Familial monoallelic CYP26B1 truncating variant causes a syndromic craniosynostosis due to haploinsufficiency ?

Autosomal recessive CYP26B1 disorder is characterised by syndromic craniosynostosis of variable severity, and survival ranging from prenatal lethality to survival into adulthood. Here we report on two related individuals of Asian-Indian origin with syndromic craniosynostosis characterised by craniosynostosis, and dysplastic radial heads, caused by monoallelic CYP26B1 likely pathogenic variant NM_019885.4:c.86C > A:p. (Ser29Ter). We propose the possibility of autosomal dominant phenotype of CYP26B1 variant.

Knobloch Syndrome in Siblings with Posterior Fossa Malformations Along with Cerebellar Midline Cleft Abnormality Caused by Biallelic COL18A1 Mutation: Case-Based Review.

Knobloch syndrome (KS) is an autosomal recessive disorder caused by biallelic pathogenic variants in COL18A1 . KS clinically manifests with the typical eye findings (high myopia, vitreoretinal degeneration, retinal detachment, and lens subluxation), variable neurological findings (occipital encephalocele, polymicrogyria, cerebellar malformations, epilepsy, and intellectual disability), and the other uncommon clinical manifestations. Literature review of all KS patients (source PubMed) was done with special reference to cerebellar abnormalities. Here, we report two siblings with typical KS with posterior fossa malformations and novel cerebellar midline cleft abnormality analyzed by whole exome sequencing. Known pathogenic homozygous variant c.2908C > T; (p.Arg970Ter) in exon 26 of COL18A1 was found as a cause for KS. These two siblings presented with early-onset severe ocular manifestations, facial dysmorphism, and variable central nervous system manifestations along with novel cerebellar midline cleft abnormality. The presence or absence of structural brain malformations and genotypes does not absolutely predict cognitive functions in KS patients. However, the presence of posterior fossa abnormality may be predictive for the development of ataxia in later life and needs further studies.

Fetal presentation of chondrodysplasia with joint dislocations, GPAPP type, caused by novel biallelic IMPAD1 variants.

Biallelic IMPAD1 pathogenic variants leads to deficiency of GPAPP (Golgi 3-prime phosphoadenosine 5-prime phosphate 3-prime phosphatase) protein and clinically causes chondrodysplasia, which is characterized by short stature with short limbs, craniofacial malformations, cleft palate, hand and foot anomalies, and various radiographic skeletal manifestations. Here we describe prenatal presentation of GPAPP deficiency caused by novel biallelic pathogenic variants, 2 base pair duplication in exon 2 of IMAPD1 gene in a patient of Asian-Indian origin. Further we report on diagnostic clues of prenatal presentation of GPAPP deficiency through ultrasonography, fetal MRI, and postmortem findings. We also provide evidence of pathophysiology of underlying GPAPP deficiency in the form of disorganization and dysplastic chondrocytes and reduced sulfation of glycoproteins through histopathology of cartilage similar to that described in mice IMPAD1 homozygous mutant model.

Late Onset Subacute Profound Biotinidase Deficiency Caused by a Novel Homozygous Variant c.466-3T>G in the BTD Gene.

Biotinidase deficiency (BD) is an autosomal recessive disorder caused by bi-allelic mutation in the BTD gene. Clinical manifestations in BD mainly depends on residual biotinidase enzyme activity, although there are some exceptions. Broadly BD disorders are classified as profound BD and partial BD. Further profound BD can be early onset, late onset, and sometimes may be asymptomatic. Clinically late-onset profound BD can present with spectrum of manifestations ranging from single organ to multiple organ involvement, typically affecting function of brain, eye, ear, and skin. Here, a first-born child to consanguineous parents with late-onset profound BD presenting with hyperventilation secondary to lactic acidosis, hypotonia, evolving spasticity, and abnormal neuroimaging findings caused by novel homozygous variant, c.466-3T>G in the BTD gene is reported.

Multicentric study to evaluate the effectiveness of Thermalytix as compared with standard screening modalities in subjects who show possible symptoms of suspected breast cancer.

INTRODUCTION: Machine learning in computer-assisted diagnostics improves sensitivity of image analysis and reduces time and effort for interpretation. Compared to standard mammograms, a thermal scan is easily scalable and is a safer screening tool. We evaluate the performance of Thermalytix (an automated thermographic screening algorithm) compared with other standard breast cancer screening modalities. METHODS: A prospective multicentre study was conducted to assess the non-inferiority of sensitivity of Thermalytix (test device) to that of standard modalities in detecting malignancy in subjects who show possible symptoms of suspected breast cancer. Standard screening modalities and Thermalytix were obtained and interpreted independently in a blinded fashion. A receiver operating characteristic (ROC) curve was constructed to identify the best cut-off point, non-inferiority margin of ≥10% to demonstrate the non-inferiority. RESULTS: We recruited 258 symptomatic women who first underwent a thermal scan, followed by mammogram and/or ultrasound. At Youden's Index of ROC curve, the test device had a sensitivity of 82.5% (95% CI 73.2 to 91.9) and specificity of 80.5% (95% CI 75.0 to 86.1) as compared with diagnostic mammogram, which had sensitivity of 92% (95% CI 80.7 to 97.8) and specificity of 45.9% (95% CI 34.3 to 57.9) when BI-RADS 3 (Breast Imaging-Reporting and Data System) was considered as test-positive. The overall area under the curve (AUC) was 0.845. For women aged <45 years, the test device had a sensitivity and specificity of 87.0% (95% CI 66.4 to 97.2) and 80.6% (95% CI 72.9 to 86.9), respectively. For women aged ≥45 years, the sensitivity and specificity were 80.5% (95% CI 65.1 to 91.2) and 86.5% (95% CI 78.0 to 92.6, respectively). CONCLUSION: We evaluated Thermalytix, a new AI-based modality for detecting breast cancer. The high AUC in both women under 45 years and above 45 years shows the potential of Thermalytix to be a supplemental diagnostic modality for all ages. Further evaluation on larger sample size is needed. TRIAL REGISTRATION NUMBER: CTRI/2017/10/0 10 115.

Hyperbaric Oxygen Therapy in the Management of Zygomatic Bone Osteomyelitis.

INTRODUCTION: Zygomatic bone osteomyelitis is a rare condition having an incidence of 1.42%. Zygomatic osteomyelitis can be due to haematogenous infection with tubercle bacillus, facial bone fractures or very rarely due to an unknown aetiology like in our case. If surgically managed alone, it would lead to complete loss of zygomatic bone, causing high morbidity to the patient in terms of function and aesthetics like loss of globe support causing dystopia, loss of facial projection causing facial asymmetry. Restoration of facial symmetry and globe support would require extensive procedures such as non-vascular bone grafting or patient-specific implant placement or microvascular bone flap transfer. MATERIALS AND METHODS: Hyperbaric oxygen therapy (HBOT) was used to try and preserve the zygoma by promoting revascularisation. The patient received 100% oxygen at 2.5 absolute atmospheric pressure for 90 min, one session per day for 5 days in a week using a mask system in a multiplace chamber. The patient was reviewed clinically and radiologically after each 5 dives of HBOT sessions. After a total of 30 dives of HBOT, CT examination was repeated. There was partial reconstitution of cortical bone without any additional residual bone lesion. Minimal residual sequestra were noted. At this stage, the patient underwent conservative sequestrectomy in contrast to extensive surgery if HBOT was not contemplated. CONCLUSION: HBOT has the potential to be a very useful adjunct in the treatment of osteomyelitis in head and neck surgery; however, there is a need for carefully designed trials, avoiding methodological bias due to the great variability of patients, infectious agents, antibiotic resistance, host factors, to broaden the evidence of this therapeutic modality.

A novel concept on volumetric assessment and quantification of gastrointestinal bleed on computed tomography angiography: Observations based on a case series.

Department of Radiology, Mazumdar Shaw Medical Centre - Narayana Multispecialty Hospital, Narayana Health, Estimation of quantity and rate of bleeding is of great value in the management of patients with acute GI bleed. Endoscopy and multiphase contrast enhanced computed tomography (MCECT) are the presently employed two important methods for this purpose. Still there is a lacuna in the methods of precise estimation of amount of bleed, which at the moment are somewhat unreliable and subjectively evaluated. We present the value of dynamic contrast-enhanced CT examination in quantitatively estimating the amount of extravasated blood with the help of three illustrative clinical examples. Technique CT examination, the methodology for assessment of quantity of bleed is presented and the discussion of existing literature regarding the estimation methods is presented.Bommasandra, Bengaluru, India.

Bosley-Salih-Alorainy syndrome in patients from India.

Bi-allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley-Salih-Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.

Endosalpingiosis of urinary bladder: report on a rare entity.

A case of endosalpingiosis of the urinary bladder is presented with imaging features on sonography and CT. Patient presented with right flank pain, dysuria and haematuria. She had h/o right renal calculus and abdominal hysterectomy 15 years ago. On sonography a polypoidal filling defect was noted and possibility of a bladder neoplasia was suggested. On cystoscopy and removal of the lesion and subsequent histo-pathological analysis revealed the diagnosis of endosalphingiosis. This report emphasizes the need for evaluation of all clinical inputs while considering the differential diagnosis of an intraluminal bladder lesion. Imaging appearance and aetio-pathology of the rare intra vesical lesion is highlighted.

The Spectrum of Cardiac Anomalies Associated with Heterotaxy: A Single-Center Study of a Large Series Based on Computed Tomography.

The aim of the study was to identify and correlate the anatomical variants of cardiac structures among patients with heterotaxy. In this retrospective cross-sectional analysis of 13 years duration, 302 patients of congenital heart diseases associated with heterotaxy were studied. All these patients had undergone a meticulous clinical evaluation, echocardiography, and cardiac computed tomography. The mean age of the cohort was 38.4 months, with 180 males and 122 females. The cohort had 184 patients of right isomerism and 118 of left isomerism. More than half of the cohort had abnormal pulmonary veins. Over 75% of the cohort had low pulmonary blood flow. Abnormal relationship of great arteries was seen in nearly 69% of the cohort. Atrio-venticular canal defect was the commonest anatomical variant. Overall, 43% of the cohort had single ventricle physiology, predominantly associated with right isomerism. Heterotaxy forms a difficult anatomical subset to comprehend due to the plethora of possible abnormalities. However, unless the cardiac and visceral anatomy is delineated well, the surgical plan becomes suboptimal and often elusive, leaving tough choices for cardiac surgeon. It is essential to obtain all the possible anatomical information using additional imaging modalities to devise a basis for a comprehensive plan for medical and surgical management. A better understanding of the genetic and molecular factors in the etiology, coupled with the application of state-of-the-art imaging techniques, is likely to add to our knowledge of heterotaxy to bring about improved surgical outcomes and a better quality of life for patients suffering from this complex entity.

Subpleural Lung Changes Adjacent to Enlarged Internal Mammary Artery in Patients with Coarctation of Aorta and Pulmonary Hypoplasia: Some Thoughts on an Interesting Observation.

Irregular pleural interface, minimally reduced lung density and/or focal subpleural cystic lung changes were noted in two patients with coarctation of aorta and in a patient with the right pulmonary hypoplasia. Lesions were distributed in the anterior segments of upper lobes, adjacent to internal mammary arteries (IMA). In view of unusual location of lung changes with unique distribution pattern prompted us to look for 'cause and effect' relation of events specific to long standing vascular pulsations, thus explaining the lung changes. While there are multiple factors for cystic lung disease, special distribution the lung changes seen in our patients leads us to explore mechanical process such as water hammer effect by dilated tortuous pulsatile IMA on the lungs as an additional etiology. A brief note on clinical and imaging appearance of our patients and discussion regarding water hammer theory are presented.

Magnetic Resonance Imaging Assessment of Pre- and Post-Surgery Myocardial Changes in Hypertrophic Cardiomyopathy: Correlation with Echocardiography.

Hypertrophic cardiomyopathy (HCM) is a common form of cardiomyopathy and a leading cause of sudden death in the young. Magnetic resonance imaging (MRI) is an established pre-operative tool for the evaluating of patients suspected with HCM for morphological assessment and identifying patients at risk of sudden death. Echocardiography and MRI are equally used in the post-treatment assessment of cardiac function and morphology. In this report, we present the comparative role of these two modalities in pre- and post-operative imaging assessment in our patients, treated surgically with the left ventricular myomectomy. Relative merits of MRI and echocardiography are presented and discussed.

Prognostic determinants of locally advanced buccal mucosa cancer: Do we need to relook the current staging criteria?

OBJECTIVES: Current guidelines advocate non-surgical treatment for T4b buccal mucosa carcinoma with surgery preferred in other stages. We investigated oncologic outcomes of this cohort in comparison with T4a cohort, treated by similar multi-modality approach of primary surgery followed by adjuvant treatment and identified prognostic determinants of survival. MATERIALS AND METHODS: Oncologic outcome of prospectively accrued 282 patients with cT4a and cT4b buccal mucosa squamous cell carcinoma were evaluated for overall survival (OS) and disease free survival (DFS) at 2 years of the whole cohort and for the subgroups of T4a and T4b patients. Multivariate Cox proportional hazards regression analysis was performed to identify prognostic determinants. RESULTS: Of 277 eligible patients treated and followed for a median period of 21 months, the OS was comparable between T4a and T4b as 64% vs 58%, (p = 0.354). The DFS between the two subgroups was 64% vs 61%, (p = 0.316). Although there was 47% pathologic down staging from the clinical stage, there was no significant difference in oncologic outcome between pT4a and pT4b (OS, 57% vs 58% for T4a and T4b, p = 0.687; DFS, 58% vs 60% for T4a and T4b, p = 0.776). On multivariate analysis, extra capsular spread (p = 0.042), lateral pterygoid muscle involvement (p = 0.035) and defaulting adjuvant treatment (p < 0.001) were independent predictors of outcome for the T4b cohort when other factors were controlled. CONCLUSIONS: Primary surgery followed by adjuvant chemo-radiotherapy offers comparable results in selected T4b gingiva and buccal mucosal cancer, suggesting the need to relook the staging criteria for oral cavity cancer.

Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79.

Spastic Paraplegia-79 (SPG79) is an autosomal recessive type of childhood onset complicated by hereditary spastic paraplegia. SPG79 is characterized by spasticity, paraplegia, optic atrophy, cerebellar signs, and other variable clinical features. Recessive, disease causing variants in Ubiquitin C-terminal hydrolase-L1 (UCHL1) gene have been implicated as a cause for SPG79 in two families till now. In this study, we report on a third family of SPG79 with two similarly affected siblings, harboring a novel homozygous splice-site variant in the UCHL1 gene (NM_004181.4: c.459+2T>C). The variant was identified by whole-exome sequencing and validated by Sanger sequencing in the family.

Autosomal recessive otofaciocervical syndrome type 2 with novel homozygous small insertion in PAX1 gene.

Otofaciocervical syndrome (OTFCS) is described as a single gene disorder of both autosomal dominant and autosomal recessive inheritance. The major clinical features of OTFCS include ear malformations (external/middle/inner ear), facial dysmorphism, shoulder girdle abnormalities, vertebral anomalies, and mild intellectual disability. The autosomal recessive form of OTFCS syndrome (OTFCS2) has been recently reported to be caused due to homozygous mutations in PAX1 gene. Here we report a third family of OTFCS2 phenotype wherein whole exome sequencing identified a novel homozygous small insertion in PAX1 as the underlying genetic cause.

Thoracic Origin of Single Right Renal Artery: Some Interesting Facets.

Two cases of thoracic origin of the right renal artery, arising from the level of D11 vertebrae detected on an incidental computed tomography examination are reported. A brief review of embryology is presented. Simultaneous variation of the origin of the right inferior phrenic artery is highlighted as a unique feature of our cases. The importance of this relatively uncommon anomaly in the clinical context is discussed.