Possible autosomal recessive inheritance in an infant with acrofacial dysostosis similar to nager syndrome

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  • 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.

    E-mail: emihci@akdeniz.edu.tr

    Article first published online in Wiley Online Library

    (wileyonlinelibrary.com): 2 August 2013

    DOI 10.1002/ajmg.a.36051INTRODUCTION

    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 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. [2012]

    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

    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-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. [2012] 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. [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 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. [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, 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

    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%)

    Absent lower eyelashes 11 (42%) Midface retrusion 17 (65%) Micrognathia 23 (88%) Ankylosis of

    temporomandibular

    joints

    2 (7%)

    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,

    abnormal teeth,

    strabismus,

    dacryostenosis,

    foot deformities,

    hallux valgus,

    arachnodactly,

    subglottic stenosis,

    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

    Informed consents were obtained from the patient parents.REFERENCES

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