Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype

Heterozygous mutations of the homeobox genes ALX4 and MSX2 cause skull defects termed enlarged parietal foramina (PFM) and cranium bifidum (CB); a single MSX2 mutation has been documented in a unique craniosynostosis (CRS) family. However, the relative mutational contribution of these genes to PFM/CB and CRS is not known and information on genotype-phenotype correlations is incomplete. We analysed ALX4 and MSX2 in 11 new unrelated cases or families with PFM/CB, 181 cases of CRS, and a single family segregating a submicroscopic deletion of 11p11.2, including ALX4. We explored the correlations between skull defect size and age, gene, and mutation type, and reviewed additional phenotypic manifestations. Four PFM cases had mutations in either ALX4 or MSX2; including previous families, we have identified six ALX4 and six MSX2 mutations, accounting for 11/13 familial, but only 1/6 sporadic cases. The deletion family confirms the delineation of a mental retardation locus to within 1.1 Mb region of 11p11.2. Overall, no significant size difference was found between ALX4- and MSX2-related skull defects, but the ALX4 mutation p.R218Q tends to result in persistent CB and is associated with anatomical abnormalities of the posterior fossa. We conclude that PFM caused by mutations in ALX4 and MSX2 have a similar prevalence and are usually clinically indistinguishable. Mutation screening has a high pickup rate in PFM, especially in familial cases, but is not indicated in CRS.     

Development and evaluation of HIV-1 subtype RNA panels for the standardization of HIV-1 NAT assays

Multiple nucleic acid-based techniques (NAT) have been implemented for testing blood and plasma donors for HIV-1 RNA which may be detected at an earlier stage of infection when HIV antigen or antibody is absent or below the limit of detection of current assays. The available NAT assays are based on different technologies. In order to evaluate the performance of nucleic acid-based techniques (NAT assays) and to allow accurate comparisons of results from different assays, it is essential to have well characterized specimens with known copy numbers as a standard. For this purpose, a comprehensive study was conducted to develop two HIV-1 RNA reference panels. The first (Panel 1) was prepared using a single specimen from the HIV-1 group M subtype B and consists of panel members with a wide range of HIV-1 RNA copy numbers. Panel 2 consists of 26 members representing HIV-1 group M subtypes A, C, D, E, F, G and groups O and N. For accurate determination of HIV-1 RNA copy numbers of each member of Panel 2, they were analyzed using various testing platforms/technologies available through the cooperation of five independent laboratories participating in the study. A consensus value for HIV RNA copy number was assigned to each member of Panel 2 based on statistical analysis of the data provided by the participants. Both panels could serve as reference panels to be used by manufacturers of HIV NAT tests to evaluate the sensitivity limits of their assays.     

Clinical dividends from the molecular genetic diagnosis of craniosynostosis

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for approximately 25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning. However, phenotypic variability can present a significant challenge to the clinical interpretation of molecular genetic tests. In particular, the difficulty of analyzing the complex interaction of genetic background and prenatal environment in determining clinical features, limits the value of identifying low penetrance mutations.     

Clinicopathological study of tuberculous brain abscess

Central nervous system tuberculosis is still one of the leading causes of morbidity in the developing world, and tuberculous abscess is one of its uncommon manifesting forms. It closely mimics a pyogenic abscess clinically, radiologically, and histologically. An accurate diagnosis is imperative due to therapeutic implications. In this study, 21 cases of tuberculous abscesses encountered over a period of 13 years (1995–2007) were reviewed to study the clinical, radiological, and histopathological spectrum of the disease. The presence of palisading epithelioid cells and sheets of foamy histiocytes, enclosing a neutrophillic exudate rich in fibrin with nuclear debris, were clues as to suspicion of a tuberculous abscess. The demonstration of acid fast bacilli in the wall of the abscess or necrotic contents by microscopy or culture is essential to confirm the diagnosis of tuberculous abscess. A high index of clinical suspicion is necessary particularly in countries endemic for tuberculosis to ensure an accurate diagnosis and application of an appropriate therapy.     

Normal sexual dimorphism in the human basal ganglia

Male and female brains differ in both structure and function. Investigating this sexual dimorphism in healthy subjects is an important first step to ultimately gain insight into sex-specific differences in behavior and risk for neuropsychiatric disorders. The basal ganglia are among the main regions containing sex steroid receptors in the brain and play a central role in cognitive (dys)functioning. However, little is known about sexual dimorphism of different basal ganglia nuclei. The aim of the present study was to investigate sex-specific differences in basal ganglia morphology using MRI. We applied automatic volumetry on anatomical MRI data of two large cohorts of healthy young adults (n = 463 and n = 541) and assessed the volume of four major nuclei of the basal ganglia: caudate nucleus, globus pallidus, nucleus accumbens, and putamen, while controlling for total gray matter volume, total white matter volume, and age of the participant. No significant sex differences were found for caudate nucleus and nucleus accumbens, but males showed significantly larger volumes for globus pallidus and putamen, as confirmed in both cohorts. These results show that sexual dimorphism is neither a general effect in the basal ganglia nor confined to just one specific nucleus, and will aid the interpretation of differences in basal ganglia (dys)function between males and females.     

Anti-CD3 mAb treatment cures PDL1-/-.NOD mice of diabetes but precipitates fatal myocarditis

Anti-CD3 mAb is an effective therapy that can reverse diabetes in NOD mice and has therapeutic potential in patients with type 1 diabetes (T1D). We administered anti-CD3 to PDL1-/-.NOD mice in order to determine whether this treatment would reverse the development of diabetes in these mice. Mice injected with anti-CD3 mAb neonatally were protected from T1D. However, all of these anti-CD3 mAb treated PDL1-/-.NOD mice developed a wasting disease between 12 and 20 weeks of age with sudden deterioration and weight loss, leading to death within 3-5 days of development of illness. Histology revealed severe inflammation in the heart and skeletal muscles. These results suggest that deficiency of PDL1 in NOD background has the potential to lead to immune-mediated tissue damage in organs other than the pancreas, but this cannot be appreciated in PDL1-/-.NOD mice as the mice develop T1D at an early age and die from diabetes prior to manifesting other autoimmune diseases.     

Lower touch sensibility in the extremities of healthy Indians: further deterioration with age

Abstract   Touch sensibility testing is a cost-effective, psychophysical measure of peripheral nerve function and impairment. However, there is limited information regarding the natural variability in touch sensibility across different populations and different age groups. We studied 568 healthy Indian volunteers without any clinical evidence of peripheral nerve disease. Touch sensibility was evaluated bilaterally in palms, feet, and heels, using Semmes-Weinstein monofilaments, with target forces ranging from 0.008 to 300 g. No differences were observed between the right and the left limbs. The lowest target force detected ranged from 0.4 to 2 g in the palms and 1.4 to 15 g in the feet. These values showed further increase with age. Women compared with men had higher sensibility in the palms in most age groups. Touch sensibility thresholds recorded in a large group of Indians were higher than that reported in other populations. These findings have clinical implications for the diagnosis of early nerve impairment in the elderly and in disease states drawing attention to geographic variations in touch sensation.     

Does choroid plexus tumour differ with age?

Choroid plexus neoplasms are rare intracranial neoplasms. Significant differences exist in their presentation and management in paediatric and adult populations. The present study aims to study the differences among the paediatric and adult population, various factors affecting the outcome, and the clinical and histological correlation. This is a retrospective study of 47 patients with choroid plexus neoplasms managed at NIMHANS from 1984 to 2004. The case records and images were retrieved and reviewed. The various histopathological features were outlined and histopathology reviewed accordingly. For follow-up, patients were contacted by letter or telephone and the necessary information obtained. Follow-up was available in 41 out of 47 patients. Sixty per cent patients were in the paediatric age group and 40% were adults. Forty-three per cent of children with tumours were less than 1 year of age. The lateral ventricle was the most common site of involvement in the paediatric group compared with the fourth ventricle in adults. Calcification is seen on CT scan more often in papillomas and in adult tumours. Invasion of surrounding parenchyma may be seen in both papillomas and carcinomas. However, in papillomas it is by nests of tumour cells compared with carcinomas wherein invasion is by individual tumour cells. Hydrocephalus is present irrespective of location and size of the tumour. Gross total excision is more feasible in adults. Large tumour size, excessive blood loss, higher incidence of carcinomas result in partial excision of these tumours in the paediatric group. Subdural collections and tumour bed haematomas are more common complications in the paediatric group after resection of tumour. These tumours have significant differences among paediatric and adult groups. Carcinomas are predominantly seen in younger children. Invasion of brain parenchyma by nests of cells does not carry a poor prognosis. The outcomes are better in adults.     

Is total excision of spinal neurenteric cysts possible?

Spinal neurenteric cysts are intradural cystic lesions. These represent a part of the spectrum of developmental anomalies. These are rare lesions. Most of the data in literature is review of case reports. This made us evaluate our results of 23 cases and review the literature. This is a retrospective study of 23 patients managed at our institute over 20 years. The slides were retrieved and histopathological features studied. Twenty patients were less than 30 years old and 21 were males. Follow-up was available for 21 patients with mean duration of 71 months (range 2 months to 23 years). The typical presentation was backache with progressive neurological deficits pertaining to the level. Atypical presentations as acute onset, recurrent episodic events and aseptic meningitis were also noted. The cervicothoracic region was the most common site. 16 patients had cyst in intradural extramedullary plane and seven had intramedullary location. Associated vertebral anomalies as hemivertebrae, Klippel-Feil and spina bifida were noted in seven patients. There were two histological types of cysts with no correlation between the type of cysts and associated vertebral anomalies and extent of outcome. Partial excision though had higher risk of recurrence, was not associated with poorer outcome. Dorsal approach is an acceptable route with reasonably good results for this lesion. Spinal neurenteric cysts present at younger age with varied clinical presentations. These are commonly located intradurally ventral to the cord. Histological types have no effect on the outcome. Total excision is the choice of treatment. However, partial excision is a feasible option in intramedullary lesions and when significant adhesions occur. Although associated with higher risk of recurrence, the outcome is still good in these patients on re-excision.