A Witteveen-Kolk Syndrome Patient with Reflux Disease and a de novo Deletion of the SIN3A Gene.

Introduction: The Witteveen-Kolk syndrome (WITKOS) (OMIM: 613406) is a heterogeneous emerging disorder caused by pathogenic variants or microdeletions encompassing the SIN3A gene (SIN3 Transcription Regulator Family Member A). It is characterized by distinctive facial features, developmental delay, intellectual disability, microcephaly, short stature, and subtle anomalies on brain magnetic resonance imaging (MRI). To date, about 50 patients have been reported in the medical literature. Patient Presentation: In this article, we reported a patient with classic findings of WITKOS including global developmental delay, microcephaly, hypotonia, vomiting, malnutrition, autistic and dysmorphic facial features, and cardiac abnormalities. Also, a barium esophagogram suggested severe motility disorder and gastroesophageal reflux disease. Affymetrix CytoScan 750K microarray showed a de novo 1.6-Mb deletion at 15q24.1q24.2, including the whole SIN3A gene. We have also summarized the clinical features of WITKOS patients in the medical literature and cardiac abnormalities detected in 4 out of 10 patients in studies that clearly state that cardiac examination was performed in the patients. Conclusion: Our findings showed that cardiac defects are not uncommon findings in WITKOS. Physicians should also be aware of reflux disease and motility disorder in patients with feeding difficulty together with early cardiac examination in terms of an improved quality of life in WITKOS patients.

Blau syndrome with a rare mutation in exon 9 of NOD2 gene.

Blau syndrome is an autosomal dominant rare disease caused by mutations in NOD2 gene. Less than 200 patients published with Blau Syndrome Worldwide. We reported a 41-year old female Turkish patient diagnosed as Blau syndrome. Granulomatous dermatitis and severe headache, as well as recurrent chest and pelvic pain have been present since she was 8 years old. Arthritis started when she was teenage, hypertension diagnosed when she was 20 and other symptoms also occurred during the lifetime (severe preeclampsia, ischemic stroke, recurrent hemiparesis, recurrent-transient-vision-loss and renal-artery-stenosis). Genomic DNA was isolated from peripheral blood and 12 genes sequenced in Autoinflammatory panel on IonTorrent-S5-NGS platform with Parseq-VariFind™AIPassay. NGS analysis showed 107 variants in in the index case, mainly benign with no strong association with Blau syndrome. Additionally, we identified one very rare missense mutation in NOD2 gene (c2803G>A, p.Val935Met) and in silico assessment of the mutation indicated possible pathogenic significance and strong association with Blau syndrome. In addition, we analyzed family members of the index case and identified the same mutation in NOD2 gene. The segregation analysis shows the presence of the same mutant allele in NOD2 gene in the index case affected sister, as well as in her son with arthralgia, while in her non affecter brother we didn't detect the Val935Met mutation in NOD2 gene. Blau Syndrome is known as a very rare disease, mainly caused by mutations in NOD2 gene. Missense mutation diagnosed in our case could be responsible for the phenotype of the index case. Our results indicate the importance of NGS testing and its major role in the detection of rare mutations that may responsible for the onset of autoinflammatory disorders.