Browse

You are looking at 1 - 10 of 33 items

Rob Gonsalves Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

Search for other papers by Rob Gonsalves in
Google Scholar
PubMed
Close
,
Kirk Aleck Division of Genetics, Phoenix Children’s Hospital, Phoenix, Arizona, USA

Search for other papers by Kirk Aleck in
Google Scholar
PubMed
Close
,
Dorothee Newbern Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

Search for other papers by Dorothee Newbern in
Google Scholar
PubMed
Close
,
Gabriel Shaibi Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

Search for other papers by Gabriel Shaibi in
Google Scholar
PubMed
Close
,
Chirag Kapadia Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

Search for other papers by Chirag Kapadia in
Google Scholar
PubMed
Close
, and
Oliver Oatman Division of Endocrinology, Phoenix Children’s Hospital, Phoenix, Arizona, USA

Search for other papers by Oliver Oatman in
Google Scholar
PubMed
Close

Summary

Single-minded homolog 1 (SIM1) is a transcription factor that plays a role in the development of both the hypothalamus and pituitary. SIM1 gene mutations are known to cause obesity in humans, and chromosomal deletions encompassing SIM1 and other genes necessary for pituitary development can cause a Prader–Willi-like syndrome with obesity and hypopituitarism. There have been no reported cases of hypopituitarism linked to a single SIM1 mutation. A 21-month-old male presented to endocrinology clinic with excessive weight gain and severe obesity. History was also notable for excessive drinking and urination. Endocrine workup revealed central hypothyroidism, partial diabetes insipidus, and central adrenal insufficiency. Genetic evaluation revealed a novel mutation in the SIM1 gene. No other genetic abnormalities to account for his obesity and hypopituitarism were identified. While we cannot definitively state this mutation is pathogenic, it is notable that SIM1 plays a role in the development of all three of the patient’s affected hormone axes. He is now 6 years old and remains on treatment for his pituitary hormone deficiencies and continues to exhibit excessive weight gain despite lifestyle interventions.

Learning points:

  • Mutations in SIM1 are a well-recognized cause of monogenic human obesity, and there have been case reports of Prader–Willi-like syndrome and hypopituitarism in patients with chromosomal deletions that contain the SIM1 gene.

  • SIM1 is expressed during the development of the hypothalamus, specifically in neuroendocrine lineages that give rise to the hormones oxytocin, arginine vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin.

  • Pituitary testing should be considered in patients with severe obesity and a known genetic abnormality affecting the SIM1 gene, particularly in the pediatric population.

Open access
Jane J Tellam Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
University of Queensland, Herston, Queensland, Australia

Search for other papers by Jane J Tellam in
Google Scholar
PubMed
Close
,
Ghusoon Abdulrasool Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia
University of Queensland, Herston, Queensland, Australia
Pathology Queensland, Australia

Search for other papers by Ghusoon Abdulrasool in
Google Scholar
PubMed
Close
, and
Louise C H Ciin Gold Coast University Hospital, Southport, Queensland, Australia
Griffith University, Southport, Queensland, Australia

Search for other papers by Louise C H Ciin in
Google Scholar
PubMed
Close

Summary

Distinguishing primary hyperparathyroidism (PHPT) from familial hypocalciuric hypercalcaemia (FHH) can be challenging. Currently, 24-h urinary calcium is used to differentiate between the two conditions in vitamin D replete patients, with urinary calcium creatinine clearance ratio (UCCR) <0.01 suggestive of FHH and >0.02 supportive of PHPT. A 26-year-old Caucasian gentleman presented with recurrent mild hypercalcaemia and inappropriately normal parathyroid hormone (PTH) following previous parathyroidectomy 3 years prior. He had symptoms of fatigue and light-headedness. He did not have any other symptoms of hypercalcaemia. His previous evaluation appeared to be consistent with PHPT as evidenced by hypercalcaemia with inappropriately normal PTH and UCCR of 0.0118 (borderline low using guidelines of >0.01 consistent with PHPT). He underwent parathyroidectomy and three parathyroid glands were removed. His calcium briefly normalised after surgery, but rose again to pre-surgery levels within 3 months. Subsequently, he presented to our centre and repeated investigations showed 24-h urinary calcium of 4.6 mmol/day and UCCR of 0.0081 which prompted assessment for FHH. His calcium-sensing receptor (CASR) gene was sequenced and a rare inactivating variant was detected. This variant was described once previously in the literature. His mother was also confirmed to have mild hypercalcaemia with hypocalciuria and, on further enquiry, had the same CASR variant. The CASR variant was classified as likely pathogenic and is consistent with the diagnosis of FHH. This case highlights the challenges in differentiating FHH from PHPT. Accurate diagnosis is vital to prevent unnecessary surgical intervention in the FHH population and is not always straightforward.

Learning points:

  • Distinguishing FHH from PHPT with co-existing vitamin D deficiency is difficult as this can mimic FHH. Therefore, ensure patients are vitamin D replete prior to performing 24-h urinary calcium collection.

  • Individuals with borderline UCCR could have either FHH or PHPT. Consider performing CASR gene sequencing for UCCR between 0.01 and 0.02.

  • Parathyroid imaging is not required for making the diagnosis of PHPT. It is performed when surgery is considered after confirming the diagnosis of PHPT.

Open access
Sara Lomelino-Pinheiro Endocrinology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

Search for other papers by Sara Lomelino-Pinheiro in
Google Scholar
PubMed
Close
,
Bastos Margarida Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal

Search for other papers by Bastos Margarida in
Google Scholar
PubMed
Close
, and
Adriana de Sousa Lages Endocrinology, Diabetes and Metabolism Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal

Search for other papers by Adriana de Sousa Lages in
Google Scholar
PubMed
Close

Summary

Familial hypomagnesemia with secondary hypocalcemia (FHSH) is a rare autosomal recessive disorder (OMIM# 602014) characterized by profound hypomagnesemia associated with hypocalcemia. It is caused by mutations in the gene encoding transient receptor potential cation channel member 6 (TRPM6). It usually presents with neurological symptoms in the first months of life. We report a case of a neonate presenting with recurrent seizures and severe hypomagnesemia. The genetic testing revealed a novel variant in the TRPM6 gene. The patient has been treated with high-dose magnesium supplementation, remaining asymptomatic and without neurological sequelae until adulthood. Early diagnosis and treatment are important to prevent irreversible neurological damage.

Learning points:

  • Loss-of-function mutations of TRPM6 are associated with FHSH.

  • FHSH should be considered in any child with refractory hypocalcemic seizures, especially in cases with serum magnesium levels as low as 0.2 mM.

  • Normocalcemia and relief of clinical symptoms can be assured by administration of high doses of magnesium.

  • Untreated, the disorder may be fatal or may result in irreversible neurological damage.

Open access
Baris Akinci Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA
Division of Endocrinology and Metabolism, Dokuz Eylul University, Izmir, Turkey

Search for other papers by Baris Akinci in
Google Scholar
PubMed
Close
,
Rasimcan Meral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Rasimcan Meral in
Google Scholar
PubMed
Close
,
Diana Rus Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Diana Rus in
Google Scholar
PubMed
Close
,
Rita Hench Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Rita Hench in
Google Scholar
PubMed
Close
,
Adam H Neidert Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Adam H Neidert in
Google Scholar
PubMed
Close
,
Frank DiPaola Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Frank DiPaola in
Google Scholar
PubMed
Close
,
Maria Westerhoff Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Maria Westerhoff in
Google Scholar
PubMed
Close
,
Simeon I Taylor Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA

Search for other papers by Simeon I Taylor in
Google Scholar
PubMed
Close
, and
Elif A Oral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

Search for other papers by Elif A Oral in
Google Scholar
PubMed
Close

Summary

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points:

  • A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.

  • Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.

  • The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.

  • Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.

  • Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Open access
Albert S Kim Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia

Search for other papers by Albert S Kim in
Google Scholar
PubMed
Close
,
Rashida Hakeem Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

Search for other papers by Rashida Hakeem in
Google Scholar
PubMed
Close
,
Azaliya Abdullah Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

Search for other papers by Azaliya Abdullah in
Google Scholar
PubMed
Close
,
Amanda J Hooper School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia

Search for other papers by Amanda J Hooper in
Google Scholar
PubMed
Close
,
Michel C Tchan The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia

Search for other papers by Michel C Tchan in
Google Scholar
PubMed
Close
,
Thushari I Alahakoon The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

Search for other papers by Thushari I Alahakoon in
Google Scholar
PubMed
Close
, and
Christian M Girgis Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
Department of Diabetes and Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

Search for other papers by Christian M Girgis in
Google Scholar
PubMed
Close

Summary

A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered.

Learning points:

  • Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels.

  • Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins.

  • Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia.

  • Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect.

  • Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.

Open access
Aisha A Tepede Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Aisha A Tepede in
Google Scholar
PubMed
Close
,
James Welch Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by James Welch in
Google Scholar
PubMed
Close
,
Maya Lee Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Maya Lee in
Google Scholar
PubMed
Close
,
Adel Mandl Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Adel Mandl in
Google Scholar
PubMed
Close
,
Sunita K Agarwal Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Sunita K Agarwal in
Google Scholar
PubMed
Close
,
Naris Nilubol National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Naris Nilubol in
Google Scholar
PubMed
Close
,
Dhaval Patel National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Dhaval Patel in
Google Scholar
PubMed
Close
,
Craig Cochran Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Craig Cochran in
Google Scholar
PubMed
Close
,
William F Simonds Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by William F Simonds in
Google Scholar
PubMed
Close
,
Lee S Weinstein Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Lee S Weinstein in
Google Scholar
PubMed
Close
,
Abhishek Jha Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Abhishek Jha in
Google Scholar
PubMed
Close
,
Corina Millo Clinical Center PET Department (CC PET), National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Corina Millo in
Google Scholar
PubMed
Close
,
Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Karel Pacak in
Google Scholar
PubMed
Close
, and
Jenny E Blau Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (NIDDK)

Search for other papers by Jenny E Blau in
Google Scholar
PubMed
Close

Summary

Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients.

Learning points:

  • 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients.

  • Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions.

  • MEN1 is implicated in the tumorigenesis of PHEO in this patient.

Open access
Sakshi Jhawar Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Sakshi Jhawar in
Google Scholar
PubMed
Close
,
Rahul Lakhotia Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Rahul Lakhotia in
Google Scholar
PubMed
Close
,
Mari Suzuki Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Mari Suzuki in
Google Scholar
PubMed
Close
,
James Welch Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by James Welch in
Google Scholar
PubMed
Close
,
Sunita K Agarwal Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Sunita K Agarwal in
Google Scholar
PubMed
Close
,
John Sharretts Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by John Sharretts in
Google Scholar
PubMed
Close
,
Maria Merino Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Maria Merino in
Google Scholar
PubMed
Close
,
Mark Ahlman Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Mark Ahlman in
Google Scholar
PubMed
Close
,
Jenny E Blau Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by Jenny E Blau in
Google Scholar
PubMed
Close
,
William F Simonds Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA

Search for other papers by William F Simonds in
Google Scholar
PubMed
Close
, and
Jaydira Del Rivero Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Search for other papers by Jaydira Del Rivero in
Google Scholar
PubMed
Close

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:

  • Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET.

  • 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.

  • Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence.

  • Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.

Open access
Andrew R Tang Division of Endocrinology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

Search for other papers by Andrew R Tang in
Google Scholar
PubMed
Close
,
Laura E Hinz Division of Endocrinology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

Search for other papers by Laura E Hinz in
Google Scholar
PubMed
Close
,
Aneal Khan Department of Medical Genetics and Pediatrics, University of Calgary, Alberta Children’s Hospital Research Institute, Calgary, Alberta, Canada

Search for other papers by Aneal Khan in
Google Scholar
PubMed
Close
, and
Gregory A Kline Division of Endocrinology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada

Search for other papers by Gregory A Kline in
Google Scholar
PubMed
Close

Summary

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.

Learning points:

  • Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.

  • HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.

  • HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.

  • Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.

Open access
Yang Timothy Du Endocrine and Metabolic Unit, Royal Adelaide Hospital

Search for other papers by Yang Timothy Du in
Google Scholar
PubMed
Close
,
Lynette Moore School of Medicine, University of Adelaide
SA Pathology, Women’s and Children’s Hospital

Search for other papers by Lynette Moore in
Google Scholar
PubMed
Close
,
Nicola K Poplawski Adult Genetics Unit, Royal Adelaide Hospital

Search for other papers by Nicola K Poplawski in
Google Scholar
PubMed
Close
, and
Sunita M C De Sousa Endocrine and Metabolic Unit, Royal Adelaide Hospital
School of Medicine, University of Adelaide
Adult Genetics Unit, Royal Adelaide Hospital
Center for Cancer Biology, SA Pathology and University of South Australia Alliance, Adelaide, South Australia, Australia

Search for other papers by Sunita M C De Sousa in
Google Scholar
PubMed
Close

Summary

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology.

Learning points:

  • Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history.

  • Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management.

  • Identification of a genetic disorder may have important implications for family planning.

Open access
Catherine D Zhang Departments of Internal Medicine, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Catherine D Zhang in
Google Scholar
PubMed
Close
,
Pavel N Pichurin Departments of Clinical Genomics, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Pavel N Pichurin in
Google Scholar
PubMed
Close
,
Aleh Bobr Departments of Laboratory Medicine and Pathology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Aleh Bobr in
Google Scholar
PubMed
Close
,
Melanie L Lyden Departments of Surgery, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Melanie L Lyden in
Google Scholar
PubMed
Close
,
William F Young Jr Departments of Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by William F Young Jr in
Google Scholar
PubMed
Close
, and
Irina Bancos Departments of Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA

Search for other papers by Irina Bancos in
Google Scholar
PubMed
Close

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:

  • PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal.

  • The diagnosis of PPNAD should prompt screening for CNC.

  • CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene.

  • Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.

Open access