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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

Elena Carrillo, Amparo Lomas, Pedro J Pinés and Cristina Lamas

Summary

Mutations in hepatocyte nuclear factor 1β gene (HNF1B) are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5) and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations.

Learning points:

  • HNF1B mutations are a rare cause of monogenic diabetes, often being a part of a multisystemic syndrome.

  • The combination of young-onset diabetes and genitourinary anomalies with slowly progressive nephropathy of non-diabetic origin in non-obese subjects should rise the suspicion of such occurrence. A family history may not be present.

  • Once diagnosis is made, treatment of diabetes with oral agents is worth trying, since the response can be sustained for a longer period than the one usually described. Oral treatment can help postpone insulinization and, once this is necessary, can help reduce the required doses.