Fertility and sexual activity in patients with Triple A syndrome.

Objective: Triple A syndrome, caused by autosomal recessively inherited mutations in the AAAS gene is characterized by alacrima, achalasia, adrenal insufficiency, and neurological impairment. To the best of our knowledge, no patients of both sexes have been reported to have offspring. Our aim was to assess the causes of infertility in male patients with this multisystemic syndrome, and to present a female patient that spontaneously conceived a child. Design: Cross-sectional study. Methods: Six males aged 19-48 years were included. Gonadotropins, testosterone, DHEAS, androstenedione, inhibin B, anti-Mullerian hormone measurements and testicular ultrasound were performed. Results: All six male patients had impaired general health and neurological symptoms including erectile and ejaculatory dysfunction. None of them had an offspring. The only demonstrated cause of infertility in our male patients was erectile and ejaculatory dysfunction which precludes sexual intercourse. Our patients had normal libido but were sexually abstinent. Except for low adrenal androgen levels, the concentrations of all measured hormones as well as testicular ultrasound were normal which may indicate the possibility of spermatogenesis in male patients with triple A syndrome. Little is known about fertility in female patients, but based on our observations spontaneous pregnancies seem to be possible. Conclusion: Our results contribute to still scarce knowledge on fertility in patients with Triple A syndrome and as well represents a foundation for further research on causes of infertility and possible treatment options.

Acromicric dysplasia due to a novel missense mutation in the fibrillin 1 gene in a three-generation family.

OBJECTIVES: Short stature is one of the most common reasons for consulting a paediatric endocrinologist. Targeted diagnosis of familial short stature can be challenging due to a broad spectrum of differential diagnoses. CASE PRESENTATION: Here we report a novel mutation in the fibrillin 1 gene (FBN1) in six family members causing a mild phenotype of acromicric dysplasia. Additionally, we present the effects of growth hormone therapy in one of the affected children. CONCLUSIONS: Acromicric dysplasia is a very rare skeletal dysplasia with a prevalence of <1 of 1.000.000 with only about 60 cases being reported worldwide. It is characterized by short stature, acromelia, mild facial dysmorphy but normal intelligence. This study aims to exemplify the clinical and molecular features of FBN1-related acromicric dysplasia and illustrates its pleiotropy by presenting a new, mild phenotype.

Obesity and COVID-19: What are the Consequences?

Obesity is an increasing health problem all over the world. In combination with the current COVID-19 pandemic, this has turned into a massive challenge as individuals with overweight and obesity at all ages show a significant increase in their risk of getting severe COVID-19. Around 20% of all patients that were hospitalized for COVID-19 suffered from obesity alone, whereas obesity in combination with other metabolic comorbidities, such as type 2 diabetes and hypertension, account for up to 60% of all hospitalizations in relation to COVID-19. Therefore, it is of immense importance to put the spotlight on the high incidence of obesity present already in childhood both by changing the individual minds and by encouraging politicians and the whole society to commence preventive interventions for achieving a better nutrition for all social classes all over the world. In the current review, we aim to explain the different pathways and mechanisms that are responsible for the increased risk of severe COVID-19 in people with overweight and obesity. Furthermore, we discuss how the pandemic has led to weight gains in many people during lockdown. At the end, we discuss the importance of preventing such an interface between a non-communicable disease like obesity and a communicable disease like COVID-19 in the future.

CYP21A2 Gene Expression in a Humanized 21-Hydroxylase Mouse Model Does Not Affect Adrenocortical Morphology and Function.

Steroid 21-hydroxylase is an enzyme of the steroid pathway that is involved in the biosynthesis of cortisol and aldosterone by hydroxylation of 17α-hydroxyprogesterone and progesterone at the C21 position. Mutations in CYP21A2, the gene encoding 21-hydroxylase, cause the most frequent form of the autosomal recessive disorder congenital adrenal hyperplasia (CAH). In this study, we generated a humanized 21-hydroxylase mouse model as the first step to the generation of mutant mice with different CAH-causing mutations. We replaced the mouse Cyp21a1 gene with the human CYP21A2 gene using homologous recombination in combination with CRISPR/Cas9 technique. The aim of this study was to characterize the new humanized mouse model. All results described are related to the homozygous animals in comparison with wild-type mice. We show analogous expression patterns of human 21-hydroxylase by the murine promoter and regulatory elements in comparison to murine 21-hydroxylase in wild-type animals. As expected, no Cyp21a1 transcript was detected in homozygous CYP21A2 adrenal glands. Alterations in adrenal gene expression were observed for Cyp11a1, Star, and Cyb11b1. These differences, however, were not pathological. Outward appearance, viability, growth, and fertility were not affected in the humanized CYP21A2 mice. Plasma steroid levels of corticosterone and aldosterone showed no pathological reduction. In addition, adrenal gland morphology and zonation were similar in both the humanized and the wild-type mice. In conclusion, humanized homozygous CYP21A2 mice developed normally and showed no differences in histological analyses, no reduction in adrenal and gonadal gene expression, or in plasma steroids in comparison with wild-type littermates.

[Long-term morbidity in congenital adrenal hyperplasia]. / Langzeitmorbidität beim adrenogenitalen Syndrom.

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders and is characterized by cortisol deficiency. The most common cause of CAH is a mutation in the CYP21A2 gene, resulting in 21-hydroxylase deficiency in the adrenal cortex. The lack of cortisol causes an increase in adrenocorticotropic hormone (ACTH), which in turn results in an excess of adrenal androgens. Aldosterone synthesis may also be impaired. The clinical manifestation of CAH depends on the residual activity of 21-hydroxylase and the subsequent lack of cortisol and adrenal androgen excess. While classic CAH is a potentially life-threatening condition, non-classic CAH is mild to asymptomatic. Therapy of classic CAH consists of glucocorticoid and mineralocorticoid substitution. Despite optimization of therapy, CAH still leads to increased morbidity and mortality in patients. The clinical consequences of androgen excess in affected women range from intrauterine virilisation of external genitalia in classic CAH patients to mild symptoms of hyperandrogenism in non-classic forms. Increased demand for cortisol during illness or physical and psychological stress situations can trigger life-threatening adrenal crises. As current glucocorticoid therapy cannot mimic the physiological circadian rhythm and is usually supraphysiological in dose to control androgen excess, therapy-associated long-term consequences such as decreased bone health and an increased cardiometabolic risk profile are common. The burden of the disease may also lead to impaired quality of life and mental health. For this reason, regular screening and follow-up of patients with CAH should be performed in specialized centers to detect and treat possible comorbidities at an early stage.