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Introduction: The effect of body mass index (BMI) and chemotherapy dose reduction on pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for locoregional breast cancer remains unclear. Contemporary studies have reported largely on trial populations and used dose-capping., Patients and Methods: Patient registries at the University of Iowa were queried to identify patients with operable breast cancer who received NAC. Dose reductions were calculated for taxanes (T), anthracyclines (A) and non-A-T chemotherapy. Clinical-pathologic characteristics, chemotherapy dose reductions, and adverse events were compared between normal (BMI <25) and overweight/obese patients (BMI ≥25). Additionally, the synergistic effect of BMI and chemotherapy dose reduction on pCR was assessed., Results: Of 171 eligible patients, 112 were overweight/obese. Chemotherapy dosing was capped in 2 patients; all others initiated full weight-based treatment. Overweight/obese patients required more frequent taxane (44.6% vs. 25.4%; P = .01) and any chemotherapy dose reductions (50.9% vs. 33.9%; P = .03). pCR was attained in 29.2% of patients. In a multivariable model, the interaction term for BMI as a continuous variable and any chemotherapy dose reduction was significant independent of the clinical stage and tumor receptor status (P = .04). For obese patients, any chemotherapy dose reduction was significantly associated with increased odds of not attaining pCR., Conclusion: During NAC, overweight/obese patients more often have chemotherapy dose reductions. Chemotherapy dose reduction in obese patients was a powerful predictor of not attaining pCR. This was not seen for normal or overweight patients. Opportunities might exist to improve pCR rates in this higher-risk group., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases., Experimental Design: We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts., Results: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity., Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087-96. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Use of breast magnetic resonance imaging (MRI) for screening and local staging of breast cancer has increased. With this, questions have emerged regarding the management and effect of extramammary findings (EMFs) reported on breast MRI., Patients and Methods: Breast MRI studies performed between January 1, 2007 and December 31, 2012 at the University of Iowa were analyzed. Data were collected regarding number and location of EMFs, characteristics of the patients who had a breast MRI, and time to first treatment among the patients who had a breast MRI for stage I-III breast cancer., Results: During the study period, 1305 breast MRIs were obtained in 772 women. An EMF was found in 140 studies (10.7%) and 113 women (14.6%). EMFs were more likely in MRIs of older patients (50 vs. 54 years, P = .004) and postmenopausal women (P = .001). Anatomically, most EMFs were seen in the liver (89 of 140) or bone (21 of 140). Eight women (0.6%) had an EMF on breast MRI that led to upstaging to stage IV breast cancer. For patients with stage I-III breast cancer, the finding of an EMF on breast MRI did not affect time to initial cancer treatment (13 vs. 14 days; P = .586)., Conclusion: EMFs on breast MRI are seen with some frequency and occur more commonly in older, postmenopausal women. In our study, most EMFs were benign and did not affect patient outcome with regard to upstaging to stage IV disease or time to cancer treatment. A very small portion of studies revealed subclinical advanced breast cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Coffin-Siris syndrome (CSS, MIM 135900), is a well-described, multiple congenital anomaly syndrome characterized by coarse facial features, hypertrichosis, sparse scalp hair, and hypo/aplastic digital nails and phalanges, typically of the 5th digits. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCA4, SMARCE1, SMARCB1, SMARCA2, ARID1B, and ARID1A) have been shown to cause not only CSS, but also related disorders including Nicolaides-Baraitser (MIM 601358) syndrome and ARID1B-intellectual disability syndrome (MIM 614562). At least 200 individuals with CSS have been found to have a mutation in the BAF pathway. However, to date, only three individuals with CSS have been reported to have pathogenic variants in SMARCE1. We report here three additional individuals with clinical features consistent with CSS and alterations in SMARCE1, one of which is novel. The probands all exhibited dysmorphic facial features, moderate developmental and cognitive delay, poor growth, and hypoplastic digital nails/phalanges, including digits not typically affected in the other genes associated with CSS. Two of the three probands had a variety of different organ system anomalies, including cardiac disease, genitourinary abnormalities, feeding difficulties, and vision abnormalities. The 3rd proband has not had further investigative studies. Although an increasing number of individuals are being diagnosed with disorders in the BAF pathway, SMARCE1 is the least common of these genes. This report doubles the number of probands with these mutations, and allows for better phenotypic information of this rare syndrome. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

In the kinase field, there are many widely held tenets about conformation-selective inhibitors that have yet to be validated using controlled experiments. We have designed, synthesized, and characterized a series of kinase inhibitor analogues of dasatinib, an FDA-approved kinase inhibitor that binds the active conformation. This inhibitor series includes two Type II inhibitors that bind the DFG-out inactive conformation and two inhibitors that bind the αC-helix-out inactive conformation. Using this series of compounds, we analyze the impact that conformation-selective inhibitors have on target binding and kinome-wide selectivity.

Worldwide malaria risk due to Plasmodium vivax makes development of vaccine against P. vivax, a high priority. Serine Repeat Antigen of P. vivax (PvSERA) is a multigene family of blood stage proteins with 12 homologues. Sequence diversity studies are important for understanding them as potential vaccine candidates. No information on N-terminal diversity of these genes is available in literature. In this paper, we evaluate the genetic polymorphism of N-terminal regions of the highly expressed member PvSERA4 and PvSERA5 genes from Indian field isolates. Our results show that PvSERA4 has deletions and insertions in Glutamine rich tetrameric repeat units contributing to its diversity. PvSERA5 also exhibits high genetic diversity with non-synonymous substitutions leading to identification of novel haplotypes from India. Our first report helps in elucidating the allelic variants of PvSERA genes in this region and contributes to evaluating their efficacy as vaccine candidates., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: GM1 gangliosidosis is a disorder due to GLB1 gene mutation., Case Characteristics: A 4-yr-old boy with neuroregression and optic atrophy with periventricular hyperintensity on magnetic resonance imaging., Outcome: Beta galactosidase enzyme activity was low which was confirmed by GLB1 sequencing., Message: We highlight the white matter changes in late infantile GM1 gangliosidosis.

Introduction: Forkhead Box P3 (FOXP3) is an essential transcription factor for the induction and development of Tregs. It plays an important role in regulation and suppression of immune responses. We tested whether FOXP3 gene variants are associated with idiopathic recurrent miscarriages (IRM)., Methods: We included 200 women with at least three unexplained spontaneous abortions before twentieth week of gestation and 300 healthy parous women. The detection of genetic variants of rs2232365, and rs5902434 SNPs were carried-out by using polymerase chain reaction (PCR) with sequence-specific primers, while rs3761548 and rs2294021 SNPs were genotyped by PCR followed by RFLP analysis. The logistic odds ratios (ORs) of idiopathic RM risk were estimated with a 95% confidence interval (CI) after maternal age adjustment. Multifactor dimension reduction (MDR) analysis was used to evaluate the potential SNP ∼ SNP interactions., Results: Single marker analysis revealed an increased risk ranged from almost 3-fold-2-fold for rs2232365, rs3761548, rs5902434 and rs2294021 SNPs in IRM cases. The mutant haplotype carriers of rs2232365, rs3761548, rs5902434 and rs2294021 SNPs showed an increased risk of 2.5-fold for IRM cases. Linkage disequilibrium analysis revealed moderate LD between rs2232365, rs3761548, rs5902434 and rs2294021 SNPs. The MDR analysis revealed 6-fold increased risk for IRM cases in four factor models of rs2232365, rs3761548, rs5902434 and rs2294021 SNPs. The maximum testing accuracy, highest cross validation consistency and greater significance was observed in four SNP model., Discussion: These results suggest that variants of FOXP3 SNPs namely; rs2232365, rs3761548, rs5902434 and rs2294021 may be associated with idiopathic RM., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To assess feasibility and recall rates for newborn screening for congenital hypothyroidism, galactosemia and biotinidase deficiency in a predominantly rural and inner city population in and around the City of Lucknow in Uttar Pradesh, India., Design: Prospective observational study., Setting: Two tertiary-care and 5 district hospitals in and around Lucknow., Participants: All babies born in above hospitals during the study period., Methods: Heel prick samples were collected after 24 hours of life. Dried blood spot TSH, total galactose and biotinidase were assayed by immunofluorometry. Age related cut-offs were applied for recall for TSH. For galactosemia and biotinidase deficiency, manufacturer-suggested recall cut-offs used initially were modified after analysis of initial data., Main Outcome Measure: Recall rate for hypothyroidism, galactosemia and biotinidase deficiency., Results: Screening was carried out for 13426 newborns, 73% of all deliveries. Eighty-five percent of those recalled for confirmatory sampling responded. Using fixed TSH cut off of 20 mIU/L yielded high recall rate of 1.39%, which decreased to 0.84% with use of age-related cut-offs. Mean TSH was higher in males, and in low birth weight and vaginally delivered babies. Eleven babies had congenital hypothyroidism. Recall rates with modified cut-offs for galactosemia and biotinidase deficiency were 0.32% and 0.16%, respectively., Conclusions: An outreach program for newborn screening can be successfully carried out in similar socio-cultural settings in India. For hypothyroidism, the high recall rate due to early discharge was addressed by age-related cut-offs.

Coffin-Siris syndrome (CSS) is a congenital disorder characterized by growth deficiency, intellectual disability, microcephaly, characteristic facial features and hypoplastic nails of the fifth fingers and/or toes. We previously identified mutations in five genes encoding subunits of the BAF complex, in 55% of CSS patients. Here we perform whole-exome sequencing in additional CSS patients, identifying de novo SOX11 mutations in two patients with a mild CSS phenotype. sox11a/b knockdown in zebrafish causes brain abnormalities, potentially explaining the brain phenotype of CSS. SOX11 is the downstream transcriptional factor of the PAX6-BAF complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development.

Plasmodium vivax malaria is geographically the most widely distributed and prevalent form of human malaria. The development of drug resistance by the parasite to existing drugs necessitates higher focus to explore and identify new drug targets. Plasmodial proteases have key roles in parasite biology and are involved in nutritional uptake, egress from infected reticulocytes, and invasion of the new target erythrocytes. Serine repeat antigens (SERA) of Plasmodium are parasite proteases that remain attractive drug targets and are important vaccine candidates due to their high expression profiles in the blood stages. SERA proteins have a unique putative papain-like cysteine protease motif that has either serine or cysteine in its active site. In P. vivax, PvSERA4 is the highest transcribed member of this multigene family. In this study, we have investigated the genetic polymorphism of PvSERA4 central protease domain and deduced its 3D model by homology modeling and also performed MD simulations to acquire refined protein structure. Sequence analysis of protease domain of PvSERA4 from Indian field isolates reveals that the central domain is highly conserved. The high sequence conservation of the PvSERA4 enzyme domain coupled with its high expression raises the possibility of it having a critical role in parasite biology and hence, being a reliable target for new selective inhibitor-based antimalarial chemotherapeutics. The 3D model showed the presence of an unusual antiparallel Beta hairpin motif between catalytic residues similar to hemoglobin binding motif of Plasmodial hemoglobinases. Our PvSERA4 model will aid in designing structure-based inhibitors against this enzyme.

Autosomal recessive cutis laxa type 2B (ARCL2B; OMIM # 612940) is a segmental progeroid disorder caused by mutations in PYCR1 encoding pyrroline-5-carboxylate reductase 1, which is part of the conserved proline de novo synthesis pathway. Here we describe 33 patients with PYCR1-related ARCL from 27 families with initial diagnoses varying between wrinkly skin syndrome, gerodermia osteodysplastica, De Barsy syndrome or more severe progeria syndromes. Given the difficult differential diagnosis of ARCL syndromes we performed a systematic comparison of clinical features of PYCR1-related ARCL. Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects. Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value. In our cohort we identified 20 different PYCR1 mutations of which seven were novel. Most of the mutations accumulated in exons 4 to 6. Missense alterations of highly conserved residues were most frequent followed by splice site changes and a single nonsense mutation. Analysis of genotype-phenotype correlation revealed that patients with mutations in the first two exons had lower average clinical scores and absent or only mild intellectual disability. Structural analyses predicted interference with PYCR1 multimerization for a subset of missense mutations. These findings have implications for the clinics as well as the pathomechanism of PYCR1-related ARCL., (© 2013.)

Increasing availability of DNA based tests in clinical practice has lead to widespread debate on the ethical issues involved. The wider usage of these tests in children has raised many questions regarding the ethics, validity of the request and its effects on childs psychosocial well-being. Though there have been much discussion with many studies attempting to address the issue, there is no consensus. Formulation of guidelines has been hampered by the diversity of tests available for varied indications and lack of research studying the effects of testing in children over a time. Some tests have valid indications with proven benefits over harms while others have less clear justification. We attempt to address this issue with the intent to sensitize the caregivers regarding various aspects to be considered before offering any genetic tests in children.

Background: This prospective study attempts to study the clinico-radiological differences between patients with syndromic AAD (SAAD), non-syndromic AAD (NSAAD), and AAD with Klippel-Feil anomaly (AADKFA) that may impact management., Methods: In 46 patients with AAD [SAAD (including Morquio, Down, Larson and Marshall syndrome and achondroplasia; n = 6); NSAAD(n = 20); and, AADKFS (n = 20)], myelopathy was graded as mild (n = 17, 37 %), moderate (15, 32.5 %) or severe (14, 30.5 %) based on Japanese Orthopaedic Association Score modified for Indian patients (mJOAS). Basilar invagination (BI), basal angle, odontoid hypoplasia, facet-joint angle, effective canal diameter, Ishihara curvature index, and angle of retroversion of odontoid and vertebral artery (VA) variations were also studied., Statistics: Clinico-radiological differences were assessed by Fisher's exact test, and mean craniometric values by Kruskal-Wallis test (p value ≤ 0.05 significant), Results: Incidence of irreducible AAD in SAAD (n = 0), NSA AD (11.55 %) and AADKFS (n = 18.90 %) showed significant difference (p = 0.01). High incidence of kyphoscoliosis (83 %) and odontoid hypoplasia (83 %) in SAAD, and assimilated atlas and BI in NSAAD and AADKFA groups were found. In AADKFA, effective canal diameter was significantly reduced(p = 0.017) with increased Ishihara index and increased angle of odontoid retroversion; 61 % patients had VA variations. Thirty-five patients underwent single-stage transoral decompression with posterior fusion (for irreducible AAD) or direct posterior stabilization (for reducible AAD). Postoperative mJOAS evaluation often revealed persistent residual myelopathy despite clinical improvement., Conclusions: Myelopathy is induced by recurrent cord trauma due to reducible AAD in SAAD, and compromised cervicomedullary canal diameter in NSAAD and AADKFA. SAAD in children may be missed due to incomplete odontoid ossification or coexisting angular deformities. In AADKFA, decisions regarding vertebral levels to be included in posterior stabilization should take into consideration intact intervening motion segments and compensatory cervical hyperlordosis. Following VA injury, endovascular primary vessel occlusion/stenting across pseudoaneurysm preempts delayed rehemorrhage.

The burden of Plasmodium vivax malaria is huge in India, affecting a large population annually. Recent reports of P. vivax contributing to severe illness and death, makes vaccine research on P. vivax malaria, a high priority. Extent of sequence variation in antigen coding genes is known to be a major hurdle in vaccine initiatives against malaria. Serine repeat antigens of Plasmodium are promising asexual blood stage vaccine candidates against malaria and have been implicated to have a key role in merozoite invasion and egress. Among the P. vivax SERA proteins, SERA4 and SERA5 are the major transcribed members in erythrocytic stages, making them encouraging candidates to be explored for their polymorphism and vaccine potential. Earlier reports suggest that diversity in these PvSERA antigens is localized to the C-terminal region of the proteins. Hence, genetic diversity study of this region seems prudent. Moreover, as there are no reports available from India, the present study aims to investigate the polymorphism in the C-terminal region of two highly transcribed members PvSERA4 and PvSERA5 in Indian field isolates. Our result of PvSERA5 demonstrates extensive genetic diversity, with major deletions, insertions and SNPs and signifies the gene to be under positive selection. On the other hand, high sequence conservation was seen in the PvSERA4 C-terminal region in Indian field isolates which was contrasting to earlier report from Thailand where they have shown diversity. Research data showcased in this study will greatly aid in gaining better understanding of antigenic variations, immune mediated selection mechanisms and the functional significance of these two vivax proteins. This study also makes a striking contribution towards understanding the antigenic repertoire of PvSERA genes in Indian isolates., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Since 1999 a lineage of the pathogen Cryptococcus gattii has been infecting humans and other animals in Canada and the Pacific Northwest of the USA. It is now the largest outbreak of a life-threatening fungal infection in a healthy population in recorded history. The high virulence of outbreak strains is closely linked to the ability of the pathogen to undergo rapid mitochondrial tubularisation and proliferation following engulfment by host phagocytes. Most outbreaks spread by geographic expansion across suitable niches, but it is known that genetic re-assortment and hybridisation can also lead to rapid range and host expansion. In the context of C. gattii, however, the likelihood of virulence traits associated with the outbreak lineages spreading to other lineages via genetic exchange is currently unknown. Here we address this question by conducting outgroup crosses between distantly related C. gattii lineages (VGII and VGIII) and ingroup crosses between isolates from the same molecular type (VGII). Systematic phenotypic characterisation shows that virulence traits are transmitted to outgroups infrequently, but readily inherited during ingroup crosses. In addition, we observed higher levels of biparental (as opposed to uniparental) mitochondrial inheritance during VGII ingroup sexual mating in this species and provide evidence for mitochondrial recombination following mating. Taken together, our data suggest that hypervirulence can spread among the C. gattii lineages VGII and VGIII, potentially creating novel hypervirulent genotypes, and that current models of uniparental mitochondrial inheritance in the Cryptococcus genus may not be universal., Competing Interests: I have read the journal's policy and have the following conflicts: Joseph Heitman is an editor for PLOS Genetics.

Cryptococcus gattii is an environmentally occurring pathogen that is responsible for causing cryptococcosis marked by pneumonia and meningoencephalitis in humans and animals. C. gattii can form long-term associations with trees and soil resulting in the production of infectious propagules (spores and desiccated yeast). The ever expanding reports of clinical and environmental isolation of C. gattii in temperate climates strongly imply C. gattii occurs world-wide. The key ability of yeast and spores to enter, survive, multiply, and exit host cells and to infect immunocompetent hosts distinguishes C. gattii as a primary pathogen and suggest evolution of C. gattii pathogenesis as a result of interaction with plants and other organisms in its environmental niche. Here we summarize the historical literature on C. gattii and recent literature supporting the world-wide occurrence of the primary pathogen C. gattii.

Wolman disease (WD) is a rare, inherited, rapidly fatal condition presenting in early infancy. The disease manifests in the first month of life with failure to thrive, vomiting, diarrhea, abdominal distension, hepatosplenomegaly and bilateral adrenal calcification and is nearly always fatal before the age of 1 year. Barring a case report of isolated fetal ascites, there is no report of intractable ascites as the presentation of WD till date. We report two siblings with WD who both had intractable ascites and required therapeutic paracentesis, albumin infusion, and diuretics to control tense ascites. Although rare, WD should be considered in the differential diagnosis of infantile ascites.

Cryptococcus neoformans is a human-pathogenic basidiomycete that commonly infects HIV/AIDS patients to cause meningoencephalitis (7, 19). C. neoformans grows as a budding yeast during vegetative growth or as hyphae during sexual reproduction. Pseudohyphal growth of C. neoformans has been observed rarely during murine and human infections but frequently during coculture with amoeba; however, the genetics underlying pseudohyphal growth are largely unknown. Our studies found that C. neoformans displays pseudohyphal growth under nitrogen-limiting conditions, especially when a small amount of ammonium is available as a sole nitrogen source. Pseudohyphal growth was observed with Cryptococcus neoformans serotypes A and D and Cryptococcus gattii. C. neoformans pseudohyphae bud to produce yeast cells and normal smooth hemispherical colonies when transferred to complete media, indicating that pseudohyphal growth is a conditional developmental stage. Subsequent analysis revealed that two ammonium permeases encoded by the AMT1 and AMT2 genes are required for pseudohyphal growth. Both amt1 and amt2 mutants are capable of forming pseudohyphae; however, amt1 amt2 double mutants do not form pseudohyphae. Interestingly, C. gattii pseudohypha formation is irreversible and involves a RAM pathway mutation that drives pseudohyphal development. We also found that pseudohyphal growth is related to the invasive growth into the medium. These results demonstrate that pseudohyphal growth is a common reversible growth pattern in C. neoformans but a mutational genetic event in C. gattii and provide new insights into understanding pseudohyphal growth of Cryptococcus.

Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H(+)-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.

Background: Hypohidrotic/anhidrotic ectodermal dysplasia (HED) is a rare Mendelian disorder affecting ectodermal tissues. The disease is primarily caused by inactivation of any one of three genes, namely ectodysplasin A1 (EDA-A1), which encodes a ligand belonging to the tumour necrosis factor (TNF) superfamily; ectodysplasin A receptor (EDAR), encoding the EDA-A1 receptor and ectodysplasin A receptor-associated death domain (EDARADD), encoding an adaptor protein. X-linked recessive (EDA-A1), the predominant form of HED, as well as autosomal recessive and dominant (EDAR and EDARADD) inheritance patterns have been identified in affected families., Objectives:   To determine the common genes causing HED in India., Methods:  We performed mutation analysis on 26 HED families from India (including 30 patients). In addition, we carried out sequence and structural analysis of missense/nonsense and insertion/deletion mutations., Results: Among the 26 families analysed, disease-causing EDAR mutations were identified in 12 (46%) while EDA-A1 mutations were detected in 11 (42%). Four novel mutations in EDAR and five in EDA-A1 were identified. More importantly, a possible founder EDAR mutation, namely c.1144G>A, was identified in five independent families, thus accounting for about one-fifth of affected families in whom mutation was detected. A majority of EDA-A1 mutations localized to the TNF-like domain while the location of EDAR mutations was more widespread., Conclusions: This is the first report of a founder EDAR mutation and of a significantly high frequency of autosomal recessive HED., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the 'o' position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified., (© 2010 John Wiley & Sons A/S.)

We present findings of a questionnaire-based survey for practicing psychiatrists in the state of Maharashtra, India as an effort to understand challenges faced and the strategies adopted while treating women in reproductive age, especially during pregnancy. Participants were asked open-ended questions to cover pre and peri-conceptional period where use of psychotropic medication might have specific consequences. The broad areas included impact of psychiatric illness on family and reproductive health, effect of treatment on fertility or obstetric outcome, contraception, pre-pregnancy counseling and vitamin supplementation, structural and functional teratogenesis, choice of psychotropes during pregnancy, obstetric complications and pregnancy outcome and neonatal withdrawal, etc. The observations from this study bring forth various issues such as peri-conceptional care and management options during pregnancy in women on psychotropic therapy. The study reveals that not the years of clinical practice but a formal training with ongoing updates about safe prescription practices and functional effects of these drugs on the developing fetus and newborn is associated with safe prescription practice during pregnancy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Spiral and comminuted fractures of the metacarpals are rotationally and axially unstable fractures with a tendency to shorten, which in turn causes significant extensor lag and loss of grip strength. We have designed a new, cheap and locally developed method of locked intramedullary nailing of these metacarpal fractures. We are presenting the results of our first 21 patients with 22 fractures treated by closed, fluoroscopically assisted, intramedullary K-wiring with proximal locking done by a specially designed locking pin., Materials and Methods: This was a retrospective, observational cohort study of all patients with spiral and comminuted fractures of metacarpals with minimum of 1 year of follow-up and average follow-up of 14 months (range, 12 to 26 months). The patients were evaluated clinico-radiologically using range of motion, extensor lag, time to healing, amount of collapse, angulation and rotation and complications., Results: All fractures had healed uneventfully with average time to union being 8 weeks. Average metacarpal shortening was 2.04 ± 0.95 mm, while the average post-operative angulation of the fracture was 4.81° ± 1.7. The metacarpophalangeal range-of-motion recovered almost fully with the average extensor lag being only 5.22° ± 2.42. Other than extensor tendinitis in two patients, there were no other complications., Conclusions: This method is cosmetically appealing, provides stable fixation, avoids periosteal stripping associated with open reduction and is associated with very low complication rate, and thus can be safely and effectively used for the treatment of these difficult fractures.

We report two cases which illustrate that enzyme assay results alone, may at times be equivocal and inconclusive in the prenatal diagnosis of storage disorders like Pompe disease and therefore, if the probands mutation is known, targeted mutation analysis of fetal DNA is the most reliable method for fetal evaluation.

Objective: Gaucher disease in India has been reported only in a few case reports from India. The aim of the study was to assess the response to enzyme replacement therapy in Indian patients with Gaucher disease., Design: Retrospective analysis of patients receiving CHO-derived recombinant macrophage-targetted glucocorebrosidase., Setting: Five centers from India with experience in treating lysosomal storage disorders., Patients: The diagnosis of Gaucher disease was confirmed by low glucocerebrosidase levels, though it was first made on splenectomy in 8 and on bone marrow examination in 9 patients. Twenty five of 52 patients diagnosed with Gaucher disease (17 Type I, 8 mild Type III) received treatment for >6 months. Indications for treatment included symptomatic anemia, thrombo-cytopenia, organomegaly, bone disease or mild neurological symptoms leading to impairment of quality of life. Patients with significant neurological involvement were excluded. The drug infusions were given intravenously every 15 days., Main Outcome Measures: Hemoglobin, platelet counts, liver and spleen volumes and growth parameters., Results: 22 of the 25 children who survived were analyzed. After 6 months of treatment, the mean (range) increase in hemoglobin was 1.5 (-3.4 to 6.1) g/dL (P=0.01) and in platelet count was 32 x 10(9)/L (-98.5 x 109 to 145.5 x10(9))/L (P=0.02). The mean (range) increase in weight was 3 kg (-5.6 to 10.5) (P=0.04) and in height was 7.1 cm (0 to 26.5) (P=0.0003). Liver size decreased by a mean (range) of 38.5% (- 5.5 to 86.7) (P=0.0003) and the spleen size by 34.8% (0 to 91.7) (P=0.004). All patients had improvement in bone pains and in 2 patients, neurological symptoms improved with others remaining static., Conclusions: This is the first reported cohort of patients in India reporting our experience with imiglucerase enzyme replacement therapy for treatment of Gaucher Disease in India.

Approximately 14,000 people with hemophilia are registered at the Hemophilia Federation of India; however, hemophilia remains under-diagnosed and many cases are not registered. In June 2009, the Government of Uttar Pradesh made anti-hemophilic factors available at a few centers, including the Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow. Consequently, the level of hemophilia care has improved considerably in recent times. Amongst the many challenges facing people with hemophilia, the development of inhibitors, which neutralize clotting factors provided by replacement therapy, is the most feared one. Healthcare professionals who treat people with hemophilia should not only be knowledgeable about the condition and committed to bettering the management of hemophilia, but also take responsibility for the judicious allocation of resources for various aspects of managing hemophilia. This manuscript aims to raise awareness regarding the detection and management of inhibitors in hemophilia based on the experience of a tertiary care hemophilia treatment centre in Uttar Pradesh, India.

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by mutations in arylsulfatase A (ARSA) gene. No work on molecular genetics of MLD has been reported from India and the mutational spectrum in Indian patients is not known. The present study was undertaken to identify mutations in arylsulfatase A gene in Indian MLD patients, to evaluate genotype-phenotype correlation, and to see the effect of the novel mutants on the protein. Twenty MLD patients (16 families) were screened by ARMS PCR for the most common mutation (c.459+1G>A). Pseudodeficiency alleles were tested by RFLP method whereas rare and novel mutations were scanned by Conformation Sensitive Gel Electrophoresis (CSGE), followed by sequencing. The genotype-phenotype correlation was also attempted. Protein homology modeling analysis was carried out for two novel missense mutations identified, to assess the effect of these mutations on the protein conformation. Nine pathogenic alleles were found in 13 patients (65%). Four previously reported mutations and five novel variants were identified. Five patients (35%) were found to have pseudodeficiency alleles, c.1049A>G (p.Asn350Ser) and c.1524+95A>G. Genotype-phenotype correlation was found to be difficult to establish. Protein modeling studies showed that the mutations cause loss of interactions leading to conformational change in ASA protein. The study identified the mutational spectrum of Indian MLD patients, which will be helpful in genetic counseling, carrier detection and establishing prenatal diagnosis. Homology modeling helped to study conformational change in protein and has implications in generating novel therapeutic molecules., (Copyright © 2010 Elsevier B.V. All rights reserved.)

In this case report we present a family with infertile, azoospermic but otherwise apparently healthy males with history of recurrent spontaneous abortions (RSA) in females. Karyotype of the infertile man revealed a reciprocal balanced translocation t(8; 13) with breakpoints at 8q22 and 13p11.2. The reported reciprocal balanced translocation is associated with azoospermia. The same translocation is probably the cause of RSA in females of the family., (© 2010 Blackwell Verlag GmbH.)

Aim. To compare the efficacy and safety of armodafinil, the R-enantiomer of modafinil, with modafinil in patients of shift work sleep disorder (SWSD). Material and Methods. This was a 12-week, randomized, comparative, double-blind, multicentric, parallel-group study in 211 patients of SWSD, receiving armodafinil (150 mg) or modafinil (200 mg) one hour prior to the night shift. Outcome Measures. Efficacy was assessed by change in stanford sleepiness score (SSS) by at least 2 grades (responder) and global assessment for efficacy. Safety was assessed by incidence of adverse events, change in laboratory parameters, ECG, and global assessment of tolerability. Results. Both modafinil and armodafinil significantly improved sleepiness mean grades as compared to baseline (P < .0001). Responder rates with armodafinil (72.12%) and modafinil (74.29%) were comparable (P = .76). Adverse event incidences were comparable. Conclusion. Armodafinil was found to be safe and effective in the treatment of SWSD in Indian patients. The study did not demonstrate any difference in efficacy and safety of armodafinil 150 mg and modafinil 200 mg.

The association of four common polymorphisms of vascular endothelial growth factors (VEGF) with recurrent miscarriages(RM) was evaluated in North Indian women for 200 patients with RM and 200 controls. The subjects were genotyped for the polymorphisms 2578C/A, 2549 18-bp I/D, 1154G/A and +936C/T. Association of VEGF genotypes, alleles and haplotypes with recurrent miscarriage were evaluated by Fisher’s exact test. 1154G/A and +936C/T modified the risk of RM. The 1154A allel and +936T allel significantly increased the risk of RM (OR = 1.485, P = 0.0210, 95% CI 1.072–2.057 and OR = 1.869, P = 0.0054, 95% CI 1.214–2.876 respectively). Risk was further increased when –1154A/A genotype and +936C/T genotype were considered (OR = 2.0, P = 0.0310,95% CI 1.068–3.747 and OR = 1.716, P = 0.0293, 95% CI 1.058–2.784 respectively). However, no association was found between 2578C/A or 2549 18-bp I/D and RM. Four haplotypes, AIAC, ADAC, CIAT and ADGT, were found to predispose to RM while the haplotypes CIAC, CDGT and ADGC were found to show protective effect. In conclusion, two common polymorphisms of the VEGF gene,1154G/A and +936C/T, increase the risk of RM in North Indian women. RM is also predisposed in the presence of haplotypes AIAC,ADAC, CIAT and ADGT., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Context: Conventional karyotyping for antenatal diagnosis is time consuming and hence there has been a growing interest in more rapid techniques for detection of chromosomal aneuploidies. Around 95% of Down syndrome cases are due to free trisomy 21., Aims: The aims of this study were to demonstrate sensitivity of DNA diagnosis of Down syndrome using polymerase chain reaction (PCR) and short tandem repeat (STR) markers, and to determine the parental origin of the nondisjoined chromosome., Methods: DNA polymorphism was studied using two tetranucleotide STR markers, D21S2055 situated at 21q22.2 and D21S11 situated at 21q21.1. PCR conditions for both markers were standardized. PCR products were analyzed in 15% poly-acrylamide gels. The results obtained by STR analysis were verified with the chromosomal analysis and quantitative fluorescent (QF)-PCR., Results: These two STR markers were able to detect 86.7% cases of trisomy 21. Parental origin of extra chromosome was assigned to 77% of detected cases., Conclusion: The PCR-based DNA diagnostic method was found to be sensitive, reproducible, and efficient, not only for diagnosis of trisomy 21, but also for tracing allelic transmission from parents to the offspring.

Rhizomelic chondrodysplasia punctata is a rare autosomal recessive disorder characterized by stippled epiphyses and rhizomelic shortening of the long bones. We report 3 subjects of rhizomelic chondrodysplasia punctata from India and the PEX7 mutations identified in them. The common PEX7-L292X allele, whose high frequency is due to a founder effect in the northern European Caucasian population, was not identified in these patients. Instead, 2 novel alleles are described, including 64&#95;65delGC, which was present on a single PEX7 haplotype and could represent a common allele in the Indian population.

The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.

The influence of nano textured front contacts on the optical wave propagation within microcrystalline thin-film silicon solar cell was investigated. Periodic triangular gratings were integrated in solar cells and the influence of the profile dimensions on the quantum efficiency and the short circuit current was studied. A Finite Difference Time Domain approach was used to rigorously solve the Maxwell's equations in two dimensions. By studying the influence of the period and height of the triangular profile, the design of the structures were optimized to achieve higher short circuit currents and quantum efficiencies. Enhancement of the short circuit current in the blue part of the spectrum is achieved for small triangular periods (P<200 nm), whereas the short circuit current in the red and infrared part of the spectrum is increased for triangular periods (P = 900nm) comparable to the optical wavelength. The influence of the surface texture on the solar cell performance will be discussed.

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

Background: 5alpha-Reductase deficiency (5RD) is an uncommon autosomal recessive disorder of sexual differentiation. It results from impaired conversion of testosterone to dihydrotestosterone due to mutations in the steroid 5alpha-reductase type 2 gene (SRD5A2). Mutations in SRD5A2 have not been previously reported in Indian patients with 5RD., Aim: To delineate the clinical features and mutations in the SRD5A2 gene in Indian patients with 5RD., Patients and Methods: The SRDSA2 gene was sequenced in two unrelated patients with elevated testosterone/dihydrotestosterone ratio and in one patient with classical clinical features and virilization at puberty (in whom the ratio could not be measured due to prior gonadectomy). The prevalence of SRD5A2 mutations was also studied in 52 healthy ethnic control subjects by PCR-RFLP., Results: Two patients, both from the north Indian state of Uttar Pradesh, carried the homozygous missense mutation p.R246Q in exon 5. Parents of both probands were heterozygous for the mutation. The mutation was absent in 52 control subjects. The third patient, with severe perineoscrotal hypospadias and micropenis, was detected to have a novel heterozygous missense mutation p.Q56H, as well as the homozygous polymorphism p.V89L, both in exon 1. The p.Q56H mutation was absent in 52 control subjects., Conclusion: p.R246Q is a common SRD5A2 mutation in 5RD patients from the Indian subcontinent.

Objective: Mutation analysis in Indian children with achondroplasia., Methods: We studied 11 sporadic cases of achondroplasia. Mutation analysis was done by PCR/RFLP (Polymerase chain reaction/Restriction fragment length polymorphism) method., Results: Nine of the 11 cases had mutation G-->A at 1138 nucleotide position in transmembrane domain of fibroblast growth-factor receptor 3 (FGFR3) gene. Substitution G-->A is a common recurrent mutation reported worldwide. In two cases we could not detect any common mutation and also in entire region of transmembrane domain sequenced. There is possibility of mutation in the other regions of FGFR3 gene in these two cases., Conclusion: Further study of these two cases is needed in order to define other genotypes resulting in achondroplasia. Postnatal diagnosis of achondroplasia depends on clinical and radiological features. Mutation detection is mainly useful for prenatal diagnosis.

Spinal, also called neurogenic, claudication is common, and in the elderly it is almost invariably caused by degenerative disease of the lumbar spine. There are, however, a few rare but important other causes that should be considered, as in this case.

Objective: Renal malformations can be associated with genetic syndromes and chromosomal disorders. Fetal autopsy including histopathological examination of kidney is important to arrive at definite diagnosis. The objective was to assess importance of fetal autopsy and histopathology., Study Design: Retrospective analysis of cases with fetal renal malformations was done. All fetuses terminated were examined with whole body radiograph, external and internal examination and histopathological examination., Result: A total of 21 cases with renal malformations were studied. Of all 3 were of bilateral renal agenesis, 4 showed autosomal recessive polycystic kidney disease and 13 showed features of multicystic kidney. Three of these had hyperplasic-enlarged bladder and autopsy confirmed urorectal septum malformations in two cases and posterior urethral valve in one case. One case had associated malformations like encephalocele that suggested diagnosis of Meckel-Gruber syndrome and another had associated lateral body wall defect. In five cases kidney was hypoplastic suggestive of Potter type IIa., Conclusion: Ultrasound is an effective diagnostic modality; however fetal autopsy after termination of pregnancy is important to arrive at a definitive diagnosis. It's important to distinguish between autosomal recessive polycystic kidney disease (ARPKD) and cystic dysplastic kidney as recurrence risk is 3% in case of cystic renal dysplasia in contrast to 25% in case of ARPKD. Gross examination may point toward syndromic diagnosis like Meckel-Gruber syndrome; hence mode of prenatal diagnosis may vary in subsequent pregnancies.

Objective: Use of soft ultrasonographic markers during routine prenatal ultrasonography (USG) may be used for the screening of aneuploidy in the low-risk population. The aim of this study was to evaluate the acceptance of an invasive test for prenatal diagnosis and to assess the role of various factors in the decision-making regarding an invasive test when confronted with risk for aneuploidy after a soft marker is detected on routine antenatal ultrasonogram., Study Design: Women were referred for USG in our department by primary obstetricians for indications such as a previous child with a congenital malformation, genetic disorder, stillbirth or in women with recurrent spontaneous abortions. Some of the women were referred after prenatal detection of a soft marker on USG. They were screened for soft markers associated with chromosomal abnormality. They were counseled regarding the age-specific risk and the risk of aneuploidy after detection of a marker in comparison to the general population's risk of Down's syndrome. They were also counseled regarding the risk of a procedure-related abortion (0.5%) following an invasive procedure before their decision regarding the use of amniocentesis was made., Result: Twenty women out of 50 (40%) opted for amniocentesis. Except in one case of trisomy 21 in a fetus with short femur and humerus, all others had normal karyotype. The uptake of the test was comparable between primigravida (33%), women with poor obstetric history (46%) and women with at least one normal live child (45%). There was no statistical difference in the uptake of invasive test based on gestational age as well. Uptake of amniocentesis was higher (78%) in cases with nuchal thickening as compared to other markers (35%)., Conclusion: Ultrasonographic detection of soft markers is associated with a high frequency of uptake for invasive prenatal testing. Increased nuchal thickening is associated with a higher acceptance of amniocentesis. Maternal age, gestational age or previous obstetric history were not associated with the decision to undergo amniocentesis.

Infantile olivopontocerebellar atrophy (OPCA) is a rare congenital disorder likely due to an intrauterine neurodegenerative condition. Characteristic presentations are failure to thrive, cerebellar ataxia, respiratory insufficiency, and hypotonia or hypertonia. A few cases with severe manifestations (eg, the Pena-Shokeir phenotype) presenting in the neonatal period have also been reported. We present a case of infantile OPCA with the Pena-Shokeir II phenotype and severe atrophy of the cerebellum and cerebral hemispheres. Comparison of prenatal sonographic findings of the fetal brain at 30 weeks' menstrual age and CT findings during the neonatal period indicated prenatal onset of the neurodegenerative process, which progressed rapidly during the last trimester., ((c) 2007 Wiley Periodicals, Inc.)

Objective: Culture-specific tools to assess longterm psychosocial outcomes for patients with disorders of sexual differentiation are scant. We conducted a study to develop tools for evaluating gender role behavior and health related quality of life for Indian adolescent patients with intersex disorders. We also studied factors important to parents while deciding sex of rearing for their baby., Methods: A 29-item gender role behavior questionnaire and an 18-item health related quality-of-life questionnaire were administered to 82 healthy controls, 13 patients with intersex disorders and 18 patients with type 1 diabetes mellitus. Internal consistency was checked by Cronbach's alpha and test-retest reliability using intra-class correlation coefficient. Responses of 28 parents to a questionnaire on factors affecting the decision of sex of rearing were recorded on a 5-point Likert scale in order of importance., Results: Cronbach's alpha was 0.92 and 0.75, and intra-class correlation coefficient 0.76 and 0.75, for the gender role behavior and quality-of-life questionnaires respectively, indicating a high degree of internal consistency and stability. The mean composite scores for healthy girls on the gender role behavior questionnaire (82.5 +/- 8.7) differed significantly from that for healthy boys (53.2 +/- 7.1, p <0.001). Factors important to parents while making decisions for sex of rearing were appearance of the genitalia, medical advice, ability to bear children and economic independence., Conclusions: We have created valid tools to study gender role behavior and quality of life in adolescent patients with intersex disorders in India. We have also identified in a quantitative way the factors of greatest importance to parents while deciding sex of rearing. These results have direct utility in the management of patients with intersex disorders in India and other similar cultures.

Objectives: To present a comprehensive analysis of autopsy findings in 206 fetuses referred to our genetic center and to assess the clinical utility of fetal autopsy in reaching a final diagnosis, which is essential for counseling regarding the risk of recurrence. We also compared the autopsy findings with prenatal ultrasound findings to evaluate the potential benefit of fetal autopsy in fetuses terminated after prenatal diagnosis of malformations., Study Design: Retrospective review of patient records in a tertiary referral genetic center in North India during 5-year period (April 2000-March 2005). This includes 206 fetuses, 138 terminated after detecting an anomaly in ultrasonogram and 68 spontaneous fetal losses. In all cases, fetal autopsy was carried out and complimented by radiography, karyotype wherever possible and histopathological examination wherever necessary. In fetuses with prenatally diagnosed malformations, ultrasound findings were compared with autopsy findings., Results: Fetal autopsy was able to provide a definite final diagnosis in 59% (122/206) cases. Fetal autopsy confirmed the ultrasound findings in all cases but two. Moreover, autopsy provided additional findings in 77 cases and of these, 24 cases had a significant change of recurrence risk., Conclusion: This study confirms the utility of fetal autopsy in identifying the cause of fetal loss, which will help in the genetic counseling of the couple. In cases with prenatally diagnosed anomalies, the new information from fetal autopsy changes the predicted probability of recurrence in 18% cases. Even though the prenatal ultrasonogram reasonably predicts the malformations, fetal autopsy gives significant additional malformations in one-third of the cases and is essential for genetic counseling.