The impact of thyroid imaging reporting and data system on the management of Bethesda III thyroid nodules.

Objectives: Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) is a heterogeneous category of fine needle aspiration cytology (FNAC); the management of this condition remains controversial. The clinical significance of such patients relies on the exclusion of malignancy. In this study, we aimed to determine the validity of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) (2017) for predicting malignancy in this specific category of patients. Methods: In this study, we analysed a cohort of patients from our previous retrospective study. This four-year retrospective cohort study included all cases undergoing surgery with a cytological diagnosis of AUS/FLUS. We enrolled 110 cases with documented final histopathological diagnoses and ultrasound examinations. Results: The study included 83 females (75.5%) and 27 males (24.5%). The overall risk of malignancy (ROM) for AUS/FLUS thyroid nodules was 47.3%. The ROMs of TI-RADS 3 (TR3), TI-RADS 4 (TR4), and TI-RADS 5 (TR5) were 43.5%, 49.4% and 40%, respectively. There was no significant association between TI-RADS and final pathological analysis. Conclusions: Repeated FNAC with initial AUS/FLUS nodules is crucial. Our findings showed that ACR TI-RADS did not contribute to the cancer risk stratification of AUS/FLUS nodules. A large prospective multi-institutional study is now required to determine the validity of ACR TI-RADS and whether other adjunct clinical, cytological, molecular, or biochemical tools could facilitate the management of patients with these heterogeneous nodules.

LGMD1D myopathy with cytoplasmic and nuclear inclusions in a Saudi family due to DNAJB6 mutation.

Autosomal dominant LGMD1D has been described in multiple families in Asia, Europe, and USA. However, to the best of our knowledge, no cases of LGMD1D have been reported among native Bedouin Saudi families. Fifty Saudi families with LGMD were analyzed and the causative underlying genes were studied utilizing genome wide linkage, homozygosity mapping, and neurological gene panel. We identified one family of a Bedouin origin with LGMD1D. Two patients had progressive proximal and distal weakness, dysphagia, and respiratory symptoms. Creatinine kinase was normal. Muscle biopsy showed marked variation in myofibers size with scattered angular atrophic fiber, necrotic fibers, and myophagocytosis, with red-rimmed vacuoles depicting a sarcoplasmic body. Heterozygous c.C287T (p.P96L) variant in exon 5 of DNAJB6 (NM_005494) gene was found. This change is localized within glycine and phenylalanine rich domain and alter an amino acid residue. Our findings will expand on the existing genotypic and phenotypic spectrum of this disorder and aid in elucidating hidden mechanisms implicated in LGMD1D.

Uncommon TERT Promoter Mutations in Pediatric Thyroid Cancer.

PURPOSE: The aim of this study was to determine the rate and significance of TERT promoter mutations that have been recently described in adult thyroid cancer (TC) but not yet in the uncommonly occurring pediatric TC. Furthermore, the role of the BRAF(V600E) mutation in the clinical outcome of pediatric TC is unknown. METHOD: The study included 55 pediatric (median age 16 years, range 9-18 years; 46 females) and 210 adult TC patients (median age 40 years, range 20-75 years; 155 females) seen during the same time period. DNA was isolated from TC tissues and subjected to direct sequencing. Genetic-clinicopathological correlations were analyzed. RESULTS: Only one case of pediatric TC was found to harbor the C228T TERT promoter mutation (1.8%). The C250T mutation was not detected in any of the 55 pediatric TC. In contrast, there was a significantly higher rate of TERT promoter mutations in the adult patients (15.7%, 33/210) compared with the pediatric patients (p = 0.003). In addition, persistent/recurrent TC was seen in 8/12 (66.7%) pediatric patients harboring the BRAF(V600E) mutation versus 14/41 (34.1%) patients harboring the wild type BRAF (p = 0.05), and when only conventional papillary TC was examined, in 7/9 (77.8%) cases harboring BRAF(V600E) mutation versus 11/33 (33.3%) cases harboring wild type BRAF (p = 0.025). CONCLUSIONS: This is the first study on TERT promoter mutations in pediatric TC, which revealed an exceedingly low prevalence, suggesting a limited role of these mutations in pediatric TC. This study also for the first time demonstrates an association of the BRAF(V600E) mutation with TC recurrence in pediatric patients.

Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome.

Congenital disorders of glycosylation are often associated with muscle weakness in apparent isolation or as part of a multi-systemic disorder. We report here the clinical and pathological features resulting from a homozygous mutation of ALG2 in an extended family. Phenotypic heterogeneity is observed among the small cohort of patients reported to date and is highlighted by our study. Linkage analysis, homozygozity mapping and whole exome sequencing followed clinical and pathological characterization of patients who presented with a congenital limb girdle pattern of weakness with no ocular or bulbar involvement. Nerve stimulation studies were consistent with a congenital myasthenic syndrome. Severity and progression of disease was variable. Muscle biopsies showed myopathic features, ragged red fibers and a sub-sarcolemmal accumulation of structurally normal mitochondria. Whole exome sequencing revealed an indel mutation c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR in exon 1 of ALG2. Mutation of ALG2 manifested as a limb girdle pattern of muscle weakness with defects at both the neuromuscular junction and sarcomere. In addition the accumulation and distribution of mitochondria in the diseased muscle and the presence of ragged red fibers were supportive of a mitochondrial myopathy. ALG2 mutation results in a heterogeneous phenotype and care should be taken in categorization and treatment of these patients.

Juvenile hyaline fibromatosis: morphologic, immunohistochemical, and ultrastructural study of three siblings.

Juvenile hyaline fibromatosis (JHF) is a rare hereditary disease characterized by the deposition of hyaline ground substance, which is described as fibrillogranular material on electron microscopy. Approximately 65 cases have been reported to date in the English language literature. We add 3 new cases of children presenting with multiple subcutaneous nodules. We have described the light microscopic, electron microscopic, and immunohistochemical features of these nodules. The characteristic chondroid appearance on light microscopy is imparted by large peripheral vesicles in the stromal cell cytoplasm. Ultrastructurally, the fibroblasts have shown evidence of defective synthesis of collagen, which is then deposited as fibrillogranular material in the matrix. Immunohistochemical studies have shown CD68+ macrophages and multinucleated histiocytic giant cells in all five specimens from our 3 cases. As far as we know, the presence of giant cells has not been reported in the literature. The main purposes of this report are to highlight the presence of macrophages as a constant constituent of the stromal cells in JHF and to review the literature on this subject.