Genotype-phenotype correlations on epidermolysis bullosa with congenital absence of skin: A comprehensive review.

Congenital absence of skin (CAS) is a clinical sign associated with the main types of epidermolysis bullosa (EB). Very few studies have investigated the genetic background that may influence the occurrence of this condition. Our objective was to investigate genotype-phenotype correlations on EB with CAS through a literature revision on the pathogenic variants previously reported. A total of 171 cases (49 EB simplex, EBS; 23 junctional EB, JEB; and 99 dystrophic EB, DEB), associated with 132 pathogenic variants in eight genes, were included in the genotype-phenotype analysis. In EBS, CAS showed to be a recurrent clinical sign in EBS with pyloric atresia (PA) and EBS associated with kelch-like protein 24; CAS was also described in patients with keratins 5/14 alterations, particularly involving severe phenotypes. In JEB, this is a common clinical sign in JEB with PA associated with premature termination codon variants and/or amino acid substitutions located in the extracellular domain of integrin α6ß4 genes. In DEB with CAS, missense variants occurring close to non-collagenous interruptions of the triple-helix domain of collagen VII appear to influence this condition. This study is the largest review of patients with EB and CAS and expands the spectrum of known variants on this phenomenon.

Diagnostics and therapy of bilateral choanal atresia in association with CHARGE syndrome.

BACKGROUND: Bilateral choanal atresia in patients with CHARGE syndrome becomes symptomatic immediately after birth. A prompt diagnosis, the implementation of sufficient preliminary measures, and the delivery of surgical therapy are crucial. This article is intended to assist in terms of diagnostics and a therapy recommendation. METHODS: We performed a retrospective study using the medical records of all newborns in the University Hospital in Bonn, diagnosed with bilateral choanal atresia and CHARGE syndrome and underwent surgery at the Department of Otorhinolaryngology, Head and Neck Surgery. RESULTS: A total of 21 patients have been treated with a unilateral or bilateral choanal atresia. 14 patients were primarily treated with transnasal endoscopy or underwent transnasal endoscopic surgery as a follow-up intervention (73.68%). Nine patients had a syndromal appearance, which was considered a definite diagnosis in six patients (five with CHARGE syndrome). All five patients with CHARGE syndrome received transnasal endoscopic treatment and a stent was inserted. DISCUSSION: Bilateral choanal atresia can be a life-threatening situation requiring acute measures. The therapeutic trend goes towards transnasal endoscopic resection. Primary intervention should be: minimally invasive, one-stage surgery, functional, and associated with low complication rates. Patency can be increased by saline irrigations, topical corticosteroids, endoscopic controls, and regular dilatation. The insertion of stents is controversially discussed but can be useful in syndromal patients. However, adjuvant therapy with a stent and mitomycin C is increasingly being abandoned. A significantly higher recurrence rate must be expected in association with CHARGE syndrome. Stenting should be considered on an individual basis. Continuous training and support of the parents are obligatory.

Choanal atresia and stenosis: Development and diseases of the nasal cavity.

Proper craniofacial development in vertebrates depends on growth and fusion of the facial processes during embryogenesis. Failure of any step in this process could lead to craniofacial anomalies such as facial clefting, which has been well studied with regard to its molecular etiology and cellular pathogenesis. Nasal cavity invagination is also a critical event in proper craniofacial development, and is required for the formation of a functional nasal cavity and airway. The nasal cavity must connect the nasopharynx with the primitive choanae to complete an airway from the nostril to the nasopharynx. In contrast to orofacial clefts, defects in nasal cavity and airway formation, such as choanal atresia (CA), in which the connection between the nasal airway and nasopharynx is physically blocked, have largely been understudied. This is also true for a narrowed connection between the nasal cavity and the nasopharynx, which is known as choanal stenosis (CS). CA occurs in approximately 1 in 5,000 live births, and can present in isolation but typically arises as part of a syndrome. Despite the fact that CA and CS usually require immediate intervention, and substantially affect the quality of life of affected individuals, the etiology and pathogenesis of CA and CS have remained elusive. In this review I focus on the process of nasal cavity development with respect to forming a functional airway and discuss the cellular behavior and molecular networks governing this process. Additionally, the etiology of human CA is discussed using examples of disorders which involve CA or CS. This article is categorized under: Signaling Pathways > Cell Fate Signaling Comparative Development and Evolution > Model Systems Birth Defects > Craniofacial and Nervous System Anomalies.

Rdh10 loss-of-function and perturbed retinoid signaling underlies the etiology of choanal atresia.

Craniofacial development is a complex process that involves sequential growth and fusion of the facial prominences. When these processes fail, congenital craniofacial anomalies can occur. For example, choanal atresia (CA) is a congenital craniofacial anomaly in which the connection between the nasal airway and nasopharynx is completely blocked. CA occurs in approximately 1/5000 live births and is a frequent component of congenital disorders such as CHARGE, Treacher Collins, Crouzon and Pfeiffer syndromes. However, the detailed cellular and molecular mechanisms underpinning the etiology and pathogenesis of CA remain elusive. In this study, we discovered that mice with mutations in retinol dehydrogenase 10 (Rdh10), which perturbs Vitamin A metabolism and retinoid signaling, exhibit fully penetrant CA. Interestingly, we demonstrate Rdh10 is specifically required in non-neural crest cells prior to E10.5 for proper choanae formation, and that in the absence of Rdh10, Fgf8 is ectopically expressed in the nasal fin. Furthermore, we found that defects in choanae development are associated with decreased cell proliferation and increased cell death in the epithelium of the developing nasal cavity, which retards invagination of the nasal cavity, and thus appears to contribute to the pathogenesis of CA. Taken together, our findings demonstrate that RDH10 is essential during the early stages of facial morphogenesis for the formation of a functional nasal airway, and furthermore establish Rdh10 mutant mice as an important model system to study CA.

[Nasal breath recovery and rhinoplasty in cleft lip and palate patient with unilateral choanal atresia].

The paper presents the analysis of clinical case of endoscopic nasal breath restoration and elimination of the secondary cleft lip nasal deformity in 27 years old patient with unilateral choanal atresia and secondary nasal deformity after rhinocheiloplasty. Preoperative examination revealed the absence of nasal breathing on collateral side due to complete bone choanal atresia. Surgical treatment included endoscopic choanal repair, elimination of the secondary nasal deformity, septoplasty, conchotomy and lateroposition of the inferior conchae. The treatment resulted in nasal breath restoration and elimination of nasal deformity. Long-term follow-up at 1 and 12 months post-operatively proved stable positive aesthetic and functional results.

Bosma arhinia microphthalmia syndrome: Clinical report and review of the literature.

Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males.

Evaluation of CHD7 as a candidate gene for choanal atresia in alpacas (Vicugna pacos).

Choanal atresia (CA) is a craniofacial malformation characterized by obstruction of the posterior nasal aperture, resulting in laborious respiratory inspiration and exhalation. Alpaca crias with CA typically develop fatal pneumonia, frequently as the result of milk aspiration during nursing, and euthanasia is usually inevitable. Nonsense or missense mutations in the CHD7 gene cause a comparable condition (CHARGE syndrome) in humans. In this study, the coding region of CHD7 was sequenced in six CA-affected alpacas. Forty-nine sequence variants were identified, of which 10 would result in amino acid changes (non-synonymous), some with potentially deleterious effects. However, none of the observed variants would result in the obvious deleterious effects caused by nonsense or missense mutations. Although a role for CHD7 mutations in CA cannot be definitively dismissed, these do not appear to be the primary cause of CA in alpacas.

Endoscopic surgery for acquired choanal atresia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: This study was designed to investigate the role of endoscopic surgery for acquired choanal atresia after radiotherapy for nasopharyngeal carcinoma. METHODS: Twenty-two patients with bilateral or unilateral acquired choanal atresia received transnasal endoscopic surgery with the aid of a powered microdebrider to open atresia choana and received endoscopic sinus surgery simultaneously if they had sinusitis. Merocel epistaxis packing was used to pack the nasal airway for 3 days postoperatively. All of the patients underwent endoscopy regularly for follow-up. RESULTS: Sixteen patients with acquired bilateral choanal atresia and 6 with unilateral choanal atresia were included in this study. The median age was 46 years old (range, 33-65 years). Twenty-one patients had sinusitis. Sixteen patients with bilateral choanal atresia and 4 patients with unilateral atresia had bilateral sinusitis. One patient with unilateral atresia had ipsilateral sinusitis. The mean follow-up period was 35 months (range, 12-72 months) after surgery. Twenty patients were symptom-free after a single operation; nasal obstruction, rhinorrhea, and xerostomia improved significantly for these patients. Two patients had unilateral restenosis that required revision surgery, and both were subsequently free from further restenosis. No complications occurred. CONCLUSION: Acquired posterior choanal atresia after radiotherapy can be successfully treated with transnasal endoscopic resection assisted by a powered instrument without stenting.

[Choanal atresia an institutional review]. / Zarosniecie nozdrzy tylnych w materiale kliniki.

UNLABELLED: Choanal atresia is a rare congenital disease, it occurs in 1/8000 live newborns. AIM OF THE STUDY: retrospective review of patients with choanal atresia treated at the Department of Pediatric Otolaryngology of Medical University in Lublin. Twenty-two children were evaluated, 16 females, 6 males, age range from 6th day to 11th year of life, operated between 2004 and 2009. We analized: age of the parents, mothers diseases during pregnancy, place of live, type of atresia, associated abnormalities, age of children at time of surgery, results of treatment. The age of parents didn't differ significantly from the mean age of parents of children without abnormality. Choanal atresia was bilateral in 10 patients (45%), unilateral in 12 cases (55%)--right-sided in 75% and left-sided in 3 children. The membranous barrier was stated in 60.7%, bone in 25%, and mixed in 14.7%. Choanal atresia was an isolated disease in 12 patients, and in 10 it was associated with other abnormalities. The most common were: central nervous system abnormalities (5 children), heart defect (5), facial dysmorphy (4), hearing loss only in 2 cases. All patients were operated with transnasal technique with stents placement for 6-8 weeks period. The necessity of repleacing the stents occurred in 4 patients because of tendency of the granulation. These problems were absent in patients who were operated during the newborn period. Undoubtedly, the transnasal technique is a procedure by choice, decision, to place a stent or not, depend on the experience of the surgeon and his/her own results.

Applying principles of physics to the airway to help explain the relationship between asthma and gastroesophageal reflux.

Gastroesophageal reflux (GER) and asthma have been linked, but the true nature of this relationship is incompletely understood. Most of the literature examining this association has implicated GER as the factor contributing to asthma. GER has also been linked to conditions of the upper airway like sinusitis and obstructive sleep apnea (OSA), and once again, usually presumed to be the causative factor. While GER seems to be capable of exacerbating airway disease, mounting evidence suggests that airway obstruction is a risk factor for developing GER. This article examines the principles of physics that predict what should occur given the anatomy of the airway and the esophagus, and provides multiple examples of disease associations that appear to support the hypothesis that airway obstruction is a significant risk factor for development of gastroesophageal reflux.

[Endonasal surgery of choanal atresia].

This paper was designed to study clinical manifestations of choanal atresia (CA) in 11 patients with a view to optimizing methods for medical and diagnostic management of this severe pathology using endonasal surgical techniques. Detailed analysis of possible causes of congenital CA and mechanisms of acquired CA was performed using computed tomography (CT) and retrograde endoscopy with the help of rigid optics. Potential of certain instruments designed and manufactured in Russia for the management of CA is demonstrated, such as retrograde 110o Sekunda endoscope and silicone horseshoe-shaped protectors. An original diagnostic algorithm is proposed allowing for the development of indications for surgical intervention, determination of its extent, and the choice of the post-operative treatment. Improved surgical instruments have been designed for the purpose. A case of hereditary CA in a child and his mother are presented along with results of treatment of nasopharyngeal scleroma in two patients. Clinical manifestations of CA concomitant with scleroma, diphtheria, and chemical chaonal burns are considered.

Effectiveness of transnasal endoscopic powered adenoidectomy in patients with choanal adenoids.

OBJECTIVES: To demonstrate the technique and efficacy of powered assisted adenoidectomy using nasal endoscopy. PATIENTS AND METHODS: Between 2002 and 2003, forty children (age ranged from 3 to 17 years) with symptoms and signs suggestive of snoring and/or obstructive sleep apnea and choanal adenoids were randomly selected and distributed in two groups. Group A underwent transnasal endoscopic powered adenoidectomy (TEPA) and group B underwent curettage adenoidectomy (CA). Both groups underwent pre- and postoperative nasal endoscopy. Direct comparisons between the two groups were made with regards to operative time, amount of blood loss, postoperative morbidity, complications, and resolution of symptoms. RESULTS: Male to female distribution was equal 1:1. The mean age of both groups was 8 years. In group A, the mean blood loss was 8.2 ml compared to 22.1 ml in group B (p<0.05). The operative time in group A was 6.1 min vs 12.3 min in group B (p<0.05). There were no operative or postoperative complications in both groups. Postoperative follow up and nasal endoscopy showed no recurrence of symptoms or adenoid remnants. CONCLUSION: Using TEPA for removing choanal adenoids is an adequate and safe method. The TEPA technique can be added to the armamentarium of techniques used by pediatric otolaryngologists.

Choanal atresia: long-term follow-up with objective evaluation of nasal airway and olfaction.

OBJECTIVE: The purpose of this study was to determine the status of nasal airway and olfaction of adult subjects born with choanal atresia (CA). STUDY DESIGN AND SETTING: A case-control study was conducted to compare the quality of nasal airway and olfaction in a group of adults born with CA to a similar group of normal subjects. Objective evaluation of nasal airway and olfaction were done respectively by acoustic rhinometry and the University of Pennsylvania Smell Identification Test (UPSIT). RESULTS: Thirty-six choanal atresia patients aged 16 to 36 were found in the medical records. Five bilateral and two unilateral cases were recruited for the study. An average score of 27/40 (moderate hyposmia) was obtained by the bilateral cases compared with 37/40 (normal) by the controls. These results were statistically significant (Wilcoxon signed rank test and sign test statistic, P = 0.03). CONCLUSIONS: Using the UPSIT, the bilateral CA patients have shown, on average, a moderate loss of the sense of smell when compared with normal controls of a similar age group. Acoustic rhinometry is not a useful study for posterior nasal conditions.

CHARGE syndrome: relations between behavioral characteristics and medical conditions.

The behaviors and medical problems in 27 persons with CHARGE syndrome were studied, because it was hypothesized that their behavior might be partly dependent on the heterogeneous medical status. With the exception of more tics, cardiac surgery was associated with positive behaviors: less withdrawn behavior, better mood, and a more easy temperament. Tube feeding was also related to positive behavior, since participants with a history of tube feeding showed less intense behavior. Cerebral deficits were associated with three problem behaviors: more intense and withdrawn behavior and a worse mood. Deaf-blindness was associated with developmental delays in expressive and overall communication level, and recurrent middle ear infections correlated with delays in written language. Of all medical conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between the participants with regard to the number of behavioral problems. Participants with heart surgery especially, had less behavior problems. The number of operations and hospitalizations was not associated with behavior, but the total length of the hospitalizations was. Long hospital stays were associated with less problem behavior, especially internalizing behaviors. Cerebral and heart problems did not result in longer hospital stays, whereas esophageal reflux did. Age effects were reflected in older participants, who showed more internalizing problems. Heart surgery and hospitalization may be protective factors, but the protection might not be the actual surgery or hospital stay, as there may be other variables that are the actual cause, such as reduced vitality or altered parent child interactions after heart surgery. The study could not confirm a significant association between medical conditions and autism found in previous studies.

De novo interstitial duplication 4(q28.1q35) associated with choanal atresia.

We report a case of direct interstitial duplication of chromosome 4 from 4q28.1 to 4q35 associated with bilateral choanal atresia. The child also had dysmorphic features including a broad nasal bridge, telecanthus, downward slanting palpebral fissures, prominent ears, mild bilateral clinodactyly of the 5th fingers and bilateral hypoplasia of the 2nd-5th toenails. There was also a slightly dilated renal collecting system. At the age of 2.5 years, he had moderate global developmental delay, short, wide and tapering fingers, and short toes with hypoplastic toenails. To our knowledge, this is the second report of choanal atresia in a patient with trisomy 4q involving this region.

Early prognostic factors for intellectual outcome in CHARGE syndrome.

CHARGE syndrome (coloboma, heart disease, atresia of the choanae, retarded growth and mental development, genital anomalies, and ear malformations and hearing loss) is a heterogeneous condition for which early prediction of intellectual outcome is important but difficult. The psychomotor milestones and intellectual outcome of a consecutive series of children with CHARGE syndrome who were observed by the same team from the neonatal period to the time of study were analyzed retrospectively. Twenty-one children (11 males and 10 females, aged from 5 to 12 years, mean 8 years 7 months, SD 2 years 5 months) were included. The influence of 19 early identifiable parameters that could be considered as deleterious for intellectual outcome was recorded. Generally, the main psychomotor milestones (0 to 4 years) were severely delayed, although intellectual outcome (at primary-school age) was satisfactory for half the children in this series. We show that extensive bilateral coloboma resulting in low vision, microcephaly, and brain malformation were the only three parameters that were predictive of poor intellectual outcome. Conversely, severe neonatal medical conditions, such as tracheotomy, conditions requiring long stays in hospital, or cardiac surgery were not predictive of poor intellectual outcome. Severe hearing loss was not found to be negatively correlated with intellectual outcome once coloboma had been taken into account.

Estenosis congénita de la abertura piriforme nasal como causa de distrés respiratorio en el recién nacido: aportación de cuatro casos diagnosticados mediante TC / Congenital nasal pyriform aperture stenosis as a cause of respiratory distress in newborns: presentation diagnosed by menas of CT

La estenosis congénita de la abertura piriforme nasal es una causa rara de obstrucción de la vía aérea en el recién nacido, que puede ser indistinguible clínicamente de la atresia de coanas, entidad esta última mucho más frecuente. La tomografía computarizada (TC) confirma el diagnóstico de esta anomalía, demostrando en detalle la alteración anatómica subyacente, pudiendo manifestarse de forma aislada o asociada a otras alteraciones. Aportamos cuatro casos de estenosis congénita de la abertura piriforme, los cuales presentaban distrés respiratorio y síntomas clínicos semejantes a los de la atresia de coanas en recién nacidos, en los cuales el diagnóstico precoz y un tratamiento conservador colocando un tubo para mantener permeable la luz, hasta que el crecimiento de la abertura piriforme permita realizar una respiración normal, consiguió la recuperación de los pacientes (AU)

Transnasal endoscopic treatment of choanal atresia without prolonged stenting.

OBJECTIVE: To analyze the outcome of transnasal endoscopic repair of choanal atresia (CA) in children without prolonged nasal stenting after surgery. DESIGN: Retrospective study. SETTING: Academic tertiary care children's hospital. PATIENTS: Forty children aged 3 days to 15 years (mean age, 41 months) who presented with unilateral (n = 26) or bilateral (n = 14) CA and underwent surgery between August 1996 and December 1999. INTERVENTION: All children underwent transnasal endoscopy with telescopes, endoscopic instruments, and a microdebrider. Nasal tubes in neonates or infants and nasal packing in older children were always removed after 2 days. Systematic revision endoscopy was performed with the patients under local or general anesthesia on days 6 to 10. All patients were then clinically and endoscopically monitored for nasal obstruction and healing during a mean follow-up period of 18 months. RESULTS: There were 16 patients with associated malformations, including 6 cases of CHARGE association (a malformative syndrome that includes coloboma, heart disease, CA, retarded development, genital hypoplasia, and ear anomalies, including hypoplasia of the external ear and hearing loss), and 14 patients (9 with bilateral CA) with a history of previous choanal surgery (4 transnasal, 4 laser, and 6 transpalatine). Postoperatively, 32 patients (80%) had normal nasal patency and a satisfactory choanal diameter, and 8 (20%) had restenosis or complete choanal closure. Six underwent a second procedure, with success. The results in all children who had been previously treated with laser or transpalatine surgery were successful. The last patient, who presented with severe Treacher Collins syndrome, is still tracheotomized. There were no significant postoperative complications. One patient died of congenital cardiopathy 6 months after surgery. CONCLUSIONS: Transnasal endoscopic repair of CA is a safe and successful technique. The use of powered instrumentation and routine postoperative revision endoscopy seems to avoid prolonged nasal stenting.