Acromelic Frontonasal Dysostosis

Sarah F. Slaney,1* Frances R. Goodman,2 Betty L.C. Eilers-Walsman,3 Bryan D. Hall,4Denise K. Williams,5 Ian D. Young,5 Richard D. Hayward,6 Barry M. Jones,6 Arnold L. Christianson,7and Robin M. Winter1

1Mothercare Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, London, UK2Molecular Medicine Unit, Institute of Child Health, London, UK3Intensive Care Nursery, Columbia Womens’ Hospital, Indianapolis, Indiana4Division of Genetics, Department of Pediatrics, Lexington, Kentucky5Clinical Genetics Service, City Hospital National Health Service Trust, Nottingham, UK6Craniofacial Unit, Great Ormond Street Hospital, London, UK7Department of Human Genetics and Developmental Biology, University of Pretoria,Pretoria, Republic of South Africa

We report on 3 male and 2 female infantswith acromelic frontonasal dysostosis. All 5had a frontonasal malformation of the faceand nasal clefting associated with strikingsymmetrical preaxial polysyndactyly of thefeet and variable tibial hypoplasia. In con-trast, the upper limbs were normal. Thisrare variant of frontonasal dysplasia mayrepresent a distinct autosomal-recessivedisorder. We suggest that the molecular ba-sis of this condition may be a perturbationof the Sonic Hedgehog (SHH) signallingpathway, which plays an important part inthe development of the midline central ner-vous system/craniofacial region and thelimbs. Am. J. Med. Genet. 83:109–116, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: acromelic frontonasal dysos-tosis; anterior cranium bif-idum; preaxial polysyndac-tyly; autosomal-recessive in-heritance

INTRODUCTION

Frontonasal dysplasia (FND) is a localized develop-mental anomaly of the craniofacial region character-ized by hypertelorism and a variable degrees of mediannasal clefting [Sedano et al., 1970]. The cause is un-clear but most cases are sporadic [Gorlin et al., 1990].There have been several reports of a rare variant ofFND in which similar craniofacial anomalies are asso-

ciated with central nervous system (CNS) malforma-tions and limb defects including tibial hypoplasia/aplasia, talipes equinovarus, and preaxial polydactylyof the feet [Sedano et al., 1970; Calli, 1971; Edwards etal., 1971; Warkany et al., 1973; Toriello et al., 1986;Neidich et al., 1988; Prescott et al., 1989; Verloes et al.,1992; Sueldo and Fernandes, 1993]. This combinationof anomalies has been called “acromelic frontonasaldysplasia” (AFND) [Verloes et al., 1992]. Here we de-scribe 5 more infants with AFND, review the pheno-typic spectrum, discuss the mode of inheritance, andsuggest candidate genes for the disorder.

CLINICAL REPORTSCase 1

This male infant was the second child of nonconsan-guineous English parents, born by normal delivery at42 weeks of gestation after an uneventful pregnancy.No specific abnormalities had been detected by routineultrasound scan at 20 weeks of gestation. At birth hishead circumference was 35.0 cm and weight was 3,700g (both 50th–75th centiles). He had severe frontonasaldysostosis with a broad nasal root, a midline nasalcleft, and complete separation of the nostrils, but with-out cleft palate. Despite these abnormalities hebreathed spontaneously without respiratory distress.There was severe hypertelorism with bilateral blepha-rophimosis (Fig. 1). His upper limbs, including hishands, were normal, but the lower limbs were short,with bilateral talipes equinovarus and preaxial poly-syndactyly of the feet (Fig. 2). He also had bilateralinguinal herniae, although the testes were descended.When he was seen at age 7 months, he was alert andvisually attentive. Formal ophthalmological assess-ment suggested normal vision with normal visual-evoked potentials. His hearing was normal. There wassome truncal hypotonia and he was not yet sitting un-supported. His head circumference was now 45.2 cm(>50th centile), and there were two palpable defects inthe skull over the parietal regions. There was a capil-

*Correspondence to: S.F. Slaney, Mothercare Unit of ClinicalGenetics and Fetal Medicine, Institute of Child Health, 30 Guil-ford St., London WC1N 1EH, UK. E-mail: s.slaney@ubht.swest.nhs.uk

Received 21 July 1998; Accepted 23 November 1998

American Journal of Medical Genetics 83:109–116 (1999)

© 1999 Wiley-Liss, Inc.

lary hemangioma on the back of his head. An abdomi-nal ultrasound scan and an echocardiogram were bothnormal. Computer-generated three-dimensional im-ages of the skull confirmed the frontonasal and parietaldefects (Fig. 3), but cranial magnetic resonance imag-ing showed no specific malformations of the brain apartfrom dilated lateral cerebral ventricles. Radiographs ofthe lower limbs showed hypoplastic tibiae, especiallyon the right, and bilateral preaxial duplications of theproximal and distal phalanges of the halluces. Chro-mosome analysis showed a normal male karyotype,46,XY. By age 15 months he had made some develop-mental progress but was not able to stand and had notyet developed speech. Craniofacial surgery was due tobe carried out when he was 18 months old, but prior tothis he died after an unexpected apneic episode.

Case 2

This male infant was born at full term weighing2,622 g (<3rd centile), to American parents who werefirst cousins once removed. The maternal grandmoth-

er’s brother and a second brother’s son had died neo-natally with “deformed faces,” although further detailsof these individuals were not available. It was un-known whether any consanguinity had occurred on herside of the family. In the first trimester of pregnancythe mother had a pyrexial illness and smoked 20 ciga-rettes per day. In the third trimester, she reported re-duced fetal movements. Multiple congenital malforma-tions were observed after birth, including frontonasaldysplasia with widely separated nares, clefting of thealae nasi, inverted V-shape of the upper lip, and aprominent mass of soft tissue over the open metopicsuture (Fig. 1). Bilateral talipes eqinovarus, absence ofthe right tibia, bilateral bifid halluces with partial syn-dactyly (Fig. 2), anal stenosis, bilateral cryptorchidism,and a presacral dimple were also noted. A skeletal sur-vey showed delayed ossification of the pubic symphysisand failure of intramembraneous bone formation in theskull vertex. A CT scan of the brain showed no en-cephalocoele or other structural anomalies. Chromo-some analysis resulted in a normal male karyotype,

Fig. 1. Craniofacial appearances of cases 1, 2, 4, and 5.

110 Slaney et al.

46,XY. An ophthalmological assessment showed mildbilateral microphthalmos. Brain-stem auditory-evokedresponses were reduced. By age 10 months he was fail-ing to thrive, his weight was 5,110 g, length was 57.1cm (both below the 3rd centile), and his head circum-ference was 43.5 cm (3rd centile). He had poor headcontrol, truncal hypotonia, and significant develop-mental delay. When reviewed at 17 months he hadmade progress and begun to use a few single words.Unfortunately at the age of 2 years and 10 months hedied of acute respiratory failure due to aspiration ofgastric contents after an episode of choking. Autopsyconfirmed the congenital abnormalities found on clini-cal examination. Detailed study of the central nervoussystem also demonstrated anomalous gyral configura-tion of the temporal lobes, hypoplasia of the right lat-eral geniculate body, hypoplasia of the right olfactorytract with agenesis of the right olfactory bulb, focalcerebellar cortical dysplasia, and abnormal distribu-tion of the visual cortex.

Case 3

This was the first child of young Pakistani parents,who were first cousins. There was no contributory fam-ily history and they have subsequently had two healthychildren. Although planned and free of any known ter-atogenic exposure, the pregnancy was not booked until

35 weeks of gestation. An ultrasound scan at this timedemonstrated major congenital abnormalities involv-ing the face and lower limbs. Spontaneous onset of la-bor occurred at 42 weeks, and delivery was by assistedbreech under general anesthetic. The infant was anactive girl in whom a number of external malforma-tions were noted. Although immediate resuscitationwas not required, she was transferred to the neonatalintensive care unit where she died at age 18 hr of re-spiratory failure. The baby’s birth weight was 3,400 g(25th centile), and her head circumference was 36.0 cm(75th centile). Facial anomalies included frontal boss-ing with widely separated sutures, hypertelorism, mi-crophthalmia, widely separated nares (approximately3 cm), and clefting of the upper alveolar margin, but noclefting of the lips or palate. In the lower limbs therewere fixed flexion deformities at the hips and knees,with talipes equinovarus bilaterally. The right leg wasshorter than the left. The left foot had seven digits, andthe right eight (Fig. 2). The upper limbs were normal.A skeletal survey confirmed a wide midline facial cleftextending from the maxilla and involving the whole ofthe sagittal skull as far as the occiput. In the axialskeleton no major abnormalities were found, althoughthere were some small cervical ribs. In the left lowerlimb, the femur, tibia, and fibula were normal. Therewas a clubfoot abnormality with a single hind foot

Fig. 2. Lower limb defects in cases 1–5, including bilateral preaxial polysyndactyly, talipes equinovarus, and short/absent tibiae.

Acromelic Frontonasal Dysostosis 111

bone, probably a talus. There were six metatarsals andan extra small vestigial medial metatarsal. The thirddigit had a single proximal phalanx and two terminalphalanges, and appeared to be the great toe (Fig. 4).Because of the central position of the putative hallux, a“mirror foot” is suggested. In the right lower limb thetibia was absent and the fibula was curved and dislo-cated. The foot was clubbed, with a single hind footbone, and there were seven metatarsals and three ad-ditional digits medial to the hallux. The digits lateral tothe great toe were normal. Cranial, cardiac, and renalultrasound scans were all normal. Chromosome analy-sis showed a normal female karyotype, 46,XX. At post-mortem, external examination confirmed the findingsdescribed above. Internal examination showed abnor-mal formation of the base of the skull, with a shallow,small posterior fossa and a foreshortened anteriorfossa. The frontal lobes were poorly developed, with noolfactory lobes. The brain was otherwise histologicallynormal. The kidneys were also symmetrically small,but normal anatomically and histologically.

Case 4

This male infant was the second child of first-cousinparents from Qatar. He had one healthy older botherbut his mother had experienced four previous first-trimester miscarriages. During the pregnancy, hydro-cephalus had been detected antenatally at 32 weeks ofgestation by ultrasound scan. In view of the head size,he was delivered by elective cesarean section at 38weeks. At birth his head circumference was 41.0 cm(>97th centile) and his was weight 3,830 g (90th cen-tile). Neonatally he had intermittent seizures whichwere treated with phenobarbitone. On examination at

age 1 week, he had a frontonasal malformation with abifid nasal tip, a low anterior hairline, and hypertri-chosis of the forehead (Fig. 1). The fontanels and su-tures were widely patent. There were limb defects in-cluding postaxial polydactyly of the hands, talipesequinovarus, and striking symmetrical preaxial poly-syndactyly of the feet (Fig. 2). Other findings includedbilateral inguinal herniae and cryptorchidism on theleft, but an ultrasound scan of the abdomen showed norenal malformations. Chromosomal analysis of thechild and his parents showed no abnormalities. Cranialultrasonography showed distension of the lateral cere-bral ventricles, especially on the left. Cranial CT im-aging confirmed a complex malformation of the CNScomprising hydrocephalus, absence of the septum pel-lucidum, agenesis of the corpus callosum, and a wide-spread neuronal migration defect. The hydrocephaluswas treated by insertion of a ventriculo-peritonealshunt at age 4 weeks, following which the baby re-turned to Qatar.

Case 5

This female infant was the eighth child of noncon-sanguineous black South African parents. The motherwas well during pregnancy, took no medication, andreported normal fetal movements. Following a normalhome delivery, the baby was said by the midwife to befull term and of average size, but no neonatal measure-ments were taken. The baby was seen at age 9 months,when her weight was 7.5 kg, length 69 cm, and headcircumference 43.5 cm (all approximating 10th centile).Facial anomalies included frontal bossing, marked hy-pertelorism, downslanting palpebral fissures, a cleftnasal tip, midfacial hypoplasia, and a narrow, highly

Fig. 3. Computer-generated three-dimensional CT image of skull of case 1, showing midline frontal and parietal bone defects.

112 Slaney et al.

arched palate (Fig. 1). She was noted to have short fifthfingers with bilateral clinodactyly, preaxial polysyn-dactyly of the left foot, and partial cutaneous syndac-tyly of the right foot (Fig. 2). She had an umbilicalhernia. Examination of the nervous system was normaland she had achieved normal developmental mile-stones. Plain skull radiographs showed an abnormalconfiguration of the frontal bones with wide separationof the orbits. The lower limbs were symmetrical withnormal tibiae, but there was duplication of the distalphalanx of the hallux of the left foot (Fig. 4). Chromo-some analysis showed a normal female karyotype,46,XX.

DISCUSSIONPhenotype of AFND

The clinical findings in the 5 new cases of AFNDreported here are compared with those of the 8 previ-ously reported cases (for which detailed clinical de-scriptions/photographs were provided) in Table I. LikeFND, the syndrome is characterized by a frontonasalmalformation of the face. This is usually very severe, asseen in cases 1–3 of this report, which correspond to

type Ia of De Myer [1967], or type D of Sedano et al.[1970]. Milder variants do nevertheless occur, as seenin cases 4 and 5. These cases have overlap with acro-callosal and Greig syndromes, but the significant hy-pertelorism and bifid nasal tip put them into the AFNDgroup. All 13 patients had wide fontanels and suturesresulting from the cranial defects. Unlike FND, how-ever, there is also a relatively high frequency of under-lying brain malformations. In addition, AFND is char-acterized by variable acromelic limb defects, often inassociation with tibial aplasia/hypoplasia.

The most consistent limb defect was preaxial poly-syndactyly of the feet, which was seen in all except oneof the half sisters reported by Warkany et al. [1973].Tibial aplasia or hypoplasia occurred in 5 of the total of10 patients and was also noted in a short report of anadditional case [Neidich et al., 1988]. Postaxial poly-dactyly of the hands (seen in 2 patients) and clefting ofthe foot (occurring in 1 patient) were more unusualfindings. Malformations of other organs were also seenon occasion, but in most cases there were no structuralanomalies of the heart, lungs, or intraabdominal or-gans. Most male babies with AFND had bilateral crypt-orchidism.

Fig. 4. X-rays of left lower limb of case 1, showing tibial hypoplasia, a broad first metatarsal, and duplication of the phalanges of the hallux. Similarfindings were seen in left feet of cases 3 and 5.

Acromelic Frontonasal Dysostosis 113

Differential Diagnosis and Inheritance

The differential diagnosis of AFND includes syn-dromes in which severe hypertelorism is associatedwith midline craniofacial anomalies and syndromeswith preaxial lower limb defects (summarized in TableII). Although most of these conditions can be excludedby clinical examination alone, the pattern of lower limbmalformations in AFND is very similar to that found inautosomal-recessive hydrolethalus syndrome [Salonenand Herva, 1990]. However, hydrolethalus is usuallyassociated with severe hydrocephalus or hydranen-cephaly and micrognathia, which are lacking in AFND.In case 3, the radiological appearances of the feet hadsome similarities to a mirror foot as seen in Laurin-Sandrow syndrome, because of the extra mediallyplaced digits [Sandrow et al., 1970]. However, this syn-drome is characterized by mirror hands, not seen inany of our patients, and is not associated with FND.

Cases 2–4 of this report were the offspring of consan-guineous marriages, as were several previously re-ported cases [Verloes et al., 1992]. This suggests thatAFND may be an autosomal-recessive disorder, unlikeFND, which generally occurs sporadically (possiblycaused by a de novo dominant mutation).

Affected half sisters with AFND who had an appar-ently normal mother have been reported [Warkany etal., 1973], but paternity was not investigated. The onlyprenatal diagnosis presently available is detailed fetalultrasonography at around 19 weeks of gestation,

which may be able to detect the cranial and limb ab-normalities.

Mechanisms of Malformation in AFND

Embryological mechanisms to account for the cranio-facial malformations seen in FND have been suggestedby several authors. If the nasal capsule fails to developproperly, the primitive brain vesicle may persist, lead-ing to anterior cranium bidifum, abnormal relative po-sitioning of the eyes in the midline, and ultimately hy-pertelorism and absence of the nasal tip [Cohen et al.,1995]. Suppression of hair growth normally occurs infields around the eyes; the wide spacing of the eyes inFND may prevent this suppression occurring in themidline, thus giving rise to the frequently-observedwidow’s peak [Smith and Cohen, 1973]. The craniofa-cial malformation in FND has therefore been regardedas a nonspecific developmental field defect arising pri-marily from failed development of the nasal capsule[Gorlin et al., 1990]. By contrast, the prominent under-lying midline and frontal structural abnormalities ofthe brain in AFND suggest that it may represent an-other example of “the face predicting the brain” [DeMyer et al., 1964]. If so, the primary embryologicalmechanism in AFND would be the opposite of that re-sponsible for HPE, in which midline frontal lobe fusionis associated with hypotelorism and/or cyclopia[Cohen and Sulik, 1992].

TABLE I. Summary of Clinical Findings in Present and Previously Reported Cases of AFND*

Date of report and first author1970,

Sedano1971,Calli

1971,Edwards

1973, Warkany

1986,Toriello

1992,Verloes

1993,Sueldo

Present report

TotalCase

1Case

2Case

1Case

2Case

3Case

4Case

5

Age when seen 7 m 5 m 9 m 5 d U 2 m TOP 1 w 7 m 2 d 1 d 1 w 9 mSex M U F F F M M F M M F M F 6 M, 6 FKaryotype 46,XY U 46,XX U 46,XX 46,XY 46,XY 46,XX 46,XY 46,XY 46,XX 46,XY 46,XX 11/11Consanguinity − U U AHS AHS − − − − + + + − 3/11Craniofacial anomaliesSevere FND + + + + + + + + + + + + + 13/13Wide fontanels/sutures + + + + + + + + + + + − + 12/13Hypertelorism + + + + + + + + + + + + + 13/13Blepharophimosis + − + − − − − − + + − − − 4/13Corneal dermoid cyst − + + − − − − − − − − − − 2/13Broad nasal root + + + + + + + + + + + + + 13/13Hypoplastic nares + + + + + − + + + + − − − 9/13Nasal pit − − − + + − − − − − − − − 2/13Notched upper lip + − + + + + + − + − − − − 7/13Cleft palate − + − − − + − + − − − − − 3/13CNS anomaliesEncephalocele − + + + − − + − − − − − − 4/13Hydrocephalus U U U + + − − − + − − + U 4/9Agenesis of the corpus callosum U U U + − + − + − − − + U 4/9Absent septum pellucidum U U U + + − − − − − − + U 3/9Developmental delay U + + − − − NA − − + NA + − 4/11Hands and feetPostaxial polydactyly of hands − − − − − + − − − − − + − 2/13Preaxial polydactyly of feet R + + − + + + + + + + + L 12/13Tibial aplasia/hypoplasia R + R − − − − + + + + − − 7/13Talipes equinovarus R + R − − − − + + + + + − 8/13Cleft foot − − − − R − − − − − − − − 2/13Other malformationsCryptorchidism + U NA NA NA + − NA + + NA + NA 5/6MInguinal herniae − − − − − − − − + − − + − 2/13Anal atresia − − − − − − − − − + − − − 1/13Renal anomaly − − U − − − − + − − − − U 1/11

*m, month; d, day; w, week; U, unknown; TOP, termination of pregnancy; M, male; F, female; AHS, affected half sibs; +, present; −, absent; R, right sideonly; L, left side only; NA, not applicable.

114 Slaney et al.

Candidate Genes for AFND

The distribution pattern of the limb abnormalities inAFND, characterized by severe involvement of thelower legs and feet, but only occasional mild involve-ment of the hands, is unusual. Several genes with hind-limb-specific patterns of expression have recently beenidentified in both chick and mouse, including membersof the Hox gene family (Hoxb9, Hoxc9, Hoxc10, andHoxc11) [Krumlauf, 1994] and the Tbx gene family(Tbx4) [Gibson-Brown et al., 1996]. Although thesegenes are not expressed in the developing CNS or cra-niofacial region, their abnormal regulation might nev-ertheless contribute to the distinctive lower limb mal-formations seen in AFND, if the gene mutated in thedisorder were to act upstream of them, in the samedevelopmental and/or molecular pathway.

One strong candidate for such a pathway is the SonicHedgehog (SHH) signalling pathway, which plays animportant role in the development of both the midlineCNS/craniofacial region and the limbs. SHH is ex-pressed in the developing notochord and neural tubefloorplate [Roelink et al., 1994], where it helps pattern

the ventral neural tube, as well as in the zone of polar-izing activity (ZPA) at the posterior margin of the de-veloping limb bud, where it helps pattern the limbalong its anterior/posterior axis [Johnson and Tabin,1997]. Patients haploinsufficient for SHH show vari-able degrees of holoprosencephaly (HPE), with hypo-telorism and/or cyclopia, the opposite defect to thatseen in AFND, but no limb abnormalities [Roessler etal., 1996]. Mice lacking both copies of Shh, however,have not only extreme HPE, but also acro- and meso-melic limb defects, more severe in the hindlimbs[Chiang et al., 1996]. GLI3, a zinc-finger transcriptionfactor which is one of the main targets of SHH signaltransduction, and which may also regulate SHH ex-pression via a negative feedback loop, is also highlyexpressed in the developing CNS and limbs [Marigo etal., 1996]. At least two different human brain-limb syn-dromes are now known to be caused by mutations inGLI3: Greig cephalopolysyndactyly (GCPS) [Vortkampet al., 1991], which enters the differential diagnosis ofAFND, since it also involves hypertelorism and pre-axial polydactyly of the feet; and Pallister-Hall syn-

TABLE II. Differential Diagnosis of AFND*

Syndrome I Cranial defect Limb defect Other findings

Acrocallosal syndrome[200990

AR Mild hypertelorism, agenesisof corpus callosum

Preaxial polydactyly of feetPostaxial polydactyly of

hands

Mental retardation, coarsefacial features

Acro-fronto-facio-nasaldysostosis [201180

AR Hypertelorism, bifid nasal tip Postaxial polydactyly ofhands, hypoplasia ofphalanges hypoplasticfibulae

Short stature, mentalretardation,microphthalmia,cataracts, macrostomia,cleft lip

Brachycephalofrontonasaldysplasia [145420

AD Broad forehead, broad nasalbridge, ptosis

Brachydactyly, syndactyly,camptodactyly

Normal stature, normalintelligence

Carpenter-Hunter syndrome U Posterior encephalocoele,hypertelorism, absentexternal nares

Postaxial polydactyly ofhands and feet, tibialduplication

Severe micromelia, fragilebones, hydrocephalus,pachygyria, cysticdysplasia of kidneys andpancreas

Craniofrontonasal dysplasia[304110

U FND with craniosynostosis,broad bifid nose

Pre- or postaxial polydactylyof limbs

Thick hair, splitting of nails,webbing of neck, slopingshoulders, femalepredominance

Griegacrocephalopolysyndactyly[175700

AD Macrocephaly, hypertelorism,broad nasal base

Preaxial polydactyly ofhands and preaxialpolysyndactyly of feet

Normal intelligence

Hartsfield syndrome U Hypertelorism withholoprosencephaly, cleft face

Ectrodactyly of all fourlimbs, hypoplastic digits

Hydrolethalus syndrome[236680

AR Hydrocephalus/hydranencephaly,micrognathia, microglossia,low-set ears

Postaxial polydactyly Septal heart defect, trachealatresia, absent pituitarygland, normal kidneys,severe hydrocephalus

Laurin-Sandrow syndrome[135750

AD Hydrocephalus, agenesis ofcorpus callosum

Mirror hands and feet,tibial/radial hypoplasia

Vertebral fusions, unusualfacial features

Pallister-Hall syndrome[146510

AD Hypopituitarism,hypothalamic hamartoma

Brachydactyly, mesoaxialpolydactyly of fingers

Imperforate anus, oralfrenulae, micropenis

Thurston median cleftlip/nose postaxialpolydactyly syndrome(OFD V) [174300

AR Midline cleft of upper lip Postaxial polydactyly ofhands and feet

Oral frenulae, wide-spacedteeth

W syndrome [311450 X-LD High forehead, hypertelorism,median cleft of upper lip

Campto/clinodactyly,subluxation at radio-ulnarjoints

Seizures, spasticity, mentalretardation, mild featuresin females, median notchin upper lip

*I, inheritance; AR, autosomal recessive; AD, autosomal dominant; U, unknown; X-LD, X-linked.

Acromelic Frontonasal Dysostosis 115

drome [Kang et al., 1997], characterized by a combina-tion of hypothalamic hamartoma, central/postaxialpolydactyly, and imperforate anus. Interestingly, anectopic ZPA expressing SHH at the anterior margin ofthe limb buds has been demonstrated in the “extra-toes” (Xt) mouse mutant, which is the murine homo-logue of GCPS, caused by loss-of-function mutations inGli3 [Hui and Joyner, 1993]. Similar aberrant SHHsignalling has also been detected in several othermouse mutants with preaxial polydactyly and hemime-lia primarily affecting the hindlimbs, strikingly similarto those seen in AFND, including Carter’s luxate (lx)[Knezevic et al., 1997], Strong’s luxoid (lst) [Chan et al.,1995], and the Alx-4 “knockout” mouse [Qu et al.,1997]. We conclude that the molecular basis of AFNDmay be a perturbation of the SHH signalling pathway.

REFERENCESCalli LJ.1971. Ocular hypertelorism and nasal agenesis (midface syn-

drome) with limb anomalies. Birth Defects 7:268.

Chan DC, Laufer E, Tabin C, Leder P. 1995. Polydactylous limbs inStrong’s luxoid mice result from ectopic polarizing activity. Develop-ment 121:1971–1978.

Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, BechyPA. 1996. Cyclopia and defective axial patterning in mice lacking SonicHedgehog gene function. Nature 383:407–413.

Cohen MM Jr, Richieri-Costa A, Guion-Almeida ML, Saavedra D. 1995.Hypertelorism: interorbital growth, measurements, and pathogeneticconsiderations. Int J Oral Maxillofac Surg 24:387–395.

Cohen MM Jr, Sulik KK. 1992. Perspectives on holoprosencephaly: part II.Central nervous system, craniofacial anatomy, syndrome commentary,diagnostic approach, and experimental studies. J Cranio Gen Dev Bio12:196–244.

De Myer W. 1967. The median cleft face syndrome. Neurology 17:961.

De Myer W, Zeman W, Palmer CG. 1964. The face predicts the brain:diagnostic significance of median facial anomalies for holoprosen-cephaly (arhiencephaly). Pediatrics 34:256–263.

Edwards WC, Askew W, Weisskopf B. 1971. Median cleft face syndrome.Am J Ophthalmol 72:202–205.

Gibson-Brown JJ, Agulnik SI, Chapman DL, Alexiou M, Garvey N, SilverLM, Papaioannou VE. 1996. Evidence of T-box genes in the evolution oflimb morphogenesis and the specification of forelimb/hindlimb identity.Development 56:93–101.

Gorlin RJ, Cohen MM Jr, Levin S. 1990. Syndromes of the head and neck,3rd ed. Oxford: Oxford University Press. p. 785.

Hui C, Joyner LA. 1993. A mouse model of Greig cephalopolysyndactylysyndrome: the extra-toes mutation contains an intragenic deletion ofthe Gli3 gene. Nat Genet 3:241–246.

Johnson RL, Tabin CJ. 1997. Molecular models for vertebrate limb devel-opment. Cell 90:979–990.

Kang S, Graham JM Jr, Haskins Olney A, Biesecker LG. 1997. GLI3frameshift mutations cause autosomal dominant Pallister-Hall syn-drome. Nat Genet 15:266–268.

Knezevic V, De Santo D, Schughart K, Huffstadt U, Chiang C, Mahon KA,Mackem S. 1997. Hoxd-12 differentially affects preaxial and postaxialchondrogenic branches in the limb and regulates Sonic Hedgehog in apositive feedback loop. Development 124:4523–4536.

Krumlauf R. 1994. Hox genes in vertebrate devlopment. Cell 78:191–201.

Marigo V, Johnson RL, Vortkamp A, Tabin CJ. 1996. Sonic Hedgehogdifferentially regulates expression of GLI and GLI3 during limb devel-opment. Dev Biol 180:273–283.

Neidich JA, Whitaker LA, Zackai EH. 1988. Frontonasal malformation:two new syndromes? Am J Med Genet Suppl 4:202–203.

Prescott KE, Sheridan-Pereira M, Manchester DK, Eilers B, Hall BD.1989. The median facial cleft/sskeletal syndrome (frontonasal dyspla-sia): a distinct subgroup with with nasal agenesis, tibial aplasia, hal-lucal polydactyly and mental retardation. Am J Med Genet [Suppl]45:59.

Qu S, Niswander KD, Ji Q, van der Meer R, Keeney D, Magnuson MA.1997. Polydactyly and ectopic ZPA formation in Alx-4 mutant mice.Development 124: 3999–4008.

Roelink H, Augsburger A, Heemskerk J, Korzh V, Norlin S, Ruiz I AltabaA, Tanabe Y, Placzek M, Edlund T, Jessell TM, Dodd J. 1994. Floorplate and motor neurone induction by vhh-1, a vertebrate homologue ofhegdehog expressed in the notochord. Cell 76:761–775.

Roessler E, Belloni E, Gaudenz, Jay P, Berta P, Scherer SW, Tsui L-C,Muenke M. 1996. Mutations in the human Sonic Hedgehog gene causeholoprosencephaly. Nat Genet 14:357–360.

Salonen R, Herva R. 1990. Syndrome of the month: hydrolethalus syn-drome. J Med Genet 27:756–759.

Sandrow RE, Sullivan PD, Steel HH. 1970. Hereditary ulnar and fibulardimelia with peculiar facies. J Bone Joint Surg (Am) 52:367–370.

Sedano HO, Cohen MM Jr, Jirasek J, Gorlin RJ. 1970. Frontonasal dys-plasia. J Pediatr 76:906–913.

Smith DW, Cohen MM Jr. 1973. Widow’s peak scalp-hair anomaly and itsrelation to ocular hypertelorism. Lancet ii:1127–1128.

Sueldo G, Fernandes MC. 1993. Frontonasal dysostosis, callosal agenesis,crossed fused ectopia, tibial hemimelia, and preaxial polydactyly offeet: severe expression of the acrocallosal syndrome? Am J Med Genet46:355–357.

Toriello HV, Radecki LL, Sharda J, Looyenga D, Mann R. 1986. Fronto-nasal dysplasia, cerebral anomalies, and polydactyly: report of a newsyndrome and discussion from a developmental field perspective. Am JMed Genet Suppl 2:89–96.

Verloes A, Gillerot Y, Walczak E, Van Maldergem L, Koulischer L. 1992.Acromelic frontonasal “dysplasia‘: further delineation of a subtype withbrain malformations and polydactyly. Am J Med Genet 42:180–183.

Vortkamp A, Gessler M, Grzeschik KH. 1991. GLI3 zinc-finger gene inter-rupted by translocations in Greig syndrome families. Nature 352:539–540.

Warkany J, Bofinger MK, Benton C. 1973. Median facial cleft syndrome inhalf sisters. Dilemmas in genetic counselling. Teratology 8:273–286.

116 Slaney et al.