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Open access

Pedro Marques, Nicola Tufton, Satya Bhattacharya, Mark Caulfield and Scott A Akker

Summary

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed.

Learning points:

  • Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels.

  • The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing’s syndrome, Liddle’s syndrome and 11-deoxycorticosterone-producing tumours.

  • DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension.

  • Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase.

  • The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.

Open access

Philip D Oddie, Benjamin B Albert, Paul L Hofman, Craig Jefferies, Stephen Laughton and Philippa J Carter

Summary

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.

Learning points:

  • Adrenocortical carcinoma is an important differential diagnosis for virilization in young children

  • Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis

  • Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.

  • Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed

  • In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

Open access

Lukas Burget, Laura Audí Parera, Monica Fernandez-Cancio, Rolf Gräni, Christoph Henzen and Christa E Flück

Summary

Steroidogenic acute regulatory protein (STAR) is a key protein for the intracellular transport of cholesterol to the mitochondrium in endocrine organs (e.g. adrenal gland, ovaries, testes) and essential for the synthesis of all steroid hormones. Several mutations have been described and the clinical phenotype varies strongly and may be grouped into classic lipoid congenital adrenal hyperplasia (LCAH), in which all steroidogenesis is disrupted, and non-classic LCAH, which resembles familial glucocorticoid deficiency (FGD), which affects predominantly adrenal functions. Classic LCAH is characterized by early and potentially life-threatening manifestation of primary adrenal insufficiency (PAI) with electrolyte disturbances and 46,XY disorder of sex development (DSD) in males as well as lack of pubertal development in both sexes. Non-classic LCAH manifests usually later in life with PAI. Nevertheless, life-long follow-up of gonadal function is warranted. We describe a 26-year-old female patient who was diagnosed with PAI early in life without detailed diagnostic work-up. At the age of 14 months, she presented with hyperpigmentation, elevated ACTH and low cortisol levels. As her older brother was diagnosed with PAI two years earlier, she was put on hydrocortisone and fludrocortisone replacement therapy before an Addisonian crisis occurred. Upon review of her case in adulthood, consanguinity was noted in the family. Genetic analysis for PAI revealed a homozygous mutation in the STAR gene (c.562C>T, p.Arg188Cys) in both siblings. This mutation has been previously described in non-classic LCAH. This case illustrates that early onset, familial PAI is likely due to autosomal recessive genetic mutations in known genes causing PAI.

Learning points:

  • In childhood-onset PAI, a genetic cause is most likely, especially in families with consanguinity.

  • Adult patients with an etiologically unsolved PAI should be reviewed repeatedly and genetic work-up should be considered.

  • Knowing the exact genetic diagnosis in PAI is essential for genetic counselling and may allow disease-specific treatment.

  • Young men and women with NCLAH due to homozygous STAR Arg188Cys mutation should be investigated for their gonadal function as hypogonadism and infertility might occur during puberty or in early adulthood.

Open access

Benjamin G Challis, Chung Thong Lim, Alison Cluroe, Ewen Cameron and Stephen O’Rahilly

Summary

McKittrick–Wheelock syndrome (MWS) is a rare consequence of severe dehydration and electrolyte depletion due to mucinous diarrhoea secondary to a rectosigmoid villous adenoma. Reported cases of MWS commonly describe hypersecretion of mucinous diarrhoea in association with dehydration, hypokalaemia, hyponatraemia, hypochloraemia and pre-renal azotemia. Hyperglycaemia and diabetes are rarely reported manifestations of MWS. Herein we describe the case of a 59-year-old woman who presented with new-onset diabetes and severe electrolyte derangement due to a giant rectal villous adenoma. Subsequent endoscopic resection of the tumour cured her diabetes and normalised electrolytes. This case describes a rare cause of ‘curable diabetes’ and indicates hyperaldosteronism and/or whole-body potassium stores as important regulators of insulin secretion and glucose homeostasis.

Learning points

  • McKittrick–Wheelock syndrome (MWS) is typically characterised by the triad of pre-renal failure, electrolyte derangement and chronic diarrhoea resulting from a secretory colonic neoplasm.

  • Hyperglycaemia and new-onset diabetes are rare clinical manifestations of MWS.

  • Hyperaldosteronism and/or hypokalaemia may worsen glucose tolerance in MWS.

  • Aggressive replacement of fluid and electrolytes is the mainstay of acute management, with definitive treatment and complete reversal of the metabolic abnormalities being achieved by endoscopic or surgical resection of the neoplasm.

Open access

V Larouche, L Snell and D V Morris

Summary

Myxoedema madness was first described as a consequence of severe hypothyroidism in 1949. Most cases were secondary to long-standing untreated primary hypothyroidism. We present the first reported case of iatrogenic myxoedema madness following radioactive iodine ablation for Graves' disease, with a second concurrent diagnosis of primary hyperaldosteronism. A 29-year-old woman presented with severe hypothyroidism, a 1-week history of psychotic behaviour and paranoid delusions 3 months after treatment with radioactive iodine ablation for Graves' disease. Her psychiatric symptoms abated with levothyroxine replacement. She was concurrently found to be hypertensive and hypokalemic. Primary hyperaldosteronism from bilateral adrenal hyperplasia was diagnosed. This case report serves as a reminder that myxoedema madness can be a complication of acute hypothyroidism following radioactive iodine ablation of Graves' disease and that primary hyperaldosteronism may be associated with autoimmune hyperthyroidism.

Learning points

  • Psychosis (myxoedema madness) can present as a neuropsychiatric manifestation of acute hypothyroidism following radioactive iodine ablation of Graves' disease.

  • Primary hyperaldosteronism may be caused by idiopathic bilateral adrenal hyperplasia even in the presence of an adrenal adenoma seen on imaging.

  • Adrenal vein sampling is a useful tool for differentiating between a unilateral aldosterone-producing adenoma, which is managed surgically, and an idiopathic bilateral adrenal hyperplasia, which is managed medically.

  • The management of autoimmune hyperthyroidism, iatrogenic hypothyroidism and primary hyperaldosteronism from bilateral idiopathic adrenal hyperplasia in patients planning pregnancy includes delaying pregnancy 6 months following radioactive iodine treatment and until patient is euthyroid for 3 months, using amiloride as opposed to spironolactone, controlling blood pressure with agents safe in pregnancy such as nifedipine and avoiding β blockers.

  • Autoimmune hyperthyroidism and primary hyperaldosteronism rarely coexist; any underlying mechanism associating the two is still unclear.

Open access

Sudeep K Rajpoot, Carlos Maggi and Amrit Bhangoo

Summary

Neonatal hyperkalemia and hyponatremia are medical conditions that require an emergent diagnosis and treatment to avoid morbidity and mortality. Here, we describe the case of a 10-day-old female baby presenting with life-threatening hyperkalemia, hyponatremia, and metabolic acidosis diagnosed as autosomal dominant pseudohypoaldosteronism type 1 (PHA1). This report aims to recognize that PHA1 may present with a life-threatening arrhythmia due to severe hyperkalemia and describes the management of such cases in neonates.

Learning points

  • PHA1 may present with a life-threatening arrhythmia.

  • Presentation of PHA can be confused with congenital adrenal hyperplasia.

  • Timing and appropriate medical management in the critical care unit prevented fatality from severe neonatal PHA.

Open access

N Amin, N S Alvi, J H Barth, H P Field, E Finlay, K Tyerman, S Frazer, G Savill, N P Wright, T Makaya and T Mushtaq

Summary

Type 1 pseudohypoaldosteronism (PHA) is a rare heterogeneous group of disorders characterised by resistance to aldosterone action. There is resultant salt wasting in the neonatal period, with hyperkalaemia and metabolic acidosis. Only after results confirm isolated resistance to aldosterone can the diagnosis of type 1 PHA be confidently made. Type 1 PHA can be further classified into i) renal type 1 (autosomal dominant (AD)) and ii) multiple target organ defect/systemic type 1 (autosomal recessive (AR)). The aim of this case series was to characterise the mode of presentation, management and short-term clinical outcomes of patients with PHA type 1. Case notes of newly diagnosed infants presenting with PHA type 1 were reviewed over a 5-year time period. Seven patients were diagnosed with PHA type 1. Initial presentation ranged from 4 to 28 days of age. Six had weight loss as a presenting feature. All subjects had hyperkalaemia, hyponatraemia, with elevated renin and aldosterone levels. Five patients have renal PHA type 1 and two patients have systemic PHA type, of whom one has had genetic testing to confirm the AR gene mutation on the SCNN1A gene. Renal PHA type 1 responds well to salt supplementation, whereas management of patients with systemic PHA type 1 proves more difficult as they are likely to get frequent episodes of electrolyte imbalance requiring urgent correction.

Learning points

  • Patients with type 1 PHA are likely to present in the neonatal period with hyponatraemia, hyperkalaemia and metabolic acidosis and can be diagnosed by the significantly elevated plasma renin activity and aldosterone levels.

  • The differential diagnosis of type 1 PHA includes adrenal disorders such as adrenal hypoplasia and congenital adrenal hyperplasia; thus, adrenal function including cortisol levels, 17-hydroxyprogesterone and a urinary steroid profile are required. Secondary (transient) causes of PHA may be due to urinary tract infections or renal anomalies; thus, urine culture and renal ultrasound scan are required respectively.

  • A differentiation between renal and systemic PHA type 1 may be made based on sodium requirements, ease of management of electrolyte imbalance, sweat test results and genetic testing.

  • Management of renal PHA type 1 is with sodium supplementation, and requirements often decrease with age.

  • Systemic PHA type 1 requires aggressive and intensive fluid and electrolyte management. Securing an enteral feeding route and i.v. access are essential to facilitate ongoing therapy.

  • In this area of the UK, the incidence of AD PHA and AR PHA was calculated to be 1:66 000 and 1:166 000 respectively.