is a tumor suppressor gene that has also been associated with monoclonal gammopathy of uncertain significance and multiple myeloma, the investigation of FDCS in the diagnostic management of patients with PBMAH and further genetic testing and screening for malignancies should be encouraged.

Management of Cushing's syndrome (CS) can be particularly challenging in older patients, compared with younger individuals, due to the lack of several clinical features associated with cortisol excess along with a greater burden of associated comorbidities. Moreover, the interpretation of diagnostic tests could be influenced by age-related physiological changes in cortisol secretion. While mortality is higher and quality of life is more impaired in the elderly with CS as compared with the younger, there is currently no agreement on the most effective therapeutic options in aged individuals, and safety data concerning medical treatment are scanty. In this review, we summarize the current knowledge about age-related differences in CS etiology, clinical presentation, treatment, and outcomes and describe the potential underlying mechanisms.