Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity.

CONTEXT: Regional variation in prevalence of genetic mutations in growth hormone deficiency (GHD) is known. AIM: Study phenotype and prevalence of mutations in GH1, GHRHR, POU1F1, PROP1 genes in GHD cohort. METHODS: One hundred and two patients {Isolated GHD (IGHD): 79; combined pituitary hormone deficiency (CPHD): 23} with orthotopic posterior pituitary were included. Auxologic, hormonal and radiological details were studied. All four genes were analysed in IGHD patients. POU1F1 and PROP1 were studied in CPHD patients. RESULTS: Of 102, 19.6% were familial cases. Height SDS, mean (SD) was - 5.14 (1.63). Peak GH, median (range) was 0.47 ng/ml (0-6.59), 72.5% patients had anterior pituitary hypoplasia (APH). Twenty mutations (novel: 11) were found in 43.1% patients (n = 44, IGHD-36, CPHD-8). GHRHR mutations (n = 32, p.Glu72* = 24) were more common than GH1 mutations (n = 4) in IGHD cohort. POU1F1 mutations (n = 6) were more common than PROP1 mutations (n = 2) in CPHD cohort. With few exceptions, this prevalence pattern is contrary to most studies in world-literature. No patients with peak GH > 4 ng/ml had mutations, signifying it as negative predictor. While many parameters were significant on univariate analysis, only positive family history and lower median peak GH levels were significant predictors of mutations on multivariate analysis in IGHD patients. CONCLUSION: At variance with world literature, we found reverse predominance of GHRHR over GH1 mutations, POU1F1 over PROP1 mutations and predominance of GHRHR p.Glu72* mutations thus re-affirming the regional diversity in GHD genetics. We report positive and negative predictors of mutations in GHD.

Phenotype-genotype spectrum of AAA syndrome from Western India and systematic review of literature.

OBJECTIVE: To study genotype-phenotype spectrum of triple A syndrome (TAS). METHODS: Retrospective chart analysis of Indian TAS patients (cohort 1, n = 8) and review of genotyped TAS cases reported in world literature (cohort 2, n = 133, 68 publications). RESULTS: Median age at presentation was 4.75 years (range: 4-10) and 5 years (range: 1-42) for cohorts 1 and 2, respectively. Alacrima, adrenal insufficiency (AI), achalasia and neurological dysfunction (ND) were seen in 8/8, 8/8, 7/8 and 4/8 patients in cohort 1, and in 99, 91, 93 and 79% patients in cohort 2, respectively. In both cohorts, alacrima was present since birth while AI and achalasia manifested before ND. Mineralocorticoid deficiency (MC) was uncommon (absent in cohort 1, 12.5% in cohort 2). In cohort 1, splice-site mutation in exon 1 (p.G14Vfs*45) was commonest, followed by a deletion in exon 8 (p.S255Vfs*36). Out of 65 mutations in cohort 2, 14 were recurrent and five exhibited regional clustering. AI was more prevalent, more often a presenting feature, and was diagnosed at younger age in T group (those with truncating mutations) as compared to NT (non-truncating mutations) group. ND was more prevalent, more common a presenting feature, with later age at onset in NT as compared to T group. CONCLUSION: Clinical profile of our patients is similar to that of patients worldwide. Alacrima is the earliest and most consistent finding. MC deficiency is uncommon. Some recurrent mutations show regional clustering. p.G14Vfs*45 and p.S255Vfs*36 account for majority of AAAS mutations in our cohort. Phenotype of T group differs from that of NT group and merits future research.

HIGH-PRECISION CONFORMAL FRACTIONATED RADIOTHERAPY IS EFFECTIVE IN ACHIEVING REMISSION IN PATIENTS WITH ACROMEGALY AFTER FAILED TRANSSPHENOIDAL SURGERY.

OBJECTIVE: Variable efficacy of pituitary radiotherapy in acromegaly is reported. Here we sought to assess the efficacy of high-precision conformal fractionated radiotherapy (CRT) in patients with acromegaly after failed TSS. METHODS: A retrospective analysis was conducted a in tertiary care referral center between 1999 to 2013 on 36 acromegaly patients (M: 16, F: 20; median age: 36.0 years) with macroadenoma and mean growth hormone (GH) and insulin-like growth factor-1 (IGF1) upper limits of normal (ULN) of 15.9 ± 14.3 ng/mL and 1.74 ± 0.43, respectively. The cohort was divided into 2 groups: 30 patients (M: 13, F: 17) who were medical treatment naïve, and 6 patients (M: 3, F: 3) who received medical treatment after CRT. RESULTS: Normalization of GH (fasting GH <1 ng/mL), normalization of IGF1 (ULN <1), and remission (normalization of GH and IGF1) were achieved in 20 (55%), 23 (63%) and 20 (55%) patients, respectively. The mean time required to achieve remission was 63 ± 33.4 months. Follow-up duration was the only predictor of achieving remission. GH level declined exponentially by 65% and 89% at 2 and 5 years, respectively. New onset hypopituitarism was noted in 33% of patients. Tumor control was achieved in 100% of patients. In groups 1 and 2, 18 (60%) and 2 (33.3%) achieved remission post-CRT, and the mean times required to achieve remission were 58.6 ± 30.7 months and 102 ± 42.4 months, respectively. CONCLUSION: High-precision CRT is an effective modality to achieve remission in patients with acromegaly after failed TSS.

Gender differences in macroprolactinomas: a single centre experience.

Macroprolactinomas are the most common functional pituitary tumours. Hypotheses proposed to explain predominance of large tumours in males are: i) diagnostic delay, as hyperprolactinaemia remains under recognised in males and ii) gender-specific difference in tumour proliferation indices. Our study objectives are to compare gender differences in clinical, biochemical, radiological features, management outcomes and cabergoline responsiveness in macroprolactinomas. Drug resistance was defined as failure to achieve prolactin normalisation and >50% reduction in tumour volume with cabergoline (3.5 mg/week dose for minimum 6 months duration). The baseline characteristics of 100 patients (56 females and 44 males) with macroprolactinoma were analysed. Drug responsiveness was analysed in 88 treatment naive patients, excluding 12 post-primary trans-sphenoidal surgery cases. We found that females (30.29±10.39 years) presented at younger mean age than males (35.23±9.91 years) (P<0.01). The most common presenting symptom was hypogonadism (oligo-amenorrhoea/infertility) in females (96.15%) and symptoms of mass effect (headache and visual field defects) in males (93.18%). Baseline mean prolactin levels were significantly lower in females (3094.36±6863.01 ng/ml) than males (7927.07±16 748.1 ng/ml) (P<0.001). Maximal tumour dimension in females (2.49±1.48 cm) was smaller than males (3.93±1.53 cm) (P<0.001). In 88 treatment naïve patients, 27.77% females and 35.29% males had resistant tumours (P=0.48). On subgrouping as per maximum tumour dimension (1.1-2 cm, 2.1-4 cm and >4 cm), gender difference in response rate was insignificant. In conclusion, macroprolactinomas are equally prevalent in both sexes. Macroprolactinomas in males predominantly present with symptoms of mass effects, as against females who present with symptoms of hypogonadism. Males harbor larger tumours but are equally cabergoline responsive as those in females.

Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing's syndrome?

Variable prevalence of subclinical Cushing's syndrome (SCS) has been reported in patients with type 2 diabetes mellitus (T2DM), making the need for screening in this population uncertain. It is unknown if this variability is solely due to study-related methodological differences or a reflection of true differences in ethnic predisposition. The objective of this study is to explore the prevalence of SCS in Asian Indian patients with T2DM. In this prospective single center study conducted in a tertiary care referral center, 993 T2DM outpatients without any discriminatory clinical features (easy bruising, facial plethora, proximal muscle weakness, and/or striae) of hypercortisolism underwent an overnight 1 mg dexamethasone suppression test (ODST). ODST serum cortisol ≥1.8 µg/dl was considered positive, and those with positive results were subjected to 48 h, 2 mg/day low dose DST (LDDST). A stepwise evaluation for endogenous hypercortisolism was planned for patients with LDDST serum cortisol ≥1.8 µg/dl. Patients with positive ODST and negative LDDST were followed up clinically and re-evaluated a year later for the development of clinically evident Cushing's syndrome (CS). In this largest single center study reported to date, we found 37 out of 993 (3.72%) patients had ODST serum cortisol ≥1.8 µg/dl. None of them had LDDST cortisol ≥1.8 µg/dl, nor did they develop clinically evident CS over a follow-up period of 1 year. Specificity of ODST for screening of CS was 96.3% in our cohort. None of the T2DM outpatients in our cohort had SCS, hence cautioning against routine biochemical screening for SCS in this cohort. We suggest screening be based on clinical suspicion only.

PITUITARY GIGANTISM--EXPERIENCE OF A SINGLE CENTER FROM WESTERN INDIA.

OBJECTIVE: Limited data are available on pituitary gigantism, as it is a rare disorder. This study was carried out to assess the clinical, hormonal, and radiologic profiles and management outcomes of patients with pituitary gigantism. METHODS: We conduced a retrospective analysis of 14 patients with pituitary gigantism who presented to a single tertiary care institute from 1990 to 2014. RESULTS: Thirteen patients were male, and 1 was female. The mean age at diagnosis was 21.9 ± 6.1 years, with a mean lag period of 6.5 ± 5.6 years. The mean height SD score at the time of diagnosis was 3.2 ± 0.6. Symptoms of tumor mass effect were the chief presenting complaint in the majority (50%) of patients, while 2 patients were asymptomatic. Six patients had hyperprolactinemia. At presentation, the nadir PGGH (postglucose GH) and insulin-like growth factor (IGF 1)-ULN (× upper limit of normal) were 63.2 ± 94.9 ng/mL and 1.98 ± 0.5, respectively. All (except 1 with mild pituitary hyperplasia) had pituitary macroadenoma. Six patients had invasive pituitary adenoma. Transsphenoidal surgery (TSS) was the primary modality of treatment in 13/14 patients, and it achieved remission in 4/13 (30.76%) patients without recurrence over a median follow-up of 7 years. Post-TSS radiotherapy (RT) achieved remission in 3/5 (60%) patients over a median follow-up of 3.5 years. None of the patients received medical management at any point of time. CONCLUSION: Gigantism is more common in males, and remission can be achieved in the majority of the patients with the help of multimodality treatment (TSS and RT).

Management issues with exogenous steroid therapy.

Glucocorticoids (GCs) are extensively used for various inflammatory and autoimmune disorders, but long term use of these agents is not without complications. Almost every GC formulations (e.g. oral, topical, inhaled, etc.) can cause systemic side effects. It can range from minor side effects (e.g. weight gain) to life-threatening effects (e.g. adrenal suppression, sepsis, etc.), which may require immediate intervention. Therefore, the decision to institute steroid therapy always requires careful consideration of the relative risk and benefit in each patient. The objectives of this study are to discuss monitoring of patients on GCs and management of the complications of GCs.