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Nager syndrome (preaxial acrofacial dysostosis): A case report
S. Kavadia, DDS, DrDent,a E. G. Kaklamanos, DDS,b K. Antoniades, DDS, MD, DrDent, DrMed,c
V. Lafazanis, MD, DrMed,d and D. Tramma, MD,e Thessaloniki, GreeceARISTOTLE UNIVERSITY OF THESSALONIKI
The Nager syndrome is a rare condition associated with craniofacial malformations such as micrognathia,zygomatic hypoplasia, cleft palate, and preaxial limb deformities. This report features a case of the Nager syndromeoccurring in a 4-year-old boy showing microdontia, thumb duplication and radioulnar synostosis, and ventricular septumdefect, characteristics not usually encountered in the published cases. (Oral Surg Oral Med Oral Pathol Oral RadiolEndod 2004;97:732-8)
The Nager syndrome, also termed preaxial acrofacial
dysostosis, is characterized by aberrations in develop-
ment of the first and second branchial arches and limb
buds.1,2 It was first recognized in a patient reported
by Nager and de Reynier3 in 1948, who used the term
acrofacial dysostosis to distinguish the condition from
mandibulofacial dysostosis. Franceschetti and Klein4 in
1949 described the same case as an atypical example of
mandibulofacial dysostosis (Treacher Collins syn-
drome). Gorlin et al5 employed the term preaxial acro-
facial dysostosis to distinguish the disorder from
postaxial acrofacial dysostosis or Wildervanck-Smith
syndrome. To date no more than 80 cases have been
reported in the literature.6,7 The majority of cases ap-
pears to represent sporadic occurrences5; thus, the mode
of inheritance remains unclear.8 Substantial evidence
supports an autosomal recessive inheritance pattern.9-13
However, Lowry,14 Weinbaum et al,15 Aylsworth
et al,16-18 and Bonthron et al19 have suggested autosomal
dominant inheritance.
Preaxial acrofacial dysostosis is of particular interest
to the dentist and maxillofacial surgeon, as affected in-
dividuals exhibit extensive mandibular and temporo-
mandibular involvement.2 The purpose of this report is
to present a case of Nager syndrome exhibiting thumb
duplication and radioulnar synostosis—features that do
not appear to have been reported coexisting in the same
individual.
aAssistant Professor, Department of Orthodontics, School of
Dentistry, Aristotle University of Thessaloniki.bPrivate practice.cAssociate Professor, Department of Oral and Maxillofacial Surgery,
School of Dentistry.dAssociate Professor, Department of Pediatrics, School of Medicine.eResearch associate, Department of Pediatrics, School of Medicine.
1079-2104/$ - see front matter
� 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.tripleo.2003.11.018
732
CASE REPORTThe patient, a 4-year-old boy, was referred to the
Department of Oral and Maxillofacial Surgery for clinical
evaluation. Because the child had been abandoned in a hospital,
little information existed regarding family history and birth
conditions. The mother was reported to be an alcoholic and
a smoker. The patient’s medical history revealed that he had
first been admitted to University Hospital at the age of 1.5
months, at which time heweighed 2360 g and had a 36-cm head
circumference—both parameters falling below the 5th percen-
tile. Moreover, the child had feeding difficulties owing to
malformations of the orofacial region, most important of which
was a severe mandibular retrusion. In addition, low-set ears,
duplication of the left thumb (Fig 1, A and B), and crypto-
rchidism were observed. Between the ages of 2 months and 2
years, the patient underwent procedures to surgically remove
the right testis and correct the double thumb (Fig 1, C).Clinical examination at the age of 4 years revealed a child
with growth retardation evidenced by a height of 92 cm (3rd
percentile) and weight of 11400 g (below the 3rd percentile).
There was no evidence of mental retardation. The forearms
were short and elbow articulation extension presented difficul-
ties. Anomalies of the lower limbs were not encountered. The
patient also exhibited characteristic facies owing to dolicho-
cephaly, hypoplastic zygomatic regions, and mandibular retru-
sion. There was no restriction of jaw movements. Observed
feeding difficulties were not attributable to velopharyngeal
incompetence, cleft palate, or soft palate agenesis. Ocular
findings included anisopthalmia, epicanthus, and downslanting
palpebral fissures due to the zygomatic hypoplasia. In addition,
dysplastic low-set ears were observed; however, no hearing
disturbances were recorded (Fig 2, A and B). A clinical oral
examination revealed microdontia of the primary dentition
(Fig 3).
The maxillofacial skeleton was examined radiographically.
The orthopantomogram observation revealed a prominent
antegonial notch, especially in the right side, deep sigmoid
notch, well developed coronoid process, and relatively under-
developed condylar process (Fig 4). On the lateral cephalogram
tracing, a convex face with protrusive lips was observed (Fig
5, A). Measurements of the internal cranial structures were
normal for the patient’s age. Upper and lower facial heights
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGYVolume 97, Number 6
Kavadia et al 733
Fig 1. A, Extraoral photograph at the age of 1.5 months. The feeding tube was placed to overcome feeding difficulties. Double
thumb is apparent. B, Detail of A showing the double thumb of the left hand.C, Photograph of the left hand at the age of 3.5 years,
after surgical correction.
Fig 2. Extraoral photographs at 4 years of age. Clinical observation reveals zygomatic hypoplasia, downslanting palpebral fissures,
and mandibular hypoplasia. In addition, the ears are low-set and greater in size relatively to the rest of the face. A, Frontal view. B,Lateral view.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGYJune 2004
734 Kavadia et al
Fig 3. Intraoral photograph of the patient. Microdontia of the primary teeth can be observed.
Fig 4. Orthopantomogram of the patient. Radiographic investigation of the maxillofacial skeleton revealed a prominent antegonial
notch, especially the right one, deep sigmoid notch, well developed coronoid process, and relatively underdeveloped condylar
process.
were normal. The distance between the lower lip and the
esthetic plane of Ricketts (E plane) was 2.6 mm (normal range
1.8-2.2 mm). Although the facial convexity measurement was
normal for the age of the patient (A perpendicular to facial
plane = 3.5 mm), point Awas posteriorly positioned relative to
the anterior cranial base (A to Na perpendicular = 3.7 mm,
normal value 0 mm), suggesting a posterior positioning of the
midface to the calvarium. The mandible exhibited short ramus
length, obtuse gonial angle (Ar-Go-Me = 140.48), and an
excessive antegonial notch. Mandibular corpus length was
51 mm, and ramus height was 41.3 mm. Posterior rotation and
positioning of the mandible were observed. Overall, the
mandibular growth pattern was dolichofacial. Dental and
dentoskeletal relationships were considered within the normal
range. However, the lower incisors had lingual position and
inclination (�II to A-Pog = 1.1 mm,�II/A-Pog = 10.68) (Fig 5, B).
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Kavadia et al 735
Fig 5. A, Lateral cephalometric radiograph of the patient. B, Tracing of the lateral cephalometric radiograph. Ricketts’ analysis and
various linear measurements are illustrated. Ba = the lowest point on the anterior margin of the foramen magnum, at the base of the
clivus; Ar = the point of intersection between the shadow of the zygomatic arch and the posterior border of the mandibular ramus;
Po = the midpoint of the upper contour of the external auditory canal; S = the midpoint of the cavity of the sella turcica; N = the
anterior point of the intersection between the nasal and the frontal bones; Or = the lowest point of the inferior margin of the orbit;
A = the innermost point on the contour of the premaxilla between anterior nasal spine and the incisor tooth; Pg = the most anterior
point on the contour of the chin; Me = the most inferior point on the mandibular symphysis; Gn = the most anterior and inferior
point on the mandibular symphysis; Go = the midpoint of the contour connecting the ramus and body of the mandible; PtV = the
line passing form Pt point perpendicular to the horizontal plane; CC = the point were the PtV line intersects with the Ba-N line; E
plane = the line tangent to the most anterior point of the soft tissue chin and the tip of the nose
In general, linear measurements concerning the facial skeleton
as well as the cranial base were smaller the accepted
norms.5,20,21 Radiographic hand and wrist examination pro-
vided an estimate of bone age of 3 years.22 More significantly,
proximal radioulnar synostosis was observed (Fig 6).
Various genitourinary anomalies were also encountered.
The left kidney was rudimentary and malposed, while the
right kidney exhibited dilation of the pelvis and calyces, as
well as disturbance of normal parenchymal architecture. The
aforementioned defects resulted in first stage chronic renal
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGYJune 2004
736 Kavadia et al
Fig 6. A, Hand, and B, wrist radiographs of the patient showing proximal radioulnar synostosis.
insufficiency. The patient also exhibited a ventricular septal
defect. There was evidence neither of respiratory disease
nor of hormonal disturbance. Based on craniofacial character-
istics and the coexisting upper limb preaxial anomalies, the
diagnosis of the Nager syndrome was confirmed (Table I).
DISCUSSIONThe Nager syndrome is a rare disorder resulting from
developmental abnormalities of the first and second
branchial arches.2 The pattern of craniofacial features
observed in preaxial acrofacial dysostosis are similar to
that seen in Treacher Collins syndrome.5,8,23-26 The
hypoplastic orbitomalar region results in downslant-
ing palpebral fissures.2,5,27,28 The lower eyelids pre-
sent lateral colobomas and a reduced number of
eyelashes.5,27,28 Mandibular hypoplasia tends to be more
severe in Nager syndrome than in Treacher Collins
syndrome,5,8 with mandibular malformations and miss-
ing joint structures contributing to extreme restriction in
jaw movement.2 Microstomia has been reported,28 and
cleft palate is common.3,27,29 Due to the aforementioned
defects, there is very little growth of the lower face.2
Congenital absence of much of the soft palate also has
been reported.27,28 Ear involvement consists of varying
degrees of external andmiddle ear malformation, leading
to temporary or permanent hearing loss.27,28,30
Limb defects, particularly preaxial anomalies, are of
diagnostic significance in Nager syndrome, and serve to
differentiate this condition from mandibulofacial dys-
ostosis.2,8 Thumb defects, once considered by definition
to be hypoplastic or aplastic in nature, may occasionally
Table I. Clinical and radiographic features commonly
encountered in preaxial acrofacial dysostosis
Common features Present case
Maxillofacial area
Zygomatic hypoplasia +
Downslanting palpeblar fissures +
Lower eyelid colobomas
Mandibular hypoplasia +
Ear involvement
External ear malformation +
Limbs
Thumb aplasia or hypoplasia
Radial defects +
OthersGenitourinary abnormalities +
Reduced stature +
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Kavadia et al 737
exhibit triphalangy or duplication. Approximately 50%
of cases may present radial hypoplasia or aplasia or
proximal radioulnar synostosis.5,6,8,24,28 The radial de-
fect is believed only to occur with concurrent agenesis of
the thumb.5 Limitation of elbow extension has also been
reported.5,28 Defects of the lower extremity also have
been described.27 Other abnormalities reported include
reduced stature, mild mental retardation, and genitouri-
nary malformations.5
Functional impairments encountered in Nager syn-
drome primarily consist of respiration and feeding dif-
ficulties, attributed to mandibular retrusion and severely
restricted jaw opening.2,31,32 The degree of hearing loss
is influenced by the extent of auricular abnormali-
ties.2,27,28,30 Speech difficulties can arise from impaired
hearing, as well as from velopharyngeal insufficiency.30
Due to very limited jaw opening in some cases and
coexisting limb abnormalities, maintenance of adequate
oral hygiene may represent a major problem, and self-
care may be impossible.2
Sulik et al1,33 have suggested that the pathogenesis of
Nager syndrome may be attributed to disturbances in
development of the proximal aspects of the maxillary
and mandibular prominences of the first branchial arch
and the apical ectodermal ridges of the limb buds. Al-
though most reported cases have been sporadic, existing
evidence supports an autosomal recessive mode of in-
heritance.9-13 Various genetic loci have been investi-
gated in attempts to determine the site of genetic
alteration responsible.34-37 Zori et al34 suggested that
the gene mutation responsible for this disorder might
reside on chromosome 9q.
In the case presented, craniofacial findings included
micrognathia, orbitomalar hypoplasia, downslanting
palpebral fissures, and dysplastic ears as well as upper
limb malformations consisting of double thumb, short
forearm, and decreased mobility of the elbow articula-
tion, fulfilling the diagnostic criteria for Nager syn-
drome. In addition, the patient showed evidence of
genitourinary anomalies previously encountered in this
condition (Table I). An interesting feature in this case
is the unusual coexistence of thumb duplication and
radioulnar synostosis.5 Moreover, microdontia of the
primary teeth is a feature not usually described in this
condition. Another finding of note was the presence of
the ventricular septal defect, a condition that has been
reported rarely in Nager syndrome in the context of
tetralogy of Fallot.38,39 Other reported cardiopulmonary
anomalies include severe aortic stenosis and right
pulmonary bronchial stenosis.37
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Pathogenesis of cleft palate in Treacher Collins, Nager, andMiller syndromes. Cleft Palate J 1989;26:209-16.
2. Vargervik K. Mandibular malformations: growth characteristicsand management in hemifacial microsomia and Nager syndrome.Acta Odontol Scand 1998;56:331-8.
3. Nager FR, de Reynier JP. Das gehororgan bei den angeborenenkopfmissbildungen. Pract Otorhinolaryngol (Basel) 1948;10(Suppl 2):1-128.
4. Franceschetti A, Klein D. The mandibulo-facial dysostosis.A new hereditary syndrome. Acta Ophthalmol 1949;27:143-224.
5. Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head andneck. Oxford monographs on medical genetics no. 19. 3rd ed.New York: Oxford; 1990. p. 652-4.
6. MacDonald MT, Gorski JL. Nager acrofacial dysostosis. J MedGenet 1993;30:779-82.
7. Fryns JP, Bonhomme A, van den Berghe H. Nager acrofacialdysostosis: an adult male with severe neurological deficit. GenetCounsel 1996;7:147-51.
8. Wang RY, Earl DL, Ruder RO, Graham JM. Syndromic earanomalies and renal ultrasounds. Pediatr 2001;108:32-41.
9. Burton BK, Nadler HL. Nager acrofacial dysostosis. J Pediatr1977;91:84-6.
10. Wagner SF, Cole J. Nager syndrome with partial duplication ofthe long arm of chromosome 2. Am J Hum Genet 1979;31:116A.
11. Pfeiffer RA, Stoess H. Acrofacial dysostosis (Nager syndrome):synopsis and report of a new case. Am J Med Genet 1983;15:255-60.
12. Hecht JT, Immken LL, Harris LF, Malini S, Scott CI Jr. TheNager syndrome. Am J Med Genet 1987;27:965-9.
13. Chemke J, Mogilner BM, Ben-Litzhak I, Zurkowsi L, Ophir D.Autosomal recessive inheritance of Nager acrofacial dysostosis.J Med Genet 1988;25:230-2.
14. Lowry B. The Nager syndrome (acrofacial dysostosis): Evidencefor autosomal dominant inheritance. Birth Defects 1977;13:195-202.
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16. Aylsworth AS, Friedman PA, Powers SK, Kahler SG. Newobservations with genetic implications in two syndromes: (1)father to son transmission of the Nager acrofacial dysostosis syn-drome; and (2) parental consanguinity in the Proteus syndrome.Am J Med Genet 1987;41:43A.
17. Aylsworth AS, Lin AE, Friedman PA. Nager acrofacialdysostosis: male-to-male transmission in 2 families. Am J MedGenet 1991;41:83-8.
18. Aylsworth AS, Lin AE. Male to male transmission in a secondfamily supports autosommal dominant inheritance in Nageracrofacial dysostosis. Am J Hum Genet 1990;47:47A.
19. Bonthron DT, Macgregor DF, Barr DGD. Nager acrofacialdysostosis: minor familial manifestations supporting dominantinheritance. Clin Genet 1993;43:127-31.
20. Saksena SS, Walker GF, Bixler D, Yu PI. A clinical atlas ofroentgenocephalometry in norma lateralis. New York: Alan R.Liss; 1987.
21. Moyers RE. Handbook of orthodontics. 4th ed. Year BookMedical Publishers; Chicago. 1988.
22. Greulich WW, Pyle SL. Radiographic atlas of skeletal de-velopment of the hand and wrist. 2nd ed. Palo Alto (Calif):Stanford University Press; 1959.
23. Krauss CM, Hassell LA, Gang DL. Anomalies in an infant withNager acrofacial dysostosis. Am J Med Genet 1985;21:761-4.
24. Giugliani R, Pereira CH. Nager’s acrofacial dysostosis withthumb duplication: report of a case. Clin Genet 1984;26:228-30.
25. Gellis SS, Feingold M, Miller D. Nager’s syndrome (Nager’sacrofacial dysostosis). Am J Dis Child 1978;132:519-20.
26. Bowen P, Harley F. Mandibulo-facial dysostosis with limbmalformations (Nager’s acrofacial dysostosis). Birth Defects1974;10:109-15.
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27. Halal F, Hermann J, Pallister PD, Opitz JM, Desgranges M-F,Grenier G. Differential diagnosis of Nager acrofacial dysostosissyndrome: report of four patients with Nager syndrome anddiscussion of other related syndromes. Am J Med Genet 1983;14:209-24.
28. Jackson IT, Bauer B, Saleh J, Sullivan C, Argenta LC. Asignificant feature of Nager’s syndrome: palatal agenesis. PlastReconstr Surg 1989;84:220-6.
29. Temtamy SA, McKusick VA. The genetics of hand malforma-tions. Birth Defects 1978;14:92-5.
30. Meyerson MD, Nisbet JB. Nager syndrome: an update of speechand hearing characteristics. Cleft Palate J 1987;24:142-51.
31. Denny A, Talsman R, Hanson P, Recinos R. Mandibulardistraction osteogenesis in very young patients to correct airwayobstruction. Plast Reoconstr Surg 2001;108:302-10.
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33. Sulik KK, Dehart DB. Retinoic-acideinduced limb malforma-tions resulting from apical ectodermal ridge cell death. Teratology1988;37:527-37.
34. Zori RT, Gray BA, Bent-Williams A, Driscoll DJ, Williams CA,Zackowski JL. Preaxial acrofacial dysostosis (Nager syndrome)associated with an inherited and apparently balanced X;9translocation: prenatal and postnatal late replication studies. AmJ Med Genet 1993;46:379-83.
35. Dreyer SD, Zhou L, Machado MA, et al. Cloning, characteriza-tion, and chromosomal assignment of the human ortholog ofmurine Zfp-37, a candidate gene for Nager syndrome. MammGenome 1998;9:458-62.
36. Norris RA, Scott KK, Moore CS, et al. Human PRRX1 andPRRX2 genes: cloning, expression, genomic localization, andexclusion as disease genes for Nager syndrome. Mamm Genome2000;11:1000-5.
37. Waggoner DJ, Ciske DJ, Dowton SB, Watson MS. Deletion of 1qin a patient with acrofacial dysostosis. Am J Med Genet 1999;82:301-4.
38. Opitz JM. Nager ‘‘syndrome’’ versus ‘‘anomaly’’ and its nosol-ogy with the postaxial acrofacial dysostosis syndrome of Geneeand Wiedemann. Am J Med Genet 1987;27:959-63.
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Reprint requests:
Dr K. Antoniades
Dept, of Oral and Maxillofacial Surgery
Dental School
Aristotle University of Thessaloniki
54 006 Thessaloniki
Greece
