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Summary
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5–15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF).
Learning points:
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Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET.
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Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins.
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Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence.
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Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.
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Summary
Ectopic ACTH-secreting pulmonary neuroendocrine tumors are rare and account for less than 5% of endogenous Cushing’s syndrome cases. We describe an unusual case of metastatic bronchial carcinoid tumor in a young woman presenting with unprovoked pulmonary emboli, which initially prevented the detection of the primary tumor on imaging. The source of ectopic ACTH was ultimately localized by a Gallium-DOTATATE scan, which demonstrated increased tracer uptake in a right middle lobe lung nodule and multiple liver nodules. The histological diagnosis was established based on a core biopsy of a hepatic lesion and the patient was started on a glucocorticoid receptor antagonist and a somatostatin analog. This case illustrates that hypercogulability can further aggravate the diagnostic challenges in ectopic ACTH syndrome. We discuss the literature on the current diagnosis and management strategies for ectopic ACTH syndrome.
Learning points:
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In a young patient with concurrent hypokalemia and uncontrolled hypertension on multiple antihypertensive agents, secondary causes of hypertension should be evaluated.
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Patients with Cushing’s syndrome can develop an acquired hypercoagulable state leading to spontaneous and postoperative venous thromboembolism.
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Pulmonary emboli may complicate the imaging of the bronchial carcinoid tumor in ectopic ACTH syndrome.
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Imaging with Gallium-68 DOTATATE PET/CT scan has the highest sensitivity and specificity in detecting ectopic ACTH-secreting tumors.
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A combination of various noninvasive biochemical tests can enhance the diagnostic accuracy in differentiating Cushing’s disease from ectopic ACTH syndrome provided they have concordant results. Bilateral inferior petrosal sinus sampling remains the gold standard.
Memorial University Medical Center, Savannah, Georgia, USA
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Pediatric Endocrinology and Diabetes Center, Kalispell Regional Medical Center, Kalispell, Montana, USA
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Laboratory of Pathology, Memorial University Medical Center, Savannah, Georgia, USA
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Summary
Steroid hormones are essential for the survival of all mammals. In adrenal glands and gonads, cytochrome P450 side chain cleavage enzyme (SCC or CYP11A1), catalyzes conversion of cholesterol to pregnenolone. We studied a patient with ambiguous genitalia by the absence of Müllerian ducts and the presence of an incompletely formed vagina, who had extremely high adrenocorticotropic hormone (ACTH) and reduced pregnenolone levels with enlarged adrenal glands. The testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells. Electron microscopy showed that the patient’s testicular mitochondrial size was small with little SCC expression within the mitochondria. The mitochondria were not close to the mitochondria-associated ER membrane (MAM), and cells were filled with the microfilaments. Our result revealed that absence of pregnenolone is associated with organelle stress, leading to altered protein organization that likely created steric hindrance in testicular cells.
Learning points:
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Testes revealed seminiferous tubules, stroma, rete testis with interstitial fibrosis and reduced number of germ cells;
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Testicular mitochondrial size was small with little SCC expression within the mitochondria;
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Absence of pregnenolone is associated with organelle stress.
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Summary
Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant.
Learning points:
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PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal.
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The diagnosis of PPNAD should prompt screening for CNC.
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CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene.
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Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.
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Summary
Pubertal gynecomastia is common, can be seen in 65% of the adolescent boys and is considered physiological. It is thought to be due to transient imbalance between the ratio of testosterone and estradiol in the early stages of puberty. It resolves in 1–2 years and requires no treatment. However, more persistent and severe pubertal gynecomastia is less common and can be associated with pathological disorders. These can be due to diminished androgen production, increased estrogen production or androgen resistance. We report a case of persistent pubertal gynecomastia due to partial androgen insensitivity syndrome (PAIS), classical hormone findings and a novel mutation in the androgen receptor (AR) gene.
Learning points:
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Laboratory testing of follicle-stimulating hormone (FSH), leutinizing hormone (LH) and testosterone for pubertal gynecomastia is most helpful in the setting of undervirization.
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The hormonal finding of very high testosterone, elevated LH and estradiol and relatively normal FSH are classical findings of PAIS.
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Gynecomastia due to PAIS will not resolve and surgery for breast reduction should be recommended.
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Summary
IgG4-related hypophysitis is an important diagnostic consideration in patients with a pituitary mass or pituitary dysfunction and can initially present with headaches, visual field deficits and/or endocrine dysfunction. Isolated IgG4-related pituitary disease is rare, with most cases of IgG4-related disease involving additional organ systems. We report the case of a teenage female patient with isolated IgG4-related hypophysitis, diagnosed after initially presenting with headaches. Our patient had no presenting endocrinologic abnormalities. She was treated with surgical resection, prednisolone and rituximab with no further progression of disease and sustained normal endocrine function. This case, the youngest described patient with isolated IgG4-related hypophysitis and uniquely lacking endocrinologic abnormalities, adds to the limited reports of isolated pituitary disease. The use of rituximab for isolated pituitary disease has never been described. While IgG4-related hypophysitis has been increasingly recognized, substantial evidence concerning the appropriate treatment and follow-up of these patients is largely lacking.
Learning points:
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IgG4-related hypophysitis most often occurs in the setting of additional organ involvement but can be an isolated finding. This diagnosis should therefore be considered in a patient presenting with pituitary abnormalities.
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Most patients with IgG4-related hypophysitis will have abnormal pituitary function, but normal functioning does not exclude this diagnosis.
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Corticosteroids have been the mainstay of therapy for IgG4-related disease, with other immunosuppressive regimens being reserved for refractory cases. Further research is needed to understand the effectiveness of corticosteroid-sparing regimens and whether there is utility in using these agents as first-line therapies.
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Summary
In this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient’s clinical course as well as a review of LHX3 mutations and the associated phenotype.
Learning points:
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Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life
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Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3
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Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations
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Summary
A 74-year-old woman presented with progressive lethargy, confusion, poor appetite and abdominal pain. She was found to have non-PTH-mediated severe hypercalcemia with renal failure and metabolic alkalosis. Extensive workup for hypercalcemia to rule out alternate etiology was unrevealing. Upon further questioning, she was taking excess calcium carbonate (Tums) for her worsening heartburn. She was diagnosed with milk-alkali syndrome (MAS). Her hypercalcemia and alkalosis recovered completely with aggressive hydration along with improvement in her renal function. High index of suspicion should be maintained and history of drug and supplements, especially calcium ingestion, should be routinely asked in patients presenting with hypercalcemia to timely diagnose MAS and prevent unnecessary tests and treatments.
Learning points:
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Suspect milk-alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements.
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Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome.
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Milk-alkali syndrome may cause severe hypercalcemia in up to 25–30% of cases.
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Summary
We report a case of a 21-year-old African American female with history of pre-diabetes, and a diagnosis of a rare leukemia, blastic-plasmacytoid dendritic neoplasm (BPDCN), who developed diabetic ketoacidosis (DKA) after the third dose of PEG-asparaginase infusion. She was successfully treated with insulin. Asparaginase is a vital part of treatment protocols for acute lymphoblastic leukemia (ALL) in combination with other chemotherapeutic drugs. Asparaginase therapy has been reported to cause hyperglycemia especially when used in conjunction with glucocorticoids for the treatment of ALL in the pediatric population. Multiple mechanisms for hyperglycemia have been hypothesized which include decreased insulin secretion, impaired insulin receptor function and excess glucagon formation. Hyperglycemia is usually self-limiting but can deteriorate to diabetic ketoacidosis. DKA is a rare adverse effect with asparaginase therapy with an incidence rate of about 0.8%.
Learning points:
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DKA is a rare finding following asparaginase therapy.
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Hyperglycemia is most commonly seen with asparaginase treatment when used along with glucocorticoid.
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Frequent blood glucose monitoring and prompt initiation of insulin treatment with hyperglycemia can prevent severe complications.
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Patients and physician education on this complication can reduce morbidity due to DKA.
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Summary
There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). Histopathologic findings from such patients who underwent partial/total pancreatomy, however, can vary widely from minimal changes to classic nesidioblastosis, making the pathologic diagnosis challenging. PGBH typically presents as postprandial hypoglycemia, as opposed to insulinoma, which presents as fasting hypoglycemia. Herein, we describe an unusual case of a patient with PGBH who initially presented with postprandial hypoglycemia three years after surgery, but later developed fasting hyperinsulinemic hypoglycemia as the disease progressed. Our hypothesis for this phenomenon is that this disease is progressive, and later in its course, the insulin release becomes dissociated from food stimulation and is increased at baseline. Future studies are needed to investigate the prevalence as well as etiology of this progression from postprandial to fasting hypoglycemia.
Learning points:
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There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH).
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Histopathologically, PGBH can vary from minimal changes to nesidioblastosis.
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Although uncommon, patients with PGBH after Roux-en-Y gastric bypass may present with both postprandial and fasting hyperinsulinemic hypoglycemia as disease progresses.
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Our hypothesis for this phenomenon is that the insulin release becomes dissociated from food stimulation and is increased at baseline with disease progression.
