STK11 Causative Variants and Copy Number Variations Identified in Thai Patients With Peutz-Jeghers Syndrome.

Introduction Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder caused by germline mutations in the serine-threonine kinase 11 (STK11) tumor suppressor gene. This syndrome is characterized by hamartomatous gastrointestinal polyps, mucocutaneous melanin pigmentation, and a higher risk of developing various cancers. Methods We summarized the clinical and molecular characteristics of five unrelated Thai patients with PJS. Denaturing high-performance liquid chromatography (DHPLC) screening, coupled with direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), were applied for the molecular analysis of STK11. Results A total of four STK11 pathogenic changeswere identified in the five PJS patients, including two frameshift variants (a novel c.199dup, p.Leu67ProfsTer96 and a known c.834_835del, p.Cys278TrpfsTer6) and two types of copy number variations (CNV), exon 1 deletion and exons 2-3 deletion. Among reported STK11 exonic deletions, exon 1 and exons 2-3 deletions were found to be the two most commonly deleted exons. Conclusion All identified STK11 mutations were null mutations that were associated with more severe PJS phenotypes and cancers. This study broadens the phenotypic and mutational spectrum of STK11 in PJS.

Neuronal Ceroid Lipofuscinoses Presenting as Rett-like Phenotype: A Two-Case Report From Thailand.

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) (hereafter described as CLN disease) comprise a rare and life-limiting set of genetically inherited neurodegenerative disorders that are characterized by abnormal lysosomal storage. The NCL disorders are, collectively, the most common group of degenerative brain disorders in children. PATIENT DESCRIPTIONS: We report two cases of CLN disease that were diagnosed and treated at the Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Both cases of CLN disease (CLN1 and CLN6 diagnosed in 2016 and 2017, respectively) profiled in this report presented with clinical features of Rett syndrome. In the first case, a 2-year-old girl presented with Rett-like clinical features, including global developmental regression and hand-wringing action. Single-gene analysis of the MECP2 gene was negative. However, PPT1 gene sequencing revealed a novel homozygous frameshift mutation, c.629_630dupGT (p.Ile211Valfs∗10). In the second case, a 7.5-year-old girl presented with ataxia, progressive myoclonic epilepsy, and Rett-like hand-wringing. A c.794_796delCCT variant in the CLN6 gene was identified by whole-exome sequencing. Fingerprint bodies from electron microscopy of the skin also supported a diagnosis of CLN disease in our second case. DISCUSSION: Presentation with clinical features of Rett syndrome has only been reported in patients diagnosed with CLN1 and CLN7 disease, and never in those with CLN6. CONCLUSIONS: Physicians should suspect and investigate for CLN disease in patients with Rett-like phenotype who are negative for MECP2 mutation, especially in patients with visual impairment and early prominent brain atrophy.

Skewed X chromosome inactivation in girls and female adolescents with autoimmune thyroid disease.

OBJECTIVE: Skewed X chromosome inactivation (XCI) was associated with female predominance in adult autoimmune thyroid disease (ATD). In normal females, skewed XCI is increased with age. Whether early-onset skewed XCI is associated with childhood ATD remains unknown. This study aimed to determine XCI skewing in paediatric ATD. DESIGN, PATIENTS AND MEASUREMENTS: Ninety-one female ATD patients, aged 3-20 years and 57 age-matched, female controls were enrolled. XCI was analysed by enzymatic digestion of DNA with methylation-sensitive enzymes followed by PCR of the polymorphic CAG repeat in the androgen receptor gene. Skewed XCI was defined as having 80% or greater of the cells preferentially inactivated on the same X chromosome. XCI pattern of the enrolled patients and parental origin of the skewed XCI were determined. RESULTS: After exclusion of samples with homozygous CAG repeats, skewed XCI was analysed in 83 patients (57 Graves' disease and 26 Hashimoto thyroiditis) and 52 controls. There was an increased frequency of skewed XCI in ATD patients as compared with the controls (23% vs 8%, P = 0.022). Patients with Hashimoto thyroiditis had greater frequency of skewed XCI than patients with Graves' disease (38% vs 16%, P = 0.023). There were no differences in clinical parameters between patients with skewed and random XCI. Analysis of 7 patients with skewed XCI showed a preferential inactivation of paternal X chromosome in 6 patients (86%). CONCLUSIONS: Frequency of skewed XCI was increased in childhood ATD. This observation suggests a possible association of skewed XCI in the development of paediatric ATD.