Congenital Midline Cervical Cleft: First Report and Genetic Analysis of Two Related Patients.

OBJECTIVES: Congenital midline cervical cleft (CMCC) is a rare congenital anterior neck anatomical anomaly. We present the case of two related patients (grandchild and maternal grandmother) who were both born with a congenital midline cervical cleft along with genetic analysis. METHODS: Clinical examination of both patients and surgical excision of the grandchild was performed. Genetic analysis with exome sequencing (ES) was conducted for both patients. RESULTS: Genetic analysis with exome sequencing (ES) revealed apparently novel single nucleotide variants in 66 genes present in both proband and grandmother. Five of these variants are predicted to cause frameshifting in the coding region of the respective genes and truncated proteins (OVGP1, TYW1B, ZAN, SSPO, FOLR3). Two of these genes (TYW1B and SSPO) have homozygous indel mutations in both patients. CONCLUSIONS: To our knowledge, this is the first case of two related patients with a congenital midline cervical cleft. The results of our genetic analysis reveal potential relevance to CMCC development.

A mutant MATR3 mouse model to explain multisystem proteinopathy.

Mutations in the Matrin 3 (MATR3) gene have been identified as a cause of amyotrophic lateral sclerosis (ALS) or vocal cord and pharyngeal weakness with distal myopathy (VCPDM). This study investigated the mechanism by which mutant MATR3 causes multisystem proteinopathy (MSP) including ALS and VCPDM. We first analyzed the muscle pathology of C57BL/6 mice injected with adeno-associated viruses expressing human WT or mutant (S85C) MATR3. We next generated transgenic mice that overexpress mutant (S85C) MATR3, driven by the CMV early enhancer/chicken ß-actin promoter, and evaluated their clinicopathological features. Intramuscular injection of viruses expressing WT and mutant MATR3 induced similar myogenic changes, including smaller myofibers with internal nuclei, and upregulated p62 and LC3-II. Mutant MATR3 transgenic mice showed decreased body weight and lower motor activity. Muscle histology demonstrated myopathic changes including fiber-size variation, internal nuclei and rimmed vacuoles. Spinal cord histology showed a reduced number of motor neurons, and activation of microglia and astrocytes. Comprehensive proteomic analyses of muscle demonstrated upregulation of proteins related to chaperones, stress response, protein degradation, and nuclear function. Overexpression of WT and mutant MATR3 similarly caused myotoxicity, recapitulating the clinicopathological features of MSP. These models will be helpful for analyzing MSP pathogenesis and for understanding the function of MATR3. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Effect of nucleic acid amplification testing on detection of extragenital gonorrhea and chlamydial infections in men who have sex with men sexually transmitted disease clinic patients.

BACKGROUND: In 2010, the Centers for Disease and Control and Prevention recommended using nucleic acid amplification tests (NAATs) for extragenital gonorrhea (GC) and chlamydia (CT) testing because of NAATs' improved sensitivity compared with culture. METHODS: In 2011, the Public Health-Seattle & King County Sexually Transmitted Disease Clinic introduced NAAT-based testing for extragenital GC and CT infection in men who have sex with men (MSM) using AptimaCombo2. We compared extragenital GC and CT test positivity and infection detection yields in the last year of culture-based testing (2010) to the first year of NAAT testing (2011). RESULTS: Test positivity of GC increased by 8% for rectal infections (9.0%-9.7%) and 12% for pharyngeal infections (5.8%-6.5%) from 2010 to 2011; CT test positivity increased 61% for rectal infections (7.4%-11.9%). Pharyngeal CT was identified in 2.3% of tested persons in 2011 (not tested in 2010). We calculated the ratio of extragenital cases per 100 urethral infections to adjust for a possible decline in GC/CT incidence in 2011; the GC rectal and pharyngeal ratios increased 77% and 66%, respectively, and the CT rectal ratio increased 127%. The proportion of infected persons with isolated extragenital infections (i.e., extragenital infections without urethral infection) increased from 43% in 2010 to 57% in 2011. CONCLUSIONS: Extragenital testing with NAAT substantially increases the number of infected MSM identified with GC or CT infection and should continue to be promoted.

Bilateral first branchial cleft anomaly with evidence of a genetic aetiology.

Anomalies of the first branchial cleft (FBC) are uncommon, and recognizing them can be difficult. Although present at birth, many cases do not become evident until later in childhood or adolescence, with an initial clinical presentation in adulthood being encountered only rarely. Typically, FBC anomalies present as a unilateral cyst, sinus, or fistula associated with the external auditory canal, or with swelling or an inflammatory opening in the peri-auricular/parotid area. They are commonly misdiagnosed and are often treated inadequately before being excised completely. A 40-year-old woman presented to the maxillofacial outpatient clinic with an episode of bilateral pre-auricular tumefaction, initially diagnosed as temporomandibular dysfunction syndrome. This was associated with bilateral pre-auricular pain that increased with mandibular movements. In relation to the patient's history, and given the bilateral presence of a pre-auricular pit, a diagnosis of FBC anomaly was made. Further investigation showed a related asymptomatic history in five other cases across four generations of the same family. The authors describe here the case, the diagnostic methodology, and the wide local excision technique used for removal of the branchial sinus.

[The role of cytokine gene polymorphisms in the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march in the children].

Interleukin 1-beta (IL-1b), its endogenous receptor antagonist (IL-1 Ra), and interleukin IL-4 have been shown to play a role in immunopathological processes, such as the development of hypertrophy of the tonsils of the lymphoid pharyngeal ring and atopic march. However, the influence of Il-1 and IL-4 gene polymorphisms as etiological factors of this pathology remains obscure. The objective of the present work was to study characteristics of gene polymorphisms of proinflammatory and proallergic cytokines depending on the degree of hypertrophy of the tonsils of the lymphoid pharyngeal ring (LPR) and atopic march to selected species of the opportunistic pathogenic biota. Polymorphisms of the following genes were investigated in the children, residents of the Kemerovo region, presenting with hypertrophic tonsils of LPR: IL-1b+3953 (C->T), IL4 (70 bp VNTR), and IL-1Ra (86 bp VNTR). IL-1b, IL-1Ra, and IL-4 genotypes were determined by PCR of autosomal DNAs obtained from 129 children presenting with hypertrophic tonsils and 41 healthy children with the use of conventional genetic-statistical methods. Odds ratios (ORs) were estimated by the logistic regression models for each locus and after adjusting polymorphisms for the neighbouring loci. The 2R, 2R, Il-1Ra and T, T IL-1b genotypes occurred more frequently in the patients with isolated adenoid vegetations (20.93% and 25.58% respectively) than in the healthy children (4.95%) (OR=3.78, p=0.049; OR=3.25, p=0.047). The results of this study indicate that IL-1b and IL-1Ra gene polymorphisms play a role in the development of clinically significant features in the lymphoid pharyngeal ring.

Gene expression in the oropharynx of children exposed to secondhand smoke.

OBJECTIVES/HYPOTHESIS: To compare gene expression in oropharyngeal mucosa of children with (ex+) and without (ex-) secondhand smoke exposure. STUDY DESIGN: Prospective case-control. METHODS: Forty-one age- and gender-matched children (2-6 years old) undergoing tonsillectomy for sleep disordered breathing at a tertiary care children's hospital were assessed for secondhand smoke exposure. Parental response to a validated questionnaire relating to secondhand smoke exposure governed inclusion. Sixteen samples were selected for microarray analysis (7 ex+, 9 ex-). Following tonsillectomy, ex vivo brushing of the mucosa isolated total RNA. Genome-wide expression profiles were generated by comparing sample RNA to a reference of all samples, assessing 27,323 cDNA clones. Microarray clones were ranked according to their ability to distinguish between the two groups using a Student t test. RESULTS: A total of 318 cDNA clones distinguished the two groups (P < .01); 180 genes were overexpressed and 138 underexpressed in ex+ samples relative to the ex- group. Independent analysis of these two groups sorted genes into disease processes and molecular functional groups, including cancer (34 genes in the overexpressed group, 29 underexpressed, P < .05), cell cycle (14 and 10), and cell growth and proliferation (7 and 11). Two of the upregulated genes, LCN2 and IQGAP1, have been previously linked to inflammation in smokers and response/repair to cellular injury in bronchial epithelium. CONCLUSIONS: Findings in this pilot study support the hypothesis that secondhand smoke exposure seems to induce gene expression changes in the oropharyngeal mucosa of exposed children, which may have significant implications for current and future disease processes.

Molecular pathways and genetic factors in the pathogenesis of laryngopharyngeal reflux.

The prevalence of laryngopharyngeal reflux (LPR) has been constantly rising in the western world and affects today an alarmingly high percentage of the general population. Even though LPR and gastroesophageal reflux disease (GERD) are both the product of gastroesophageal reflux and seem to be sibling disorders, they constitute largely different pathological entities. While GERD has been for a long time identified as a source of esophageal disease, LPR has only recently been associated with head and neck disorders. Despite the high incidence of LPR and its great impact on patients' quality of life, little is known regarding its pathogenesis. On the other hand, studying the molecular and genetic basis of a disease is of fundamental importance in medicine as it offers better insight into the pathogenesis and opens new, disease-specific therapeutic trends. The aim of this study is to enlighten any known or suspected molecular mechanisms that contribute to the pathogenesis of LPR, and to suggest new trends for future research.

[Intraductal breast papillomas in patients with Costello syndrome]. / Papilomas intraductales de mama en paciente afectada de síndrome de Costello.

Costello syndrome is a multisystemic congenital disorder with a very low prevalence. The pathogenesis remains unclear and predisposes to the development of tumors of ectodermal origin. Diagnosis is clinical, based on findings of mental and growth retardation and a characteristic phenotype. We report the case of a patient with Costello syndrome who was referred to our unit with a suspected diagnosis of intraductal papilloma based on the presence of various episodes of nipple discharge. Postoperative histopathological study confirmed the diagnosis of multiple intraductal papilloma. We review the literature on the topic and discuss the advisability of aggressive surgical therapy, given the predisposition of these patients to develop both benign and malignant tumors.

Oculopharyngeal muscular dystrophy and distal myopathy. Intrafamilial difference in the onset and distribution of muscular involvement.

A family is reported which included a patient with a variant form of oculopharyngeal muscular dystrophy. The patient's son suffered from infantile muscular dystrophy with a distal distribution in the lower extremities and no oculopharyngeal symptoms. Case 1, the father, showed blepharoptosis, but no limitation of ocular movements. Case 2, the son, showed early onset of weakness and more rapid progression of muscle involvement than the father. In both patients EMG, muscle biopsies and elevated serum CPK indicated the myopathic nature of the disorder. A muscle biopsy specimen in Case 2 showed abundant rimmed vacuoles and abnormal filaments 13-19 nm in diameter in the sarcoplasm, usually reported to occur in inclusion body myositis. The findings indicate that oculopharyngeal muscular dystrophy and distal myopathy are related in their etiology and distal myopathy and inclusion body myositis are regarded as variant forms of the same disease.