Summary

Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs*17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs*17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future.

Learning points

• Non-classic 3βHSD2 is likely underdiagnosed.

• Late diagnosis of mild non-classic 3βHSD2 does occur and one should be aware of this diagnosis.

• Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections.

• Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.

Summary

This case report describes a rare presentation of ectopic Cushing’s syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (⁶⁸Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A ¹⁸F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous.

Learning points

• Medullary thyroid carcinoma may secrete CRH and cause ectopic CS.

• Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test.

• Plasma CRH measurements can be useful in selected cases.

Summary

Iron metabolism and markers hereof are altered in anorexia nervosa (AN) but far from completely understood. We report a case of extreme hyperferritinemia in a patient with AN and discuss the possible mechanisms and current knowledge about the association between hyperferritinemia and AN. A 20-year-old woman with a history of AN presented with bradycardia, weariness, and malaise in addition to an incidentally very high ferritin level. The symptoms disappeared spontaneously after a short admission. There were no signs suggestive of systemic, hematological, or malignant disease causing the very high concentration of ferritin. Her body weight was in decline, leading up to admission, but did initially increase after discharge accompanied by declining ferritin concentration. However, a clear association between ferritin dynamics and weight changes or physical activity was not identified and neither were other causes of the hyperferritinemia. Around one in four patients with AN have increased ferritin concentrations. Our case represents the highest ferritin concentration reported in a patient with AN without other underlying causes or comorbidities.

Learning points

• Perturbed iron metabolism is frequent in restrictive type anorexia nervosa but incompletely understood.

• Altered ferritin in anorexia nervosa may be linked to nutritional status.

Summary

A 72-year-old man with type 2 diabetes volunteered to participate in the control group of a clinical study. The study evaluated non-alcoholic fatty liver disease in patients with kidney disease. The patient was followed at a gastroenterology department due to Crohn’s disease and post-operative bile acid malabsorption. The patient had no symptoms or biochemical findings suggesting liver disease. Surprisingly, a transient elastography (FibroScan^®) suggested advanced fibrosis with a median of 16.1 kPa. A liver biopsy showed non-alcoholic steatohepatitis (NASH)-cirrhosis. The diagnosis was only made incidentally and highlights how NASH-cirrhosis may be overlooked due to the lack of symptoms.

Learning points

• Clinicians treating high-risk populations, including patients with type 2 diabetes and/or components of the metabolic syndrome, should be aware of the frequently occurring co-existence with non-alcoholic fatty liver disease (NAFLD) and especially non-alcoholic steatohepatitis (NASH).

• Liver enzymes may be in the normal range even in people with steatosis, NASH, or even cirrhosis.

• The diagnosis of NAFLD should include evaluation of hepatic fibrosis as this is the most important prognostic factor for liver-related complications and mortality.

• Guidelines about systematic screening for NAFLD in patients with type 2 diabetes are incongruent.

Summary

This rare case describes the course of a pregnancy in a patient with a disseminated small intestinal neuroendocrine tumor. The patient received treatment with first-generation somatostatin ligand receptor (SLR) every 4 weeks and had stable disease for several years before her pregnancy. First-generation SLR treatment was initially paused after detection of the pregnancy. During pregnancy, the patient experienced moderate gastro-intestinal discomfort and fatigue, which was considered predominantly pregnancy related. However, since symptoms could be linked to the patient’s cancer, treatment was resumed after the first trimester. Chromogranin-A measurements remained stable throughout pregnancy and was paralleled by the absence of diarrhea and only minor flushing. She gave birth by elective caesarean section in week 37 to a healthy baby. Subsequent follow up imaging immediately after and 10 months postpartum showed no disease progression. The safety profile of SLR treatment during pregnancy in the context of disseminated neuroendocrine tumors (NET) is discussed.

Learning points

• Neuroendocrine neoplasms (NEN) are rare cancers often occurring in the gastro-intestinal tract or lungs.

• Many patients with NEN live for several years with disseminated disease.

• SLR treatment has been given to pregnant patients before; often patients with acromegaly. Pregnancies are reported uneventful.

• This patient completed an uneventful pregnancy while receiving SLR treatment for disseminated neuroendocrine disease and gave birth to a healthy baby.

• More research regarding long term effects and safety signals of SLR treatment during pregnancy are much needed.

Summary

During pregnancy, maternal tissues become increasingly insensitive to insulin in order to liberate nutritional supply to the growing fetus, but occasionally insulin resistance in pregnancy becomes severe and the treatment challenging. We report a rare and clinically difficult case of extreme insulin resistance with daily insulin requirements of 1420 IU/day during pregnancy in an obese 36-year-old woman with type 2 diabetes (T2D) and polycystic ovary syndrome (PCOS). The woman was referred to the outpatient clinic at gestational week 12 + 2 with a hemoglobin A1c (HbA1c) at 59 mmol/mol. Insulin treatment was initiated immediately using Novomix 30, and the doses were progressively increased, peaking at 1420 units/day at week 34 + 4. At week 35 + 0, there was an abrupt fall in insulin requirements, but with no signs of placental insufficiency. At week 36 + 1 a, healthy baby with no hypoglycemia was delivered by cesarean section. Blood samples were taken late in pregnancy to search for causes of extreme insulin resistance and showed high levels of C-peptide, proinsulin, insulin-like growth factor (IGF-1), mannan-binding-lectin (MBL) and leptin. CRP was mildly elevated, but otherwise, levels of inflammatory markers were normal. Insulin antibodies were undetectable, and no mutations in the insulin receptor (INSR) gene were found. The explanation for the severe insulin resistance, in this case, can be ascribed to PCOS, obesity, profound weight gain, hyperleptinemia and inactivity. This is the first case of extreme insulin resistance during pregnancy, with insulin requirements close to 1500 IU/day with a successful outcome, illustrating the importance of a close interdisciplinary collaboration between patient, obstetricians and endocrinologists.

Learning points

• This is the first case of extreme insulin resistance during pregnancy, with insulin requirements of up to 1420 IU/day with a successful outcome without significant fetal macrosomia and hypoglycemia.

• Obesity, PCOS, T2D and high levels of leptin and IGF-1 are predictors of severe insulin resistance in pregnancy.

• A close collaboration between patient, obstetricians and endocrinologists is crucial for tailoring the best possible treatment for pregnant women with diabetes, beneficial for both the mother and her child.

Learning points:

• MEN1 patients will develop parathyroid disease, which eventually will lead to surgical treatment with removal of the pathological glands.

• Preoperatively usage of MRI combined with PET tracers such as ¹¹C-methionine and ¹⁸F-Fluorocholine are able to detect parathyroid pathology with a higher sensitivity than conventional imaging.

• Techniques using intraoperatively angiography with fluorescence and florescent dyes allow surgeons to verify the vascularization of each parathyroid gland.

• Optimization of noninvasive preoperative imaging techniques and intraoperative fluorescent imaging are valuable tools and should be taken into consideration when performing PTX consecutively in the same patient to avoid postoperative complications.

Summary

Excessive intake of licorice may cause pseudohyperaldosteronism which, in turn, may lead to hypertension and hypokalemia. Severe hypokalemia may lead to electrocardiogram (ECG) changes including long QT interval potentially progressing into malignant arrhythmias. Here we present a 43-year-old woman admitted to the hospital with chest pain and a stinging sensation in the upper extremities. Her peak blood pressure was 177/98 mmHg and the blood test revealed low plasma potassium of 1.9 mmol/L. The ECG revealed flattened T-waves and long QT interval. Prior to admission, the patient had increased licorice ingestion to a total of some 70 g daily. The licorice intake was stopped and potassium was administrated orally and intravenously. Plasma potassium normalized and the ECG changes remitted. To our knowledge a few other cases of licorice-induced pseudohyperaldosteronism and long QT interval have previously been reported. This underlines the importance of quantifying licorice intake in younger people with unexplained high blood pressure and low potassium.

Learning points:

• Even small amounts of licorice daily may increase the risk of developing hypertension; therefore, licorice should be asked for specifically.

• Even though licorice intake is very easy to cover in the patient’s history, it is often missed.

• Excessive licorice intake may course severe hypokalemia causing long QT interval in the ECG recording, potentially progressing into arrhythmias and even cardiac arrest/sudden death.

• Hypokalemia <3 mmol/L and present ECG changes should be treated with potassium intravenously.

• Licorice-induced hypertension may be associated with syndrome of apparent mineralocorticoid excess (SAME). Plasma renin and aldosterone are both low at diagnosis and normalize when licorice is stopped.

Learning points:

• 11C-Methionine PET/CT and 18F-Fluorocholine PET/CT often visualizes the parathyroid adenoma in case of negative Tc-99m-MIBI SPECT/CT.

• A cold nodule in Tc-99m Pertechnetat thyroid scintigraphy with a negative Sestamibi scintigraphy has a very low probability of being malignant.

• However, the pretest likelihood of thyroid cancer in a cold nodule with increased Sestamibi uptake is low.

• 11C-Methionine PET might have a potential incremental value in increasing the pretest likelihood of thyroid malignancy in a cold nodule with highly increased Sestamibi uptake.

Learning points:

• Gain-of-function mutations in GCK cause familial hyperinsulinemic hypoglycemia.

• Hypoglycemia during pregnancy may have serious health implications for mother and fetus.

• Pregnancy with hyperinsulinism represents a medical dilemma as hypoglycemia as well as octreotide treatment may pose a risk of fetal growth restriction.

• In some cases of familial hyperinsulinemic hypoglycemia, blood glucose levels can be successfully managed through diet only.