Hereditary Hypophosphatemic Rickets with Hypercalciuria Presenting with Enthesopathy, Renal Cysts, and High Serum c-Terminal FGF23: Single-Center Experience and Systematic Review.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of phosphate homeostasis. We describe a single-center experience of genetically proven HHRH families and perform systematic review phenotype-genotype correlation in reported biallelic probands and their monoallelic relatives. Detailed clinical, biochemical, radiological, and genetic data were retrieved from our center and a systematic review of Pub-Med and Embase databases for patients and relatives who were genetically proven. Total of nine subjects (probands:5) carrying biallelic SLC34A3 mutations (novel:2) from our center had a spectrum from rickets/osteomalacia to normal BMD, with hypophosphatemia and hypercalciuria in all. We describe the first case of genetically proven HHRH with enthesopathy. Elevated FGF23 in another patient with hypophosphatemia, iron deficiency anemia, and noncirrhotic periportal fibrosis led to initial misdiagnosis as tumoral osteomalacia. On systematic review of 58 probands (with biallelic SLC34A3 mutations; 35 males), early-onset HHRH and renal calcification were present in ~ 70% and late-onset HHRH in 10%. c.575C > T p.(Ser192Leu) variant occurred in 53% of probands without skeletal involvement. Among 110 relatives harboring monoallelic SLC34A3 mutation at median age 38 years, renal calcification, hypophosphatemia, high 1,25(OH)2D, and hypercalciuria were observed in ~30%, 22.3%, 40%, and 38.8%, respectively. Renal calcifications correlated with age but were similar across truncating and non-truncating variants. Although most relatives were asymptomatic for bone involvement, 6/12(50%) had low bone mineral density. We describe the first monocentric HHRH case series from India with varied phenotypes. In a systematic review, frequent renal calcifications and low BMD in relatives with monoallelic variants (HHRH trait) merit identification.

Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

Pituitary apoplexy in cushing's disease: a single center study and systematic literature review.

INTRODUCTION: Pituitary apoplexy (PA) in Cushing's disease (CD) is rare with data limited to case reports/series. METHODS: We retrospectively reviewed case records of PA in CD managed at our center from 1987 to 2023 and performed a systematic literature review. RESULTS: We identified 58 patients (44 females), including twelve from our center (12/315 CD, yielding a PA prevalence in CD of 3.8%) and forty six from systematic review. The median age at PA diagnosis was 35 years. The most common presentation was type A (79.3%) and symptom was headache (89.6%), with a median Pituitary Apoplexy Score (PAS) of 2. Median cortisol and ACTH levels were 24.9 µg/dl and 94.1 pg/ml, respectively. Apoplexy was the first manifestation of underlying CD in 55.2% of cases, with 31.1% (14/45) presenting with hypocortisolemia (serum cortisol ≤ 5.0 µg/dl), underscoring the importance of recognizing clinical signs/symptoms of hypercortisolism. The median largest tumor dimension was 1.7 cm (53/58 were macroadenomas). PA was managed surgically in 57.8% of cases, with the remainder conservatively managed. All five PA cases in CD with microadenoma achieved remission through conservative management, though two later relapsed. Among treatment-naïve CD patients with macroadenoma, PA-related neuro-deficit improvement was comparable between surgical and conservative groups. However, a greater proportion of surgically managed patients remained in remission longer (70% vs. 38.5%; p = 0.07), for an average of 31 vs. 10.5 months. CONCLUSION: PA in CD is more commonly associated with macroadenomas, may present with hypocortisolemia, and surgical treatment tends towards higher and longer-lasting remission rates.

Luteinizing hormone ß-subunit deficiency: Report of a novel LHB likely pathogenic variant and a systematic review of the published literature.

CONTEXT: Selective deficiency of ß-subunit of luteinizing hormone (LHB) is a rare disease with scarce data on its characteristics. OBJECTIVES: To describe a male with LHB deficiency and systematically review the literature. DESIGN AND PATIENTS: Description of a male patient with LHB deficiency and a systematic review of LHB deficiency patients published to date (10 males and 3 females) as per PRISMA guidelines. RESULTS: A 36-year-old Asian Indian male presented with infertility. On evaluation, he had sexual maturity of Tanner's stage 3, low testosterone (0.23 ng/ml), low LH (0.44 mIU/ml), high follicle-stimulating hormone (FSH, 22.4 mIU/ml), and a novel homozygous missense likely pathogenic variant (p.Cys46Arg) in LHB. In the molecular dynamics simulation study, this variant interferes with heterodimerization of alpha-beta subunits. Eleven males with pathogenic variants in LHB reported to date, presented at a median age of 29 (17-38) years, most commonly with delayed puberty. Clinical and biochemical profiles were similar to those of our patient. In the majority, testosterone monotherapy modestly increased testicular volume whereas human chorionic gonadotropin (hCG) monotherapy also improved spermatogenesis. In females, oligomenorrhoea after spontaneous menarche was the most common manifestation. Ten pathogenic/likely pathogenic variants (three in-frame deletions, three missense, two splice-site, one nonsense, and one frameshift variants) have been reported in nine index patients. CONCLUSION: We report a novel likely pathogenic LHB variant in an Asian Indian patient. The typical phenotype in male patients with LHB deficiency is delayed puberty with low testosterone, low LH, and normal to high FSH and hCG monotherapy being the best therapeutic option.

17ß hydroxysteroid dehydrogenase 3 deficiency in 46,XY disorders of sex development: Our experience and a gender role-focused systematic review.

OBJECTIVES: To describe Asian Indian patients with 17ß hydroxysteroid dehydrogenase 3 (17ßHSD3) deficiency and to perform a systematic review to determine the factors influencing gender role in 46,XY disorder of sex development (DSD) due to 17ßHSD3 deficiency. PATIENTS AND DESIGN: We present the phenotypic and genotypic data of 10 patients (9 probands and 1 affected family member) with 17ßHSD3 deficiency from our 46,XY DSD cohort (N = 150; Western India) and a systematic review of 152 probands with genetically proven, index 17ßHSD3 deficiency patients from the world literature to identify the determinants of gender role. RESULTS: 17ßHSD3 deficiency was the third most common (6%) cause of non-dysgenetic 46,XY DSD in our cohort. Five patients each had prepubertal (atypical genitalia) and pubertal (primary amenorrhoea) presentations. Six patients were initially reared as female of whom two (one each in prepubertal and pubertal age) changed their gender role. Ten pathogenic molecular variants (six novel) were observed. In the systematic review, initial male sex of rearing was uncommon (10.5%) and was associated with atypical genitalia, higher testosterone/androstenedione (T/A) ratio and Asian origin. Gender role change to male was seen in 10.3% of patients with initial female sex of rearing and was associated with Asian origin but unrelated to pubertal androgens or molecular variant severity. It has not been reported in patients of European origin. CONCLUSIONS: We report the first Indian case series of 17ßHSD3 deficiency, the third most common cause of 46,XY DSD, with six novel molecular variants. Distinct geographical differences in the frequency of initial male sex of rearing and gender role change to male in those initially reared as females in 17ßHSD3 deficiency were noted which needs further evaluation for the underlying molecular mechanisms.

Clinical Spectrum of Adrenal Cushing's Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience.

To describe the differences in presentation, biochemistry, and radiological evaluation of various etiologies of adrenal Cushing's syndrome (CS) from a single center. To emphasize caution for interpretation of plasma adrenocorticotropic hormone (ACTH), as a spuriously unsuppressed ACTH level by immunometric assay may lead to therapeutic misadventures in adrenal CS. DESIGN: Retrospective, single-center, observational study. METHODS: Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed. RESULTS: Cortisol secreting ACC presented at 38(1-50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9-40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state. CONCLUSIONS: Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.

Expanding genetic spectrum and discriminatory role of steroid profiling by LC-MS/MS in 11ß-hydroxylase deficiency.

OBJECTIVE: To report clinical, hormonal and structural effects of CYP11B1 pathogenic variations in Indian patients with 11ß-hydroxylase deficiency (11ßOHD) and find hormonal criteria that accurately distinguish 11ßOHD from 21α-hydroxylase deficiency (21OHD). DESIGN: Retrospective record review of genetically diagnosed patients with 11ßOHD. PATIENTS AND MEASUREMENTS: Clinical features, hormonal parameters at diagnosis (by immunoassay) and recent follow-up of 13 genetically proven 11ßOHD patients managed at our centre were retrospectively reviewed. ACTH-stimulated serum adrenal steroids (measured by LC-MS/MS) of 11ßOHD were compared with those of simple virilizing and non-classic 21OHD. Structural analysis of the observed pathogenic variations was performed by computational modelling. RESULTS: Nine (four females) and four (all females) patients had classic and non-classic disease, respectively. All 11ßOHD patients had elevated ACTH-stimulated serum 11-deoxycortisol (26.5-342.7 nmol/L) whereas none had elevated serum 17-hydroxyprogesterone (4.2-21.2 nmol/L); both hormonal parameters distinguished 11ßOHD from 21OHD with 100% accuracy. ACTH-stimulated serum cortisol, but not 11-deoxycortisol, clearly distinguished classic (<70 nmol/L) from non-classic (>160 nmol/L) disease. Thirteen (eight novel, two recurrent) pathogenic variants were observed. Only missense mutations were observed among patients with non-classic disease. Computational modelling predicted the possible affection of enzyme structure and function for all the observed missense mutations. CONCLUSIONS: This first Indian study describes 13 11ßOHD patients, including four with the rarer non-classic variant. A total of eight novel pathogenic variants were identified in our study, highlighting regional genetic heterogeneity. Measurement of ACTH-stimulated adrenal steroids by LC-MS/MS will help avoid the misdiagnosis of 11ßOHD as 21OHD and has potential to distinguish classic from non-classic 11ßOHD.

POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature.

CONTEXT: POU1F1 mutations are prevalent in Indian CPHD cohorts. Genotype-phenotype correlation is not well-studied. AIM: To describe phenotypic and genotypic spectrum of POU1F1 mutations in our CPHD cohort and present systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in world literature. METHODS: Retrospective study of POU1F1 mutation-positive patients from a western-Indian center. PRISMA guidelines based pubmed search of published literature of all mutation-positive patients. RESULTS: Our cohort had 15 POU1F1 mutation-positive patients (9 index, 6 relatives). All had severe GH, TSH and prolactin deficiencies (GHD, TSHD and PD). TSHD was diagnosed earliest followed by GHD (median ages: TSHD-6 months, GHD-3 years), while PD was more variable. Two sisters had central precocious puberty at 7 years of age. Pubic hair was deficient in all post-pubertal patients (females: P1-P2, males: P3-P4). Splice-site/intronic/frameshift mutations were most common, while missense/nonsense mutations were less frequent (33%). Review of world literature yielded 114 patients (82 index patients) from 58 studies. GHD was present in all patients. TSHD was spared in 12.5% and PD in 4.4% patients. Missense/nonsense mutations accounted for 75% of spectrum. Phenotype-genotype analysis revealed higher mean peak-GH levels (1.1 vs 0.2 ng/ml, p = 0.008) and lower prevalence of anterior-pituitary hypoplasia (63.6% vs 86.3%, p = 0.03) in patients with heterozygous than homozygous and compound heterozygous mutations. CONCLUSIONS: We present largest series of POU1F1 mutation-positive patients. Precocious puberty and defective pubarche are lesser-appreciated phenotypic features. Our mutation spectrum is different from that of world literature. Patients with heterozygous mutations have milder phenotype.

Cabergoline may act as a radioprotective agent in Cushing's disease.

CONTEXT: Conventional fractionated radiotherapy (CRT) achieves control of pathological hypercortisolism in 75%-80% of patients with persistent or recurrent Cushing's disease (CD), over a mean period of 18-24 months. Medical therapy is recommended as bridge therapy while awaiting RT effect. OBJECTIVE: To determine long-term outcome of CRT and its predictors in CD patients. DESIGN, SETTING AND PATIENTS: This is a retrospective case record analysis of 42 patients with CD who received CRT as a treatment modality and had at least 12 months post-RT follow-up. The dose delivered was 45 Gy in 25 fractions over 5 weeks. Demographic details, hormonal evaluation and radiological data were extracted from case records. Dexamethasone suppressed cortisol at cut-off of 1.8 µg/dL was used to define remission or recurrence. Possible predictors for remission and recurrence were analysed. RESULTS: The mean age at the time of CRT administration was 23.7 ± 10.7 (range: 12-48) years. A total of 29 (69%) patients achieved remission 26.5 ± 28.5 (median: 18, range: 3-120) months after RT, while 13 (31%) patients had persistent disease at last follow-up. There were no significant predictors of disease remission after CRT. Six (20.7%) patients had recurrence after a documented initial remission. Recurrence occurred 66.6 ± 25.9 (median: 74; range: 18 to 90) months after documented remission. Recurrence of the disease was exclusively seen in patients who received peri-RT cabergoline. Peri-CRT use of cabergoline was significantly associated with increased recurrence rates (P = .016). CONCLUSION: Use of cabergoline in the peri-CRT period did not affect initial remission after CRT but was associated with increased recurrence after initial remission in CD.

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.

SYMPATHETIC PARAGANGLIOMA: A SINGLE-CENTER EXPERIENCE FROM WESTERN INDIA.

OBJECTIVE: Most of the Indian studies on pheochromocytoma/paraganglioma (PCC/PGL) have focused on PCC, and there is a paucity of information regarding sympathetic paraganglioma (sPGL). Here, we describe the clinical, biochemical, and imaging features of sPGL compared with PCC. METHODS: This retrospective study included 75 patients with sPGL and 150 patients with PCC. Diagnosis of PCC/PGL was based on surgical histopathology, and if histopathology was not available, on biochemistry and/or radiology. RESULTS: sPGL was more frequently detected incidentally ( P = .03), normetanephrine-secreting ( P<.01), and metastatic compared with PCC ( P≤.01). sPGL was most commonly located in the organ of Zuckerkandl (OOZ) (49%) and infradiaphragmatic area above the OOZ (27%). Patients with mediastinal sPGL were significantly older than those with sPGL in the OOZ ( P = .03). Primary tumors of metastatic sPGL were significantly larger than those without metastasis (7.8 ± 4 cm vs. 5.6 ± 3.2 cm; P = .004). Percentage arterial enhancement (PAE) >100% was seen in 98% of sPGLs. CONCLUSION: Incidental presentation, normetanephrine-secreting phenotype, and metastatic disease were more frequent in patients with sPGL than those with PCC. sPGL arose most commonly in the OOZ. Tumor size is an independent predictor of malignancy among sPGL patients. PAE >100% is almost a universal finding in sPGL, and its absence is a sensitive parameter to differentiate sPGL from other abdominal masses. ABBREVIATIONS: AP = arterial phase; CECT = contrast-enhanced computed tomography; CT = computed tomography; DP = delayed phase; EVP = early venous phase; FDG = fluorodeoxyglucose; fPFMN = fractionated plasma free metanephrine; HU = Hounsfield units; MIBG = metaiodobenzylguanidine; MRI = magnetic resonance imaging; OOZ = organ of Zuckerkandl; PAE = percentage arterial enhancement; PCC = pheochromocytoma; PET = positron emission tomography; PFNMN = plasma free normetanephrine; PGL = paraganglioma; PRRT = peptide receptor radionuclide therapy; PVE = percentage venous enhancement; sPGL = sympathetic paraganglioma; UP = unenhanced phase; VMA = vanillyl mandelic acid.

Inhibitory role of transforming growth factor ß2 in experimental autoimmune anterior uveitis.

PURPOSE: Experimental autoimmune anterior uveitis (EAAU) is a clinically relevant animal model for human idiopathic anterior uveitis (IAU). The role of the immunomodulator transforming growth factor ß2 (TGF-ß2) in EAAU pathology is unknown. In this study, we investigated the regulatory role of TGF-ß2 in EAAU. METHODS: EAAU was induced in male Lewis rats by footpad injection of melanin-associated antigen (MAA). TGF-ß2 was administered intravenously (iv) in MAA-sensitized rats during the induction of EAAU, or after the clinical onset of uveitis. MAA-sensitized rats injected similarly with an equal volume of PBS served as control. Animals were examined daily between days 7 and 30 post-injection for the clinical signs of uveitis using slit lamp biomicroscopy. Animals were sacrificed at various time points and eyes were harvested for histological analysis to assess the course and severity of inflammation. For histopathological analysis, paraffin sections of harvested eyes were stained with hematoxylin and eosin. Popliteal lymph nodes (LNs) were used for CD4+CD25+FoxP3+ T regulatory (Tregs) population analysis and for CD4+ T cell proliferation assay. RESULTS: Administration of recombinant TGF-ß2 during the early stages of EAAU prevented the induction of uveitis. Compared to PBS, the presence of TGF-ß2 in the cell culture significantly (p < 0.05) inhibited the proliferation of CD4+ T cells in response to MAA. In MAA-sensitized Lewis rats, iv treatment with recombinant TGF-ß2 resulted in significantly (p < 0.05) increased percentage of Tregs compared to animals treated similarly with PBS. Thus, TGF-ß2 inhibited the induction of EAAU by inhibiting CD4+ T cell proliferation and increasing the number of Tregs. Injection of TGF-ß2 in rats with active EAAU resulted in diminished disease activity. Unfortunately, this treatment did not lead to the early resolution of EAAU. CONCLUSIONS: TGF-ß2 plays a critical role in regulation of intraocular inflammation in EAAU. Findings reported in this study improve our understanding of immunopathology of IAU and suggest that recombinant TGF-ß2 may be a promising therapeutic agent for human IAU.

Coexistent Pituitary Adenoma with Rathke's Cleft Cyst: A Case Series.

Objective: Co existent pituitary adenoma and Rathke's cleft cyst (RCC) is a rare entity. Purpose of this study is to describe the clinical presentation, imaging findings, and management of patients with this combination. Methods: Retrospective review of records from a single tertiary care center for a period of three years [2009-2012]. Results: Out of the total 284 pituitary adenoma patients in the study period, there were four patients one each of Cushing's disease, acromegaly, prolactinoma and non-secretory pituitary adenoma with coexisting RCC in all. Three of these were diagnosed to have coexisting RCC in preoperative MRI. All of them underwent transphenoidal excision of the lesions. Histopathology confirmed the collision sellar lesions in all four. Conclusions: It is difficult to diagnose coexisting RCC preoperatively due to variable size, position and signal intensity. However when a nonenhancing cyst is incidentally detected by MRI in a patient with pituitary adenoma, the possibility of a coexisting RCC should be considered.

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration-Like Phenotype.

In the mouse, membrane cofactor protein (CD46), a key regulator of the alternative pathway of the complement system, is only expressed in the eye and on the inner acrosomal membrane of spermatozoa. We noted that although Cd46(-/-) mice have normal systemic alternative pathway activating ability, lack of CD46 leads to dysregulated complement activation in the eye, as evidenced by increased deposition of C5b-9 in the retinal pigment epithelium (RPE) and choroid. A knockout of CD46 induced the following cardinal features of human dry age-related macular degeneration (AMD) in 12-month-old male and female mice: accumulation of autofluorescent material in and hypertrophy of the RPE, dense deposits in and thickening of Bruch's membrane, loss of photoreceptors, cells in subretinal space, and a reduction of choroidal vessels. Collectively, our results demonstrate spontaneous age-related degenerative changes in the retina, RPE, and choroid of Cd46(-/-) mice that are consistent with human dry AMD. These findings provide the exciting possibility of using Cd46(-/-) mice as a convenient and reliable animal model for dry AMD. Having such a relatively straight-forward model for dry AMD should provide valuable insights into pathogenesis and a test model system for novel drug targets. More important, tissue-specific expression of CD46 gives the Cd46(-/-) mouse model of dry AMD a unique advantage over other mouse models using knockout strains.

Percentage arterial enhancement: An objective index for accurate identification of parathyroid adenoma/hyperplasia in primary hyperparathyroidism.

BACKGROUND: Radiation exposure to neck by four-dimensional computerized tomography (4DCT) is relatively high and limits its use as a first-line investigation in evaluation of primary hyperparathyroidism (PHPT). Radiation exposure can be reduced by restricting the number of CT phases. Our aim was to study the performance of 4DCT in cohort of surgery-naïve PHPT patients, and to evaluate percentage enhancement as an objective radiological index to discriminate parathyroid lesions (adenoma/hyperplasia) from thyroid tissue and lymph nodes. MATERIALS AND METHOD: Retrospective study of 49 PHPT patients {(44 single-gland diseases (SGD) and five multiple-gland disease (MGD)} who underwent 4DCT (unenhanced, early arterial, early venous and delayed venous phase) pre-operatively. Two radiologists who were blinded to surgical location of parathyroid lesions examined the scans. Attenuation values were recorded for parathyroid lesions (n=50), thyroid gland (n=50) and lymph nodes (n=12) in different phases. Percentage enhancement for different phases was calculated as "(HU in a specific enhanced phase-HU in unenhanced phase)/HU in unenhanced phase" ×100. RESULTS: Inter-rater reliability between the two radiologists was 0.83 (Cohen's kappa). In SGD, sensitivity and PPV were 93.18% and 98.8% for lateralization, and 89.77% and 95.18% for quadrant localization, respectively. In MGD, 4DCT showed 50% sensitivity and 100% PPV. Percentage arterial enhancement showed highest area under curve (AUC=0.992) for differentiation of parathyroid lesions from thyroid tissue and lymph nodes. A cut-off value of 128.9% showed 95.8% sensitivity and 100% specificity for the identification of parathyroid lesions. CONCLUSIONS: We propose that percentage arterial enhancement can be used as an objective radiological index for accurate identification of parathyroid adenoma/hyperplasia.

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.

Effect of aspirin on models of retinal pigment epithelium pathology.

BACKGROUND: To characterize the effect of aspirin (ASA) in mouse models of choroidal neovascularization (CNV) and retinal degeneration. METHODS: In vivo: Male C57BL/6 mice were given ASA in food or regular rodent diet. CNV was induced by argon laser photocoagulation. Subretinal injections of polyethylene glycol 400 (PEG-400) were administered to induce retinal degeneration. CNV size, laser spot area and mean intensity of VEGF in the laser injured zones were measured. In the PEG injected eyes the thickness of retinal pigment epithelium (RPE) and choroid was measured. In vitro: Human ARPE-19 cells were treated with 0.5 or 2.0 mM/L of ASA for 72 h. ELISA was used to measure the concentration of VEGF and CCL-2 in the supernatants. Additionally, damaged RPE monolayer was treated with ASA (0.5 or 2.0 mM/L) and vehicle separately. Size of damaged area was measured. ELISA was used to measure secretion of VEGF-A and CCL-2 by damaged cells after 24 h. RESULTS: No statistically significant effect of ASA on CNV size, laser spot size or VEGF expression was noted in CNV model. In the PEG model, ASA did not have any effect on RPE and choroid thickness; however, a significant increase in RPE atrophy was observed (P = 0.02 + 38%). In addition, ASA had a significant effect on the ability of the RPE cells to regenerate and become confluent after mechanical damage. CONCLUSIONS: ASA at doses consumed clinically for various medical causes may not worsen CNV in human subjects. However, ASA may increase RPE atrophy when consumed over long periods of time.

Complement regulatory protein CD46 protects against choroidal neovascularization in mice.

Dysregulation of the complement system is increasingly recognized as a contributing factor in age-related macular degeneration. Although the complement regulator CD46 is expressed ubiquitously in humans, in mouse it was previously thought to be expressed only on spermatozoa. We detected CD46 mRNA and protein in the posterior ocular segment (neuronal retina, retinal pigment epithelium, and choroid) of wild-type (WT) C57BL/6J mice. Cd46(-/-) knockout mice exhibited increased levels of the membrane attack complex and of vascular endothelial growth factor (VEGF) in the retina and choroid. The Cd46(-/-) mice were also more susceptible to laser-induced choroidal neovascularization (CNV). In Cd46(-/-) mice, 19% of laser spots were positive for CNV at day 2 after treatment, but no positive spots were detected in WT mice. At day 3, 42% of laser spots were positive in Cd46(-/-) mice, but only 11% in WT mice. A fully developed CNV complex was noted in both Cd46(-/-) and WT mice at day 7; however, lesion size was significantly (P < 0.05) increased in Cd46(-/-) mice. Our findings provide evidence for expression of CD46 in the mouse eye and a role for CD46 in protection against laser-induced CNV. We propose that the Cd46(-/-) mouse has a greater susceptibility to experimental CNV because of insufficient complement inhibition, which leads to increased membrane attack complex deposition and VEGF expression.

Primary (autoimmune) hypophysitis: a single centre experience.

BACKGROUND: Autoimmune hypophysitis (AH) is a rare autoimmune inflammatory disorder of pituitary gland. OBJECTIVE: To analyse clinical, hormonal, radiological features and management outcomes of AH. DESIGN: Retrospective analysis of patients with primary hypophysitis (where secondary causes of hypophysitis were ruled out) was carried out from 2006 to 2012. AH emerged as the most plausible aetiology and the diagnosis of exclusion. RESULTS: Twenty-four patients with AH (21 females and 3 males) were evaluated. They presented with symptoms of expanding sellar mass (83.3%), symptoms of anterior pituitary hormone deficiencies (58.3%), and diabetes insipidus (16.7%). The anterior pituitary hormonal axes affected were cortisol (75%), thyroid (58.33%) and gonadotropin (50%). All had sellar mass on magnetic resonance imaging, which was symmetrical (91.7%) and homogenously enhancing (91.7%). Stalk thickening, suprasellar extension, loss of posterior pituitary hyperintensity and parasellar T2 dark sign were seen in 87.5, 87.5, 71.5, and 50% respectively. In addition to hormone replacement, five (20.83%) patients underwent trans-sphenoidal surgery, fifteen (62.5%) were watchfully monitored, while four cases (16.67%) received steroid pulse therapy. On follow up imaging, the sellar mass regressed in all, while, stalk thickening was persistent in 13/19 (68.4%) non-operated patients at median follow up of 1 year. Pituitary hormone axis recovery was seen in 10 (41.67%) and was seen in cortisol 10/18 (55.5%) followed by gonadotropin 5/12 (41.67%) axis. CONCLUSION: Characteristic radiology helps in diagnosis of AH even without tissue diagnosis. Non-operative treatment is the preferred treatment modality. Steroid pulse therapy potentially improves pituitary axis recovery.

HRPT2- (CDC73) RELATED HEREDITARY HYPERPARATHYROIDISM: A CASE SERIES FROM WESTERN INDIA.

OBJECTIVE: To describe a case series of HRPT2- (CDC73) related hereditary primary hyperparathyroidism (PHPT) from western India. METHODS: We present a case series of 4 families (7 patients) with PHPT caused by CDC73 gene mutations. RESULTS: The mean age of presentation of the 4 index cases was 27.25 ± 9.8 years. Two family members were identified through biochemical screening (Cases 1b and 2b), while 1 mutation-positive family member did not manifest any features of PHPT or hyperparathyroidism jaw tumor syndrome (HPT-JT) syndrome (Case 2c). Biochemistry showed increased serum calcium (mean: 13.21 ± 1.24 mg/dL), low serum phosphorus (mean: 1.78 ± 0.44 mg/dL), and high parathyroid hormone (PTH, mean: 936 ± 586.9 pg/mL). All patients had a uniglandular presentation and underwent single adenoma excision initially except Cases 2a and 2b, who underwent subtotal parathyroidectomy at baseline. Two cases experienced PHPT recurrence (Cases 3 and 4), while 1 remained uncured due to parathyroid carcinoma (Case 1a). Other associated syndromic features like ossifying jaw fibromas were present in 2 patients, renal cysts in 3 patients, and uterine involvement in 2 patients. Two families had novel germline CDC73 mutations (Families 1 and 3), while the other 2 had reported mutations. Family 2 had familial isolated PHPT without any other features of HPT-JT syndrome. CONCLUSION: Our findings reaffirm the need for genetic analysis of patients with PHPT, especially those with younger age of disease onset; recurrent disease; and associated features like polycystic kidneys, endometrial involvement, ossifying jaw tumors, or parathyroid carcinoma.