Correction to: Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

The published online version contain mistake in the author list. Instead of "A.M.Ilyas" it should have been "M.Ilyas ".

Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members. Exome sequencing was performed in three families, with probands referred for epilepsy, autism, and absent speech (Family 1); epileptic spasms (Family 2); and connective tissue disorders (Family 3.) Pathogenic variants in TSC1 or TSC2 were identified in nine individuals, including relatives with limited or no medical concerns at the time of testing. Of the nine individuals reported here, six had post-diagnosis examinations and three met clinical diagnostic criteria for TSC. One did not meet clinical criteria for a possible or definite diagnosis of TSC, and two had only a possible clinical diagnosis following post-diagnosis workup. These individuals as well as their mothers demonstrated limited features that would not raise concern for TSC in the absence of molecular results. In addition, three individuals exhibited epilepsy with normal brain MRIs, and two without seizures or intellectual disability had MRI findings fulfilling major criteria for TSC highlighting the difficulty providers face when relying on clinical criteria to guide genetic testing. Given the importance of a timely TSC diagnosis for clinical management, such cases demonstrate a potential benefit for clinical criteria to include seizures and an unbiased molecular approach to genetic testing.

The molecular characterisation of Cryptosporidium species in relinquished dogs in Great Britain: a novel zoonotic risk?

Surveillance was conducted to investigate the occurrence of protozoan parasites of the genus Cryptosporidium in dogs newly admitted to a dog rehoming charity in London, Great Britain. Voided faecal samples were collected from all new admissions between 2011 and 2012 during six separate 4-week sampling periods. Information on host signalment, including age, breed and reason for submission and faecal consistency, was collected. Polymerase Chain Reaction (PCR) targeting the 18S ribosomal RNA gene, confirmed by sequencing, was conducted on the faecal samples to detect Cryptosporidium genomic DNA and determine Cryptosporidium identity. In total, 677 dogs were included in the study. The prevalence of Cryptosporidium-positive faecal samples was 4.6% (31/676). There were positive samples in all of the six sampling periods. Cryptosporidium canis (n = 28), C. parvum (n = 2) and C. andersoni (n = 1) were identified. Sixty KDa glycoprotein (gp60) gene amplicon sequencing of the C. parvum samples identified genotypes IIaA17G1R1 and IIaA15G2R1 for the first time from a dog. There were no significant associations between signalment data and Cryptosporidium status. While this was a study of one rehoming shelter, the presence of the potentially zoonotic C. parvum and C. canis in dogs highlights a public health concern. Further research is needed to better understand the epidemiology and potential impacts of Cryptosporidium infection in dogs.

Whole-exome sequencing identified a variant in EFTUD2 gene in establishing a genetic diagnosis.

OBJECTIVES: Craniofacial anomalies are complex and have an overlapping phenotype. Mandibulofacial Dysostosis and Oculo-Auriculo-Vertebral Spectrum are conditions that share common craniofacial phenotype and present a challenge in arriving at a diagnosis. In this report, we present a case of female proband who was given a differential diagnosis of Treacher Collins syndrome or Hemifacial Microsomia without certainty. Prior genetic testing reported negative for 22q deletion and FGFR screenings. The objective of this study was to demonstrate the critical role of whole-exome sequencing in establishing a genetic diagnosis of the proband. SETTING AND SAMPLE POPULATION: The participants were 14½-year-old affected female proband/parent trio. MATERIALS AND METHODS: Proband/parent trio were enrolled in the study. Surgical tissue sample from the proband and parental blood samples were collected and prepared for whole-exome sequencing. Illumina HiSeq 2500 instrument was used for sequencing (125 nucleotide reads/84X coverage). Analyses of variants were performed using custom-developed software, RUNES and VIKING. RESULTS: Variant analyses following whole-exome sequencing identified a heterozygous de novo pathogenic variant, c.259C>T (p.Gln87*), in EFTUD2 (NM_004247.3) gene in the proband. Previous studies have reported that the variants in EFTUD2 gene were associated with Mandibulofacial Dysostosis with Microcephaly. CONCLUSION: Patients with facial asymmetry, micrognathia, choanal atresia and microcephaly should be analyzed for variants in EFTUD2 gene. Next-generation sequencing techniques, such as whole-exome sequencing offer great promise to improve the understanding of etiologies of sporadic genetic diseases.

A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.

SUMMARY: A new case of familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) due to a novel compound heterozygous mutation in N-acetylgalactosaminyltransferase 3 (GALNT3) and with new phenotypic findings is presented. The response in serum phosphate and fibroblast growth factor 23 (FGF23) to medical treatment is detailed. This case expands the genotype and phenotype of FTC/HHS and gives insight into its treatment and pathophysiology. INTRODUCTION: FTC and HHS are caused by mutations in FGF23, GALNT3, or KLOTHO. They are characterized by hyperphosphatemia, increased phosphate reabsorption, and elevated or inappropriately normal serum 1,25-dihydroxyvitamin D(3) (1,25-D(3)); FTC is associated with calcific masses, and HHS with diaphyseal hyperostosis. METHODS: A 36-year-old woman presented with abnormal dental X-rays at age 12 and was hyperphosphatemic at 22. She underwent radiographic, biochemical and genetic testing, and medical treatment. RESULTS: Serum phosphorus was 7.3 mg/dL (2.5-4.8), TmP/GFR 6.99 mg/100 mL (2.97-4.45), 1,25-D(3) 35 pg/mL (22-67). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septa of the soft tissue in the lower extremities, and cortical thickening of the long bones. Her total hip Z score was 1.9. C-terminus serum FGF23 was 1,210 RU/mL (20-108), but intact FGF23 was 7.4 pg/mL (10-50). DNA sequencing determined she was a compound heterozygote for mutations in GALNT3. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23. CONCLUSIONS: This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23.

Magnetic resonance imaging and computed tomography in the assessment of mandibular invasion by squamous cell carcinoma of the oral cavity. Influence on surgical management and post-operative course.

INTRODUCTION: Preoperative evaluation of the bone for invasion by oral cavity squamous cell carcinoma remains challenging. The aim of our study was to compare the accuracy of MRI and CT in detecting mandibular invasion by oral squamous cell carcinoma of the oral cavity, with histologic results as the reference standard, and to assess the influence on surgical management and post-operative course. PATIENTS AND METHODS: Patients who were clinically suspected of having bone invasion from oral cavity carcinoma were retrospectively included. A single senior radiologist reviewed MRI images and CT-scans, independently, for the presence or absence of mandibular invasion. The different surgical procedures were compared in terms of length of hospital stay and occurrence of surgical complications. RESULTS: Histological mandibular invasion occurred in 9 of 35 patients (25.7%). None of the preoperative imaging tests failed to detect bone invasion which resulted in a sensitivity of 100% for both MRI and CT. CT had slightly higher specificity than MRI (61.9% and 57.1% respectively) in predicting bone invasion, but no statistically significant difference was found (P=0.32). Specificity of CT and MRI was higher in the edentulous group (75% and 625% respectively) than in the dentate group (53.8% both), although no statistically significant difference was found. The length of hospital stay was increased in the segmental resection group (25±14.5 days) compared to the marginal resection group (13±4.6 days; P=0.004) and to the hemimandibulectomy group (15±7.2 days; P=0.014). Occurrence of post-operative complications, across all categories, was increased in the segmental resection group (70%, n=7/10; P=0.006) compared to the marginal resection group (8.3%, n=1/12) and to the hemimandibulectomy group (23.1%, n=3/13; P=0.04). CONCLUSION: MRI and CT being equivalent in detecting mandibular invasion, we suggest MRI as single imaging technique in the preoperative assessment of oral cavity SCC. Specificity could be increased if combined with PET/CT, in order to reduce the number of unnecessary mandibular interruptions.

[Surgical treatment of Obstructive Sleep Apnea Syndrome. Functional assessment]. / Chirurgie du syndrome d'apnées-hypopnées obstructives du sommeil. Évaluation fonctionnelle.

INTRODUCTION: Obstructive Sleep Apnea Syndrome (OSAS), when associated with adverse skeletal dysmorphia, can be managed by curative surgery i.e. advanced maxillomandibular associated with genioplasty and uvulopalatoglossoplasty ("6 in 1"). The purpose of this study was to assess the functional impact of this procedure. MATERIALS AND METHODS: This retrospective study was made on 27 patients with OSAS surgically treated between 1998 and 2009. The functional results were considered satisfactory when postoperative apnea/hypopnea index (AHI) was <15/h and/or at least decreased by 50%. RESULTS: After surgical treatment, the AHI dropped below 15/h for 70.4%, and for 92.6% it was at least decreased by 50%, one year after surgery. A significant concomitant decrease of the body mass index (BMI) was also observed. DISCUSSION: This "6 in 1" surgical management seemed to effectively treat OSAS in the selected cases.