Mastocytosis in a Case of Noonan Syndrome Caused by a De Novo Pathogenic CBL Variant.

Noonan syndrome is an autosomal dominant disease characterized by multi-organ disorders caused by variants of genes involved in the RAS/MAPK signaling pathway. The nine causative genes including PTPN11 and CBL have been identified. Mastocytosis is a disease characterized by mast cell proliferation in skin, bone marrow, and other organs. To date, no previous cases of Noonan syndrome with mastocytosis caused by a pathogenic CBL variant have been reported. A boy was diagnosed with Noonan syndrome at 8 months of age with facial features and minor anomaly of his body. He presented with brown nodules of 5-10 mm on his body since the age of 2 months. The patient was diagnosed with mastocytosis by a biopsy specimen from brown nodules, which showed infiltration of mast cells. Whole-exome sequencing of the parent-patient trio revealed a de novo pathogenic CBL variant. The occurrence of mastocytosis may be a cue for the analysis of the CBL gene in Noonan syndrome. The CBL gene is involved in mastocytosis and various cancers. In the case of the pathogenic variant, long-term follow-up for the risk of cancers related to the CBL variant is necessary.

Clinical course of a Japanese patient with developmental delay linked to a small 6q16.1 deletion.

There is only one report of patients with developmental delay due to a 6q16.1 deletion that does not contain the SIM1 gene. A 3-year-old female showed strabismus, cleft soft palate, hypotonia at birth, and global developmental delay. Exome sequencing detected a de novo 6q16.1 deletion (chr6: 99282717-100062596) (hg19). The following genes were included in this region: POU3F2, FBXL4, FAXC, COQ3, PNISR, USP45, TSTD3, CCNC, and PRDM13.

Clinical course of epilepsy and white matter abnormality linked to a novel DYRK1A variant.

Epilepsy and white matter abnormality have been reported in DYRK1A-related intellectual disability syndrome; however, the clinical course has yet to be elucidated. Here, we report the clinical course of an 18-year-old male with a novel heterozygous DYRK1A variant (NM_001396.4: c.957C>G, p.Tyr319*); based on previous reports, epilepsy with this syndrome tends to be well controlled. Follow-up MRIs of the patient's lesion revealed slightly reduced signal intensity compared to the first image.

Duchenne muscular dystrophy-like phenotype in an LGMD2I patient with novel FKRP gene variants.

A 32-year-old man initially received a diagnosis of Duchenne muscular dystrophy (DMD). Genetic analysis revealed two novel heterozygous FKRP variants: c.169G>A (p.Glu57Lys) and c.692G>A (p.Trp231*). These results indicated that the patient had limb-girdle muscular dystrophy type 2I (LGMD2I) caused by recessive FKRP variants. Patients with LGMD2I and DMD have many overlapping phenotypes. LGMD2I should be considered in patients who have a DMD phenotype but not a DMD pathogenic variant.

Recurrent Erythema Nodosum in a Child with a SHOC2 Gene Mutation.

We report the case of a 6-year-old male who developed recurrent erythema nodosum (EN) at the age of 3 years. The patient exhibited hypertelorism, low-set ears, micrognathia, moderate intellectual disability, thin long fingers, loose anagen hair, and prominent palmoplantar wrinkles. A heterozygous single nucleotide variant in the SHOC2 gene (c.4 A > G, p.S2G) was identified. Patients with a SHOC2 mutation exhibit a unique combination of ectodermal abnormalities including darkly pigmented skin and loose anagen hair. This report is the first to describe EN in a patient with SHOC2 mutation, and to examine the patient's hair using scanning electron microscopy. We hypothesize that the RAS/MAPK pathway is associated with the pathogenesis of cutaneous lesions in patients with SHOC2 mutations via autoinflammation and disturbance of epithelial stem cells.

Clinical Diagnosis of Mendelian Disorders Using a Comprehensive Gene-Targeted Panel Test for Next-Generation Sequencing.

BACKGROUND: Genetic diagnoses provide beneficial information to patients and families. However, traditional genetic diagnoses are often difficult even for experienced clinicians and require recognition of characteristic patterns of signs or symptoms to guide targeted genetic testing for the confirmation of diagnoses. Next-generation sequencing (NGS) is a powerful genetic diagnostic tool. However, whole-genome and whole-exome sequencing (WES) are expensive, and the interpretation of results is difficult. Hence, target gene capture sequencing of gene panels has recently been applied to genetic diagnoses. Herein, we demonstrate that targeted sequencing approaches using gene panel testing are highly efficient for the diagnosis of Mendelian disorders. METHODS: NGS using TruSight one gene panel was performed in 17 families and 20 patients, and we developed a bioinformatic pipeline at our institution for detecting mutations. RESULTS: We detected causative mutations in 6 of 17 (35%) families. In particular, 11 (65%) families had syndromic diagnosis and 6 (35%) had no syndromic diagnosis before NGS testing. The number of positive diagnoses was 5 of 11 (45%) in the syndromic group and were 1 of 6 (17%) among patients of the no syndromic diagnosis group. CONCLUSION: Diagnostic yields in the present study were higher than in previous reports of genetic and chromosomal tests and WES. The present comprehensive gene-targeted panel test is a powerful diagnostic tool for Mendelian disorders.