Smoking and alcohol consumption with the risk of 11 common otolaryngological diseases: a bidirectional Mendelian randomization.

PURPOSE: In this study, a bidirectional mendelian randomization was applied to evaluate the association of smoking and alcohol consumption with 11 otolaryngological diseases. METHODS: A total of 85,22,34 and 7 single nucleotide polymorphisms were used as instrumental variables for smoking initiation, cigarettes per day, alcoholic drinks per week and alcohol consumption, respectively. Genetic associations with 11 common otolaryngological diseases were obtained from the UK Biobank and FinnGen dataset. IVW, weighted median, MR-Egger, MR-PRESSO and leave-one-out method were used in this analysis. RESULTS: Smoking initiation increased the risk of vocal cord and larynx diseases (OR 1.002; 95% CI 1.001-1.004; P = 4 × 10-4), head and neck cancer (OR 1.001; 95% CI 0.999-1.003; P = 0.027), thyroid cancer (OR 1.538; 95% CI 1.006-2.351; P = 0.047) and sleep apnoea (OR 1.286; 95% CI 1.099-1.506; P = 0.002). Cigarettes per day was associated with chronic sinusitis (OR 1.152; 95% CI 1.002-1.324; P = 0.046), chronic rhinitis and pharyngitis (OR 1.200; 95% CI 1.033-1.393; P = 0.017), vocal cord and larynx diseases (OR 1.001; 95% CI 0.999-1.002; P = 0.021) and head and neck cancer (OR 1.001; 95% CI 0.999-1.003; P = 0.017). Alcoholic drinks per week only was significantly associated with the risk of head and neck cancer (OR 1.003; 95% CI 1.001-1.006; P = 0.014). However, there was no evidence to support that genetically predicted alcohol consumption increased the risk of otolaryngological diseases. Reverse MR also did not find outcomes effect on exposures. CONCLUSION: This study shows that smoking and heavy alcohol consumption promote the occurrence of some otolaryngological diseases indicating that lifestyle modification might be beneficial in preventing otolaryngological diseases.

Differential clinicopathologic features of EGPA-associated neuropathy with and without ANCA.

OBJECTIVE: To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs). METHODS: We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients. RESULTS: Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, p < 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p < 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p < 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels (p < 0.01) and epineurial vessels occluded by intraluminal eosinophils (p < 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group (p < 0.01). CONCLUSIONS: This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms: ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients.

Otolaryngologic manifestations of Noonan syndrome.

Noonan syndrome is an autosomal dominant disorder with associated anomalies that include short stature, congenital heart defects, developmental delay, and characteristic facial features among other abnormalities. Articulation deficiency and language delay are often present and require speech therapy. Otitis media and hearing loss have been reported to be common in these patients. We performed a retrospective chart review of pediatric patients who were diagnosed with Noonan syndrome at our tertiary care center from January 1979 through December 2009. We found 19 such patients. Of these, 8 had received single-specialty care at our hospital; it is not known if they had received otolaryngologic care from an outside provider. These 8 patients were not included in our study. The remaining 11 patients-6 boys and 5 girls, aged 1 to 19 years (mean: 9.2)-had all received multidisciplinary care at our institution; 9 of them had received care from an otolaryngologist at our center. Of this group, 7 had history of feeding difficulty, 6 had experienced speech delay that required speech therapy, 6 had undergone placement of a pressure equalization tube, 4 had undergone adenoidectomy with or without tonsillectomy, and 1 had been treated with endoscopic sinus surgery. Although this study is limited by our small number of patients, our results suggest that early otolaryngologist involvement must be considered in the care of children with Noonan syndrome because many have evidence of eustachian tube dysfunction, hearing loss, and speech delay.

Expressions and roles of periostin in otolaryngological diseases.

Periostin is a 90-kDa member of the fasciclin-containing family; it functions as part of matricellular proteins, and its production by airway epithelial cells is induced by IL-4 and IL-13. Periostin is secreted by fibroblasts and upregulated in the airway epithelia of patients with bronchial asthma; it is considered to contribute to remodeling under this pathological condition. However, despite many studies in diverse research areas, our overall understanding of this intriguing molecule is still inadequate. Here, we integrate the available evidence on periostin expression and its roles in otolaryngological diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, aspirin-induced asthma, organized hematoma, eosinophilic otitis media, and IgG4-related disease. Periostin might be involved as an important structural mediator in pathological processes such as insult and injury, Th2-driven inflammation, extracellular matrix restructuring, fibrosclerosis, tumor angiogenesis, and tissue remodeling.

The otolaryngologic manifestations of Sotos syndrome.

OBJECTIVE: Soto's syndrome is a genetic disorder caused by mutations in the NSD1 gene. It is characterized by excessive growth in early life. It features craniofacial abnormalities, developmental delay, hypotonia and advanced bone age. A review of the current literature reveals only chronic otitis media and conductive hearing loss as otolaryngologic manifestations of Soto's syndrome. Our objective was to determine if there are additional manifestations relevant to the otolaryngologist. METHODS: We performed a retrospective case series in which the Department of Defense electronic medical record was searched for ICD 9 code 253.0 (acromegaly/gigantism). Records were reviewed for genetic testing indicative of Soto's syndrome. These records were further analyzed for evidence of otolaryngologic problems. RESULTS: Seventeen patients were identified with five having confirmed NSD1 mutations consistent with Soto's syndrome. Of these, 4/5 had otolaryngologic problems such as conductive hearing loss, aspiration, laryngomalacia, obstructive sleep apnea and sensorineural hearing loss. CONCLUSIONS: Currently there is no description in the literature of these additional manifestations of Soto's syndrome. We present this case series to support the idea that an otolaryngologist should be involved in the multidisciplinary care required for these patients.

Head and neck manifestations of 22q11.2 deletion syndromes.

The allelic loss of 22q11.2 results in various developmental failures of pharyngeal pouch derivatives ("22q11.2 deletion syndromes", 22q.11DS), consequently affecting the anatomy and physiology of head and neck (H&N) organs. The objective of this paper was to describe those manifestations. Two 22q11.2DS patients with H&N manifestations were studied along with a comprehensive review of the English literature, from 1975 to 2010 regarding the associated H&N malformations among 22q11.2DS. A 24-year-old mentally disabled 22q11.2DS male presented with right hemithyroid enlargement, causing significant compressive signs. Sonography revealed a homogeneous 8 × 3 cm lesion, replacing almost the entire thyroid lobe. Fine needle aspiration revealed colloid material and abundant eosinophils. The hemithyroidectomy specimen confirmed follicular adenoma. A 19-year-old mentally disabled 22q11.2DS female underwent CT-angiography due to an upper GI bleeding. The study revealed a vascular malformation in the infratemporal fossa. Reviewing the reported data regarding 22q11.2DS-associated H&N malformations revealed abnormalities and malfunctions of the thyroid gland, parathyroid glands, thymus agenesis, cleft palate, carotid artery aberrations, malformations of the larynx and trachea and esophageal dysmotility. 22q11.DS patients may present with H&N anatomical abnormalities, along with hormonal dysfunctions, which require special awareness once treatment is offered, especially when concerning anesthetic and surgical aspects. In addition, hSNF5/INI1, a tumor suppressor gene, detected at location 22q11.2 was described to be "knocked out" in some patients. This may be associated with H&N tumors reported in these patients.

Genetic basis of conditions commonly seen in ORL practice.

As science continues to unravel the genetic basis of disease, an understanding of genetics has become increasingly critical to the practicing clinician. Otorhinolaryngology, a comprehensive specialty in which the physician is responsible for delivering both medical and surgical care within their scope of practice, requires the practitioner to have a fund of knowledge in genetics to effectively communicate and counsel patients. This introductory chapter highlights what is known about the complexity of the human genome and various applications of genetics throughout the field of otorhinolaryngology to be discussed in subsequent chapters. These entities include the genetics of hearing impairment, skull base tumors, molecular genetics in head and neck cancer and systemic diseases with otolaryngologic features.

Basic medical genetics for the otolaryngologist.

Medical genetics is becoming an increasingly important part of the practice of medicine across every medical specialty. For otolaryngologists, understanding the genetic basis of hearing loss, tumors of the head and neck and other otolaryngologic conditions is crucial to effectively incorporating medical genetics information, tools and services into patient care. A clinician who understands the genetic basis of disease, mechanisms of genetic mutation and patterns of inheritance will be positioned to diagnose genetic conditions, interpret genetic test results, assess genetic risks for relatives of patients and refer patients and families for medical genetics and other specialty care. The family medical history is an indispensible tool that, when used properly, can aid in the recognition of genetic susceptibilities within a family and offer opportunities for early intervention. However, obtaining a family medical history is not as simple as it might seem. Knowing what questions to ask, how to properly draw a pedigree and how to recognize patterns of inheritance are critical to obtaining an informative family medical history and using the information in a clinical setting. This article provides a brief introduction to basic medical genetics that includes descriptions of the human genome, the genetic basis of human disease and patterns of inheritance, and a primer for collecting family medical history information.

Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterised by the development of multiple nervous system tumours, ocular abnormalities, and skin tumours. Although classically considered a disease of adults, initial signs and/or symptoms may be evident in childhood and are often unrecognised. OBJECTIVES: The aim of this study was to identify the earliest clinical presentations of NF2 and to characterise the clinical course and outcome in children with NF2. METHODS: We have performed a retrospective (years 1990-1998) and prospective (years 1998-2004) study of 24 patients (10 males, 14 females; currently aged 4 to 22 years) fulfilling the revised (Manchester) NF2 criteria seen at the Universities of Catania and Rome, Italy. RESULTS: Causes of referral prior to a definitive diagnosis of NF2 were: 1) Ophthalmologic problems: early onset lens opacities (n = 3); strabismus (n = 3) and amblyopia (n = 3) (due to underlying cranial nerves and/or brain tumours); 2) Otolaryngology problems: hearing loss and tinnitus (n = 2) in early teens disregarded or treated as ear infections; hoarse (n = 1) or bitonal (n = 1) voice; 3) Neurological dysfunction: seizures secondary to intracranial meningioma (n = 1) or vestibular schwannomas (VS) (n = 1), neurological dysfunction related to brainstem and/or spinal cord tumours (n = 7), isolated and multiple cranial nerve deficits (n = 10), and peripheral neuropathy secondary to schwannomas (n = 4); 4) Skin manifestations: schwannomas misdiagnosed as neurofibromas because of associated café-au-lait spots (n = 2); café-au-lait spots (n = 8) and skin tumours (n = 3). A family history was relevant in 20 % of the patients. Molecular genetic analysis of the NF2 gene revealed typical truncating mutations in all the 5 familial cases and in 2/10 sporadic cases analysed. CONCLUSIONS: Children with NF2 often first come to medical attention because of ocular, subtle skin, or neurological problems the significance of which is realised when they later present with more classical symptoms due to bilateral VS or other intracranial tumours. The clinical course at this young age is highly variable, depending on tumour burden, early surgical intervention, surgical outcome after tumour resection, and complications.

[Anomalies of the skull in cleidocranial dysplasia]. / Schädelanomalien bei Dysostosis cleidocranialis. Eine HNO-ärztliche und kraniofaziale Röntgenstudie.

BACKGROUND: The description of the otorhinolaryngeal and craniofacial anomalies in patients with cleidocranial dysplasia. METHODS: For this study, 26 patients with cleidocranial dysplasia were examined after their medical history had been recorded. The main focus was placed on otorhinolaryngological and orthodontic findings. RESULTS: The portion of spontaneous mutations in our patient population was 46.1%. All patients exhibited otorhinolaryngological and craniofacial anomalies. While single ENT-anomalies were expressed in 76.9%-92.3% of the patients, the craniofacial findings were distributed over 84.6%-92.3%. CONCLUSION: The expression of this rare disorder is variable and its symptomatology not always distinct. Otorhinolaryngological and craniofacial anomalies are often apparent. Appropriate treatment can significantly contribute to an improvement in the patient's quality of life. In cases of ambiguous findings, we recommend consultation with an experienced clinician as well as genetic counselling.

[Clinical implications of molecular genetic research in otorhinolaryngology]. / Molekulargenetische Aspekte in der Otorhinolaryngologie.

Molecular-genetic research in Otolaryngology has seen a rapid advancement during the last ten years, especially in the fields of otology and head and neck tumors. The results of this basic research have now started to be implemented in the clinic. In otology the understanding of auditive function has dramatically improved. The syndromic and non-syndromic forms of hereditary hearing impairment can be subdivided into their underlying genetic defects, as more and more genes are identified. Diagnostic of syndromic hearing loss has been improved and can be done earlier. But the molecular-genetic analysis is still time-consuming and difficult. Currently, in our clinic, only patients with suspected Pendred-syndrome, representing the most frequent syndrome with hearing impairment, undergo a routine search for mutation detection in the corresponding gene SLC26A4. A multitude of genes and mutations are seen in the non-syndromic forms of hereditary hearing impairment. The gene gap-junction-protein beta2, encoding connexin 26, is encountered most frequently. Its prevalence in Switzerland is high with about 20% in the non-syndromic group. A molecular-genetic analysis of connexin 26 is offered in cases of congenital hearing loss. Another analysis, which has been implemented in the clinic, is the sequencing of Wolfram-syndrome gene 1 in familial low-frequency hearing loss. This gene seems to be involved in the majority of families with this type of hearing loss. Gene therapy for hearing loss is currently not an option in the clinical field. The different steps in carcinogenesis of head and neck cancer have further been elucidated by molecular-genetic research. Clinical applications are the establishment of risk-profiles for tumor-development and defining prognostic markers as well as the development of new treatment strategies based on genetic therapy.

Otolaryngologic manifestations of the 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 chromosome deletion syndrome occurs at a frequency of 1 in 4000 live births. Fluorescent in situ hybridization is a reliable means of testing for this genetic abnormality. OBJECTIVE: To describe the otolaryngologic manifestations of the 22q11.2 deletion syndrome to improve recognition and management of these disorders. PATIENTS AND DESIGN: A retrospective medical record review of 102 patients with chromosome 22q 11.2 deletions confirmed by fluorescent in situ hybridization. SETTING: A multidisciplinary 22q11.2 deletion clinic at an academic children's hospital. OUTCOME MEASURE: All otolaryngologic problems were recorded, including facial dysmorphic features, velopharyngeal insufficiency, speech and airway abnormalities, feeding difficulties, gastroesophageal reflux, hearing loss, otitis media, sinus problems, and vascular anomalies. Additionally, available objective test results were recorded, including those from audiograms, imaging studies, endoscopies, speech evaluations, and vascular studies. RESULTS: Dysmorphic facial features were found in most patients. Velopharyngeal incompetence was noted in 76 patients, while overt submucosal clefts were found in 11 patients. Most patients had speech and language delays. In addition, 53 patients had chronic or recurrent otitis media, and 28 had recurrent sinorhinitis. Furthermore, feeding problems were found in 48 patients, while vascular anomalies of the head and neck were found in 16 patients. CONCLUSION: Otolaryngologic abnormalities are relatively common and important to recognize with the 22q11.2 deletion syndrome.

Gene expression: a review of clinical applications in otorhinolaryngology-head and neck surgery.

Tissue engineering is a multidisciplinary area of research aimed at regeneration of tissues and restoration of function of organs through implantation of cells/tissues grown outside the body or stimulating cells to grow into implanted matrix. In this short review, we aim to examine current techniques in gene expression analysis and their relevant clinical applications to the field of otorhinolaryngology-head and neck surgery.

Otolaryngological manifestations of velocardiofacial syndrome: a retrospective review of 35 patients.

OBJECTIVE: Because many patients with velocardiofacial syndrome (VCFS) are first examined by otolaryngologists for ear or speech problems before being diagnosed with VCFS, we describe a series of patients with this genetic disorder, which is associated with multiple anomalies, including velopharyngeal insufficiency, cardiac defects, characteristic facial features, and learning disabilities. STUDY DESIGN: We retrospectively analyzed the medical charts and available nasoendoscopic observations for 35 patients who were diagnosed with VCFS and who had a microscopic deletion in chromosome 22q11 as shown by DNA probe and fluorescence in situ hybridization. RESULTS: For most patients, the medical chart documented cardiac anomalies, velopharyngeal insufficiency with hypernasal speech, and characteristic facial features including nasal, auricular, craniofacial, and ocular abnormalities. Incidence of middle ear infection with associated conductive hearing loss was also high and necessitated early placement of pressure equalization tubes. Some patients were treated with adenoidectomy for chronic otitis media; consequently, velopharyngeal insufficiency and hypernasal speech worsened. Nasoendoscopic examination as documented in the medical chart showed occult cleft palate, a small adenoid pad, and pulsation in the muscular wall. CONCLUSION: Otolaryngologists have an important role in diagnosis and treatment of persons with VCFS and therefore should familiarize themselves with the typical history and most frequent head and neck manifestations of this syndrome.

Life and death in otolaryngology: mechanisms of apoptosis and its role in the pathology and treatment of disease.

OBJECTIVES: To review recent advances in our understanding of programmed cell death, or apoptosis, and discuss implications of these basic science advances in our understanding of causes and potential treatments of a variety of diseases of the head and neck. DATA SOURCES: Basic science literature relevant to the study of apoptosis and its clinical implications. CONCLUSIONS: Apoptosis is now understood to be important in the normal development and survival of all multicellular organisms. Deregulation of this normally tightly controlled process underlies a variety of disease states, including neoplasia, autoimmune disease, and disorders of the central nervous system. A better understanding of this process and its regulation may help otolaryngologists better understand diseases relevant to this specialty and will lead to improved therapeutic interventions.

[Manifestation of tuberous sclerosis in the ENT area]. / Manifestation einer tuberösen Sklerose im HNO-Bereich.

Tuberous sclerosis (Bourneville-Pringle's disease) is a rare, largely autosomal dominant neurocutaneous disease. The disease can also result from spontaneous mutations. Although strongly variable in its manifestation, manifestations are typically characterized by involvement of the central nervous system (early childhood seizures), skin (facial angiofibromas) and kidneys (angiomyolipomas). In the case described, a 67-year-old female patient complained exclusively of obstructed nasal breathing that was found to be due to angiofibromas in the nasal vestibule. Oral fibromas were asymptomatic, while fibromas in the facial region resulted in some cosmetic changes. This exclusively ENT manifestation of a patient with tuberous sclerosis has not been described previously. As treatment, the fibromas were ablated by an Nd:YAG laser under local anesthesia. Other therapeutic options are described. Additional clarification of all organ manifestations is advisable in view of numerous possible pathologies present. Genetic consultation is also recommended, particularly for patients with an oligosymptomatic variant.

[Manifestation of Urbach-Wiethe syndrome in the ENT area]. / Zur Manifestation des Urbach-Wiethe-Syndroms im HNO-Bereich.

Urbach-Wiethe's syndrome (hyalinosis cutis et mucosae) is a rare genetic defect of probably autosomal recessive origin. The exact nature concerning the pathogenesis of this disorder is still controversial. A characteristic symptom in early childhood might bei hoarseness, later on manifestations with hyalin deposits in the larynx, oral cavity and oropharynx might occur as well as yellowish-white papular deposits in the skin. The overall prognosis of this disease is good, therapeutic intervention might be necessary for functional purposes (narrowing of the laryngeal lumen) and consists of surgical removal of the lesions.

[Hyalinosis cutis et mucosae of the ear-nose-throat]. / Hyalinosis cutis et mucosae im Hals-Nasen-Ohren-Bereich.

Hyalinosis cutis et mucosae (HCM) is a rare autosomal recessive disease of unknown aetiology and pathogenesis. In the skin and mucous membranes there is characteristically a deposition of hyaline-like material in the papillary dermis, around the small blood vessels and around skin appendages. Besides the manifold skin lesions, the mucous membranes affected are found in the nasal and oral cavities, pharynx and larynx. The latter causes the most characteristic symptom, namely, hoarseness, from birth. The lesions of the vessel walls are the most significant histopathological alterations. Ultrastructurally, massive deposits of amorphous, hyaline-like material in the dermis, reduction in number and size of the collagen fibrils and, finally, thickening of the basal laminae could be observed. The findings suggest an abnormal production of noncollagenous proteins as well as the alteration of the lysosomal systems of fibroblasts, endothelial cells and pericytes in the pathogenesis of hyalinosis.