Pituitary stalk interruption syndrome due to novel ROBO1 mutation presenting as combined pituitary hormone deficiency and central diabetes insipidus.

OBJECTIVES: The genetic causes of pituitary stalk interruption syndrome (PSIS) remain elusive in 95 % of cases. The roundabout receptor-1 gene (ROBO1) plays critical roles in axonal guidance and cell migration. Recently, mutations in the ROBO1 gene have been reported patients with PSIS. CASE PRESENTATION: We report a 2.9-year-old boy with PSIS who presented with combined pituitary hormone deficiency, central diabetes insipidus, and the classical triad of MRI findings. Through clinical exome sequencing using next-generation sequencing techniques, a previously unidentified novel heterozygous frame shift mutation in the ROBO1 gene was identified. This is the first report of ROBO1 mutation associated with posterior pituitary dysfunction. CONCLUSIONS: We conclude and emphasize that ROBO1 should be investigated in patients with PSIS. Our case is unique in the published literature in that we are first time reporting posterior pituitary dysfunction as manifestation of ROBO1 mutation. The full clinical spectrum of the mutations may not be fully known.

Metabolic Abnormalities, Inflammatory Markers and Endothelial Dysfunction in Hyperprolactinemia due to Prolactinoma before and after Normalization of Serum Prolactin: A Prospective Case Control Study.

Background: Hyperprolactinemia is associated with obesity, dyslipidemia, insulin resistance, and low-grade inflammation which may promote endothelial dysfunction (EnD). Limited work has been done on EnD in prolactinomas and we, therefore, studied serum markers of inflammation and EnD in patients with prolactinomas before and after treatment with dopamine agonists. Methodology: Fifty-six treatment naïve patients with prolactinomas and fifty-three (apparently healthy age and sex-matched) controls were enrolled in the study and subjected to clinical assessment and laboratory investigations including blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, urea, creatinine, uric acid, erythrocyte sedimentation rate (ESR), highly sensitive C-reactive protein (hsCRP) and markers of EnD i.e., intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Patients were treated with a dopamine agonist (cabergoline) and parameters (like ESR, hsCRP, ICAM-1, and VCAM-1) were measured at 12 weeks. Results: The majority of the patients (84%) were female, more than half (52%) had metabolic syndrome and over a third (36%) were obese. Blood glucose fasting, HbA1c, lipid fractions, ESR, hsCRP, ICAM-1, and VCAM-1 were significantly higher in patients than in controls. Median ICAM-1 was 1331.95 ng/ml (IQR 803.43-1825.99) in patients vs 753.04 ng/ml (IQR 402.04-871.55) in controls, P < 0.001 and median VCAM-1in patients was 971.35 ng/ml (IQR 695.03-1285.23) as against 634.56 ng/ml (IQR 177.49-946.50) in controls, p0.001. Serum ICAM-1 and VCAM-1 correlated positively with hsCRP. On multivariate regression analysis, serum hsCRP was the only significant predictor of change in ICAM-1 and VCAM-1. Normalization of serum PRL with CAB resulted in a significant decrease in metabolic parameters, ESR, hsCRP, ICAM-1, and VCAM-1. Conclusion: Hyperprolactinemia because of prolactinoma is associated with EnD secondary to systemic inflammation and metabolic abnormalities which improve after treatment with DA.

Thyroid Autoimmunity and Subclinical Hypothyroidism in Prolactinoma: A Case Control Study.

Background: This study was aimed at determining the frequency of thyroid autoimmunity and subclinical hypothyroidism in patients with hyperprolactinemia due to prolactinoma compared to well-matched healthy controls. Methods: This was a cross-sectional study wherein 78 treatment naïve prolactinoma patients and ninety-two healthy control subjects were recruited. Serum prolactin (PRL), thyroid-stimulating hormone (TSH), total thyroxine (T4), circulating anti-thyroid peroxidase (anti-TPO), and anti-thyroglobulin (anti-Tg) antibody levels were measured in all study subjects. Progression of the antibody-positive population to subclinical hypothyroidism was determined. Results: The median PRL level among patients was 166 ng/ml (IQR 85-467) compared to 11.4 ng/ml (IQR 8.5-15.9) in controls (P < 0.001). There was no significant difference in levels of T4 (P = 0.83) and TSH (P = 0.82) between the cases and controls. Overall, 25% of patients had the presence of anti-thyroid antibodies as compared to 20% of controls (P = 0.56). SCH was more common in antibody-positive hyperprolactinemia subjects compared with antibody-positive controls. Conclusion: We did not find an increased prevalence of thyroid autoimmunity among untreated prolactinoma patients compared to healthy controls. At the same time, subclinical hypothyroidism was more common in thyroid antibody-positive patients with hyperprolactinemia than positive controls.

High prevalence of coronary artery calcification and increased risk for coronary artery disease in patients with Sheehan syndrome-A case-control study.

OBJECTIVE: Patients with Sheehan syndrome (SS) are predisposed to coronary artery disease (CAD) due to risk factors like abdominal obesity, dyslipidemia and chronic inflammation. In addition to estimate CAD risk enhancers like high sensitive C reactive protein (hsCRP), apolipoprotein B (ApoB) and lipoprotein A [Lp(a)], this study applies Framingham risk score (FRS) and coronary artery calcium (CAC) score to compute a 10-year probability of cardiovascular (CV) events in SS patients. DESIGN: Case-control study Sixty-three SS patients, on a stable hormonal replacement treatment except for growth hormone and 65 age, body mass index and parity-matched controls. MEASUREMENTS: Measurement of serum hsCRP, ApoB and Lp(a) and estimation of CAC with 16-row multislice computed tomography scanner. RESULTS: The concentrations of hsCRP, ApoB and Lp(a) were significantly higher in SS patients than in controls (p < .01). After calculating FRS, 95.2% of SS patients were classified as low risk, 4.8% as intermediate risk and all controls were classified as low risk for probable CV events. CAC was detected in 50.7% SS patients and 7.6% controls (p = .006). According to the CAC score, 26.9% SS patients were classified as at risk (CAC > 10) for incident CV events as against 1.6% controls. The mean Multi-Ethnic Study of Atherosclerosis (MESA) score was significantly higher in patients with SS than controls. CAC corelated significantly with fasting blood glucose (r = .316), ApoB (r = .549), LP(a) (r = .310) and FRS (r = .294). CONCLUSION: Significant number of asymptomatic SS patients have high coronary artery calcium score and are classified at risk for CAD.

Multiple Uterine Leiomyomas in Multiple Endocrine Neoplasia Type 1 with a Novel MEN1 Gene Mutation.

To report the clinical, hormonal, and genetic features of a female with multiple endocrine neoplasia type 1 (MEN1) with multiple uterine leiomyomas. The study was conducted at a tertiary care endocrinology unit. A 27-year-old female was diagnosed with prolactinoma, primary hyperparathyroidism (PHPT), and multiple uterine leiomyomas. In view of prolactinoma and PHPT, a clinical diagnosis of MEN1 syndrome was made. She also had multiple uterine leiomyomas for which myomectomy was done. Genetic analysis revealed a novel mutation c.1763C>T, p.S588L of MEN1 gene. The association of uterine leiomyomas with MEN1 is exceptionally rare. This is the first report of multiple uterine leiomyomas in a patient with MEN1 from our country and the first report of this mutation in the MEN1 gene in the world. We conclude that in the presence of multiple uterine leiomyomas and endocrine tumor, clinical examination and laboratory evaluation may uncover the diagnosis of MEN1 syndrome in these patients.

Presentation, Morbidity and Treatment Outcome of Acromegaly Patients at a Single Centre.

INTRODUCTION: The management of acromegaly, a rare and potentially curable disease, has undergone a paradigm shift in the past few decades. Many of the treatment modalities recommended for acromegaly are either too expensive or not available in many parts of India. There is a dearth of treatment and outcome data in Indian patients. AIM: Our aim was to study the clinical presentation, hormonal profile, radiology, management, and outcome of the disease at our center. MATERIALS AND METHODS: Fifty one patients with acromegaly who attended the Department of Endocrinology, SKIMS, Srinagar, between October 2015 and April 2017, were included in the study. Clinical and hormonal profiles, comorbidities, treatment modalities, and outcome were evaluated. RESULTS: The gender distribution was equal with the mean age of 42.3 ± 10.9 years at diagnosis. The majority (41) of the patients had macroadenoma. The most common presenting manifestations were acral enlargement and headache. Hypertension was present in 23, musculoskeletal manifestations in 19, and diabetes mellitus in 11 patients. Surgery was the most common method of treatment. Preoperatively only one patient with micro-adenoma had hypocortisolism, which was persistent in postoperative period, while no patient had preoperative or postoperative hypothyroidism or hypogonadism. As per the present consensus criteria, 23.7% patients achieved disease control (40% with microadenoma and only 19.5% with macroadenoma). The surgical complications occurred in 5 patients-CSF leak in 3 meningitis in 2 patients all except one having macroadenoma. CONCLUSIONS: The presentation of disease was generally comparable to that reported in literature. Cure rates were significantly lower than those reported from many large centers.

FSH ß-subunit mutations in two sisters: the first report from the Indian sub-continent and review of previous cases.

Isolated FSH deficiency due to mutations in the gene for ß-subunit of FSH is an extremely rare autosomal recessive disease of which only eleven cases have been reported so far. The clinical features include absent breast development and primary amenorrhea in females and azoospermia with normal testosterone levels in males. In this study we report two Kashmiri sisters born to native Kashmiri consanguineous parents with failure of onset of puberty. Hormonal evaluation revealed undetectable serum FSH and estradiol and high LH. Genetic analysis of FSH ß-gene identified one nonsense mutation (c.343C > T:p. Arg115Stop) in exon 3. The two sisters were homozygous for this nonsense mutation while the parents were heterozygous. Incorporation of a stop codon at 115 codon position is predicted to result in the formation of truncated FSH ß protein, lacking 14 amino acid from the carboxy-terminus (p.Arg115Stop). Very recently, this same mutation was reported for the first time in a Chinese male. Ours is the first ever report of any FSH ß-subunit mutation from the Indian sub-continent and this particular mutation in any female from anywhere in the world. We conclude and emphasize that this diagnosis should be considered in girls with delayed puberty and selective deficiency of FSH.

Clinical and laboratory profile of primary hyperparathyroidism in Kashmir Valley: A single-center experience.

BACKGROUND: Although primary hyperparathyroidism (PHPT) has become an asymptomatic disease in the West, in India, PHPT is still an uncommonly diagnosed, overtly symptomatic disease with skeletal, muscular, and renal manifestations. AIMS: To describe the profile and surgical outcome of 78 consecutive PHPT patients over a period of two decades at a single center. MATERIALS AND METHODS: All patients who underwent evaluation and surgery for PHPT from January 1996 to December 2015 were included. Evaluation included measurement of serum total calcium, inorganic phosphorus, alkaline phosphatase, intact parathyroid hormone, 25-hydroxy Vitamin D, 24 hour urinary calcium and radiological survey. Ultrasonography neck and technetium-99m sestamibi scan were used for preoperative localization. RESULTS: A total of 78 patients were identified during the two decades of whom 29 patients were studied retrospectively and 49 patients prospectively. Mean age of patients was 44.72 ± 12.46, and male:female ratio was 1:6. The most common presenting features were nephrolithiasis and/or nephrocalcinosis (64.10%), bone pain (44.1%), abdominal pain (39%), constipation (26%), and myopathy (14.10%). Fractures were present only in 10.25%, and brown tumors in 6.41% patients. The cure rate in our series was 96.15%. The mean parathyroid gland weight was 2.05 ± 3.03 g. None of the 41 patients in whom long-term follow-up was available, had recurrence of PHPT. CONCLUSIONS: The profile of PHPT is changing with older age at presentation, and emergence of renal stone disease and decline in overt skeletal disease as common presentation. The parathyroid weight in our study resembles that reported from developed countries.

CARDIAC STRUCTURAL AND FUNCTIONAL ABNORMALITIES IN FEMALES WITH UNTREATED HYPOPITUITARISM DUE TO SHEEHAN SYNDROME: RESPONSE TO HORMONE REPLACEMENT THERAPY.

OBJECTIVE: Data on cardiac abnormalities in females with untreated hypopituitarism are limited. We investigated echocardiographic abnormalities in females with untreated hypopituitarism and their response to treatment. METHODS: Twenty-three females with treatment-naïve hypopituitarism and 30 matched healthy controls were evaluated for cardiac structure and function. Echocardiographic evaluation was done at presentation and after achieving a euthyroid and eucortisol state. RESULTS: Fourteen (61%) patients had mitral regurgitation, and 11 (48%) had pericardial effusion as against none among controls. Indices of left ventricular (LV) size like LV end diastolic dimension (LVEDD; 44.5 ± 3.5 mm in cases vs. 47.6 ± 3.8 mm in controls, P = .004), and LV diastolic volume (LVEDV; 91.8 ± 18.0 mL versus 106.5 ± 20.4 mL, P = .009) were significantly lower in the SS group compared with controls. LV mass (LVM) was 70.8 ± 19.2 g in cases and 108.0 ± 33.2 g in controls (P = .02). Similarly, indices of LV systolic function like stroke volume (SV; 59.1 ± 12.0 mL in cases and 74.4 ± 15.8 mL in controls; P = .000), ejection fraction (EF; 64.3 ± 6.2 % in cases against 69.9 ± 9.2 % in controls; P = .03), and fractional shortening (FS; 34.9 ± 4.7% versus 40.1 ± 4.4%, P = .000) were significantly decreased in patients compared with controls. Cardiac abnormalities normalized with restoration of a euthyroid and eucortisol state. CONCLUSION: Pericardial effusion, mitral regurgitation, and diminished LVM are common in females with untreated hypopituitarism. ABBREVIATIONS: ACTH = adrenocorticotrophic hormone BMI = body mass index DT = deceleration time EDV = end-diastolic volume EF = ejection fraction FS = fractional shortening GH = growth hormone IGF-1 = insulin growth factor-1 ITT = insulin tolerance test IVSd = interventricular septal diameter LH = luteinizing hormone LV = left ventricular LVEDD = LV end diastolic dimension LVEDV = LV end diastolic volume LVM = LV mass MRI = magnetic resonance imaging MVP = mitral value prolapse PPH = postpartum hemorrhage PWd = posterior wall diameter SS = Sheehan syndrome SV = stroke volume T3 = triiodothyronine T4 = thyroxine TSH = thyroid-stimulating hormone.

Calcitriol-mediated Reversible Hypercalcemia in a Patient with Primary Adrenal Lymphoma.

Primary adrenal lymphomas (PAL) are rare occurrences with only less than 150 cases reported in the literature. Two-thirds of these cases were reported in the last decade due to the advancements in imaging techniques and immunohistochemistry. The non-specific signs and symptoms have resulted in a delayed onset of symptoms and diagnosis of these tumors. Reports of the results of chemotherapy are not gratifying, and most patients die within one year of the diagnosis. We report a 65-year-old male with adrenal non-Hodgkin's lymphoma (NHL), who presented with hypercalcemia and renal failure. We reviewed all adrenal NHL cases presented with hypercalcemia and attempted to comprehend its etiology and overall survival effect.

L-asparaginase induced hypoglycemia in a case of acute lymphoblastic leukemia: a patient report.

L-asparaginase (L-Asp) is an essential component of acute lymphoblastic leukemia (ALL) treatment protocols and its use has been associated with many adverse effects. We report a case of a 15-year-old boy with ALL who developed L-Asp induced hypoglycemia. To the best of our knowledge, only one such case has been reported previously.

Insulin resistance, metabolic syndrome and chronic low grade inflammation in Sheehan's syndrome on standard replacement therapy: a case control study.

BACKGROUND: Increased clustering of metabolic risk factors has been demonstrated in patients with hypopituitarism on standard replacement therapy. This usually has been attributed to persistent growth hormone deficiency, though contribution from underlying etiology of hypopituitarism cannot be underestimated. We, therefore, studied conventional metabolic risk factors and pro inflammatory markers in a cohort of hypopituitary patients in whom the etiology was Sheehan's syndrome. MATERIAL & METHODS: We studied 30 GH naive patients with Sheehan's syndrome (SS) on standard replacement therapy and compared with healthy age, BMI and parity matched controls. All subjects were normotensive, non-diabetic, non-smokers and none had history of any acute or chronic illness. We recorded height, weight, BMI, waist circumference and waist hip ratio, besides measuring biochemical parameters like lipid profile, fasting plasma glucose and insulin, sVCAM-1, ICAM-1 and hsCRP. RESULTS: Metabolic syndrome and impaired glucose tolerance were more common with SS patients. Similarly total cholesterol (mean ± SD, 5.21 ± 0.98 vs 4.57 ± 0.88, P = 0.00), LDL-cholesterol (3.15 ± 0.90 vs 2.67 ± 0.75, P = 0.02), triglycerides (2.14 ± 1.00 vs 1.43 ± 0.45, P = 0.00) and pro-inflammatory markers i.e. hsCRP (3.95 ± 2.58 vs 1.45 ± 2.77, P = 0.00) were significantly higher in patients with SS. hsCRP positively correlated with fasting insulin (r = 0.40, P = 0.02), HOMA-IR (r = 0.38, P = 0.03) and negatively with HDL (r = - 0.33, P = 0.05). CONCLUSIONS: GH naïve SS patients on standard replacement therapy have increased clustering of metabolic and pro-inflammatory risk factors.

Dissociated hypopituitarism after spontaneous pituitary apoplexy in acromegaly.

INTRODUCTION: Pituitary apoplexy is an uncommon event and usually occurs in non-functioning pituitary tumors. Among the functioning tumors, prolactinomas are the ones most likely to apoplexy. Apoplexy in growth hormone (GH) producing adenomas is a very rare event with less than thirty cases reported worldwide. OBJECTIVE: To describe a case of spontaneous pituitary apoplexy in acromegaly. CASE REPORT: A 55 year old smoker male presented to the our outpatient clinic in 2004 with complaints of gradual onset increase in the size of hands and feet, bilateral knee pain, increased sweating and blurring of vision. Investigations uncovered diabetes mellitus by a casual blood glucose of 243 mg/dl and HbA1c of 8.5%. Growth hormone suppression test using 75 gram oral glucose showed a 60 minute growth hormone of 105 ng/ml. Magnetic resonance imaging of the sellar region showed a 12.0 mm × 10.0 mm pituitary adenoma. The patient was planned for transsphenoidal tumor decompression. However, the patient was lost to follow up. Eight-years later, he presented in the emergency department of our institute with sudden onset headache, vomiting and decreased level of consciousness of one day duration. CT scan of the head with focus on the sella was suggestive of apoplexy which was later confirmed by the MRI of the sellar region. CONCLUSION: Although acromegaly can remit following apoplexy of the responsible pituitary adenoma, long term follow up is needed for early detection of the development of deficiency of pituitary hormones which may occur over years following the event as well as to detect tumor regrowth which again may occur several years later.

Role of cervical ultrasonography in primary hyperparathyroidism.

AIM: To evaluate the role of USG in the preoperative localization of parathyroid adenomas in patients with symptomatic hyperparathyroidism and to compare its usefulness with that of scintigraphy scan and postoperative findings. MATERIAL AND METHODS: Twenty-five patients with symptomatic primary hyperparathyroidism were subjected to USG of the neck and nuclear scintigraphy, followed by surgery. The results were independently analyzed and compared with per-operative findings. RESULTS: The 25 patients had a total of 28 abnormal glands: 22 solitary adenomas, and 6 multiple adenomas (two each in three patients). USG detected 20 out of 22 solitary adenomas and three out of six multiple adenomas. USG missed five abnormal glands, two of which were in the neck and three in the mediastinum. Scintigraphy was positive in 26 abnormal glands, out of which 22 were single and four were multiple. Two abnormal glands were missed: one in the neck and one in the mediastinum. CONCLUSION: As limited neck dissection for primary hyperparathyroidism becomes increasingly popular, USG has been found to be a sensitive, specific, and easily available noninvasive investigation for parathyroid localization. It can be easily offered to patients as a method for preoperative localization prior to limited parathyroid surgery outside tertiary care settings.

Juvenile fibrocalculous pancreatopathy--a patient report.

Fibrocalculous pancreatopathy (FCPP) is a secondary form of diabetes mellitus (DM) with obscure etiology. Recently various gene mutations have been reported in patients with FCPP from the Indian subcontinent. Initially termed tropical pancreatic diabetes, FCPP is uncommon and is characterized by pancreatic calcifications. The diagnosis is made in the third decade of life in most patients with the onset of abdominal pain and DM. We report a female child with DM diagnosed at the age of 3 years who had been managed with insulin but was ketosis resistant. The diagnosis of FCPP was made 3 years later. There were no mutations at N34S and P55S in the SPINK1 gene.

Epidemiologic aspects of postpartum pituitary hypofunction (Sheehan's syndrome).

Two hundred seventy-nine (3.20%) of the 8,730 parous females aged 20-39 years and 124 (4.18%) of 2,970 parous females aged 40 years or older who were screened were suspected to have Sheehan's syndrome; 115 and 55 of these females in the two age groups were fully evaluated, and 98 and 51 of them, respectively, were proven to have Sheehan's syndrome. At these rates, the projected number of women with Sheehan's syndrome among a total population of parous females aged > or =20 years (12,32,827, as per census data) would be 38,691 in the Kashmir valley of the Indian subcontinent.

Epidemiologic and etiologic aspects of hirsutism in Kashmiri women in the Indian subcontinent.

OBJECTIVE: To assess the prevalence of hirsutism and study its etiology in the Kashmir Valley of the Indian subcontinent. DESIGN: Prospective random sample of the general population attending outpatient medical clinics and prospective evaluation of hirsute patients referred to our endocrinology clinic. SETTING: A tertiary care hospital and district-level primary care hospitals. PATIENT(S): Five thousand women attending various hospitals for reasons unrelated to hirsutism and 150 consecutive women referred for hirsutism. INTERVENTION(S): Assessment of body hair as per the Ferriman and Gallwey scoring system and an investigative protocol including detailed clinical assessment with endocrinologic workup including estimations of gonadotropins, PRL, T, and 17-hydroxyprogesterone and abdominopelvic ultrasound. MAIN OUTCOME MEASURE(S): Presence and cause of hirsutism. RESULT(S): Of 4,780 adult women for whom adequate data were available, 504 (10.5%) had hirsutism, among whom 484 (10.1%) had mild (score of 6-9) and 20 (0.4%) had moderate hirsutism (score of 10-14). The etiology of hirsutism revealed idiopathic hirsutism in 38.7%, polycystic ovary syndrome (PCOS) in 37.3%, postmenopausal state in 9.2%, adrenal tumors in 2.1%, congenital adrenal hyperplasia in 1.4%, and drug-induced hirsutism in 0.7%. The cause remained undetermined in 10.6% of patients for whom the available information was not adequate. CONCLUSION(S): Hirsutism is as common a problem in the Kashmir Valley (India) as elsewhere in the world. Idiopathic hirsutism (38.7%), PCOS (37.3%), and postmenopausal state (9.2%) are common causes of hirsutism. Late-onset congenital adrenal hyperplasia is a relatively uncommon cause of hirsutism in the Kashmir Valley.