A novel mutation in PRKAR1A gene in a patient with Carney complex presenting with pituitary macroadenoma, acromegaly, Cushing's syndrome and recurrent atrial myxoma

SUMMARY Carney complex (CNC) is a rare syndrome of multiple endocrine and non-endocrine tumors. In this paper we present a 23-year-old Iranian woman with CNC who harbored a novel mutation (c.642dupT) in PRKAR1A gene. This patient presented with pituitary macroadenoma, acromegaly, recurrent atrial myxoma, Cushing's syndrome secondary to primary pigmented nodular adrenocortical disease and pigmented schwanoma of the skin. PRKAR1A gene was PCR amplified using genomic DNA and analyzed for sequence variants which revealed the novel mutation resulting in substitution of amino acid cysteine instead of the naturally occurring valine in the peptide chain and a premature stop codon at position 18 (V215CfsX18). This change leads to development of tumors in different organs due to lack of tumor suppressive activity secondary to failure of synthesis of the related protein.

A novel mutation in PRKAR1A gene in a patient with Carney complex presenting with pituitary macroadenoma, acromegaly, Cushing's syndrome and recurrent atrial myxoma.

Carney complex (CNC) is a rare syndrome of multiple endocrine and non-endocrine tumors. In this paper we present a 23-year-old Iranian woman with CNC who harbored a novel mutation (c.642dupT) in PRKAR1A gene. This patient presented with pituitary macroadenoma, acromegaly, recurrent atrial myxoma, Cushing's syndrome secondary to primary pigmented nodular adrenocortical disease and pigmented schwanoma of the skin. PRKAR1A gene was PCR amplified using genomic DNA and analyzed for sequence variants which revealed the novel mutation resulting in substitution of amino acid cysteine instead of the naturally occurring valine in the peptide chain and a premature stop codon at position 18 (V215CfsX18). This change leads to development of tumors in different organs due to lack of tumor suppressive activity secondary to failure of synthesis of the related protein.

Ectopic cushing's syndrome due to corticotropin releasing hormone.

Cushing's syndrome (CS) secondary to corticotropin releasing hormone (CRH) producing tumors is rare. In this paper we present an Iranian patient who was admitted to our hospital with classic signs and symptoms of CS. Laboratory evaluation revealed high serum and urine cortisol which could not be suppressed with dexamethasone. Abdominal CT scan revealed a mass in abdominal cavity. A percutaneous needle biopsy was performed and histopathologic evaluation revealed that the mass was a neuroendocrine tumor. A multi-disciplinary approach including resection of the mass, bilateral adrenalectomy somatostatin analogue and chemotherapy was applied for management of the disease. Extensive review of English literature focusing on the topic from 1971 to 2018 revealed that there have been only 75 similar cases. Clinical, laboratory, imaging, histopathologic characteristics and managements of these patients will also be discussed in this paper.

Hereditary Vitamin D Resistant Rickets: Clinical, Laboratory, and Genetic Characteristics of 2 Iranian Siblings.

PURPOSE AND METHODS: Hereditary vitamin D resistant rickets (HVDRR) is a rare disease that presents with signs and symptoms of rickets, alopecia, and growth retardation during the early years of life. The disease is caused by mutations in the vitamin D receptor (VDR) gene, which leads to unresponsiveness of the mutant receptor to 1-25(OH) 2 D3. The disease is transmitted as an autosomal recessive disorder and is found with equal frequency in males and females. The disease is rarely encountered and only about 100 cases are reported so far. The current paper reported the clinical and laboratory characteristics of 2 Iranian siblings with this disorder. RESULTS AND CONCLUSION: They presented with rickets, growth retardation, muscle weakness, hypocalcemia and alopecia totalis since early childhood, and were followed up for 27 years. Sequencing of the DNA extracted from the peripheral white blood cells showed a missense G to A mutation in exon number 4 (g.30994 G > A) that led to the methionine substitution for the naturally occurring valine at position 26 in the DNA binding domain (DBD) of the VDR.

Hypocalcemia and osteomalacia after bariatric surgery.

INTRODUCTION: Obesity has become a major health problem not only in industrialized societies but also in developing countries. Multiple studies have shown that bariatric surgery has been effective in reducing substantial amount of weight and also the comorbidities and is being performed more frequently as an established treatment. Due to anatomical and physiological alterations after surgery that impairs absorption of vitamin D and calcium, two fundamental factors in bone formation, their intestinal absorption is highly compromised. CASE REPORT: We present a 48-year-old woman who was visited in emergency room for generalized bone pain, perioral paresthesia and carpopedal spasm. She had undergone bariatric surgery 15 years ago. Chvostek's sign and Trousseau's sign were positive. Examination of thoracic ribs elicited severe pain on palpation. Laboratory evaluation revealed: Ca = 6.1 mg/dL, P= 2.1 mg/dL, alkaline phosphatase = 432 (160-303), PTH=541 pg/mL, and 25(OH)D3= 3 ng/mL. Whole body bone scan showed increased uptake in the anterior arc of left 6th rib, posterior arc of left 6th and 12th ribs with increased uptake of costochondral joints. CONCLUSION: Our case highlights the possible consequences that bariatric surgery may have on bone and mineral health and the need for regular and proactive follow-up of the patients.

Ectopic Cushing's syndrome secondary to lung and mediastinal tumours -- report from a tertiary care centre in Iran.

INTRODUCTION: Ectopic Cushing`s syndrome (ECS) secondary to neuroendocrine tumours (NETs) of the lung and mediastinum are rarely encountered. In this study, we present our experience in Iran on 15 patients with ECS secondary to lung and mediastinal tumours over a period of 27 years. MATERIAL AND METHODS: Since 1985, 15 patients with ECS secondary to lung and mediastinal tumours have been diagnosed and prospectively followed by the endocrinology team of Taleghani Hospital, Tehran, Iran. The clinical signs and symptoms, laboratory findings, radiological features, immunohistochemical characteristics, management strategies and outcome data are here presented. RESULTS: There were six women and nine men, aged 26-70 years, all presenting with typical features of Cushing's syndrome. Based on histopathologic evaluations, four patients had small cell lung cancer (SCLC) and seven patients had pulmonary NETs, one patient had a thymic NET, and one case was diagnosed as a lung tumourlet. The mean ± SD serum cortisol, 24h urine free cortisol and plasma ACTH were 47.2 ± 20.5 µg/dL, 2,702 ± 5,439 µg/day, and 220 ± 147 pg/mL, respectively. Pulmonary lesions ranged in diameter from 1.1 to 4 cm (mean 1.9 ± 1.1 cm). One patient had a 10 cm mediastinal mass. The duration of follow up in these cases was between one month and seven years (mean 29.9 ± 27.5 months). The four patients with SCLC died within three months of diagnosis. CONCLUSION: Our data demonstrates the protean clinical and laboratory manifestations of ECS secondary to lung and mediastinal tumours, the problems encountered in diagnosis, and the need for a multidisciplinary approach. This study confirms other series from Western Europe and North America that, unlike the SCLC patients who show a poor outlook, ECS secondary to lung carcinoids has a more favourable prognosis.

Treatment of invasive silent somatotroph pituitary adenoma with temozolomide. Report of a case and review of the literature.

Improved imaging techniques have contributed to increased diagnosis of pituitary tumors. These tumor types can be microadenomas or macroadenomas and can either be functional or non-functional. Atypical or aggressive pituitary adenomas are tumors that rapidly increase in size and may invade into the suprasellar or parasellar regions. They are characterized by a Ki-67 nuclear labeling index greater than 10 %. Management of these tumors is difficult, and many recur after surgery. Temozolomide, a second generation alkylating agent, has been showing promising results in the treatment of these tumors. The patient was a 39-year-old male diagnosed with an invasive silent somatotroph pituitary macroadenoma treated with temozolomide after surgery. We present the case along with the review of the literature of the therapeutic effects of temozolomide in somatotroph macroadenomas.

A novel succinate dehydrogenase type B mutation in an Iranian family. Its genetic and clinical evaluation.

Succinate Dehydrogenase-B (SDH-B) gene mutations constitute one of the most frequent forms of hereditary paragangliomas (PGL). Genetic study is advised in all cases for the evaluation of tumour behaviour, the selection of optimal management and the surveillance of the first degree relatives. There are limited data on the genetic characteristics of patients with PGLs from Middle East countries, and to our knowledge this is the first study from Iran. We present the clinical and genetic characteristics of a 29-year old woman who presented with hypertension secondary to a para-aortic PGL. She was shown to have a novel mutation in the SDH-B gene and her family was subsequently screened. We also emphasize the problems in diagnosing and treating patients in this region.

Functioning adrenocortical tumors in children-secretory behavior.

OBJECTIVE: Adrenocortical tumors are rare childhood neoplasms. More than 95% are functional and present with virilization, Cushing's syndrome, hypertension, or hyperestrogenism. The objective of this paper is to present the clinical, laboratory and pathological findings of this rare disease and to highlight the secretory behavior of these tumors. METHODS: Clinical and laboratory data of seven Iranian children and adolescents aged between 2 and 16 years with functioning adrenocortical tumors are presented. Five patients had virilization and two had Cushing's syndrome at the time of diagnosis. In all subjects, the tumors were removed successfully by open surgery, during which a blood sample was drawn from the corresponding adrenal vein for hormonal evaluation. RESULTS: Peripheral blood evaluation revealed that in addition to the dominant hormone (testosterone in the cases presenting with virilization and cortisol in those with Cushing's syndrome), significant amounts of other hormones were secreted from these tumors. Adrenal vein evaluation revealed that testosterone, dehydroepiandrosterone sulfate, estradiol, 17(OH) progesterone, and cortisol were directly released from the tumor. The tumors weighed between 36-103 grams. The patients have since been followed for 5 to 20 years, and there have been no signs or symptoms of relapse in any of the patients. CONCLUSIONS: The study shows that functioning adrenocortical tumors should be considered in children and adolescents presenting with hyperandrogenism, Cushing's syndrome, or hyperestrogenism. A diagnosis of a functioning adrenocortical tumor requires surgical removal as early as possible to prevent the untoward effects of virilization or corticosteroid excess. Evaluation of adrenal vein hormones showed that the steroids are secreted directly from the tumor and peripheral conversion has little contribution to the serum levels.

Ectopic acromegaly due to growth hormone releasing hormone.

Acromegaly secondary to extra-pituitary tumors secreting growth hormone releasing hormone (GHRH) is rarely encountered. We review the literature on ectopic acromegaly and present the index report of ectopic acromegaly secondary to GHRH secretion from a mediastinal paraganglioma. Clinical and pathological manifestations and therapeutic management of 99 patients with ectopic acromegaly are reviewed. Acromegaly secondary to ectopic GHRH secretion is usually caused by a neuroendocrine tumor in the lung and pancreas. We report an additional cause of ectopic acromegaly from a mediastinal paraganglioma. Diagnostic criteria of ectopic GHRH syndrome include biochemical and pathologic tumoral confirmation of GHRH secretion and expression. Management of ectopic acromegaly consists of surgical resection of the primary tumor and biochemical normalization, with possible adjuvant use of somatostatin analogs. The review demonstrates that there are several tumor types, including paragangliomas which may secrete GHRH, leading to acromegaly. Clinical and laboratory manifestations of the syndrome and challenges in diagnosis and management of these rarely encountered patients require early diagnosis and appropriate treatment to prevent long-term morbidity and mortality with ectopic acromegaly.

Cushing syndrome secondary to a thymic carcinoid tumor due to multiple endocrine neoplasia type 1.

OBJECTIVE: To present an Iranian patient with a nonclassic form of multiple endocrine neoplasia type 1 (MEN 1) who presented with ectopic Cushing syndrome (CS) secondary to a corticotropin (ACTH)-producing thymic neuroendocrine tumor (NET), recurrent renal stones, and a giant cell granuloma of the jaw due to primary hyperparathyroidism (PHPT) without involvement of the pituitary or pancreas. METHODS: Relevant imaging and hormonal evaluations were performed. The patient was operated on 2 occasions for a thymic NET and on 3 occasions for PHPT. DNA from a peripheral blood sample was extracted for sequencing of the MEN1 gene. RESULT: Histopathologic evaluation of the thymic tumor removed during the first surgery showed an atypical carcinoid tumor with a Ki-67 labeling index of 5%. Evaluation after the second surgery revealed an invasive carcinoid tumor with a Ki-67 labeling index of 30%. Parathyroid pathology was suggestive of glandular hyperplasia. Menin gene sequencing revealed a novel frameshift mutation c.1642_1648dup in exon 10. CONCLUSION: This case of MEN 1 is unusual because most thymic NETs in MEN 1 are nonfunctional, and secretion of ACTH or other ectopic hormones rarely occurs. In patients presenting with thymic NETs, the possibility of MEN 1 should be considered, especially in the presence of hyperparathyroidism. This case also demonstrates that the behavior of thymic NETs can change over time from slow-growing tumors to highly invasive neoplasia, and that ectopic ACTH can be produced by these tumors in the context of MEN 1.

Postpartum hypercalcemia secondary to a neuroendocrine tumor of pancreas; a case report and review of literature.

Parathyroid hormone-related protein producing pancreatic neuroendocrine tumors have been infrequently reported. Herein, we report a case of an Iranian woman who had such a tumor during pregnancy, and gave birth to a female neonate with esophago-tracheal fistula and imperforated anus. Hypercalcemia was diagnosed at postpartum because of elevated serum calcium levels in the neonate and neurologic deterioration of the mother. Extensive literature review revealed 42 cases with pancreatic neuroendocrine tumors and hypercalcaemia. The clinical and laboratory findings of such patients are reviewed in this manuscript.

Cortisol and estradiol secretion by a benign virilizing adrenocortical tumor in a prepubertal girl.

We report a 5.5 year-old girl with a benign adrenocortical adenoma who presented with virilization and rapid growth. She did not have any clinical features of isosexual precocity or, except for hypertension, Cushing's syndrome. Measurement of hormones in adrenal vein blood obtained at surgery showed high concentrations of testosterone, cortisol, estradiol and intermediary substrates. Elevated levels of hormones detected in the peripheral blood were released directly from the tumor and were not the result of peripheral interconversion. Hyperandrogenism can obscure the clinical features of Cushing's syndrome and estrogen hypersecretion in patients with functional adrenal tumors.