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CLINICAL REPORT

Possible Autosomal Recessive Inheritance inan Infant With Acrofacial Dysostosis Similar toNager Syndrome

Banu Guzel Nur,1 Francois P. Bernier,2 Osman Oztekin,3 Fırat 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, Turkey

Manuscript Received: 12 July 2012; Manuscript Accepted: 25 April 2013

How 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:2311–2315.

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 1q12–q21were 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 limb

malformations; tracheostomy; prenatal diagnosis

Conflict of interest: None.�Correspondence to:

Assoc. Prof. Dr. Ercan Mihci M.D., Department of Pediatric Genetics,

Akdeniz University School of Medicine, 07059 Antalya, Turkey.

E-mail: emihci@akdeniz.edu.tr

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 2 August 2013

DOI 10.1002/ajmg.a.36051

INTRODUCTION

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 [1948]. 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 a

2013 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. [2012]

recently demonstrated that mutations in SF3B4—a component of

the pre-mRNA spliceosomal complex—is 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 Nager

2311

2312 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

syndrome. 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 couple’s 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 (10–50th

centile), her birth lengthwas 41 cm (10–50th centile), and her head

circumference was 31 cm (50–90th 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. 2313

Chromosome 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

mutations.

DISCUSSION

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-son

FIG. 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. [2012] who identified heterozygous

mutations in SF3B4—acomponent 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. [2012] 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 A

short 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. [2012] shown in

Table I.

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, muscular

FIG. 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

syndrome.

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. [1987] 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

techniques.

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.

Features

Bernier et al. patient

(a total of 26 patients) Present patient

Inheritance 19 Sporadic;

7 autosomal dominant

Autosomal

recessive

Gender 18 female; 8 male Female

Age (years) Mean 14.5 years 1 day

Downslanding palpebral

fissures

20 (31%) þ

Absent lower eyelashes 11 (42%) �Midface retrusion 17 (65%) þMicrognathia 23 (88%) þAnkylosis of

temporomandibular

joints

2 (7%) �

Abnormal palate 15 (57%) þTracheostomy 9 (34%) þAbnormal ears 19 (73%) þHearing loss 19 (73%) þRadial ray abnormality 10 (38%) þAbnormal thumbs 22 (84%) Unilateral

Radioulnar synostosis 14 (53%) �Development delay 6 (23%) �Congenital heart defect 3 (11%) þOther malformations Diaphragmatic hernia,

abnormal teeth,

strabismus,

dacryostenosis,

foot deformities,

hallux valgus,

arachnodactly,

subglottic stenosis,

clubfoot, renal anomaly,

limited range of

motion in extremities

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NUR ET AL. 2315

was 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

Informed consents were obtained from the patient parents.

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