Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes has gained attention during the last few decades, as they might be useful in the diagnosis, treatment and management of several human disorders, including endocrine and oncological diseases. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer, still characterized by high mortality and morbidity due to both endocrine and oncological complications. Despite the rarity of this disease, recently, the role of ncRNA has been quite extensively evaluated in ACC. In order to better explore the role of the ncRNA in human ACC, this review summarizes the current knowledge on ncRNA dysregulation in ACC and its potential role in the diagnosis, treatment, and management of this tumor.

Arterial hypertension is characterised by elevated blood pressure (BP) leading to cardiovascular morbidity and mortality, and organ damage. Its prevalence in childhood is around 5% and children should be screened from 3 years of age. Hypertension in childhood or adolescence requires exclusion of a secondary cause. Adrenal disorders frequently underlie secondary hypertension. presenting with imbalances of BP and pleiotropic clinical presentations. Examples are rare genetic defects leading to increased mineralocorticoid activity such as Congenital Adrenal Hyperplasia (CAH) due to 11β-hydroxylase gene ( CYP11B1 ) or 17-hydroxylase gene (CYP17A1) mutation, and Familial Hyperaldosteronism (FH), due to 11β-hydroxylase 1 ( CYP11B1 ) and 11β-hydroxylase 2 ( CYP11B2 ) gene fusion, or to mutations of other genes involved in aldosterone production such as those codifying the chloride-voltage gated channel 2 ( CLCN2 ), the potassium inwardly rectifying channel subfamily J member 5 ( KCNJ5 ), and the calcium voltage-gated channel subunitsα1 H and D (CACNA1H and CACNA1D). The differential diagnosis of childhood hypertension also includes endogenous hypercortisolism (Cushing’s syndrome) or phaeochromocytomas/paragangliomas, neoplastic conditions potentially caused by germinal genetic alterations, in a specific familial syndrome. Lastly, peripheral glucocorticoid and mineralocorticoid pathway disorders due to germline mutations in HSD-11B2 , codifying the enzyme 11β-dehydrogenase type 2, NR3C1 and NR3C2 genes codifying the nuclear receptor subfamily 3 group C members 1 and 2 may also be responsible. A systematic diagnostic approach based on published guidelines is still lacking, and diagnostic suspicions with referral for gene sequencing need to be identified. This review discusses the known causes of endocrine hypertension in children and adolescents, with an emphasis on prevalence, clinical presentation, genetic predisposition and therapeutic strategies.