J Med Genet 1993 30: 779-782

SYNDROME OF THE MONTH

Nager acrofacial dysostosis

Marie T McDonald, Jerome L Gorski

Departments ofPediatrics andCommunicableDiseases, University ofMichigan MedicalCenter, Ann Arbor,MI 48109-0688, USA.M T McDonald

Department ofHuman Genetics,University ofMichigan MedicalCenter, Ann Arbor,MI 48109-0688, USA.J L Gorski

Correspondence toDr Gorski, Division ofPediatric Genetics, 3570Medical Science ResearchBuilding II, Box 0688,University of MichiganMedical Center, Ann Arbor,MI 48109-0688, USA.

Nager acrofacial dysostosis (NAD) is an inher-ited disorder of facial, limb, and skeletal mor-phogenesis. The disorder was recognised as aspecific entity by Nager and de Reynier in1948,' but was probably first reported bySlingenberg in 1908.2 Here we present asummary of 76 previously reported cases"'9with the addition of two new cases. In somefamilies, NAD is inherited as a pleiotropicautosomal dominant condition with markedlyvariable penetrance and expressivity. How-ever, the occurrence of affected sibs with nor-mal parents suggests potential genetic hetero-geneity and an additional autosomal recessiveform.

Clinical featuresThe main clinical features consist of cranio-facial, limb, and musculoskeletal anomalies.Less frequently, other malformations have alsobeen reported. The common clinical featuresofNAD are summarised in the table.

CRANIOFACIALThe facial features of NAD are distinctive;cardinal features include downward slantingpalpebral fissures, malar hypoplasia, a highnasal bridge, micrognathia, and external eardefects (figs 1 and 2). Extension of scalp haironto the cheeks, a reduced number of eye-lashes, and lower lid colobomas occur lessfrequently. The most common external earanomalies include external auditory canal ste-nosis and low set positioning. Posteriorrotation and preauricular skin tags have beenobserved less frequently.'01516 Hearing loss isan important feature; it is typically bilateral,conductive, and of the order of 50 to 70 dB.Even in the absence of external ear anomalies,ossicular chain malformations may occur. Thepredominant oral findings include cleft palateand an absent soft palate. Cleft lip, velo-pharyngeal insufficiency, and foreshorteningof the soft palate occur less frequently. Hypo-plasia of the larynx or epiglottis occurs rarely. 17Temporomandibular joint fibrosis and ankylo-

2238sis may occur.

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Figure 1 Photographs of proband's face (A) and hands (B,C) at 4 monthsNAD features include downward slanting palpebral fissures, malar hypoplasiinasal bridge, dysmorphic pinnae, a low set left ear, and micrognathia (A). Tithumb is hypoplastic and fixed in a flexed position (B); the right thumb is ab.

LIMB DEFECTSLimb anomalies are a cardinal sign of NADand, in combination with the characteristicfacial features, are diagnostic. Typical limbabnormalities include preaxial anomalies(hypoplastic or absent thumbs and radii) andproximal radioulnar synostosis (fig 3). Thumbanomalies are usually asymmetrical. Dupli-cated'8 and triphalangeal thumbs689may occur.Infrequent hand anomalies include syndac-tyly, clinodactyly, and camptodactyly. A var-iety of lower limb anomalies have beenreported, including phocomelia,9 dislocatedhips,72'22 talipes equinovarus, metatarsusvarus,"1 and an absent tibia/fibula.916 1920 Toeabnormalities include overlapping toes, syn-dactyly, isolated cases of absent toes,2' hypo-plastic toes,22 posteriorly placed hypoplastichalluces,'0 hallux valgus,'5 broad hallux,26 dor-

( sal angulation of the second toe,26 and medialdeviation of the toes."2' Limb reduction de-fects were a prominent feature in sevencases.9 10 16 20 25 27

SKELETAL ANOMALIESof age. Abnormalities of the axial skeleton have in-a, a high cluded thoracolumbar scoliosis528 and cervical'he left

126 3 1728,sent (c). vertebral2 and rib anomalies."2

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Figure 2 Photographs of the face (A) and left hand (B) of the proband's mother. NAD features includedownward slanting palpebral fissures, malar hypoplasia, a high nasal bridge, dysmorphic pinnae, and a low set leftear (A); she had a repaired cleft palate (not shown). The left thumb is hypoplastic and fixed in extension; noflexion creases are present (B).

Figure 3 Radiographs of proband's left hand (A) and arm (B) at 4 months of age. The first metacarpal andphalanges are hypoplastic (A) and proximal radioulnar synostosis is present (B).

OTHER MALFORMATIONSA variety of other structural anomalies havebeen reported less frequently. Genitourinaryabnormalities have included vesicoureteralreflux,'8 unilateral renal agenesis externalgenital hypoplasia," 16 duplicated ureter,'6 andbicornuate uterus.'627 Gastrointestinal abnor-malities have included gastroschisis29 andHirschsprung's disease. " Cardiovascularmalformations have included tetralogy ofFallot,'2030 a ventricular septal defect,'6 andsubvalvular muscular obstruction of the rightventricular outflow tract.8 Central nervoussystem anomalies have included micro-cephaly,I1'24 28 31 aqueductal stenosis resulting inhydrocephalus,20 and polymicrogyria.'0

GeneticsMost cases of NAD have been sporadic withno recognised affected family members. No

karyotypic abnormality has been reported. Sixcases of parent to child transmission have beenreported>'2 (mother to child in three cases,father to son in three cases). In the family wereport here, an affected son (fig 1) was born toan affected mother (fig 2), displaying probableautosomal dominant inheritance. Another ex-ample of autosomal dominant inheritance wasreported by Weinbaum et al.'3 The probandhad typical features of NAD and milder clini-cal features were present in five other familymembers spanning four generations. NAD hasbeen found to display a wide range of pene-trance and expressivity (table). For example,Le Merrer et al9 reported an infant with lethalNAD with severe mandibulofacial dysostosisand phocomelia. The mother, however, wasrelatively mildly affected with features includ-ing downward slanting palpebral fissures,malar hypoplasia, a hypoplastic right thumb,and a triphalangeal right thumb. In addition,

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Nager acrofacial dysostosis

Primary clinical features of Nager acrofacial dyostosis (NAD).

Present casestApparently autosomal Autosomal

Clinical features Published cases* Proband Mother recessive casest dominant cases§

CraniofacialMalar hypoplasia 67/67 + + 7/7 13/13Downward slanting palpebral fissures 61/61 + + 6/6 12/12Reduced number of eyelashes 20/25 + - 1/3 5/6Lower lid coloboma 15/30 - - 3/3 1/5High nasal bridge 43/44 + + 4/4 4/4Micrognathia 68/69 + + 6/6 13/13Cleft palate 26/36 - + 2/2 5/6Absent soft palate 14/14 -

Cleft lip 6/60 - - 2/5 1/9Extension of hair onto cheek 10/14 - - 3/5External ear defects 51/56 + + 8/9 8/10External auditory canal atresia 48/52 - + 8/8 6/8Low set ears 39/39 + + 3/3 6/6Conductive hearing loss 33/35 + + 5/5 6/6Limb defectsAbsent thumb 44/67 + - 6/6 6/7Hypoplastic thumb 33/69 + + 4/4 11/11Radial hypo/aplasia 34/34 - - 5/5 3/5Proximal radioulnar synostosis 16/19 + 5/6 2/2Other structural anomaliesCentral nervous system 6Cardiovascular system 4 1Gastrointestinal tract 3 1Genitourinary 7 1

* Clinical features previously reported in 76 cases of NAD.A9t NAD family described in this report; affected family members include the proband (fig 1) and his mother (fig 2).+ Five previously reported families with normal parents and 2 affected sibs."§ These eight families include the NAD family described in this report (figs 1 and 2) and seven previously reported cases showingvertical transmission.>'

Halal et aP8 described a child with typicalNAD whose mother's features were limited tomicrognathia. These case reports are mostconsistent with NAD being inherited as anautosomal dominant trait with variable pene-trance and expressivity.The occurrence of consanguinity in two

cases'63' and the observation of six familieswith normal parents and two affected sibs'8have suggested that NAD may also be inheritedas an autosomal recessive trait. In the casereported by Byrd et al,8 the affected sibs werefemale monozygotic twins, an observation con-sistent with either autosomal recessive or auto-somal dominant inheritance. As shown in thetable, the apparently dominant and recessiveforms of NAD have phenotypic overlap; theclinical features of the patients with a presumablyautosomal recessive form ofNAD were similarto those reported for affected family membersshowing autosomal dominant inheritance. Nophenotypic features distinguished either groupof patients. In addition, the clinical features ofpatients with an apparently sporadic form ofNAD were indistinguishable from those of theinherited cases. Although these cases indicatethat genetic heterogeneity is likely, it is notpossible to exclude parental germline mosai-cism4' as a possible explanation for some of thecases attributed to an autosomal recessive trait.

Growth and developmentGenerally, growth was reported as normal.However, short stature was reported in 11cases. In the 76 reported cases, developmentwas reported as normal in 22 and delayed infour cases; isolated speech and language delaysoccurred in eight cases. No developmentaldetails were available in 30 cases; 15 affectedpatients died in the perinatal period and 15affected patients were reported as newborns orinfants. In 10 cases, no details regarding de-

velopment were provided. Mental retardationwas reported in two affected subjects.2428 De-velopmental delays, particularly in the area ofspeech and language, were attributed to hear-ing loss, frequent admissions to hospital, andother medical problems.

Natural history and managementFifteen affected subjects (20%) were stillbornor died in the neonatal period. Most of thesewere severely affected with facial clefting andsevere limb reduction anomalies. Most of thesecases had structural anomalies of the cardio-vascular, gastrointestinal, or genitourinarysystems. Respiratory distress, as a result ofmandibular hypoplasia and palatal anomalies,contributed to the cause of death in nine of the15 cases. Several surgical techniques have beenused to maintain airway patency. Tongue-lipsuturing, gavage feeding, gastrostomy, andtracheostomy have all been described in NADpatients; gastrostomy or gavage feeding wasnecessary in most of the reported cases.Measures taken to protect airway patency,such as tracheostomy and gastrostomy, mayinterfere with normal oral motor developmentand result in speech and language delays. Earlyaudiological evaluations and speech therapyare recommended. A multidisciplinary teamapproach with the involvement of neonato-logy, paediatrics, otolaryngology, plastic sur-gery, dentistry, reconstructive hand surgery,and genetics best meets the many needs of theNAD patient. The prenatal diagnosis ofNADhas been described.4 19

Differential diagnosisMandibulofacial dysostosis (Treacher-Collinssyndrome) and maxillofacial dysostosis havefacial features closely resembling NAD butlack the limb abnormalities. Postaxial acro-

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facial dysostosis syndrome4142 can be differen-tiated from NAD by the involvement of thefifth digital ray of all four limbs and the highfrequency of accessory nipples. The Genee-Wiedemann syndrome is characterised bypostaxial limb involvement with involvementof the ulna and fibula, facial dysostosis, andcup shaped auricles. Wagner and Cole43reported a case of a male infant with a duplica-tion of 2q31 qter with some features suggestiveof NAD, including downward slanting palpe-bral fissures, shallow orbits, posteriorlyrotated ears, a hypoplastic mandible, and shortradii; however, cardinal features ofNAD, suchas hypoplastic thumbs, cleft palate, and deaf-ness, were not present. Although Fontainesyndrome44 has some features in common withNAD, such as cleft palate and micrognathia,the hand and feet anomalies are different andconsist of ectrodactyly and cleft hands andfeet. Radial ray defects occur in a number ofother syndromes such as Holt-Oram syn-

drome, VATER association, TAR syndrome,and Fanconi syndrome.

We thank the patient and family for theircontinued cooperation and Susan Williamsonand Diane Voss for assistance in preparing themanuscript. This work was supported in partby the State of Michigan Department of Pub-lic Health Newborn Screening and GeneticServices Project to JLG.

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