CLINICAL REPORTPossible Autosomal Recessive Inheritance inan Infant With Acrofacial Dysostosis Similar toNager Syndrome
Banu Guzel Nur,1 Francois P. Bernier,2 Osman Oztekin,3 Frat Kardelen,4 Salih Kalay,3
Jillian S. Parboosingh,2 and Ercan Mihci1*1Department of Pediatric Genetics, Akdeniz University School of Medicine, Antalya, Turkey2Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada3Department of Pediatric Neonatology, Akdeniz University School of Medicine, Antalya, Turkey4Department of Pediatric Cardiology, Akdeniz University School of Medicine, Antalya, TurkeyManuscript Received: 12 July 2012; Manuscript Accepted: 25 April 2013How to Cite this Article:Nur BG, Bernier FP, Oztekin O, Kardelen
F, Kalay S, Parboosingh JS, Mihci E. 2013.
Possible autosomal recessive inheritance in
an infant with acrofacial dysostosis similar
to Nager syndrome.
Am J Med Genet Part A 161A:23112315.The acrofacial dysostosis syndromes, which are characterized by
malformations of the craniofacial region and limbs, are a clini-
cally heterogeneous groupofdisorders.Basedprimarily on theof
the pattern of limb defects two major groups have emerged:
Nager syndrome with predominantly preaxial malformations
plusmandibulofacial dysostosis (severemicrognathia andmalar
hypoplasia) and Miller syndrome with postaxial malformations
plusmandibulofacial dysostosis.Among these syndromes,Nager
syndrome is a rare condition but the most common form of
acrofacial dysostosis. Most cases are sporadic, while autosomal
dominant and autosomal recessive inheritance patterns have
been reported. Recently, heterozygous mutations in the SF3B4
gene on chromosome 1q12q21were found to be responsible for
a subset of sporadic and autosomal dominant cases.Wepresent a
female infant born to consanguineous parents with craniofacial
features resembling Nager syndrome and a unilateral preaxial
limbmalformation. Mutation analysis of coding exons of SF3B4
did not identify any mutations. This couple also had a deceased
child who had similar clinical features. We conclude that, the
presence of consanguinity and absence of mutation in SF3B4,
provides evidence in support of a recessive form of Nager
syndrome. 2013 Wiley Periodicals, Inc.
Key words: Nager syndrome; acrofacial dysostosis; preaxial limbmalformations; tracheostomy; prenatal diagnosisConflict of interest: None.Correspondence to:Assoc. Prof. Dr. Ercan Mihci M.D., Department of Pediatric Genetics,
Akdeniz University School of Medicine, 07059 Antalya, Turkey.
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 2 August 2013
The acrofacial dysostoses are a heterogeneous group of disorders
involving craniofacial and limb abnormalities. Nager syndrome
(NS OMIM #154400) is the most common form of acrofacial
disostosis, first defined by Nager and de Reynier . NS is a
rare syndrome, with fewer than 100 patients described in the
literature. The incidence is 3:1,000,000 in Finland [Halonen
et al., 2006]. Nager syndrome is a pleiotropic disorder with variable
expressivity [McDonald and Gorski, 1993]. It is characterized by a2013 Wiley Periodicals, Inc.mandibulofacial dysostosis with preaxial limb malformations in-
cluding radial limb hypoplasia and absence or hypoplasia of the
thumb. The main facial features include severe micrognathia and
malar hypoplasia. The main problems experienced by affected
infants are upper airway obstruction leading to feeding and respi-
ratory difficulties. Neonatal death due to respiratory distress have
been reported [Herrmann et al., 2005].
Most patients appear to represent simplex cases; however,
autosomal dominant and autosomal recessive inheritance patterns
have been reported [Zhang et al., 2010]. The pattern of inheritance
in most families was unclear until recently. Bernier et al. 
recently demonstrated that mutations in SF3B4a component of
the pre-mRNA spliceosomal complexis responsible for Nager
syndrome [Bernier et al., 2012]. In their report, all autosomal
dominant families and 60% of their sporadic cases were found
to have mutations in SF3B4 supporting the hypothesis that Nager2311
2312 AMERICAN JOURNAL OF MEDICAL GENETICS PART Asyndrome. The presence of sporadic cases without the mutation
suggested heterogeneity for Nager syndrome.
We report on a female infant with a condition resembling Nager
syndrome and a unilateral preaxial limb defect. The consanguinity
between the parents and the presence of another affected sib in the
family suggests autosomal recessive inheritance. The patient does
not have a coding mutation in SF3B4, the only known gene
responsible for Nager syndrome.CLINICAL REPORT
This female infant was born at the 32ndweek of gestation by vaginal
delivery as the third child of healhty first cousin parents. Second
trimester prenatal ultrasounds showed micrognathia, and possible
ear anomaly. The family declined amniocentesis. The couples first
child died in early neonatal period with a history of similar clinical
findings without a specific diagnosis (Fig. 1). Family history is
unremarkable otherwise and the parents are healthy with no
dysmorphic features. Her APGAR scores were 4 at 1 min and 6
at 5 min. She showed immediate evidence of respiratory distress
and intubation was attempted at delivery room but failed due to
severe micrognathia. An oropharyngeal airway was initially used
and then a tracheostomy was placed.FIG. 1. The pedigree of the patient.On physical examination, her birth weight was 1,850 g (1050th
centile), her birth lengthwas 41 cm (1050th centile), and her head
circumference was 31 cm (5090th centile). She had multiple
dysmorphic features consistent with Nager syndrome including
low-set, malformed, and posteriorly rotated ears, bilateral absence
of the antihelices and cruses of helices, bilateral atretic auditory
canals, downslanting palpebral fissures, microretrognathia, prom-
inent premaxilla, cleft palate, broad nasal bridge, long philtrum,
hypoplastic nipples, broad and short left thumb, and left thumbnail
hypoplasia (Figs. 2A,B and 3). Examination of the right thumb and
forearm was normal.
Her lateral cranial radiographs revealed severe microretrogna-
thia. Her limb radiographs showed bilateral shortness of the radial
bone (Fig. 4). Echocardiography detected a secumdum atrial septal
defect,muscular ventricular septal defect, and subaortic ventricular
septal defect (Fig. 5). Temporal computarized tomography showed
bilateral auditory canal stenosis, and cranial magnetic resonance
imaging revealed bilateral mild intra-ventricular hemorrhage.
Audiological examination showed bilateral severe conductive hear-
ing loss. Results of abdominal ultrasound and opthalmologic
examination were both normal.
Complete blood count and routine biochemistry tests for
renal, liver, and thyroid function were within normal limits.
FIG. 2. Facial phenotype of the patient. Lateral view (A) and frontal view (B) on the second day of life showing severe microretrognathia,
prominent pre-maxilla, dysplastic ear, low set ear, atretic auditory canal, and tracheostomy.
NUR ET AL. 2313Chromosome analysis of peripheral blood using high resolution
binding technique showed a normal 46,XX karyotype. Sequencing
of the coding exons of SF3B4 did not identify any pathogenic
The pathogenesis of Nager syndrome may be attributed to dis-
turbances in development of the proximal aspects of the maxillary
andmandibularprominences of thefirst and secondbranchial arch,
and the apical ectodermal ridges of the limbbuds [Sulik et al., 1989].
Although most reported patients have been sporadic, the occur-
rence of several affected individuals within families suggests an
underlying inherited genetic cause. A family with father-to-sonFIG. 3. Limb phenotype of the patient. Left thumb shortness
and left thumb nail hypoplasia.transmission and a family with mother-to-son transmission
strongly support the hypothesis that some cases of Nager syndrome
occur in individuals who are heterozygous for dominantly
expressed, autosomal mutations [Hall, 1989; Aylsworth et al.,
1991]. In addition, there are only a few patients reported with
apparent autosomal recessive transmission [Chemke et al., 1988].
In our family, the presence of consanguinity and two affected
siblings of different genders supports previous suggestions of an
autosomal recessive mode of inheritance of Nager syndrome, at
least in some families.
Recently, autosomal dominant inheritance of Nager syndrome
was confirmed by Bernier et al.  who identified heterozygous
mutations in SF3B4acomponent of thePre-mRNASpliceosomal
Complex. They reported 35 families affected by sporadic or familial
(autosomal dominatly inherited) Nager syndrome and in 20 fami-
lies SF3B4 gene mutation identified. Eighteen different SF3B4 gene
mutation were identified and all were predicted to result in a
truncated protein suggesting that Nager syndrome was the result
of SF3B4 haploinsufficiency [Bernier et al., 2012]. It is anticipated
that Nager syndrome will eventually be confirmed as genetically
heterogenous as mutations in SF3B4 gene were identified in only
57%of patients in the Bernier et al.  cohort. In our patient, an
SF3B4 mutation was not detected which may lead to further
research in identification of a gene responsible for an autosomal
recessive form of Nager syndrome.
Nager syndrome is relatively easily recognized in the neonatal
period due to the characteristic facial features [Paladini et al., 2003].
The mandibulofacial features of Nager syndrome include down-
slantingpalpebral fissures, highnasal bridge,malar andmandibular
hypoplasia, maxillary hypoplasia, severe microretrognathia, absent
velum, atretic external auditory canals, and small, malformed or
low-set ears. The preaxial limb malformations include hypoplastic
or missing thumbs, hypoplastic radii, radioulnar synostosis, and
shortened humerus bones. Although mild learning disability,
growth delay, short stature, and conductive hearing loss are com-
mon in these patients, most have normal intelligence [Halal
et al., 1983; Hecht et al., 1987]. In our patient, the features are
consistent with Nager syndrome, but the presence of a broad and
FIG. 4. Radiographic imaging of patients. Severe microretrognathia on cranial radiography (A), right and left radial hypoplasia, and thumb
hypoplasia on the bilateral limb radiography (B).
2314 AMERICAN JOURNAL OF MEDICAL GENETICS PART Ashort left thumb is an unusual finding of this syndrome and
further genotype/phenotype will be required to determine if this
clinical feature distinguishes a sub-catergory of Nager syndrome.
Comparison of the clinical features of our patient and Nager
syndrome patients reported by Bernier et al.  shown in
Congenital heart defects are not among common features of
Nager syndrome. However, various defects have been reported
on several occasions [Schonenberg, 1968; Thompson et al., 1985;
Bernier et al., 2012]. Our patient had a complex congential
heart defect including a secundum atrial septal defect, muscularFIG. 5. Echocardiographic imaging showing secundum atrial
septal defect, muscular ventricular septal defect, and subaortic
ventricular septal defect.ventricular septal defect, and subaortic ventricular septal defect.
This finding might expand the clinical spectrum of Nager
Differential diagnosis of mandibular hypoplasia include Nager
syndrome, Miller syndrome, Treacher Collins syndrome, Richieri-
Costa-Pereira syndrome, acrofacial dysostosis syndrome-type
Rodriguez, and mandibulofacial dysostosis with microcephaly
(craniofacialmalformations associatedwithmicrocephaly, choanal
atresia, sensorineural hearing loss, cleft palata) [Walter-Nicolet
et al., 1999; Zhang et al., 2010; Favaro et al., 2011; Lines et al., 2012].
Our patient is distinguished from these other syndromes with
typical facial features of a mandibulofacial defect, preaxial limb
defects, and normal head circumference. The atypical appearance
of thumbs (short and broad) as well as the presence of consanguini-
ty may indicate that in fact our patient has a novel subtype of
acrofacial dysotosis. Additional molecular studies are being
performed and may be required to further understand the classifi-
cation of acrofacial dysostoses.
The diagnosis of Nager syndrome can be feasible prenatally, as
early as 22nd gestation week and must be suspected if severe
micrognathia, forearm shortening and absence of one or more
digits are detected.Hecht et al.  identifiedNager syndrome in
a newborn infant and in a subsequent sib by prenatal ultrasonog-
raphy [Hecht et al., 1987]. In these patients, severe microretrog-
nathiamay result in acute upper airway obstruction after birth, and
feeding difficulties during neonatal period. Tracheostomy may be
necessary to secure breathing and a gastrostomy for feeding. Radial
ray anomalies (or you can used malformations) may require
surgical correction. Therefore prenatal diagnosis is essential to
help the parents to make their decision and the physician to be
adequately prepared for postnatal cares [Paladini et al., 2003].
In our patient facial abnormality was suspected by prenatal ultra-
sonography but the parent declined other advanced imaging
In conclusion, the family we report is highly suggestive of an
autosomal recessive acrofacial dysotosis similar toNager syndrome.
Mutation analysis for the single gene known to date, namely SF3B4
TABLE I. Clinical Features of Present Patient and NagerSyndrome Patients Reported by Bernier et al.
Bernier et al. patient
(a total of 26 patients) Present patient
Inheritance 19 Sporadic;
7 autosomal dominant
Gender 18 female; 8 male Female
Age (years) Mean 14.5 years 1 day
Absent lower eyelashes 11 (42%) Midface retrusion 17 (65%) Micrognathia 23 (88%) Ankylosis of
Abnormal palate 15 (57%) Tracheostomy 9 (34%) Abnormal ears 19 (73%) Hearing loss 19 (73%) Radial ray abnormality 10 (38%) Abnormal thumbs 22 (84%) Unilateral
Radioulnar synostosis 14 (53%) Development delay 6 (23%) Congenital heart defect 3 (11%) Other malformations Diaphragmatic hernia,
clubfoot, renal anomaly,
limited range of
motion in extremities
NUR ET AL. 2315was negative. Clarification of the genetic basis of acrofacial
dysotoses is crucial to further help delineate genotype/phenotype
correlation and also determine inheritance pattern in order to
provide accurate genetic counseling.ACKNOWLEDGMENTS
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