Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress.

BACKGROUND: Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells. METHODS AND RESULTS: In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects. CONCLUSIONS: This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.

Distinguishing deficiencies in the steroidogenic acute regulatory protein and the cholesterol side chain cleavage enzyme causing neonatal adrenal failure.

OBJECTIVES: To determine the genetic basis of disordered steroidogenesis in Kuwaiti siblings. STUDY DESIGN: Two siblings (46,XX and 46,XY) had normal female external genitalia and severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Abdominal ultrasonography showed normal size adrenal glands, suggesting cholesterol side chain cleavage enzyme (P450scc) deficiency. The CYP11A1 gene encoding P450scc and the STAR gene encoding the steroidogenic acute regulatory protein (StAR) were directly sequenced from leukocyte DNA. RESULTS: All exons and intron/exon boundaries of the CYP11A1 gene were normal; the STAR gene was homozygous for a novel 14-base deletion/frameshift in exon 4 (g.4643_4656del), so that no functional protein could be produced. Both parents and an unaffected sibling were heterozygous; zygosity was confirmed with a BsmF1 restriction fragment length polymorphism. CONCLUSIONS: Unlike most patients with StAR deficiency, our patients did not have the massive adrenal hyperplasia typical of congenital lipoid adrenal hyperplasia. The distinction between StAR and P450scc deficiency may require gene sequencing.

Mineralocorticoid deficiency in hemorrhagic shock.

BACKGROUND: In the critically ill, mineralocorticoid deficiency (MD) is associated with greater disease severity, the development of acute renal insufficiency, and increased mortality. We hypothesized that severely injured trauma patients presenting with hemorrhagic shock would demonstrate a high degree of MD. We also hypothesized that MD in these patients would be associated with increased length of stay, hypotension, fluid requirements, and acute kidney injury (AKI). MATERIALS AND METHODS: Thirty-two trauma patients in hemorrhagic shock on admission to the trauma bay (SBP <90 mm Hg × 2) were enrolled. Blood samples were obtained on ICU admission and 8, 16, 24, and 48 hours later. Plasma aldosterone (PA) and renin (PR) were assayed by radioimmunoassay. MD was defined as a ratio of PA/PR ≤2. Demographic data, injury severity score, ICU and hospital length of stay, fluid requirements, mean arterial pressure, serum sodium, hypotension, and risk for AKI were compared for patients with and without MD. RESULTS: At ICU admission, 48% of patients met criteria for MD. Patients with MD were significantly more likely to experience hypotension (MAP ≤60 mm Hg) during the study period. MD patients required significantly more units of blood in 48 h than non-MD patients (13 [7-22] versus 5 [2-7], P = 0.015) and had increased crystalloid requirements (18L [14-23] versus 9L [6-10], P < 0.001). MD patients were at higher risk for AKI according to RIFLE and AKIN criteria. CONCLUSIONS: MD is a common entity in trauma patients presenting in hemorrhagic shock. Patients with MD required a more aggressive resuscitative effort, were more likely to experience hypotension, and had a higher risk of AKI than non-MD patients. Future studies are needed to fully understand the impact of MD following trauma and the potential role for hormonal replacement therapy.

Homozygous nonsense and frameshift mutations of the ACTH receptor in children with familial glucocorticoid deficiency (FGD) are not associated with long-term mineralocorticoid deficiency.

OBJECTIVE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. DESIGN: Clinical review of patients with nonsense MC2R mutations. PATIENTS: Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. RESULTS: Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. CONCLUSION: Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.

Primary Adrenal Insufficiency: Managing Mineralocorticoid Replacement Therapy.

Context: Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome. Design: Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure. Results: The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement. Conclusions: The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed.

News about the genetics of congenital primary adrenal insufficiency.

Primary adrenal insufficiency (PAI) is characterized by impaired production of steroid hormones due to an adrenal cortex defect. This condition incurs a risk of acute insufficiency which may be life-threatening. Today, 80% of pediatric forms of PAI have a genetic origin but 5% have no clear genetic support. Recently discovered mutations in genes relating to oxidative stress have opened the way to research on genes unrelated to the adrenal gland. Identification of causal mutations in a gene responsible for PAI allows genetic counseling, guidance of follow-up and prevention of complications. This is particularly true for stress oxidative anomalies, as extra-adrenal manifestations may occur due to the sensitivity to oxidative stress of other organs such as the heart, thyroid, liver, kidney and pancreas.

An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency.

CONTEXT: Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes. OBJECTIVE: The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations. PATIENTS AND DESIGN: We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1. RESULTS: The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins. CONCLUSIONS: We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.

Mineralocorticoid deficiency in post-operative cerebral salt wasting.

Acute hyponatremia, following neurosurgery, results from inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting (CSW). CSW is due to abnormally high atrial or brain natriuretic peptides (ANP, BNP), which block all stimulators of zona glomerulosa steroidogenesis, resulting in mineralocorticoid deficiency. A 3 year-old girl presented CSW at day 4, after resection of craniopharyngioma and hypophysectomy. Hyponatremia, hyperkalemia and high natriuresis occurred on day 8, with low renin and aldosterone and elevated BNP 120.3 ng/ml (undetectable before surgery). Fludrocortisone 100 microg/day controlled natriuresis and restored electrolytes within 24 hours. A 5 year-old boy presented CSW at day 6 after partial resection of optic glioma. Fludocortisone 100 microg/day restored electrolytes within 8 hours. ANP was elevated, 60.6 ng/l, aldosterone and renin were low. Fludrocortisone supplementation should be considered in CSW, as excessive natriuresis is controlled, and electrolytes are easily restored, avoiding life-threatening complications of this complex disorder.

Functioning adrenal adenoma in association with congenital adrenal hyperplasia.

We report a case of a young hypertensive male who was first seen in 1998 with a right thalamic haemorrhage and uncontrolled hypertension. CT abdomen showed a right adrenal tumour and a hyperplastic left adrenal gland. Laparoscopic adrenalectomy performed followed by histopathological examination confirmed the diagnosis of adrenal adenoma. He subsequently presented to us again a year later with persistent hyperkalaemia and asymptomatic hyponatraemia. Further investigations strongly suggested the presence of isolated mineralocorticoid deficiency with normal cortisol levels. This was confirmed to be due to partial or late-onset congenital adrenal hyperplasia (CAH). We discuss the association of partial CAH and adrenal tumours and the unmasking of the mineralocorticoid deficiency following adrenalectomy.

Non-Virilizing Congenital Adrenal Hyperplasia in a Female Patient with a Novel HSD3B2 Mutation.

Classic 3ß-hydroxysteroid dehydrogenase type 2 (3ß-HSD II) deficiency causes congenital adrenal hyperplasia with glucocorticoid, mineralocorticoid, and sex steroid deficiency. We present a female patient with congenital adrenal hyperplasia detected in newborn screening due to elevated 17OH-progesterone. Female external genitalia and non-measurable androgen levels elicited the suspicion of a defect early in the steroid cascade. Two loss-of-function HSD3B2 mutations (1 novel) were detected and confirmed in silico. We argue that in a girl with glucocorticoid and mineralocorticoid deficiency without virilization, 3ß-HSD II deficiency is an important differential diagnosis. 17OH-progesterone may initially be elevated due to placental and peripheral activity of 3ß-HSD I, whereas dehydroepiandrosterone may not be increased.

Sugar or salt? The relative roles of the glucocorticoid and mineralocorticoid axes in traumatic shock.

BACKGROUND: Glucocorticoid deficiency (GD) has been proposed as a key contributor to shock states, but the presence and role of acute mineralocorticoid deficiency may be of equal or greater significance. We sought to analyze the incidence and degree of acute mineralocorticoid deficiency and GD in an animal model of severe hemorrhage and shock. METHODS: Fifty-seven swine underwent 35% volume-controlled hemorrhage followed by aortic cross-clamping for 50 minutes to induce truncal ischemia-reperfusion. Protocol-guided resuscitation was performed. Laboratory analysis included cortisol, aldosterone, and plasma renin activity. The aldosterone-to-renin ratio (ARR) was calculated at each time point, and changes were correlated to markers of perfusion. RESULTS: Mean baseline cortisol levels were 5.8 µg/dL. Following hemorrhage, there was a significant increase in mean cortisol to 9.2 µg/dL (p < 0.001). After 1 hour of reperfusion, there was no change in mean cortisol levels (9.8 µg/dL, p = 0.12). Mean baseline aldosterone was 13.3 pg/mL. Aldosterone levels before cross-clamp removal increased significantly to 115.1 pg/mL (p < 0.001) and then rapidly declined to 49.2 pg/mL (p < 0.001) after 1 hour of reperfusion. Conversely, baseline plasma renin activity was 0.75 ng/mL per hour and increased significantly before cross-clamp removal (1.8) and at 1 hour (8.9, both p < 0.001). The ARR at baseline was 96.1 and increased to 113.5 (p = 0.68) before cross-clamp removal but significantly declined following 1 hour of reperfusion to 7.6 (p < 0.001). Overall, this represented a 93% reduction in mean ARR following reperfusion. The degree of aldosterone deficiency correlated with degree of systemic shock as measured by arterial base deficit (r = 0.47, p = 0.04), while cortisol showed no correlation. CONCLUSION: Hemorrhagic shock with ischemia-reperfusion injury resulted in only modest impact on the glucocorticoid axis, but major dysfunction of the mineralocorticoid axis and severe hyperreninemic hypoaldosteronism. The degree of aldosterone deficiency may provide prognostic information or offer potential targets for pharmacologic intervention. LEVEL OF EVIDENCE: Diagnostic study, level III.

Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population.

We report a population-wide analysis of all patients with 21-hydroxylase deficiency (21-OHD) found in Finland, a country with a genetically well defined population, in which the effects of other genetic and environmental factors on the phenotype can be expected to be low. In total, 120 patients were identified, and their clinical status was evaluated. Blood samples for CYP21 genotype determination could be obtained from 78 (65%) patients, and their phenotypes were compared with their genotypes. In general, the severity of gene defects correlated well with clinical expression. All patients carrying mutations with the most drastic effects on enzymatic activity had the salt-wasting form of 21-OHD. The I2 splice mutation, which in some reports has been connected with clinical variation, was constantly associated with severe mineralocorticoid deficiency. However, patients with I172N as the determining mutation expressed a wide spectrum of phenotypes; the variation could not be attributed to additional mutations. Although genetically affected males with the nonclassical form had not been clinically diagnosed, our study suggests that nonclassical 21-OHD is substantially more rare in Finland than elsewhere, as indicated by both clinical evaluation and mutational screening.

Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia.

A number of patients with ACTH unresponsiveness resulting in glucocorticoid deficiency with normal mineralocorticoid activity have been described. This could be due to an inherited defect within the adrenal gland causing primary unresponsiveness to ACTH or to an inherited progressive degenerative process. The association of achalasia, lack of lacrimation, and glucocorticoid deficiency in two pairs of siblings with normal mineralocorticoid activity has been recently reported. Our case describes an 8.8-yr-old female with glucocorticoid insufficiency, partial mineralocorticoid deficiency, achalasia, and evidence of decreased lacrimation. Sodium depletion produced hyponatremia, and she was unable to increase her plasma aldosterone levels sufficiently, although PRA was markedly elevated. Our case may be part of a progressive degenerative process, possibly affecting both the autonomic nerve structures and the adrenal gland, leading not only to glucocorticoid deficiency but also to abnormal mineralocorticoid secretion.

Requirement of mineralocorticoid in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Marginal salt loss occurs in patients with congenital adrenal hyperplasia due to 11 beta-hydroxylase (11-OHase) deficiency treated with dexamethasone and is accompanied by increased PRA. The present study was undertaken to evaluate the effect of the stimulated renin-angiotensin system on pituitary-adrenal suppression. Seven patients with 11-OHase deficiency were subjected to a series of treatments with dexamethasone, cortisol, and combined cortisol and 9 alpha-fluorohydrocortisone. The latter combination suppressed PRA and sodium excretion, and produced better control of the pituitary-adrenal axis, as measured by plasma ACTA and serum 11-deoxycortisol. We conclude that in children with 11-OHase deficiency, PRA needs to be monitored, and when it is elevated, mineralocorticoid replacement is indicated.

Disorders of mineralocorticoid synthesis.

Abnormalities of mineralocorticoid synthesis and/or metabolism profoundly affect the regulation of electrolyte and water balance and of blood pressure. Characteristic changes in extracellular potassium, sodium and hydrogen ion concentrations are usually diagnostic. Serious deficiency may be acquired, for example in Addison's disease, or inherited. In most of the inherited syndromes, the precise molecular changes in specific steroidogenic enzymes have been identified. Mineralocorticoid excess may be caused by aldosterone or 11-deoxycorticosterone by inadequate conversion of cortisol to cortisone by 11beta-hydroxysteroid dehydrogenase type 2 in target tissues (see Chapter 4), by glucocorticoid receptor deficiency or by constitutive activation of renal sodium channels. Changes in electrolyte balance and renin as well as the abnormal pattern of corticosteroid metabolism are usually diagnostic. Where these abnormalities are inherited (e.g. 11beta- or l7alpha-hydroxylase deficiencies, glucocorticoid remediable hyperaldosteronism (GRA), receptor defects, Liddle's syndrome), the molecular basis is again usually known and, in some cases, may provide the simplest diagnostic tests. Primary aldosteronism, although readily identifiable, presents problems of differential diagnosis, important because optimal treatment is different for each variant. Moreover, the mechanisms by which the variants develop are poorly understood. Finally, a significant proportion of patients with essential hypertension show characteristics of mild mineralocorticoid excess, for example low renin levels. Is this relevant to pathophysiology and, if so, is the effect induced via classic mechanisms of action or through newly discovered direct actions on the brain, heart and blood vessels? These questions are the subject of current research.

Variable presentation of X-linked adrenal hypoplasia congenita.

We present a family with X-linked adrenal hypoplasia congenita (AHC) due to a truncation mutation in the DAX1 gene. The three patient reports demonstrate variable clinical and biochemical features at presentation. They presented with adrenal crises at 3 years, 4 weeks, and 3 weeks. Mineralocorticoid deficiency preceded glucocorticoid deficiency in patient 3 and an early ultrasound indicated normal sized adrenal tissue. Genetic analysis showed that potential female carriers were unaffected.

[Two cases of mineralocorticoids deficiency as first endocrine manifestation of APECED syndrome]. / A propos de deux cas de déficit en minéralo-corticoïdes dû à une première manifestation endocrinienne du syndrome APECED.

The Authors report two cases of APECED syndrome (Auto-immune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) revealed by hyponatremia due to isolated mineralocorticoids deficiency. Such cases illustrate the variable endocrine features revealing the syndrome. The mechanisms underlying the auto-immune destruction of the adrenals are discussed.

[Diagnosis and therapy of patients with adrenocortical insufficiency]. / Diagnostiek en therapie bij patiënten met bijnierschorsinsufficiëntie.

Most symptoms and signs of adrenocortical insufficiency are aspecific. For a definitive diagnosis a stimulation test is often needed. In case of secondary adrenocortical insufficiency glucocorticoid substitution nearly always suffices. Patients with primary adrenocortical insufficiency need substitution not only with glucocorticoids but also with mineralocorticoids. A standard daily dose of 30 mg hydrocortisone as glucocorticoid substitution is too high for many patients, while for some a standard daily dose of 0.1 mg fludrocortisone as mineralocorticoid substitution is too low. Patients with adrenocortical insufficiency need adequate instructions about what to do in case of stress, such as a (febrile) illness or trauma. Duration and severity of the suppression of the pituitary-adrenal axis by the use of pharmacological amounts of glucocorticoids are highly variable. When pharmacological amounts of glucocorticoids (> 7.5 mg prednisone daily) are used for 3 weeks or longer, a clinically relevant suppression of the pituitary-adrenal axis is possible, and this may persist for one year after discontinuing the use of glucocorticoids.

[Management of congenital adrenal hyperplasia]. / A congenitalis adrenalis hyperplasia kezeléséröl.

This review deals with the current problems in the management of classical 21-hydroxylase deficiency from the fetal life to the puberty. The clinical consequences of 21-hydroxylase deficiency reflect the disordered physiology--impaired secretion of glucocorticoids and mineralocorticoids, and excessive secretion of androgens. Current therapy is intended to correct the disordered physiology by replacing mineralocorticoid and glucocorticoid hormones, thereby reducing the ACTH-driven increase in adrenal androgen secretion. Treated patients should expect a normal life span and reproductive potential. This can be achieved by careful attention to regular measurements of clinical parameters and biochemical indices of control.

Adrenal disorders in human immunodeficiency virus (HIV) infected patients.

Human Immunodeficiency Virus (HIV) infection is associated with adrenal disorders, which must not be underestimated. Adrenal morphologic changes are primarily related to opportunistic infections, mostly by cytomegalovirus and mycobacteria, and malignant tumours such as non-Hodgkin's lymphoma and Kaposi's sarcoma. The most frequent biological alteration reported to date is the increases in cortisol concentrations which results from a decrease in cortisol metabolism and hyperactivity of the hypothalamo-pituitary-adrenal axis commonly referred to as pseudo-Cushing's syndrome. These modifications can be a consequence of antiretroviral therapy and do not require any investigation or specific treatment. Conversely, adrenal insufficiency, either iatrogenic or secondary to glandular infiltration by neoplasms or infections, needs long-term substitution with hydrocortisone, but at present occurs more rarely and usually at late stages of disease progression. The impact of HIV infection on the other adrenocortical functions has been less reported in the literature although several studies show low levels of adrenal androgens, especially dehydroepiandrostenedione (DHEA). Impairment in mineralocorticoid function appears occasional and remains a subject of debate.