Nager Syndrome: A Case Report

Nager syndrome (preaxial acrofacial dysostosis) is rare and mostly sporadic. We present a caseof Nager syndrome in Taiwan. Craniofacial findings included micrognathia, malar hypoplasia,downslanting palpebral fissures, cleft palate, and ear anomalies. Radial defects consisted ofhypoplastic thumb, short forearm, and proximal radioulnar synostosis. Patent ductus arteriosus, atrial septal defect, lower limb deformities, and uncommon flat nasal bridge were noted.Nasal endotube passing through a narrowing oropharynx region or oral airway is life-savingbefore tracheostomy is performed on patients with Nager syndrome and restricted jaw openingand glossoptosis.

Copyright©2012, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rightsreserved.

1. Introduction

Nager syndrome was first recognized by Nager and de Reynierin 1948. They used the term acrofacial dysostosis to describetheir patient.The syndrome (preaxial acrofacial dysostosis)is due to aberrations in development of the first and secondbranchial arches and limb buds.The main clinical featuresconsist of craniofacial, limb and musculoskeletal anomalies.Less frequently, other malformations have also been reported.Most cases appear to be sporadic, however, autosomaldominant or autosomal recessive inheritance has been mentioned.The occurrence of affected siblings withnormal parents suggests potential genetic heterogeneity andan additional autosomal recessive form.Thus, the patternof inheritance remains unclear. Severe airway obstruction isthe major cause of morbidity and mortality. Early intervention with tracheostomy has been emphasized.Tracheotomy should be considered to stabilize the respiratorysituation promptly. We report here the first case of Nagersyndrome diagnosed in Taiwan. A 3-year-old girl presentedwith severe phenotype and uncommon flat nasal bridge, butdid not receive tracheostomy.

2. Case Report

This 3-year-old girl was first transferred to our hospitalwhen she was 3 weeks old. She was born to a healthy mother of Gravida 3 Para 3 (G3P3), 40 weeks of gestationalage via normal spontaneous delivery; the birth body weightwas 2680 g. No specific family history was noted regardingcraniofacial disorders. Intubation was attempted soonafter birth but failed because of severe micrognathia.Oropharyngeal airway was used first and then shifted tonasopharyngeal airway (3.0 Fr. E-T tube, with room air). Onphysical examination, the patient presented with severemicrognathia, bilaterally small downslanting palpebralfissures, malar hypoplasia, flat nasal bridge, cleft palate,and low-set, posterior-rotated ears with ear canal atresia(Figure 1). Deformities of both forearms, with radialdeviation of the wrists and club feet were found. Cardiacecho showed patent ductus arteriosus of 3.8 mm and atrialseptal defect of 3.0 mm, secundum type with left-to-rightshunt, which closed spontaneously later. Patent ductusarteriosus was occluded by Amplatzer ductal occluderwhen the patient was 1 year old. Brain echo and bloodkaryotyping showed normal results. Imaging study revealedglossoptosis and retrognathia, resulting in oropharyngealairway narrowing (Figure 2), proximal radioulnar synostosis, and radial hypoplasia (Figure 3). Neither tracheostomy nor gastrostomy was executed by decision of thefamily.

At 1 year and 6 months old, the patient only needednasopharyngeal airway when sleeping, but was free duringdaytime. Rehabilitation proceeded regularly for the limitation of elbow extension and thumb dysplasia (Figure 4).The patient could open her mouth but only to a limitedextent, owing to ankylosis of the temporomandibular joint.Hypoplastic, overlapping toes were obvious. At 3 years and4 months, she still had blurred speech and swallowingincoordination. She could walk and jump. She had normalintelligence. Her body height was 90.8 cm (10-25^thpercentile); body weight was 11.6 kg (3^rdpercentile); headcircumference was 46.6 cm (10^thpercentile). She worea hearing aid due to bilateral conductive hearing loss(50-60 dB), and had received dental management due toabnormal teething and caries.

3. Discussion

Nager syndrome shares similar craniofacial features withTreacher Collins syndrome, including micrognathia, malarhypoplasia, downslanting palpebral fissures, and earanomalies, but mandibular hypoplasia tends to be moresevere.4It can be distinguished from Treacher Collinssyndrome by preaxial upper-limb deformities, such asthumb anomaly, radial defect and radioulnar synostosis.Limb anomalies are a cardinal sign of Nager syndrome and,in combination with the characteristic facial features, arediagnostic.5In Finland, the incidence of Nager syndromehas been estimated as 3:1,000,000.11No more than 80 caseshave been reported to date.4,5,12Nager syndrome is so rarethat this is the first reported case in Taiwan.

A distinct acrofacial dysostosis case, which might bea new form of the disease, has been proposed by Zhanget al.13To investigate the etiology of the phenotype,whole-genome, high-resolution array comparative genomichybridization analysis was carried out, revealing twocryptic duplications, 1p36.33 and 1q21.3-q22. They alsosuggested that two genes,VWA1andPYGO2, might be thecandidate genes for the abnormal phenotype of this case.13However, the etiology of Nager syndrome is still unclear,without any gene having been identified to date.

In the case presented here, craniofacial findingsincluded micrognathia, malar hypoplasia, downslantingpalpebral fissures, cleft palate, and ear anomalies, as wellas radial defects consisting of hypoplastic thumb, shortforearm, and proximal radioulnar synostosis, fulfilling thediagnostic criteria for Nager syndrome. The patient hada severe typical phenotype with uncommon flat nasalbridge, which was different from other reported cases.5Forpsychological and physiological issues, she might needsurgical correction of micrognathia eventually. However, primary mandibular distraction osteogenesis is not able toguarantee sufficient stabilization of the respiratory situation, given the small bone structures; this approach shouldbe reserved for older and larger patients.14A policy of earlyand aggressive surgical management for hemifacial disorders had been pursued in the past, and an audit of outcomewas undertaken to confirm whether or not this policy had been justified. The outcome for children with Nagersyndrome was less successful (60%). The worst outcomeoccurred in a mixed group of three children with othersyndromes; two of whom failed decannulation.

Recommended rehabilitative strategies include prespeech feeding activities (especially if gastrostomy tubesare present), oral language stimulation, individualizedspeech/language therapy, and early audiological evaluationand amplification.16Restricted jaw opening and glossoptosis make intubation difficult. Nasal endotube passingthrough a narrowing oropharynx region or oral airway is lifesaving before tracheostomy is performed. Gastrostomyshould be considered to improve nutritional status forpatients with swallowing incoordination. Intensive dentaltherapy and orthopedic management should also beincluded for the integrity of treatment.