Diagnosis and Treatment > Investigation > Plasma renin activity
You are looking at 1 - 4 of 4 items
Search for other papers by Philip D Oddie in
Google Scholar
PubMed
Search for other papers by Benjamin B Albert in
Google Scholar
PubMed
Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand
Search for other papers by Paul L Hofman in
Google Scholar
PubMed
Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand
Search for other papers by Craig Jefferies in
Google Scholar
PubMed
Search for other papers by Stephen Laughton in
Google Scholar
PubMed
Search for other papers by Philippa J Carter in
Google Scholar
PubMed
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.
Division of Pediatric Endocrinology, Memorial University Medical Center, Savannah, Georgia, USA
Search for other papers by Anil Piya in
Google Scholar
PubMed
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA
Search for other papers by Jasmeet Kaur in
Google Scholar
PubMed
Augusta University School of Medicine, Augusta, Georgia, USA
Search for other papers by Alan M Rice in
Google Scholar
PubMed
Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia, USA
Search for other papers by Himangshu S Bose in
Google Scholar
PubMed
Summary
Cholesterol transport into the mitochondria is required for synthesis of the first steroid, pregnenolone. Cholesterol is transported by the steroidogenic acute regulatory protein (STAR), which acts at the outer mitochondrial membrane prior to its import. Mutations in the STAR protein result in lipoid congenital adrenal hyperplasia (CAH). Although the STAR protein consists of seven exons, biochemical analysis in nonsteroidogenic COS-1 cells showed that the first two were not essential for pregnenolone synthesis. Here, we present a patient with ambiguous genitalia, salt-lossing crisis within two weeks after birth and low cortisol levels. Sequence analysis of the STAR, including the exon–intron boundaries, showed the complete deletion of exon 1 as well as more than 50 nucleotides upstream of STAR promoter. Mitochondrial protein import with the translated protein through synthesis cassette of the mutant STAR lacking exon 1 showed protein translation, but it is less likely to have synthesized without a promoter in our patient. Thus, a full-length STAR gene is necessary for physiological mitochondrial cholesterol transport in vivo.
Learning points:
-
STAR exon 1 deletion caused lipoid CAH.
-
Exon 1 substitution does not affect biochemical activity.
-
StAR promoter is responsible for gonadal development.
Search for other papers by Yael R Nobel in
Google Scholar
PubMed
Search for other papers by Maya B Lodish in
Google Scholar
PubMed
Search for other papers by Margarita Raygada in
Google Scholar
PubMed
Search for other papers by Jaydira Del Rivero in
Google Scholar
PubMed
Search for other papers by Fabio R Faucz in
Google Scholar
PubMed
Search for other papers by Smita B Abraham in
Google Scholar
PubMed
Search for other papers by Charalampos Lyssikatos in
Google Scholar
PubMed
Search for other papers by Elena Belyavskaya in
Google Scholar
PubMed
Search for other papers by Constantine A Stratakis in
Google Scholar
PubMed
Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baltimore, Maryland, 21287, USA
Suburban Hospital, Bethesda, Maryland, 20814, USA
Search for other papers by Mihail Zilbermint in
Google Scholar
PubMed
Summary
Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4–5.1 mmol/l), aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6–4.3 ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia.
Learning points
-
PHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.
-
PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).
-
Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.
-
High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment.
Search for other papers by Chrisanthi Marakaki in
Google Scholar
PubMed
Search for other papers by Anna Papadopoulou in
Google Scholar
PubMed
Search for other papers by Olga Karapanou in
Google Scholar
PubMed
Search for other papers by Dimitrios T Papadimitriou in
Google Scholar
PubMed
Search for other papers by Kleanthis Kleanthous in
Google Scholar
PubMed
Search for other papers by Anastasios Papadimitriou in
Google Scholar
PubMed
Summary
11β-hydroxylase deficiency (11β-OHD), an autosomal recessive inherited disorder, accounts for 5–8% of congenital adrenal hyperplasia. In Greece, no cases of 11β-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11-deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11β-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens.
Learning points
-
11β-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5–8% of cases with an incidence of 1:100 000–1:200 000 live births in non-consanguineous populations.
-
Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reported
-
Regarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls.
-
Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients.
-
Diagnosis lies upon elevated 11-deoxycortisol and DOC plus upstream precursors, such as 17α-hydroxyprogesterone and Δ4-androstenedione.
-
The established treatment of steroid 11β-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms.