Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians.

BACKGROUND: Congenital isolated hypogonadotropic hypogonadism (IHH) is caused due to defect in GnRH neuronal development, migration and action. Although genetic aetiology of IHH is increasingly being studied, Asian Indian data on phenotypic spectrum and genetic basis are scarce. OBJECTIVE: To investigate the phenotypic and genotypic spectrum of IHH in Asian Indian subjects. DESIGN, SETTING AND SUBJECTS: A cohort of 135 IHH probands were characterized phenotypically for reproductive and nonreproductive features and screened for rare sequence variations (RSVs) in five genes KAL1, FGFR1, FGF8, GNRHR and KISS1R. RESULT: Of 135 probands [56 normosmic IHH (nIHH) and 79 Kallmann syndrome (KS)], 20 were familial cases. KS group had more male dominance (M:F ratio of 8:1) as compared to nIHH group (M:F ratio of 1·5:1). Complete absence of puberty was more prevalent in KS probands (81% in KS vs 46% in nIHH). The prevalence of MRI abnormalities was more in anosmic group (92·8%) as compared to hyposmic (37·5%) and normosmic groups (15·4%). No particular nonreproductive phenotypic predominance was seen in any group. Genotyping revealed rare sequence variation (RSV) detection rate of 15·5% in five genes studied: (KAL1 - 4·4%, FGFR1 - 4·4%, GNRHR - 6·7%, oligogenicity - 1·5%). Prevalence of RSV was more common in familial cases (35%) as compared to sporadic (12·2%). GNRHR RSV p.C279Y (not reported in patients of ethnicities other than south Asians) was recurring in four unrelated patients. CONCLUSION: In our cohort, 60% were KS with majority of males and a severe reproductive phenotype as against nIHH. Contribution of the genetic burden for the five genes studied was 15·5%. RSV p.C279Y in GNRHR may have a founder effect originating from south Asia. This study provides a model for molecular and phenotypic representation of Asian Indian subjects with IHH.

Endocervical crypt involvement by high-grade cervical intraepithelial neoplasia after large loop excision of transformation zone: do we need a different follow-up strategy?

AIMS: The aim of this study was to determine the effect of endocervical crypt involvement in specimens with clear margins on recurrence following large loop excision of transformation zone (LLETZ). MATERIAL AND METHODS: This was an observational cohort study. In the colposcopy unit in a university teaching hospital we prospectively collected data for women who underwent LLETZ treatment for high-grade cervical intraepithelial neoplasia (CIN) between 2003 and 2004. We determined the difference in recurrence rate and need for repeat treatment between groups with and without crypt involvement in the primary histology. We prospectively collected data of follow up until 2010. The recurrence was analyzed using Cox regression. RESULTS: A total of 309 women had complete excision of the margins following LLETZ treatment for CIN 2 or 3. There was no significant difference in age between groups with (30.2) and without (29.7) crypt involvement (P<0.25). There was a significant difference in the prevalence of abnormal smear results before and after LLETZ between groups with or without crypt involvement (P=0.043). The need to perform a repeated treatment was significantly different between groups with and without crypt involvement (P<0.024). A full model significantly predicted recurrence of cervical pathology (P<0.009) that necessitated treatment when crypt involvement was present. The odds ratio for repeat treatment with crypt involvement was 2.67 (confidence interval, 1.27-5.64). CONCLUSIONS: Our study showed that positive involvement of endocervical crypt by CIN in a cervical loop excision specimen increases the frequency of subsequent episodes of treatment.

Breast incidentalomas on 18-Fluorodeoxyglucose positron emission tomography-computed tomography performed for a non-mammary cause: Significance and outcomes.

INTRODUCTION: The aim of the study was to determine the rate of malignancy in breast incidentalomas found on 18-Fluorodeoxyglucose Positron Emission Tomography-Computed tomography (18 FDG PET-CT) performed for non-mammary causes and evaluate outcomes. METHODS: A single-centre, retrospective review of 5728 18-FDG PET-CT scans performed between January 1, 2017 and April 30, 2019 was undertaken. Cases with known primary breast cancer or metastases to the breast in the previous ten years were excluded. Diagnosis was confirmed with breast imaging, histology and 2-year follow-up. Data analysed included age, the pattern of uptake on 18-FDG PET-CT, lesion size and BIRADS score. RESULTS: Thirty-two Breast incidentalomas were identified in 27/5728 scans (0.47%). 18 lesions (56.3%) were malignant. Five underwent curative surgery. Nine lesions (28.1%) were benign and five (15.6%) were false positive. CONCLUSION: Breast incidentalomas are uncommon on 18-FDG PET-CT but require work-up for malignancy. BIRADS score has a high sensitivity and specificity for malignancy in18-FDG PET-CT incidentalomas but age, size of the lesion and the pattern of uptake on 18-FDG PET-CT were not useful in differentiating benign from malignant incidentalomas.

Cushing disease with pregnancy.

Pregnancy occurs rarely in patients with Cushing syndrome (CS) due to hypercortisolism. So far, about 150 cases of CS in pregnancy have been reported in the literature. We describe a 22-year-old female who presented in pregnancy with clinical features of CS. She delivered at 34 weeks of gestation and baby had transient adrenal insufficiency in the neonatal period. Mother underwent transsphenoidal surgery 1 year postpartum and on follow up she is under remission. Neonatal hypoadrenalism should be anticipated in maternal CS.

Carcinosarcoma arising in a uterine leiomyoma: report of a unique neoplasm.

Malignant transformation of a uterine leiomyoma is an exceedingly rare phenomenon. Previous reported examples of malignant neoplasms to arise so include leiomyosarcoma, angiosarcoma, and malignant mesenchymoma. We report an intramural carcinosarcoma arising in a uterine leiomyoma in a 38-year-old woman. This case is unique in being the first recorded carcinosarcoma arising within a uterine leiomyoma and the first example of an epithelial neoplasm to do so. We discuss the differential diagnosis and possible pathogenesis of the tumor that has likely arisen secondary to epitheliogenesis in a mesenchymal neoplasm.

Pheochromocytoma and medullary thyroid carcinoma in a pregnant multiple endocrine neoplasia-2A patient.

OBJECTIVE: We describe a rare combination of pheochromocytoma and medullary thyroid carcinoma (MTC) during pregnancy. METHODS: Twenty-three-years old lady, primigravida, was detected to be hypertensive at 12 weeks of gestation and was found to have left adrenal mass on routine obstetric scan. She had a goitre on examination which was proven to be MTC on fine needle aspiration cytology. Twenty-four hours urinary vanillyl mandelic acid and serum calcitonin levels were elevated. After adequate α and ß blockade she underwent left adrenalectomy during second trimester of gestation with no significant perioperative complications. Twelve days later she underwent total thyroidectomy. RESULTS: Adrenal mass was confirmed to be pheochromocytoma while MTC was confirmed in the thyroidectomy specimen. Post-operatively, she was normotensive and delivered a healthy female baby at term. Both mother and the baby tested positive for germline RET mutation (C634W) in exon 11. CONCLUSION: We describe a rare case of pregnant multiple endocrine neoplasia-2A patient with pheochromocytoma and MTC.

Diagnostic efficacy of midnight cortisol and midnight ACTH in the diagnosis and localisation of Cushing's syndrome.

Classical tests for diagnosis of Cushing's syndrome (CS) like urine free cortisol and dexamethasone suppression tests have limitations in various clinical settings. This study evaluated the usefulness of sleeping midnight serum cortisol (SMNC) as a diagnostic test for hypercortisolemia. A simultaneously done midnight plasma ACTH level was used to classify the disease as ACTH dependent or independent. Standard biochemical tests, SMNC, midnight plasma ACTH and appropriate imaging evaluated patients with a clinical suspicion of Cushing's syndrome. We evaluated 43 patients with CS comprising of 34 patients with Cushing's disease (CD), 2 patients with thymic carcinoid producing ectopic CS, 5 patients with adrenal carcinoma and 2 with adrenal adenoma. Thirteen patients with clinical suspicion were also evaluated with the above tests and CS was ruled out. SMNC, midnight plasma ACTH and dexamethasone suppressed cortisol was collected from patients with a suspicion of CS. SMNC was evaluated against histopathology as the gold standard. SMNC achieved 100% sensitivity in the diagnosis of endogenous CS at cut offs of 138 nmol/l and below. Raising the cut off to 207 nmol/l resulted in a test sensitivity of 90.5%. At a cut off of 1.65 pmol/l, midnight plasma ACTH could distinguish ACTH independent causes of CS with 100% sensitivity. We concluded that a single midnight collection could identify all patients with CS and classify the ACTH status at the proposed cut offs.

Radiotherapy in paediatric Cushing's disease: efficacy and long term follow up of pituitary function.

Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing's disease (CD). We report long-term efficacy and anterior pituitary function in a cohort of paediatric CD patients treated with RT. Between 1988 and 2008, from our cohort of 48 paediatric CD patients, eight paediatric CD patients (5 males and 3 females) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of eight whose long term follow up is available, four patients were cured by RT. Minimum follow up of 2 years is available for all patients. Four patients achieved cure after RT. Two patients were not cured even after follow up of 60 and 132 months, respectively. Out of four uncured patients, two of them had suppressible low dose dexamethasone cortisol with altered circadian rhythm suggesting possibility of response in near future with follow up of just 26 months. Five patients were hypogonadal and one patient was hypothyroid. All patients were below their target height at the time of last follow up. None of the patients had posterior pituitary dysfunction. This series of patients illustrates the efficacy and long-term follow up of pituitary function in children with CD treated with RT. This study also emphasizes the need of growth hormone statues assessment and timely intervention.

Bone age and factors affecting skeletal maturation at diagnosis of paediatric Cushing's disease.

Paediatric Cushing's disease (CD) is usually associated with growth retardation, but there are only few published data on skeletal maturation at diagnosis. We analysed factors contributing to skeletal maturation and final height in Asian Indian patients with paediatric CD. We conducted retrospective analysis of 48 patients (29 males; 19 females) with mean age: 14.84 years at diagnosis (range 9-19 years). A single observer using the Greulich Pyle method determined the bone age (BA) of each child. BA delay, i.e. the difference between chronological age (CA) and BA, was compared with clinical and biochemical variables. BA delay was present in 35/48 (73%) patients (mean delay 1.6 years, range 0.5-5 years) and correlated negatively with height SDS (r = -0.594, P < 0.001) and positively with CA at diagnosis (r = 0.247, P < 0.05). There was no correlation with duration of symptoms before diagnosis, basal cortisol, midnight cortisol, ACTH or percentage suppression of low dose dexamethasone suppression cortisol (LDDST). We could not demonstrate any relationship between the duration of history before diagnosis and height SDS at final height. Mean final height SDS in patients was -1.84. We found that most children with CD had delayed BA and correlated significantly with CA and height SDS at diagnosis. Early diagnosis may reduce delay in skeletal maturation and thus contribute to optimal catch-up growth.

Clinical profile and long term follow up of children and adolescents with prolactinomas.

We report clinical presentation, response to medical treatment, and long-term follow-up of 39 children and adolescents with prolactinoma (F:M; 30:9) (30 macro and 9 microadenoma) diagnosed at the age of 9-20 years. Mean duration of follow up was 56 months. All patients were treated with bromocriptine (BC) at doses ranging from 2.5 to 20 mg/day or by cabergoline at doses ranging from 0.5 to 2 mg/week orally. Two patients received external conventional radiotherapy after surgery. In patients with macroprolactinoma (F:M; 21:9), headache and/or visual defects were the first symptoms. All females had primary or secondary amenorrhea. Growth arrest was not observed in any patient and pubertal development was appropriate for their age. Spontaneous or provocative galactorrhea was observed in 23 patients (all females) and none of male patient had gynecomastia. Mean serum prolactin (PRL) concentration at the time of diagnosis was 322.50 ng/ml in patients with microadenoma, 522.38 ng/ml in patients with macroadenoma and 2,294.86 ng/ml in patients with macroadenoma with suprasellar extension. In 25 patients, BC normalized PRL levels and caused variable, but significant, tumor shrinkage. Cabergoline normalized PRL concentrations in 14 patients. Pregnancy occurred in 6 patients while on treatment. Pregnancies were uncomplicated, and the patients delivered normal newborns at term. Impairment of other pituitary hormone secretion was documented at the time of diagnosis in only one patient. Postoperatively six patients had other pituitary hormone deficiencies. In conclusion, the medical treatment with dopaminergic compounds is effective and safe in patients with prolactinoma with onset in childhood, allowing preservation of the anterior pituitary function.

Utility of single luteinizing hormone determination 3 h after depot leuprolide in monitoring therapy of gonadotropin-dependent precocious puberty.

To determine utility of luteinizing hormone (LH) estimation, post intramuscular (IM) depot leuprolide in comparison with subcutaneous leuprolide stimulation test. Test for monitoring therapy in patients with gonadotropin dependent precocious puberty (GDPP). In seven patients of GDPP, who were treated with 11.25 mg depot leuprolide, the LH peak after subcutaneous (sc) test was compared with LH at hourly interval for 4 h after IM depot leuprolide for 13 tests and 3rd hour value for next ten tests. These two values were compared both before and after therapy. Before therapy, the mean +/- SD LH peak after subcutaneous leuprolide stimulation test was 20.6 +/- 7.85 IU/l (range 9.64-30.4 IU/l), and it was 27.3 +/- 12.21 IU/l 3 h after the first depot leuprolide injection (range 10.5-45.4 IU/l). During therapy, the mean +/- SD of LH peak after sc stimulation test was 1.96 +/- 0.75 IU/l (range 1.1-3.1 IU/l), and it was 2.58 +/- 0.54 IU/l (range 1.4-3.4 IU/l) 3 h after depot leuprolide injection. Three-hour LH value following IM depot leuprolide injection (11.25 mg) can be used for monitoring therapy in patients with GDPP because of its convenience and cost effectiveness.

Pituitary tuberculosis.

Tuberculous involvement of pituitary is extremely rare and is usually not suspected while dealing with pituitary adenomas, even in patients with history of systemic tuberculosis. We report a case of pituitary tuberculoma in a patient who was undergoing treatment for prostatic tuberculosis. Although diagnosis of sellar tuberculomas is difficult on clinical and radiological examinations, pituitary tuberculomas should be considered in the differential diagnosis of suprasellar masses, especially in developing countries as the condition is potentially curable with antituberculous treatment.

Laparoscopic transmesocolic excision of paraganglioma in the organ of Zuckerkandl.

Extra-adrenal pheochromocytomas (paragangliomas) are rare. We report the case of a 20-year-old female at 15 weeks gestation, who was detected to have a large paraganglioma (6.5 x 5 cm) in the organ of Zuckerkandl during an antenatal visit. After medical termination of the pregnancy, successful laparoscopic excision of the paraganglioma was performed.

Cushing's disease: management outcome in a tertiary care centre.

UNLABELLED: Cushing's syndrome (CS) can pose a challenge in diagnosis and management. Successful management of CS needs accurate localization of the site of lesion. Present article narrates experience of a single center dealing with large number of patients with CS and highlights difficulties in diagnosis as well as management of Cushing's disease (CD). METHODS: All patients with CD, where histopathological lesion was documented were studied to evaluate yield from different diagnostic tests. Diagnosis was established by standard 2 days low dose dexamethasone suppression test. Localization of the lesion was achieved with high dose dexamethasone suppression (HDDS) and imaging. Inferior petrosal sinus sampling (IPSS) was used whenever diagnosis was not arrived at with the standard tests. RESULTS: Out of 100 consecutive patients of CS seen, 69 had CD. HDDS had sensitivity of 70% and specificity of 99% in localizing the lesion. Imaging localized the lesion in 68% of patients. Combination of HDDS and imaging localized the lesion in 90% of patients. IPSS helped to localise the lesion in remaining 10% of patients. Transsphenoidal surgery was carried out in 65/69 patients. Cure rate for microadenoma was 77% and for macroadenoma was 36%. Mortality and morbidity rate was 7% and 7% respectively. 2nd TSS, radiotherapy and bilateral adrenalectomy were the additional modalities used in that order, in patients who were not cured or who had recurrence. CONCLUSION: Management of CS is best carried in a center where a team of experienced endocrinologist and neurosurgeon is available.

Laparoscopic adrenalectomy: Gaining experience by graded approach.

INTRODUCTION: Laparoscopic adrenalectomy (LA) has become a gold standard in management of most of the adrenal disorders. Though report on the first laparoscopic adrenalectomy dates back to 1992, there is no series of LA reported from India. Starting Feb 2001, a graded approach to LA was undertaken in our center. Till March 2006, a total of 34 laparoscopic adrenalectomies were performed with success. MATERIALS AND METHODS: The endocrinology department primarily evaluated all patients. Patients were divided into Group A - unilateral LA and Group B - bilateral LA (BLA). The indications in Group A were pheochromocytoma (n=7), Conn's syndrome (n=3), Cushing's adenoma (n=2), incidentaloma (n=2); and in Group B, Cushing's disease (CD) following failed trans-sphenoid pituitary surgery (n = 8); ectopic ACTH- producing Cushing's syndrome (n=1) and congenital adrenal hyperplasia (CAH) (n=1). The lateral transabdominal route was used. RESULTS: The age group varied from 12-54 years, with mean age of 28.21 years. Average duration of surgery in Group A was 166.43 min (40-270 min) and 190 min (150-310 min) in Group B. Average blood loss was 136.93 cc (20-400 cc) in Group A and 92.5 cc (40-260 cc) in Group B. There was one conversion in each group. Mean duration of surgical stay was 1.8 days (1-3 days) in Group A and 2.6 days (2-4 days) in Group B. All the patients in both groups were cured of their illness. Three patients in Group B developed Nelson's syndrome. The mean follow up was of 24.16 months (4-61 months). CONCLUSION: LA though technically demanding, is feasible and safe. Graded approach to LA is the key to success.

Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma.

BACKGROUND: Genetic aetiology of pheochromocytoma (PCC) and paraganglioma (PGL) is increasingly being studied; however, Asian Indian data on this aspect are scarce. OBJECTIVE: To study the prevalence of germline mutations and genotype-phenotype correlation in Asian Indian PCC/PGL patients. DESIGN: In this study, 150 index patients (M:F, 73:77) with PCC/PGL were evaluated. Phenotypic data were collected. Germline mutations in five susceptibility genes (RET, VHL, SDHB, SDHD and SDHC) were tested by sequencing and NF1 was diagnosed according to phenotype. RESULT: Of the total population, 49 (32.7%) PCC/PGL patients had germline mutations (VHL: 23 (15.3%), RET: 13 (8.7%), SDHB: 9 (6%), SDHD: 2 (1.3%) and NF1: 2 (1.3%)). Amongst the 30 patients with familial and/or syndromic presentation, all had germline mutations (VHL: 14 (46.7%), RET: 13 (43.3%), SDHB: 1 (3.3%) and NF1: 2 (6.7%)). Out of 120 patients with apparently sporadic presentation, 19 (15.8%) had a germline mutation (VHL: 9 (7.5%), SDHB: 8 (6.7%) and SDHD: 2 (1.7%)). Mutation carriers were younger (29.9 ± 14.5 years vs 36.8 ± 14.9; P = 0.01) and had a higher prevalence of bilateral PCC (26.5% vs 2.9%, P < 0.001) and multifocal tumours (12.2% vs 0.96%, P = 0.06). Based on syndromic features, metastasis, location and number of tumours, around 96% mutations in our cohort could be detected by appropriately selected single gene testing. CONCLUSION: Asian Indians with PCC/PGL differ from Western cohorts in having preponderance of VHL mutations in multifocal tumours and apparently sporadic unilateral PCC. Syndromic presentation, metastasis, location and number of PCC/PGL can be effectively used for guiding genetic prioritisation.

Short term use of octreotide in acromegaly.

A 44-year gentleman with acromegaly underwent transphenoidal excision of pituitary macroadenoma followed by radiotherapy. Since he had poor glycemic control necessitating multiple insulin doses, he was started on subcutaneous octreotide. With this, his blood sugars came under control rapidly and insulin could be withdrawn fully. This case report highlights the use of octreotide in a specific clinical situation in acromegaly to improve the quality of life.

Inferior petrosal sinus sampling in the diagnostic evaluation of Cushing's syndrome: K.E.M. experience.

INTRODUCTION: An overlap in the clinical and biochemical features of the more common pituitary Cushing's disease and the rare ectopic ACTH secreting tumors often leads to a diagnostic dilemma. High quality computed imaging modalities have a poor sensitivity and do not always help in localising the tumor. Inferior petrosal sinus sampling (IPSS) with measurement of ACTH levels localizes the source of excess ACTH secretion and aids in the differential diagnosis of ACTH dependant Cushing's syndrome. AIMS AND OBJECTIVES: To analyze the efficacy of inferior petrosal sinus sampling in the basal state and its role in the diagnostic evaluation in patients of Cushing's syndrome. MATERIAL AND METHODS: Forty four patients of proven Cushing's syndrome underwent HDDS and pituitary imaging followed by IPSS (unstimulated). The data was analysed in 39 patients with definite histopathological diagnosis which included 34 patients with Cushing's disease, four with ectopic Cushing's syndrome and one with adrenal carcinoma. A centre:periphery ratio of plasma ACTH levels of > or =2 was considered diagnostic of Cushing's disease. RESULTS: Cannulation rate was 100%. No neurological complications were encountered. IPSS could correctly localize the lesion in 23 of 34 patients of Cushing's disease (sensitivity: 67.6%). All patients of ectopic Cushing's syndrome and adrenal carcinoma had a ratio of <2 (specificity: 100%). IPSS helped in localization of the lesion and improved the diagnostic yield from 26.7% to 73.5%. CONCLUSIONS: IPSS helps in localization in patients of Cushing's syndrome with a diagnostic dilemma and should be carried out only in centers with suitable expertise.

Correlation of number of intrathyroid lymphocytes with antimicrosomal antibody titer in Hashimoto's thyroiditis.

The variants of Hashimoto's thyroiditis (classic, florid, and fibrotic types) differ in clinical manifestations, laboratory tests, and morphology. The titers of autoantibodies correlate with the degree of thyroidal lymphocytic infiltration (Wislon et al., 1998(5)) It appears that the density of lymphocytes is inversely proportional to antimicrosomal antibody (AMA) titer. The aim of the present study is to determine the precise relationship between the number of lymphocytes and AMA titer. It may be useful to predict the onset of the disease in subclinically hypothyroid patients. In 62 cases of cytologically confirmed Hashimoto's thyroiditis, the number of lymphocytes per high-power field was counted and correlated with AMA titer. The grading of lymphocytes was done as 1 (<10/HPF), 2 (11-20/HPF), and 3 (>/=21/HPF). The results showed no correlation between lymphocyte number and AMA titer.