Biodosimetric analysis of head and neck cancer patients undergoing radiotherapy by dicentric chromosome aberration assay.

BACKGROUND: Biodosimetry is the quantification of absorbed radiation dose using biological material obtained from an exposed individual. Radiation can cause different types of chromosomal aberrations, including stable aberrations like translocations and unstable ones like micronuclei, dicentric chromosomes (DC), acentric, and ring forms. Dicentric chromosome assay has become the "gold standard" for cytogenetic biodosimetry due to its reproducibility, specificity (low baseline rates), and sensitivity to low doses. Using existing calibration curves and models obtained from in vitro irradiation of blood, the yield of DCs can be used to estimate the average whole-body absorbed dose. PURPOSE: To evaluate and compare the in vivo dose-response relation of DC aberration formation in peripheral blood lymphocytes of head and neck cancer (HNC) patients undergoing radiotherapy (RT) alone, cisplatin-based chemoradiation (CCRT), accelerated fractionation RT (AFRT), and CCRT with gefitinib (GCRT). METHODOLOGY: This prospective observational and analytical study was conducted from 2018 to 2021 in the Department of Radiation Oncology and Genetic Lab of tertiary care, teaching hospital after approval from the Institutional Ethics Committee. Biodosimetric analysis was done weekly in patients undergoing RT (n = 20) versus CCRT (n = 20), CCRT (n = 12) versus AFRT (n = 12), and CCRT (n = 6) versus GCRT (n = 6). The yield of DCs was measured in blood samples taken before starting treatment, that is, day 0 and during RT on days 6, 11, and 16 in RT alone versus CCRT; on days 7 and 13 in CCRT versus AFRT; and days 6 and 11 in CCRT versus GCRT from a blood sample drawn 1-2 h after RT. Phytohemagglutinin-stimulated lymphocytes were cultured using heparinized blood in RPMI-1640 medium supplemented with fetal bovine serum. Cells were arrested at metaphase using demecolcine, harvested by centrifugation, mounted, and stained with Giemsa. Cytogenetic analysis was performed by analyzing at least 100 metaphases with well-spread chromosomes. DC aberrations and acentric fragments were identified and recorded. To standardize the findings as per the customized field for every patient, the mean DC yield per cm2 of the irradiated area was calculated and compared. RESULTS: The mean yield of DC/cm2 in the CCRT group was greater than the RT alone group by 16.33%, 28.57%, and 18.68% on days 6, 11, and 16 of treatment, respectively. This difference between the two groups at day 6 (P = 0.001), day 11 (P < 0.001), and day 16 (P < 0.001) was found to be statistically significant. The mean yield of DC/cm2 in the CCRT group was greater than the AFRT group by 7.9% and 18.3% on days 7 and 13 of treatment, respectively. This difference at day 7 (P < 0.001) and day 13 (P < 0.001) was found to be statistically significant. The mean yield of DC/cm2 in the CCRT group was greater than the GCRT group by 22.7% and 21.8% on days 6 and 11 of treatment, respectively. The difference at day 6 (P = 0.01) was statistically significant but, on day 11 (P = 0.065) this difference was found insignificant. CONCLUSION: There is a dose-dependent increase in the yield of DCs in lymphocytes of HNC patients undergoing RT with subsequent fractions. Cisplatin-based chemoradiation is the superior method of treatment intensification radio-biologically proven by higher DC yield.

Correlation of pain perception and fentanyl consumption after major abdominal surgery with CGRP 4218T/C polymorphism: A prospective interventional study.

Background and Aims: Genetic polymorphisms contribute to patients' variability in pain perception and response to opioid treatment. The present study evaluated the association of calcitonin gene-related peptide (CGRP) 4218T/C polymorphisms with fentanyl consumption over 24 h postoperatively in patients after major abdominal surgery. Methods: Eighty-five patients undergoing major abdominal surgery under general anaesthesia were recruited. For postoperative analgesia, epidural fentanyl and intravenous paracetamol were provided. The CGRP 4218T/C genotype was analysed, and the association between the genotype of the patient and the total consumption of fentanyl in the first 24 h after surgery was assessed. The association between different genotypes, the severity of postoperative pain and the side effects of opioids were also studied. Results: Our study population distribution included 52.9% of the T/T genotype (wild homozygote), 35.3% of the T/C genotype (heterozygote) and 11.8% of the C/C genotype (mutant homozygote). Mean (standard deviation) total fentanyl consumption in the first 24 h was found to be highest in the C/C group (212.0 [7.5] µg), followed by the T/T group (182.8 [9.9] µg) and was the least in the T/C group (159.6 [7.5] µg). The C/C group reported higher pain scores in all the study periods. There was no significant difference in the side effects of opioids, such as nausea, vomiting, sedation among different genotypes of CGRP 4218T/C. Conclusion: The polymorphism of CGRP 4218T/C affects postoperative pain perception and analgesic consumption. Patients with the C/C genotype had higher postoperative fentanyl consumption and pain scores.

Is Omicron really mild? - Comparative analysis of comorbidities and disease outcomes associated with SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants.

PURPOSE: Multiple variants of SARS-CoV-2 from Alpha to Omicron have an estimated 6.1 million deaths globally till date. These variants have been found to vary in transmissibility and severity. The present study deals with comparison of morbidity and mortality with SARS-CoV-2 Omicron (B.1.1.529) and Delta (B.1.617.2) variants. MATERIALS AND METHOD: An observational retrospective cohort study was conducted on a cohort of laboratory confirmed patients of SARS-CoV-2 diagnosed by qRT-PCR of nasopharyngeal swabs in periods; April-2021 and January-2022; that were sequenced and variants were recorded. Patients were invited for a telephonic interview after voluntary and informed consent was obtained from each participant wherein, the demographics, co-morbidities, oxygen requirement and mortality outcomes of the patients were enquired about. RESULTS: A total of 200 patients, with 100 from each period were included in the study. Major comorbidities in patients included hypertension, diabetes mellitus and pulmonary disease. Patients who succumbed to the Delta variant (26%) were higher as compared to the Omicron variant (10%); with the elderly (68 â€‹± â€‹9.7 â€‹years) having significant mortality during the Omicron variant. The mortality was increased in patients with comorbidities as with hypertension (53.8%, 70%), diabetes mellitus (26.9%, 40%), chronic pulmonary disease (30.8%, 20%), and smoking (15.4%, 40%) in the patients infected with both Delta and Omicron variants, respectively. CONCLUSION: The study concluded that the newer strains of SARS-CoV-2 have potential of high transmissibility and milder disease for the population by large, however, for patients with comorbidities have a higher proportion of adverse outcomes, irrespective of the variant.

Anastrozole-mediated modulation of mitochondrial activity by inhibition of mitochondrial permeability transition pore opening: an initial perspective.

The mitochondrial permeability transition pore (mtPTP) plays a vital role in altering the structure and function of mitochondria. Cyclophilin D (CypD) is a mitochondrial protein that regulates mtPTP function and a known drug target for therapeutic studies involving mitochondria. While the effect of aromatase inhibition on the mtPTP has been studied previously, the effect of anastrozole on the mtPTP has not been completely elucidated. The role of anastrozole in modulating the mtPTP was evaluated by docking, molecular dynamics and network-guided studies using human CypD data. The peripheral blood mononuclear cells (PBMCs) of patients with mitochondrial disorders and healthy controls were treated with anastrozole and evaluated for mitochondrial permeability transition pore (mtPTP) function and apoptosis using a flow cytometer. Spectrophotometry was employed for estimating total ATP levels. The anastrozole-CypD complex is more stable than cyclosporin A (CsA)-CypD. Anastrozole performed better than cyclosporine in inhibiting mtPTP. Additional effects included inducing mitochondrial membrane depolarization and a reduction in mitochondrial swelling and superoxide generation, intrinsic caspase-3 activity and cellular apoptosis, along with an increase in ATP levels. Anastrozole may serve as a potential therapeutic agent for mitochondrial disorders and ameliorate the clinical phenotype by regulating the activity of mtPTP. However, further studies are required to substantiate our preliminary findings.Communicated by Ramaswamy H. Sarma.

Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia.

BACKGROUND: C-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models. METHODS: Exome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants. RESULTS: Two homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9. CONCLUSION: In conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Role of melatonin mediated G-CSF induction in hematopoietic system of gamma-irradiated mice.

AIMS: Hematopoietic acute radiation syndrome (H-ARS) can cause lethality, and therefore, the necessity of a safe radioprotector. The present study was focused on investigating the role of melatonin in granulocytes colony-stimulating factor (G-CSF) and related mechanisms underlying the reduction of DNA damage in hematopoietic system of irradiated mice. MAIN METHODS: C57BL/6 male mice were exposed to 2, 5, and 7.5Gy of whole-body irradiation (WBI), 30 min after intra-peritoneal administration of melatonin with different doses. Mice were sacrificed at different time intervals after WBI, and bone marrow, splenocytes, and peripheral blood lymphocytes were isolated for studying various parameters including micronuclei (MN), cell cycle, comet, γ-H2AX, gene expression, amino acid profiling, and hematology. KEY FINDINGS: Melatonin100mg/kg ameliorated radiation (7.5Gy and 5Gy) induced MN frequency and cell death in bone marrow without mortality. At 24 h of post-WBI (2Gy), the frequency of micronucleated polychromatic erythrocytes (mnPCE) with different melatonin doses revealed 20 mg/kg as optimal i.p. dose for protecting the hematopoietic system against radiation injury. In comet assay, a significant reduction in radiation-induced % DNA tail (p ≤ 0.05) was observed at this dose. Melatonin reduced γ-H2AX foci/cell and eventually reached to the control level. Melatonin also decreased blood arginine levels in mice after 24 h of WBI. The gene expression of G-CSF, Bcl-2-associated X protein (BAX), and Bcl2 indicated the role of melatonin in G-CSF regulation and downstream pro-survival pathways along with anti-apoptotic activity. SIGNIFICANCE: The results revealed that melatonin recovers the hematopoietic system of irradiated mice by inducing G-CSF mediated radioprotection.

Evaluation of the Utility of Amino Acid Citrulline as a Surrogate Metabolomic Biomarker for the Diagnosis of Celiac Disease.

INTRODUCTION: Citrulline is regarded as a biomarker for celiac disease (CD). Its utility for assessment and evaluation of additive predictive value for latent, potential CD and first degree relatives (FDRs) needs exploration. METHOD: Consecutive 558 index cases diagnosed as per European Society for Pediatric Gastroenterology and Nutrition (ESPGHAN) 2012 guidelines and their 1565 FDRs were evaluated over five and half year period. Serology negative FDRs at initial visit and follow ups were served as controls. HLA typing for DQ2 and DQ8 genotypes, along with plasma and dried blood spot (DBS) filter paper citrulline were evaluated. RESULTS: Median plasma citrulline values were 20.1 and 37.33 µMol/l in cases and controls (P < .001). Cut off values for Marsh grade 3a, 3b, and 3c were 35.0, 32.8, 25.26 µMol/l in CD patients and 36.51, 30.10, 25.26 µMol/l in biopsy proven FDR. Increasing trends of plasma citrulline levels with decreasing tTG-IgA levels were observed on follow up. Low plasma citrulline levels were observed with HLA DQ 2.5 genotype (P < .05). Agreement between DBS and plasma citrulline was 94.8%. CONCLUSION: Citrulline is a good surrogate biomarker for identification of histopathological grade of damage, extent of mucosal recovery and has negative correlation with tTG-IgA. It identifies the silent and latent phase of CD. DBS citrulline provides adequate information and can be used for monitoring CD patients at remote locations.

Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population.

Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by formation of hamartomas and broad phenotypic spectrum including seizures, mental retardation, renal dysfunction, skin manifestations and brain tubers. It is inherited in an autosomal dominant pattern, caused due to mutation in either TSC1 or TSC2 genes. Seizures are one of the major presenting symptoms of TSC that helps in early diagnosis. The present study describes the mutation spectrum in TSC1 and TSC2 genes in TSC patients and their association with neurocognitive-behavioral phenotypes. Ninety-eight TSC patients were enrolled for TSC genetic testing after detailed clinical and neurobehavioral assessment. Large genomic rearrangement testing was performed by multiplex ligation-dependent probe amplification (MLPA) technique for all cases and Sanger sequencing was performed for MLPA negative cases. Large rearrangements were identified in approximately 1% in TSC1 and 14.3% in TSC2 genes. The present study observed the presence of duplications in two (2%) cases, both involving TSC2/PKD1 contiguous genes which to the best of our knowledge is reported for the first time. 8.1% of small variants were identified in the TSC1 gene and 85.7% in TSC2 gene, out of which 23 were novel variations and no variants were found in six (6.1%) cases. This study provides a representative picture of the distribution of variants in the TSC1 and TSC2 genes in Indian population along with the detailed assessment of neurological symptoms. This is the largest cohort study from India providing an overview of comprehensive clinical and molecular spectrum.

Loes Score: Clinical and Radiological Profile of 22 Patients of X-Linked Adrenoleukodystrophy: Case Series from a Single Center.

Introduction X-linked adrenoleukodystrophy (X-ALD) is a devastating disease with a wide spectrum of presentation ranging from asymptomatic to a rapidly progressive childhood cerebral form. The gene responsible for adrenoleukodystrophy is ABCD1 gene, required for ß oxidation of fatty acids in various tissues. While biochemical and molecular techniques are available to confirm the diagnosis, brain magnetic resonance imaging (MRI) utilizing Loes score has been used for both prognosis and timely direction of hematopoietic stem cell therapy. Materials and Methods During the study period of 2016 to 2020, 22 individuals including 19 individuals with features suggestive of X-ALD and 3 asymptomatic siblings were evaluated from a single center in North India. After biochemical and molecular confirmation of the disease, detailed clinical and radiological findings using MRI brain were documented. A radiological scoring pattern proposed by Loes was employed to identify the severity of the disorder. Results The most common clinical presentations were visual difficulty and muscular weakness (58%). All symptomatic individuals had classic neuroimaging findings in the form of hyperintensities involving the parieto-occipital area and splenium of corpus callosum. Severe involvement in the form of global atrophy was observed in 52.6% of individuals. Asymptomatic siblings also showed neurological involvement based on MRI with highest Loes score of 9 in one individual. Conclusion This case series describes the clinical and radiological profile and employment of Loes score in individuals with X-ALD. Early identification of asymptomatic individuals by neuroimaging and use of Loes severity score for monitoring and disease progression will help in making therapeutic decisions in a timely manner.

Phenotypic and genotypic spectrum of CTSK variants in a cohort of twenty-five Indian patients with pycnodysostosis.

BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia with easily recognizable clinical features and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 25 Indian patients with pycnodysostosis from 20 families. METHODS: Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the CTSK gene. Novel variants were systematically assessed by prediction softwares and protein modelling. The pathogenicity of variant was established based on ACMG-AMP criteria. An attempt was also made to establish a genotype-phenotype correlation and devise a diagnostic scoring system based on clinical and radiological findings. RESULTS: Consanguinity and positive family history were present in 65% (13/20) and 45% (9/20) of the families respectively. Short stature and fractures were the predominant presenting complaints and was evident in 96% (24/25) and 32% (8/25) of affected individuals respectively. Gestalt facial phenotype and acro-osteolysis were present in 76% (19/25) and 82.6% (19/23) of the individuals respectively. Hepatosplenomegaly was present in 15% (3/20) of the individuals with one of them having severe anaemia. Causative sequence variations were identified in all of them. A total of 19 variants were identified from 20 families amongst which 10 were novel. Homozygous variants were identified in 90% (18/20) families. Amongst the novel variants, there was a considerable proportion (40%) of frameshift variants (4/10). No significant genotype-phenotype correlation was noted. Scoring based on clinical and radiological findings led to the proposal that a minimum of 2 scores in each category is required in addition to high bone density to diagnose pycnodysostosis with certainty. CONCLUSION: This study delineated the genotypic and phenotypic characterisation of Indian patients with pycnodysostosis with identification of 10 novel variants. We also attempted to develop a clinically useful diagnostic scoring system which requires further validation.

Generation of induced pluripotent stem cell line (IGIBi007-A) from a patient with a novel acromesomelic dysplasia, PRKG2 type (AMDP).

Biallelic PRKG2 (Protein Kinase, cGMP dependent Type-2) mutations cause a novel acromesomelic dysplasia PRKG2 type. We report generation of induced pluripotent stem cell line from lymphoblastoid cell lines of the patient carrying the reported frameshift mutation (p.Asn164Lysfs*2). The derived iPSC line exhibits all the features of pluripotency, free of major genetic alterations due to reprogramming process and has the capability to differentiate into three germ layers. This iPSC cell line may provide an opportunity to investigate the effect of PRKG2 mutations upon FGF (fibroblast-growth-factor) induced MAPK signalling involved in chondrocyte proliferation in-vitro and may aid in possible therapeutic screening of novel biomolecules.

Duchenne Muscular Dystrophy: Genetic and Clinical Profile in the Population of Rajasthan, India.

Background: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscular dystrophy that affects young boys and is caused by mutation of the dystrophin gene located over X chromosome. Materials and Methods: In this prospective study, 120 clinically diagnosed DMD patients were tested for exon deletions, duplication or point mutation. Results: Of the 120 clinically suspected DMD patients, the diagnosis of DMD was confirmed by the genetic study or muscle biopsy in 116 patients. The mean age of onset was 3.2 years and the mean age at presentation was 7.2 years. 110/120 cases were confirmed by genetic testing and six were by absence of staining for dystrophin on muscle biopsy. DMD gene deletion was present in 78.5%, duplication in 5.3% and point mutation in 11.2% cases. 70.3% of patients had deletion located at a distal hot spot region. Single exon deletion was found in 16.5%. Distal hotspot exons 47, 48 and 50 were the commonly deleted exons. Conclusions: In our study, 94.8% cases showed genetic change in the DMD gene. Muscle biopsy was the choice of investigation in earlier days. Detection of DMD by DNA based method eliminates the need to do an invasive procedure for diagnosis. Hence the genetic testing should be the investigation of choice in suspected cases of DMD. The pattern of deletion, obtained in the population of Rajasthan was similar when compared with other ethnic groups of the Indian population. It would be helpful for researchers to develop drugs specific to exons or for ongoing mutation-specific therapies.

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

A prospective study of catch-up growth among Indian children with celiac disease.

OBJECTIVES: The study was done to investigate the response of the gluten-free diet (GFD) on growth and other biochemical parameters in newly diagnosed children with celiac disease (CD). We also determined the association of Marsh biopsy classification and the response in haematological parameters among the children with GFD over the follow-up time. METHODS: A prospective observational study was conducted for 1.5 years where children aged 1-10 years with newly confirmed CD (as per Marsh classification) without pre-existing chronic disease were enrolled. Individual anthropometry, biochemical and haematological parameters were recorded on enrolment and compared with 1, 3 and 6 months (follow-up) after initiating GFD (as per World Health Organization growth charts). STATISTICAL ANALYSIS: The data were entered in MS Excel spreadsheet and analysis was done using Statistical Package for Social Sciences version 21.0. A P value of < 0.05 was considered significant. RESULTS: A total of 51 (out of 55) children with CD completed 6-month follow-up. A significant improvement in the growth and biochemical parameters was seen at 6-month follow-up with the GFD (P < 0.05). There was a significantly decreasing Hb (at enrolment and at 3 months) with increasing Marsh biopsy grade-it was significantly less with Marsh 3C and more with Marsh 3A. A significantly better %Hb improvement was seen in children with Marsh biopsy 3C as compared to 3A and 3B (P < 0.05). We found no significant association of Marsh biopsy with Malabsorption, type of anaemia and Serum ferritin levels (P > 0.05). CONCLUSIONS: GFD showed significant improvement in the growth and development of the child with a significant reduction in anaemia at 6 months. With increasing grade of Marsh biopsy, the severity of anaemia increases but after the initiation of GFD, such children show significantly better improvement in %Hb over time.

Gingival manifestations of tuberculosis in pediatric patients: series of 4 cases.

OBJECTIVE: The aim of the study was to evaluate the gingival manifestations of tuberculosis (TB) in the oral cavity in pediatric patients. STUDY DESIGN: Four pediatric patients were enrolled in the study. Clinical symptoms, auxiliary examinations, treatments, and outcomes were recorded and analyzed. Four pediatric patients who presented with atypical gingival lesions were thoroughly examined for local and systemic signs and symptoms, and a detailed history was obtained. All relevant investigations led to a definitive diagnosis of oral tuberculous lesions. On the basis of the final diagnosis, antitubercular therapy (ATT) was started for all the pediatric patients, and outcomes were measured. RESULTS: All 4 patients responded very well to the treatment, with complete resolution of the lesions within 6 months after the initiation of ATT. CONCLUSIONS: Health care professionals should rule out TB as one of the differential diagnoses in pediatric patients with atypical gingival lesions. ATT is strongly recommended for the treatment of oral TB to achieve good clinical outcomes. Rapid molecular tests based on nucleic amplification should be utilized for the diagnosis of TB in children and also for extrapulmonary TB because they are much faster and reliable compared with conventional methods.

Clinicoradiologic follow up of cherubism with aggressive characteristics: a series of 3 cases.

Cherubism is a rare autosomal dominant disorder characterized by replacement of bone with fibrous tissue containing multinucleated giant cells. It manifests as bilateral mandibular and/or maxillary enlargement. The 2017 World Health Organization classification lists cherubism as a giant cell lesion of the jaws, distinct from fibro-osseous disorders. We discuss 3 cases of familial cherubism having aggressive characteristics and present clinicoradiologic evaluations of the lesions over 12, 18, and 1.5 years, respectively. Follow-up was observational, without active intervention. Analysis of the lesions for change in size and functional impairments was correlated with periodic imaging. All patients are currently being monitored. The outcome in 2 cases has been excellent without intervention, but 1 case had extensive involvement of the jaws and involvement of the condyle and orbit. A secondary giant cell lesion involved the palate in one patient's mother, who had had cherubic lesions in childhood.

Genetic alteration of Exon 5 of the PTEN gene in Indian patients with ameloblastoma.

OBJECTIVE: The PI3K/Akt/mTOR pathway is one of the signaling pathways associated with the pathogenesis of ameloblastoma. The phosphatase and tensin (PTEN) homologue controls cell migration and proliferation. It monitors the level of Akt and maintains cellular integrity. The aim of the present study was to study the genetic alteration of Exon 5 of the PTEN gene in Indian patients with ameloblastoma. STUDY DESIGN: Total DNA was extracted from formalin-fixed paraffin-embedded tissue samples from 20 cases with solid multicystic ameloblastoma (SMA) and from 10 cases with normal tooth germ. Exon 5 of the PTEN gene, was assessed for its role in the pathogenesis of ameloblastoma. RESULTS: Five of 20 cases of SMA showed genetic alteration. Of these cases 3 (15%) showed silent mutation, 1 (5%) showed change in amino acid sequence from valine to glutamic acid, and 1 (5%) showed nonsense-mediated mRNA decay. CONCLUSIONS: The present study showed 25% somatic mutational frequency in exonic region 5 of the PTEN gene. This may indicate its role in the pathogenesis of ameloblastoma.

Split hand-foot malformation and a novel WNT10B mutation.

We report an Indian girl with split-hand/foot malformation (SHFM), sparse hair, and interrupted eyebrows, who carries a novel homozygous deletion c.695_697delACA in WNT10B. The variant is deduced to cause an in-frame deletion of Asn residue 232 (p.Asn232del). According to the protein model, this single amino acid deletion at the critical position in the protein structure is likely to severely affect the protein structure and function. This deletion is likely to lead decreased lifetime and make it unable to bind to its receptors and other ligands. The patient and all family members had normal bone density and they were not obese like some of the patients with WNT10B variants. Here we report a patient with SHFM6 who carried a novel WNT10B mutation. Sparse hair and interrupted eyebrows may be associated findings of SHFM6.