ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome.

Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11's role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina's Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.

Anticentromere antibody positive Ackerman's Syndrome with Granulomatous Anterior Uveitis.

Ackerman's Syndrome or Intersticial Granulomatous Dermatitis with Arthritis has been an issue of increasing number of reports in the last decade which had focused its heterogeneous cutaneous and rheumatologic expression besides the initial manifestations reported by Ackerman and his group. Granulomatosis anterior uveitis has not been previously described. Some patients are reported to have positive autoantibodies but association with anticentromere antibodies has not been previously described as well, to our knowledge. We report a new case of Ackerman Syndrome with cutaneous, articular and ocular involvement with positive anticentromere antibodies successfully treated with systemic steroids, methotrexate, hydroxychloroquine and cyclosporine. The ocular involvement and the association of anticentromere antibodies lead us to hypothesize that constellation of symptoms and autoimmune mechanisms of this uncommon multisystemic syndrome are yet to be clarified.

Neonatal Serum Phosphorus Levels and Enamel Defects in Very Low Birth Weight Infants.

BACKGROUND: Very low birth weight (VLBW) infants miss out on the period of greatest mineral accretion that occurs during the last trimester of pregnancy and are at higher risk of enamel defects. No studies have well described the relationship between neonatal nutrition and dental outcomes in preterm, VLBW infants. The objective of this study was to assess the differences in nutrition biomarkers, feeding intake, and comorbidities among VLBW infants with and without enamel defects. METHODS: A retrospective chart review of VLBW infants recruited for an ongoing longitudinal dental study between 2007 and 2010 was done. Participants were classified as cases and controls according to the presence/absence of developmental defects of enamel at 8 and/or 18-20 and/or 36 months. Demographics and medical and nutrition data were abstracted from 76 subjects' medical charts. RESULTS: Of the 76 VLBW subjects, 62% had enamel defects (hypoplasia and/or opacity). The only significant variable in the logistic regression analysis was that infants with a 1-mg/dL increase in serum phosphorus levels had a 68% reduction in the odds of having enamel hypoplasia (odds ratio, 0.322; P = .024). CONCLUSION: Neonatal lower serum phosphorus levels are significantly associated with enamel hypoplasia in VLBW infants younger than 3 years.

[Features of blood's microelement structure of children of Khabarovsk area with dentition anomalies].

The content of microelements in blood corpuscles and in serum of children was defined by atomic-absorption method. Deficiency of essential microelements (iodine, copper, nickel) was established and the content of selenium and zinc in the majority of the surveyed children was raised.

Investigating the etiology of multiple tooth agenesis in three sisters with severe oligodontia.

OBJECTIVES: To describe the dentofacial phenotypes of three sisters with severe non-syndromic oligodontia, to report on the mutation analysis in three genes, previously shown to cause various phenotypes of non-syndromic oligodontia and in two other suspected genes. Based on the phenotypes in the pedigree of this family, the different possible patterns of transmission are discussed. METHODS: Anamnestic data and a panoramic radiograph were taken to study the phenotype of the three sisters and their first-degree relatives. Blood samples were also taken to obtain their karyotypes and DNA samples. Mutational screening was performed for the MSX1, PAX9, AXIN2, DLX1 and DLX2 genes. RESULTS: The probands' pedigree showed evidence for a recessive or multifactorial inheritance pattern. Normal chromosomal karyotypes were found and - despite the severe oligodontia present in all three sisters - no mutation appeared to be present in the five genes studied so far in these patients. CONCLUSIONS: In the three sisters reported, their common oligodontia phenotype is not caused by mutations in the coding regions of MSX1, PAX9, AXIN2, DLX1 or DLX2 genes, but genetic factors most probably play a role as all three sisters were affected. Environmental and epigenetic factors as well as genes regulating odontogenesis need further in vivo and in vitro investigation to explain the phenotypic heterogeneity and to increase our understanding of the odontogenic processes.