Limb-body wall complex: Literature review and case report.

INTRODUCTION: Body wall anomalies comprise a wide range of malformations. Limb-Body wall complex (LBWC) represents the most severe presentation of this group, with life threatening malformations in practically all the cases, including craniofacial, body wall defects, and limb anomalies. There is no consensus about its etiology and folding and gastrulation defects have been involved. Also, impaired angiogenesis has been proposed as a causative process. CASE REPORT: We present the case of a masculine stillborn, product of the first pregnancy in a 15-year-old, apparently healthy mother. He was delivered at 31 weeks of gestation due to an early rupture of membranes. He presented with multiple malformations including a wide body wall defect with multiple organ herniation and meromelia of the lower right limb. DISCUSSION AND CONCLUSIONS: LBWC represents a severe and invariably fatal pathology. There are no described risk factors, nevertheless, this case presented in a teenage mother, a well-described risk factor for other body wall anomalies. Its diagnosis allows us to discriminate between other pathologies that require prenatal or postnatal specialized treatment.

Monodactyly in a patient with CHARGE syndrome: An additional case report.

CHARGE syndrome is a rare autosomal dominant syndrome characterized by multiple congenital anomalies including coloboma, heart defects, ear anomalies, and developmental delay, caused by pathogenic variants in the CHD7 gene. The discovery of the molecular basis of this syndrome increased the number of cases reported and expanded the phenotype and clinical variability. Limb anomalies are occasional clinical findings in this syndrome, present in about 30% of reported cases. The occurrence of limb anomalies in this syndrome suggests that it should be considered as part of the phenotypic spectrum. Here, we describe an individual with CHARGE syndrome presenting unilateral monodactyly.

Severe Adams-Oliver Syndrome after Maternal COVID-19 Infection Could Be Another Effect of the SARS-CoV-2 Inflammatory Storm? Case Report.

Background. Adams-Oliver syndrome is a congenital disease whose main findings are aplasia cutis congenita of the scalp and terminal transverse limb defects. The pathogenesis is unknown, but it is postulated that ischemic events in susceptible tissues cause the lesions in the embryonic period.Case report. We present a newborn with a severe phenotype of Adams-Oliver syndrome. The infant's mother had a SARS-CoV-2 infection in the first trimester of pregnancy. Prenatal ultrasound indicates a probable worsening of the disease after the first trimester.Conclusion. This study shows a previously unpublished severe AOS phenotype in a term newborn. There are some signs that the disease could have progressed beyond the first trimester, either spontaneously or by the inflammatory mechanisms of SARS-CoV-2.

Hipocondroplasia en pediatría: reporte de un caso / Hypocondroplasya in pediatrics: case study / Hipocondroplasia em pediatia: relato de caso

La hipocondroplasia es una displasia esquelética caracterizada por baja estatura, constitución robusta, brazos y piernas desproporcionadamente cortos, manos y pies anchos y cortos, leve laxitud articular y macrocefalia. Los niños generalmente se presentan como pequeños, con velocidad de crecimiento disminuida, que conduce a una baja estatura y desproporción de las extremidades. La hipocondroplasia en la mayoría de los casos se hereda con carácter autosómico dominante, aunque se detectan numerosos casos esporádicos. El diagnóstico requiere una exhaustiva anamnesis y adecuada exploración física. Es importante valorar algunos indicadores de crecimiento como: peso para la edad, longitud/talla para la edad, relación entre peso y longitud/talla, velocidad de crecimiento, talla diana genética, medidas de segmentos corporales, entre otros. Las radiografías esqueléticas permiten diagnosticar la mayoría de las displasias óseas. Los estudios moleculares suelen ser la prueba de confirmación y se solicitan ante una sospecha diagnóstica. Es importante incluir las displasias óseas en el diagnóstico diferencial de la talla baja y tenerlas en cuenta ante cualquier caso de talla baja disarmónica con alteraciones fenotípicas. La hipocondroplasia en la actualidad, no es una indicación aprobada para tratamiento con hormona del crecimiento. Se presenta un caso clínico de una niña de 14 meses, con talla baja severa, desproporcionada, que presentó dificultades para llegar al diagnóstico definitivo de hipocondroplasia.

Hypochondroplasia is a skeletal dysplasia characterized by short height, robust build, disproportionately short arms and legs, short and broad hands and feet, mild joint laxity, and macrocephaly. Children generally show slow growth rate, which leads to short stature and limb disproportion. Hypochondroplasia is mostly inherited with an autosomal dominant character, although many sporadic cases have been detected. Diagnosis requires a thorough history and adequate physical examination. It is important to assess some growth indicators such as: weight for age, length/height for age, relationship between weight and length/height, growth speed, genetic target height, measurements of body segments, among others. Skeletal XRs can diagnose most bone dysplasias. Molecular studies are usually the confirmatory test and are requested when a diagnosis is suspected. It is important to include bone dysplasias in the differential diagnosis of short stature and to take them into account for any disharmonious short stature with phenotypic alterations. Hypochondroplasia is currently not an approved indication for growth hormone therapy. We present a clinical case of a 14-month-old girl, with a severe, disproportionate short stature, who presented difficulties in her definitive hypochondroplasia diagnosis.

A hipocondroplasia é uma displasia esquelética caracterizada por baixa estatura, constituição robusta, braços e pernas desproporcionalmente curtos, mãos e pés largos e curtos, frouxidão articular leve e macrocefalia. As crianças geralmente são pequenas, com diminuição da velocidade de crescimento, o que leva à baixa estatura e desproporção dos membros. A hipocondroplasia na maioria dos casos é herdada com caráter autossômico dominante, embora sejam detectados numerosos casos esporádicos. O diagnóstico requer uma história completa e um exame físico adequado. É importante avaliar alguns indicadores de crescimento como: peso para idade, comprimento/altura para idade, relação entre peso e comprimento/altura, taxa de crescimento, estatura alvo genético, medidas de segmentos corporais, entre outros. As radiografias esqueléticas permitem o diagnóstico da maioria das displasias ósseas. Os estudos moleculares são geralmente o teste de confirmação e são solicitados quando há suspeita de diagnóstico. É importante incluir as displasias ósseas no diagnóstico diferencial da baixa estatura e considerá-las em qualquer caso de baixa estatura desarmônica com alterações fenotípicas. A hipocondroplasia não é atualmente uma indicação aprovada para o tratamento com hormônio de crescimento. Apresenta-se o caso clínico de uma menina de 14 meses, com baixa estatura grave e desproporcional, que apresentou dificuldades em chegar ao diagnóstico definitivo de hipocondroplasia.

Intrafamilial phenotypic variability in autosomal recessive DOCK6-related Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is diagnosed in presence of aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). The autosomal recessive (AR) DOCK6-related form of AOS is most often associated with a severe phenotype including also central nervous system and ocular abnormalities. We report a sister and brother with different expression of the phenotype. Both were compound heterozygous pathogenic variants in the DOCK6 gene, including a heterozygous c.5939+2T > C intronic variant that was maternally inherited, and a heterozygous deletion of exons 10 to 21 that was paternally inherited. The sister had microcephaly, periventricular calcifications, minor retinal vasculopathy, and mild impaired neurodevelopment, but only very subtle limb abnormalities and no ACC. Her brother showed a classical DOCK6-related AOS phenotype, including a severe bilateral peripheral ischemic retinopathy. From a review of 22 molecularly confirmed cases with DOCK6-related AOS with ophthalmic examination, we found that 16 of them had retinal vascular pathology (72.7%), confirming as the major ocular anomaly. Documented intrafamilial variability in our family and the evidence revised from previous reports, confirm that AR DOCK6-related AOS expressivity can produce a "milder" phenotype without ACC or TTLD, which could be underdiagnosed in simplex cases because it is difficult to recognize out of a familial context. Therefore, in order to know its real magnitude is required the future inclusion of DOCK6 gene in NGS panels directed to the study of simplex cases of patients with microcephaly, periventricular calcifications, retinal vasculopathy, and/or cardiovascular defects.

Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Ocular Phenotype of Peters-Plus Syndrome.

PURPOSE: Peters-plus syndrome is a rare, autosomal recessive congenital disorder of glycosylation caused by mutations in the gene B3GLCT. A detailed description of the ocular findings is currently lacking in the scientific literature. We report a case series of Peters-plus syndrome with deep ocular phenotyping using anterior segment optical coherence tomography and ultrasound biomicroscopy. Where available, we describe the histology of host corneal buttons. METHODS: A retrospective chart review of patients with Peters-plus syndrome was conducted under the care of the senior author between January 2000 and June 2019. Demographic and clinical data including ocular and systemic features, ophthalmic imaging, and molecular diagnostic reports were collected. RESULTS: Four cases of Peters-plus syndrome were identified. Three patients were male and 1 was female. Five of the 8 eyes had an avascular paracentral ring opacity with relative central clearing. The paracentral opacity is due to iridocorneal adhesion and the relative central clearing associated with posterior stromal thinning. One eye had persistent fetal vasculature and microphthalmia, which has not previously been reported. One eye from each of 2 patients had a significantly different phenotype with a large vascularized central corneal opacity. CONCLUSIONS: The most common ocular phenotype seen in Peters-plus syndrome is an avascular paracentral ring opacity with relative central clearing. A different phenotype with a large vascularized corneal opacity may also be observed.

High-Resolution Melting Analysis for Rapid Detection of Mutations in Patients with FGFR3-Related Skeletal Dysplasias.

Background: Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are related to skeletal dysplasias (SDs): acondroplasia (ACH), hypochodroplasia (HCH) and type I (TDI) and II (TDII) tanatophoric dysplasias. This study was designed to standardize and implement a high-resolution melting (HRM) technique to identify mutations in patients with these phenotypes. Methods: Initially, FGFR3 gene segments from 84 patients were PCR amplified and subjected to Sanger sequencing. Samples from 29 patients positive for mutations were analyzed by HRM. Results: Twelve of the patients FGFR3 mutations had ACH (six g.16081 G > A, three g.16081 G > C and three g.16081 G > A + g.16002 C > T); thirteen of patients with HCH had FGFR3 mutations (eight g.17333 C > A, five g.17333 C > G and five were negative); and four patients with DTI had FGFR3 mutations (three g.13526 C > T and one g.16051G > T and two patients with DTII (presented mutation g.17852 A > G). When analyzing the four SDs altogether, an overlap of the dissociation curves was observed, making genotyping difficult. When analyzed separately, however, the HRM analysis method proved to be efficient for discriminating among the mutations for each SD type, except for those patients carrying additional polymorphism concomitant to the recurrent mutation. Conclusion: We conclude that for recurrent mutations in the FGFR3 gene, that the HRM technique can be used as a faster, reliable and less expensive genotyping routine for the diagnosis of these pathologies than Sanger sequencing.

Congenital limb deficiency: Genetic investigation of 44 individuals presenting mainly longitudinal defects in isolated or syndromic forms.

Congenital limb deficiency (CLD), one of the most common congenital anomalies, is characterized by hypoplasia/aplasia of one or more limb bones and can be isolated or syndromic. The etiology in CLD is heterogeneous, including environmental and genetic factors. A fraction remains with no etiological factor identified. We report the study of 44 Brazilian individuals presenting isolated or syndromic CLD, mainly with longitudinal defects. Genetic investigation included particularly next-generation sequencing (NGS) and/or chromosomal microarray. The overall diagnostic yield was 45.7%, ranging from 60.9% in the syndromic to 16.7% in the non-syndromic group. In TAR syndrome, a common variant in 3´UTR of RBM8A, in trans with 1q21.1 microdeletion, was detected, corroborating the importance of this recently reported variant in individuals of African ancestry. NGS established a diagnosis in three individuals in syndromes recently reported or still under delineation (an acrofacial dysostosis, Coats plus and Verheij syndromes), suggesting a broader phenotypic spectrum in these disorders. Although a low rate of molecular detection in non-syndromic forms was observed, it is still possible that variants in non-coding regions and small CNVs, not detected by the techniques applied in this study, could play a role in the etiology of CLD.

Caudal Regression Syndrome-A Review Focusing on Genetic Associations.

Caudal regression syndrome (CRS) represents a spectrum of clinical phenotypes with varying degrees of malformation of the lower body with involvement of structures deriving from all 3 layers of the trilaminar embryo. We review areas of active investigation in the diagnosis, etiology, epidemiology, and treatment of the disease with a focus on underlying genetics. CRS pathobiology is complex and multifactorial with a significant contribution from environmental factors as evidenced in twin studies. Contemporary genomic and genetic investigations in both human primary tissue and murine in vitro and in vivo models implicate various genes associated with caudal differentiation and neural cell migration in embryogenesis. A large number of identified targets center around the metabolic regulation of retinoic acid and its derivatives. Dysregulation of retinoic acid homeostasis has been associated with abnormal embryonic cell migration, differentiation, and organogenesis with resulting malformations and agenesis in both a laboratory and a clinical setting. There appears to be a significant overlap in potential genetic targets with CRS and other developmental syndromes with similar presentations, such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) association. CRS represents a spectrum of caudal developmental abnormalities with treatment options limited to mild and moderate expressions of disease. Continued research is necessary to further clarify mechanisms of disease pathobiology and complex polygenetic and environmental interaction. Despite this, progress has been made in identifying genetic targets and downstream effectors contributing to preclinical and clinical progression.

Dolor fantasma en niños y jóvenes amputados congénitos: prevalencia y características clínicas / Phantom pain in children and youth with congenital amputations: prevalence and clinical characteristics

Introducción: El dolor es una patología discapacitante, que en niños está siendo abordada en los últimos tiempos, siendo el dolor fantasma en amputados congénitos una complicación impensada hace algunos años, considerando teorías que describían que carecían de la madurez biológica suficiente para experimentarlo. Actualmente, existe literatura que reconoce una prevalencia de dolor fantasma de 3,7 a 20% en la población de amputados congénitos. Objetivo general: Evaluar población de amputados congénitos del Instituto Teletón Santiago para determinar incidencia, prevalencia lápsica y características clínicas del dolor fantasma. Pacientes y Métodos: Estudio descriptivo de prevalencia, con revisión de ficha clínica para registro de variables demográficas y clínicas, y aplicación de encuesta telefónica al total de pacientes que asintieran y contaran con el consentimiento de sus padres. Se incluyó a todos los pacientes de 10 o más años; se excluyó a los con hipoacusia asociada o con imposibilidad administrativa para contactarlos. Resultados: 57 pacientes, edad promedio 18,6 años, 59,6% con deficiencia longitudinal. Ningún paciente presentó dolor fantasma en el último mes en la población estudiada. La prevalecia lápsica fue de 7,0%. Un 24,6% refirió además presentar sensación fantasma alguna vez en su vida y un 5,3% haber presentado dolor en el último año. Conclusión: Existe dolor fantasma en la población de pacientes amputados congénitos en los rangos de prevalencia encontrados en la literatura internacional contribuyendo a la evidencia existente. Este es el primer estudio en nuestro país que evalúa dolor en deficiencias congénitas y constituye una línea de base para estudios adicionales.

Introduction: Pain is a crippling pathology, which has been addressed in children only in recent times, and phantom pain in congenital amputees was a complication unthought to exist some years ago, considering theories that described that they lacked biological maturity enough to experience it. Currently, there is literature that recognizes a prevalence of phantom pain of 3.7 to 20% in congenital amputees. Overall objective: To evaluate the in vivo amputee population of Instituto Teletón Santiago, to determine incidence, lapses prevalence and clinical characteristics of phantom pain in these patients. Patients and Methods: A prevalence descriptive study was carried out, with a review of the clinical files to register demographic and clinical variables and application of a telephone survey to the total number of Instituto Teletón Santiago patients who agreed to participate and had the consent of their parents. We included all patients aged 10 years and over; excluding those with associated hearing loss, or inability to contact for administrative reasons. Results: 57 patients, mean age 18,6 years, 59,6% with longitudinal deficiency. No patient refered phantom pain during de last month in the study population. The lapsic prevalence was 7,0%. 24,6% of the population studied reported phantom feeling at som time in their lives and 5,3% had phantom pain during the last year. Conclusion: There is phantom pain in the population of congenital amputees in the prevalence ranges found in the international literature contributing to the existing evidence. This is the first study in our country that evaluates pain in congenital deficiencies and constitutes a baseline for additional studies.

Síndrome de Grebe: Reporte de un caso / Grebe syndrome. Case report

La condrodisplasia de Grebe es un trastorno raro autosómico recesivo que pertenece al grupo de las osteocondrodisplasias. Clínicamente se caracteriza por un severo dismorfismo con una marcada micromelia y deformidad de las extremidades inferiores y superiores. Conocer este tipo de síndrome orienta a dar mejores diagnósticos y permite el diagnóstico diferencial con patologías más comunes, como la acondroplasia. Se presenta una paciente de 35 años con diagnóstico de síndrome de Grebe desde los 10 años. El síndrome de Grebe tiene una muy baja incidencia; por este motivo, es poco conocido por el cuerpo médico en general y aun menos para los ortopedistas, quienes serán los encargados de tratar a estos pacientes. Nivel de Evidencia: IV

Grebe syndrome is a rare autosomal recessive disorder that belongs to the group of osteochondrodysplasias. Clinically, it is characterized by severe dysmorphism, marked micromelia and deformities of the lower and upper limbs. Recognition of this syndrome allows to give better diagnoses and to establish a differential diagnosis with more common pathologies, such as achondroplasia. We present a 35-year-old woman with diagnosis of Grebe syndrome at the age of 10. Grebe syndrome has a very low incidence; therefore, it is unknown by general physicians and still less by orthopedic surgeons, who will treat these patients. Level of Evidence: IV

Dentoalveolar Abscesses Not Associated with Caries or Trauma: A Diagnostic Hallmark of Hypophosphatemic Rickets Initially Misdiagnosed as Hypochondroplasia.

Hypophosphatemic rickets is a rare genetic disorder involving the regulation of fibroblast growth factor 23 (FGF23), a phosphaturic agent, clinically showing bowing of the legs, short stature and dentoalveolar abscesses. A 7-year-old boy, with previous hypochondroplasia diagnosis, was referred to our pediatric dentistry clinic presenting short stature, bone deformities and sinus tracts at deciduous teeth apex levels not related with trauma, restorations or dental caries. After deciduous teeth extraction, due to root resorption and mobility, light microscopy exhibited typical hypophosphatemic dentin, and micro-computed tomography revealed tubular clefts and porosities throughout the teeth. Laboratory tests confirmed the HR diagnosis, after which the treatment was initiated.

Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family.

Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unknown, modifying factors can influence the final phenotype.

Asociación LACHT con hipoplasia de la vía aérea superior. Caso clínico / LACHT association with hypoplasia of the upper airway. Clinical case

Resumen Introducción: La asociación Mardini-Nyhan o LACHT es una condición clínica de baja prevalência que cursa con alteraciones pulmonares, cardíacas y de las extremidades. Su etiología no está clara mente documentada hasta la fecha. Objetivo: Describir el caso de una niña de 4 meses y realizar una revisión de la literatura de los casos reportados sobre esta asociación, con el propósito de exponer las alteraciones encontradas y de esta forma orientar el diagnóstico temprano de esta entidad. Caso clínico: Niña de 4 meses de edad que ingresa a cuidado intensivo en insuficiencia respiratoria mixta, con alteraciones pulmonares, cardíacas y de extremidades que cumplen criterios para la asociación LACTH, se documenta adicionalmente hipoplasia de la vía aérea superior, que empeora la evolución, aumenta la dificultad en la ventilación mecánica y favorece el desenlace fatal a los 7 días de hospitali zación. Conclusiones: La asociación LACTH es una patología poco prevalente en la cual los hallazgos clínicos permiten sospechar el diagnóstico. Es caso clínico sería el primer caso diagnosticado en el continente americano y el caso número 11 descrito en la literatura mundial, aportando como nuevo hallazgo la asociación con hipoplasia de la vía aérea superior.

Abstract Introduction: The Mardini-Nyhan or LACHT association is a clinical condition of low prevalence that presents with pulmonary, cardiac and limb abnormalities, in which genetic etiology is not clearly documented to date. Objective: To describe the case of a 4-month-old child and the literature review of cases reported on this association, with the purpose of exposing the alterations found and thus gui de the early diagnosis of this entity. Clinical case: 4 months old girl, who admitted to intensive care in mixed respiratory failure, with pulmonary, cardiac and limb disorders that meet criteria for LACHT association, additionally documents hypoplasia of the upper airway, which worsens the evolution, increases the difficulty in mechanical ventilation and favors the fatal outcome at 7 days of hospita lization. Conclusions: LACTH association is a rare pathology in which the clinical findings make it possible to suspect the diagnosis, this is the first case diagnosed in the Americas and the number 11 case in the world literature and brings as a new finding the association with hypoplasia of the upper airway.

Phenotypic and genotypic aspects of Townes-Brock syndrome: case report of patient in southern Brazil with a new SALL1 hotspot region nonsense mutation.

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare autosomal dominant condition characterized by renal, anal, limb, and auditory abnormalities. TBS diagnosis can be challenging in settings where genetic analysis is not readily available. TBS traits overlap with those of Goldenhar and VACTERL syndromes. CASE PRESENTATION: Here, we present the case of a 5-year-old Brazilian boy born with an anorectal abnormality, limb and external ears malformations, genitourinary anomalies, and a congenital heart defect. Genetic analysis revealed a SALL1 nonsense mutation. The case is discussed in the context of the current literature. CONCLUSIONS: Because of the variability in TBS clinical presentation, genetic analysis is key to the differential diagnosis of TBS relative to phenotypically similar syndromes.

[LACHT association with hypoplasia of the upper airway. Clinical case]. / Asociación LACHT con hipoplasia de la vía aérea superior. Caso clínico.

INTRODUCTION: The Mardini-Nyhan or LACHT association is a clinical condition of low prevalence that presents with pulmonary, cardiac and limb abnormalities, in which genetic etiology is not clearly documented to date. OBJECTIVE: To describe the case of a 4-month-old child and the literature review of cases reported on this association, with the purpose of exposing the alterations found and thus gui de the early diagnosis of this entity. CLINICAL CASE: 4 months old girl, who admitted to intensive care in mixed respiratory failure, with pulmonary, cardiac and limb disorders that meet criteria for LACHT association, additionally documents hypoplasia of the upper airway, which worsens the evolution, increases the difficulty in mechanical ventilation and favors the fatal outcome at 7 days of hospita lization. CONCLUSIONS: LACTH association is a rare pathology in which the clinical findings make it possible to suspect the diagnosis, this is the first case diagnosed in the Americas and the number 11 case in the world literature and brings as a new finding the association with hypoplasia of the upper airway.