Subependymal Calcifications Research Articles

Spotlight on Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC).

Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC) is a rare syndrome caused by biallelic mutations in the JAM3 gene with significant intrafamilial variability in clinical presentation and brain imaging phenotypes. The clinical presentation of HDBSCC includes severe recurrent hemorrhages involving the brain parenchyma and the ventricles beginning in utero and continuing in infancy together with dense central cataracts present at birth. This comprehensive review documents reported cases on this unique condition and describes its genetic, neuroradiologic and ophthalmic features. It should be included in the differential diagnosis of children with congenital cataracts and neurodevelopmental abnormalities. Unique clinical, imaging findings and genetic testing can help the diagnosis.

A case of Giant Renal Angiomyolipoma in Tuberous Sclerosis Complex

ABSTRACT:Angiomyolipomas also referred to as renal hamartoma is a benign lesion.They are either sporadic or associated with syndromes like tuberous sclerosis. Here we present a case of 58yrs old male patient, who presented with left sided abdominal pain for 1month.On examination over face Adenoma Sebaceum was present.Ultrasound abdomen and contrast enhanced computed tomography showed bilateral renal angiomyolipoma with aneurysm over left side.On plain computed tomography of head subependymal calcifications were present.Left Nephrectomy was done and histopathology revealed Angiomyolipoma.

Comprehensive analysis of gene mutation and phenotype of tuberous sclerosis complex in China

Objective To summarize the clinical features of tuberous sclerosis complex(TSC), the distribution and description of TSC gene, and to probe into the correlation of genotype with phenotype. Methods According to the 1998 International Tuberous Sclerosis Complex Diagnostic Criteria, a total of163 TSC patients with pathogenic mutation in TSC gene(3 cases were detected in our hospital, and the other 160 cases were collected from other institutions in China) were enrolled, and their gene detection results and clinical data were analyzed. Results Among 163 cases, TSC1 mutation(31 cases) accounted for 19.02% [32.26%(10/31) in exon 15, 16.13%(5/31) in exon 21, 12.90%(4/31) in exon 18], and TSC2mutation(132 cases) accounted for 80.98% [9.85%(13/132) in exon 37, 7.58%(10/132) in exon 40, 6.82%(9/132) in exon 33]. The proportion of base replacement in TSC1 was 41.94%(13/31), and 52.27%(69/132) in TSC2. Male patients exhibited significantly more subependymal nodules or calcifications than the female patients(χ2 =8.016, P =0.005). Sporadic patients exhibited significantly more cortical tubers than familial patients(χ2 =6.273, P =0.012). Patients with TSC2 mutations had significantly higher frequencies of hypomelanotic macules than patients with TSC1 mutations(χ2 =6.756, P =0.009). Patients with missense mutations were more likely to have facial angiofibromas compared with patients with other mutations(χ2 =4.438, P =0.035). Conclusions Exon 15, 21 and 18 of TSC1 and exon 37, 40 and 33 of TSC2 accounted for higher percentage of mutations. Correlating genotypes with phenotypes should facilitate the individualized treatment and prognostic assessment of tuberous sclerosis complex.

An Uncommon Case of Neurofibromatosis Type 2: A Tribute to the Intracranial Calcifications

Neurofibromatosis Type 2 (NF2) is a genetic disorder associated with schwannomas, meningiomas, and ependymomas. Intracranial calcifications, either tumoral or non-tumoral, are relatively lesser known features of NF2. Here, we present a case of NF2, in which the diagnosis was suspected due to the presence of choroid plexus and subependymal calcifications, although no obvious schwannoma or meningioma was detected initially on standard computed tomography or magnetic resonance imaging. This case highlights the importance of further evaluation with appropriate imaging techniques.

Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts.

We have recently shown that the hemorrhagic destruction of the brain, subependymal, calcification, and congenital cataracts is caused by biallelic mutations in the gene encoding junctional adhesion molecule 3 (JAM3) protein. Affected members from three new families underwent detailed clinical examination including imaging of the brain. Affected individuals presented with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. All patients had a catastrophic clinical course resulting in death. Sequencing the coding exons of JAM3 revealed three novel homozygous mutations: c.2T>G (p.M1R), c.346G>A (p.E116K), and c.656G>A (p.C219Y). The p.M1R mutation affects the start codon and therefore is predicted to impair protein synthesis. Cellular studies showed that the p.C219Y mutation resulted in a significant retention of the mutated protein in the endoplasmic reticulum, suggesting a trafficking defect. The p.E116K mutant traffics normally to the plasma membrane as the wild-type and may have lost its function due to the lack of interaction with an interacting partner. Our data further support the importance of JAM3 in the development and function of the vascular system and the brain.

Evaluation of chronic headache by computed tomography: a retrospective study

Objective: To find out the proportion of intracranial abnormalities in patients with chronic headache without neurologic abnormality with the use of computed tomography (CT) and to compare the results with similar studies done previously. Materials and methods: CT images of 56 patients with chronic/recurrent headache and normal neurological findings were reviewed retrospectively. In 38 of 56 patients, both plain and contrast enhanced CT were done. Patients were divided into three groups according to the CT findings: those with no abnormality, those with minor abnormality (that did not alter patient management) and those with clinically significant abnormality. Proportion of patients in each group was found out and results were compared with previous studies with similar study design. Z test was used to evaluate whether the difference in proportions of patients in our study and previous study was statistically significant or not. Results: Of the 56 patients, 50 had normal CT (89.28 %), four had minor abnormality (7.14%) that did not alter patient management and two had significant lesions (3.57%). Contrast enhanced CT did not improve lesion detection. The minor findings detected were sub-ependymal calcifications of Tuberous sclerosis, calcified neurocysticercosis and old lacunar infarctions in external capsule. Clinically significant lesions detected were small ring enhancing lesion (neurocysticercosis or tuberculoma) and pineal cyst. Results of this study were compared with previous study with similar study design. The Z test showed that the difference in proportions in these studies was not statistically significant (p =0.0708 for minor findings and p =0.2033 for significant findings). Conclusion: The proportion of intracranial abnormalities detected by CT in this study was similar to that of previous studies. The use of intravenous contrast material administration did not improve its yield. This corroborates the evidence that the ability of CT scan in detecting significant intracranial pathology is poor in patients with chronic headache without neurologic abnormality.DOI: http://dx.doi.org/10.3126/jonmc.v1i2.7301 Journal of Nobel Medical College (2012), Vol.1 No.2 p.57-63

Unusual Presentation of Tuberous Sclerosis Complex

A 47-year-old woman presented with acute abdominal pain, hematuria, signs of hemorrhagic shock and presence of a palpable mass in the right hypochondria at physical examination. Total body computed tomography showed bilateral renal angiomyolipoma (AML), voluminous abdominal mass of annexial origin (Fig. 1A, 1B), pulmonary lymphangioleiomyomatosis (LAM) (Fig. 1C), and multiple subependymal calcification in the brain (Fig. 1D). After failure of selective transarterial embolization of the right kidney, the patient underwent exeresis of the abdominal mass and right nephrectomy (2200 g).

Exposure to Lymphocytic Choriomeningitis Virus, New York, USA

To the Editor: Lymphocytic choriomeningitis virus (LCMV) is an arenavirus carried by the house mouse, Mus musculus. Human infections can range from mild febrile illness to severe encephalitis and disseminated disease (1). Infection during pregnancy is associated with teratogenic effects, including congenital hydrocephalus and chorioretinitis (2). The overall occurrence of human exposure to LCMV is not known. Two large US serosurveys suggest that 3%–5% of persons tested had previous LCMV exposure as measured by immunoglobulin (Ig) G (3,4). In 2002, LCMV-associated congenital subependymal calcifications, hydrocephalus, and chorioretinitis were confirmed for 2 children in central Syracuse, Onondaga County, New York, USA. In 2009, the Centers for Disease Control and Prevention confirmed another case of LCMV-associated congenital hydrocephalus and chorioretinitis in a child from the same neighborhood. For each of the 3 cases, the mother’s history included exposure to mice during pregnancy. One mother also had a pet guinea pig, which had negative results for LCMV by serologic testing and reverse transcription PCR of kidney tissue (5). Congenital LCMV is rarely reported to public health departments or in the literature. Therefore, to better understand the magnitude of LCMV exposure in the general population of Onondaga County, we conducted a serosurvey. The American Red Cross provided the Wadsworth Center of the New York State Department of Health with blood or serum samples collected from persons >16 years of age at blood drives during August 2009. Information about date of birth, sex, and county and ZIP code of residence was provided. A subset of samples from blood donors residing in Onondaga County were tested at the Centers for Disease and Prevention by ELISA for LCMV IgM and IgG as described (4). State and federal institutional review board approval was obtained for this study. Samples from 562 blood donors were tested. Mean age of donors was 48 years (median 50 ± 15 SD, range 17–79 years). LCMV IgG was detected in 2 (0.4%) samples (titer >400) and was undetectable in all other samples. LCMV IgM was not detected in any samples. Of the 25 donors who reported residing in 1 of the 2 ZIP codes as the case-patients with congenital LCMV, none had positive test results. Given our findings, little evidence supports a high level of human exposure to LCMV in Onondaga County. Compared with previously reported seroprevalences of 3%–5%, the proportion of persons exposed to LCMV was lower than expected (3,4). The same serologic assay was used in this study and the 2 previous US serosurveys, suggesting that the different results are not an artifact of different assays. Additionally, persons tested in the current survey were older than those tested in previous serosurveys (median 50 vs. 23 [3] and 40 years [4], respectively). Because IgG against LCMV can persist for years, seroprevalence would be expected to be higher for an older population as a result of more chances for exposure. Also, a serosurvey of >1,000 hospitalized persons from upstate New York in the 1970s detected no positive antibody titers (6), consistent with our findings. Our serosurvey had a few limitations. Blood samples from an entire county cannot detect potential household- or neighborhood-scale areas of increased risk for LCMV exposure, which may be related to focal distribution of populations of LCMV-infected house mice. Serosurveys of house mice have previously shown evidence for clustering of LCMV-infected individuals (7); however, the prevalence of LCMV in house mice in Onondaga County is unknown. Additionally, because blood donors were volunteers, the population sampled did not necessarily reflect the population at risk for LCMV exposure. Despite these considerations, the low prevalence of LCMV antibodies suggests low occurrence of LCMV exposure in this population. Although little is known about frequency of human exposure and infection, LCMV seems to be rare with a propensity for inducing severe disease. LCMV infection has been associated with high incidence of clinical disease, including a pet hamster–associated outbreak in 1973–1974 that resulted in at least 181 cases and 46 hospitalizations in 12 states (8). LCMV-related disease is reportable in only 3 states (Wisconsin, Massachusetts, Arizona) and 1 city (New York, New York) and is considered to be widely undertested and underdiagnosed. A recent survey of health care providers in Connecticut found that LCMV diagnostic tests were not requested for all patients suspected to have LCMV infection (9); thus, missed diagnoses are possible. Additional studies are needed to understand the incidence of LCMV-related disease and LCMV seroprevalence in the general population (10).

A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

The tight junction, or zonula occludens, is a specialized cell-cell junction that regulates epithelial and endothelial permeability, and it is an essential component of the blood-brain barrier in the cerebrovascular endothelium. In addition to functioning as a diffusion barrier, tight junctions are also involved in signal transduction. In this study, we identified a homozygous mutation in the tight-junction protein gene JAM3 in a large consanguineous family from the United Arab Emirates. Some members of this family had a rare autosomal-recessive syndrome characterized by severe hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Their clinical presentation overlaps with some reported cases of pseudo-TORCH syndrome as well as with cases involving mutations in occludin, another component of the tight-junction complex. However, massive intracranial hemorrhage distinguishes these patients from others. Homozygosity mapping identified the disease locus in this family on chromosome 11q25 with a maximum multipoint LOD score of 6.15. Sequence analysis of genes in the candidate interval uncovered a mutation in the canonical splice-donor site of intron 5 of JAM3. RT-PCR analysis of a patient lymphoblast cell line confirmed abnormal splicing, leading to a frameshift mutation with early termination. JAM3 is known to be present in vascular endothelium, although its roles in cerebral vasculature have not been implicated. Our results suggest that JAM3 is essential for maintaining the integrity of the cerebrovascular endothelium as well as for normal lens development in humans.

Two novel TSC2 mutations in Chinese patients with tuberous sclerosis complex and a literature review of 20 patients reported in China

Conflicts of interest: None declared. Tuberous sclerosis complex (TSC, OMIM 191100) is an autosomal dominant disorder characterized by the development of multiple hamartomas involving many organs, especially the brain, kidneys, heart and skin. Most patients with TSC mutations have been reported in America, Europe and Japan. Two genes (TSC1 and TSC2) responsible for this disease have been identified, and both of them are speculated to be a kind of tumour suppressor gene.1, 2 We report one multiple‐generation family and one sporadic case of TSC, each with a novel mutation of TSC2, and present a literature review of 20 patients of Chinese origin with TSC mutations reported since 1994. One three‐generation family (Fig. 1) and one sporadic case were identified through probands from Anhui province of China. In the TSC family, all affected individuals belonging to three consecutive generations had similar clinical manifestations as indicated in Table 1 and showed an autosomal dominant inheritance pattern. Detailed information of brain computed tomography (CT) or magnetic resonance imaging (MRI) was not available from the proband. The sporadic case showed epilepsy, moderate mental retardation and facial angiofibromas. Brain CT and MRI revealed subependymal calcifications and cortical tubers. Lesional skin biopsy from the probands revealed the typical histopathological characteristics of TSC. Blood samples were obtained from all available family members and 100 unrelated population‐matched volunteers.

Prenatal pseudocysts of the germinal matrix in preterm infants.

Sonographic characteristics of germinal-matrix (PGM) pseudocysts of prenatal origin detected on cranial ultrasound in preterm newborns were correlated with their outcomes. PGM cysts were classified as typical or atypical, according to their location. Typical PGM cysts were present at the head of the caudate nucleus or slightly medially, adjacent to the foramen of Monro. Cysts were defined as atypical when they were located subependymally elsewhere. Only one infant of 16 with a typical PGM cyst presented with psychomotor retardation. His cerebral scan also showed subependymal calcifications due to cytomegalovirus infection. Three babies had cysts in the frontal periventricular zones (atypical PGM cyst). They had negative cranial MRI (12-15 months of age) and normal neurological follow-up (24 months). In conclusion, isolated prenatal PGM cysts in preterm infants correlate with a normal outcome.

Chylous Pleural Effusion in Tuberous Sclerosis

We report on a male patient with tuberous sclerosis (adenoma sebaceum and digital fibromas, renal angiomyolipomas and subependymal brain calcifications), who presented with chylothorax. Chest CT scan did not show pulmonary parenchymal alterations, but only a moderate enlargement of the paracaval mediastinal lymph nodes. Tuberous sclerosis with lung involvement presents clinical, radiologic and pathologic manifestations similar to those of lymphangioleiomyomatosis. The pulmonary manifestations of tuberous sclerosis and lymphangioleiomyomatosis have been observed almost exclusively in women, and it has been suggested that they represent opposite ends of a spectrum of presentations of the same entity. Based on these considerations the formation of a chylothorax in a male with tuberous sclerosis constitutes an extremely rare finding.

Tuberous sclerosis: diagnostic and surgical considerations.

Twenty-six patients with tuberous sclerosis have been reviewed from the standpoints of CT diagnosis and surgical indications. It was concluded that a diagnosis can be made on the basis of subependymal calcification but not on the basis of cortical calcifications or low density lesions alone. Enhancing lesions, especially at the foramen of Munro, must be considered to be tumors and should be excised if there are symptoms of obstruction. The transcallosal approach is preferred. Asymptomatic enhancing lesions may be followed by periodic scans; if no enhancing lesions are present routine follow-up scans do not appear to be useful.

CT Scans and Tuberous Sclerosis

To the Editor.— The article by Martin et al (235:2323, 1976) indicates that the diagnosis of tuberous sclerosis in a patient may be confirmed by identification of subependymal calcifications on computerized axial tomography (CT). From their series of patients, they imply that a normal CT scan (eg, patient 6) may exclude the diagnosis of tuberous sclerosis. We have performed numerous CT scans on patients at risk for tuberous sclerous. Two patients with the diagnosis of tuberous sclerosis on the basis of retinal astrocytomas, seizures, mental retardation, and depigmented lesions did not have CT evidence of subependymal calcification, whereas an asymptomatic mother of an infant with tuberous sclerosis had an abnormal CT scan (Figure). This mother is a registered nurse and has no stigmata of tuberous sclerosis by history or physical examination. From these and other observations, we have concluded that, like many other laboratory studies, the CT scan is helpful