Am. J. Hum. Genet.

61:1405–1412, 1997

Autosomal Dominant Postaxial Polydactyly, Nail Dystrophy, and Dental

Abnormalities Map to Chromosome 4p16, in the Region Containing
the Ellis–van Creveld Syndrome Locus
Timothy D. Howard,1 Alan E. Guttmacher,3,4 Wendy McKinnon,3 Mridula Sharma,1
Victor A. McKusick,2 and Ethylin Wang Jabs1,2
1
Departments of Pediatrics and Surgery and 2Department of Medicine, Center for Medical Genetics, Johns Hopkins School of Medicine,
Baltimore; and Departments of 3Pediatrics and 4Medicine, Vermont Regional Genetics Center, University of Vermont College of Medicine,
Burlington

Summary Introduction

We have studied a four-generation family with features Weyers acrofacial dysostosis (Curry-Hall syndrome;
of Weyers acrofacial dysostosis, in which the proband OMIM 193530 [http://www.ncbi.nlm.nih.gov/Omim/])
has a more severe phenotype, resembling Ellis–van Crev- is an autosomal dominant condition characterized by
eld syndrome. Weyers acrofacial dysostosis is an auto- hypotelorism, an abnormal mandible, incisors abnormal
somal dominant condition with dental anomalies, nail in shape and number, a single central incisor, conical
dystrophy, postaxial polydactyly, and mild short stature. teeth, postaxial polydactyly type A or type B, hypo-
Ellis–van Creveld syndrome is a similar condition, with plastic or dysplastic nails, and short stature. It was first
autosomal recessive inheritance and the additional fea- reported in three unrelated cases (Weyers 1952), and
tures of disproportionate dwarfism, thoracic dysplasia, three additional families have since been described
and congenital heart disease. Linkage and haplotype (Curry and Hall 1979; Roubicek and Spranger 1984;
analysis determined that the disease locus in this pedigree Shapiro et al. 1984).
resides on chromosome 4p16, distal to the genetic Ellis–van Creveld syndrome (OMIM 225500 [http://
marker D4S3007 and within a 17-cM region flanking www.ncbi.nlm.nih.gov/Omim/]) (Ellis and van Creveld
the genetic locus D4S2366. This region includes the El- 1940) is a rare autosomal recessive disproportionate
lis–van Creveld syndrome locus, which previously was dwarfism that is most prevalent in the Amish population
reported to map within a 3-cM region between genetic (McKusick et al. 1964). It is characterized by lip defects
markers D4S2957 and D4S827. Either the genes for the (oral frenula), dental abnormalities (neonatal teeth, hy-
condition in our family and for Ellis–van Creveld syn- podontia, and premature tooth loss), cardiac malfor-
drome are near one another or these two conditions are mations (atrial septal defect and single atrium), geni-
allelic with mutations in the same gene. These data also tourinary anomalies (epispadias and hypospadias),
raise the possibility that Weyers acrofacial dysostosis is skeletal abnormalities (postaxial polydactyly type A,
the heterozygous expression of a mutation that, in ho- brachydactyly, fusion of the capitate and hamate, genu
mozygous form, causes the autosomal recessive disorder valgum, and distal limb shortening), and nail dysplasia
Ellis–van Creveld syndrome. (McKusick et al. 1964; Biggerstaff and Mazaheri 1968;
Taylor et al. 1984). Weyers acrofacial dysostosis has
some features in common with, but is distinct from,
Ellis–van Creveld syndrome (table 1) (Gorlin et al. 1990,
pp. 201–204). The two syndromes are dissimilar in
mode of inheritance and phenotypic severity.
Linkage analysis of 12 families with Ellis–van Creveld
syndrome previously mapped the locus to a 3-cM region
Received June 30, 1997; accepted for publication October 1, 1997;
between the genetic loci D4S2957 and D4S827 on chro-
electronically published November 26, 1997. mosome 4p16.1 (Polymeropoulos et al. 1996). The max-
Address for correspondence and reprints: Dr. Ethylin Wang Jabs, imum two-point LOD score (Zmax) observed was 6.91
Center for Medical Genetics, Johns Hopkins School of Medicine, (recombination fraction [v] of .02) with a genetic marker
600 North Wolfe Street, Baltimore, MD 21287-3914. E-mail:
for the MSX1 homeobox gene. Subsequent sequencing
[email protected]
䉷 1997 by The American Society of Human Genetics. All rights reserved. of both MSX1 exons in two patients and one obligate
0002-9297/97/6106-0026$02.00 carrier of Ellis–van Creveld syndrome ruled out the pos-

1405
1406 Am. J. Hum. Genet. 61:1405–1412, 1997

Table 1
Phenotype of the Family and Related Syndromes
Other Affected Ellis–van Creveld Jeune Asphyxiating Weyers Acrofa-
Proband (IV:4) Family Members Syndrome Thoracic Dysplasia cial Dysostosis
Short stature ⫹ Mild ⫹ Mild Mild
Abnormal frenula ⫹ ⫹ ⫹ ⫺ ⫹
Natal teeth ⫺ ⫺ ⫹ ⫺ ⫺
Hypodontia ⫹ ⫹ ⫹ ⫺ ⫹
Conical teeth ⫹ ⫹ ⫹ ? ⫹
Mandibular anomalies ⫺ ⫺ ⫺ ⫺ ⫹/⫺
Retinal degeneration ⫺ ⫺ ⫺ ⫹ ⫺
Postaxial polydactyly Hands and feet Hands and feet Hands; sometimes feet ⫹/⫺; if present, usu- Hands and/or
ally hands and feet feet
Onychodystrophy ⫹ ⫹ ⫹ ⫺ ⫹
Thoracic dysplasia ⫹ ⫺ ⫹ ⫹ ⫺
Cardiac findings Patent ductus arter- ⫺ Atrial septal defect, ⫺ ⫺
iosus, ventricular atrioventricular sep-
septal defect tal anomaly
Hepatic/pancreatic ⫺ ⫺ ⫺ ⫹ ⫺
abnormalities
Renal abnormality ⫺ ⫺ ⫺ ⫹ ⫺
Radiological findings Flat acetabular roof ⫺ Fifth carpal in distal Flat acetabular roof ⫺
with pointed pel- row of wrist, multi- with pointed pelvic
vic prominence ple ossification cen- prominence
ters in hamate, flat
acetabular roof with
pointed pelvic
prominence
Lethal in newborns ⫺ ⫺ ⫹/⫺ Often ⫺
Inheritance ? Autosomal Autosomal recessive Autosomal recessive Autosomal
dominant dominant
Chromosomal linkage 4p16 4p16 4p16 ? 4p16?
NOTE.—A plus sign (⫹) indicates present; a minus sign (⫺) indicates absent; a plus/minus sign (⫹/⫺) indicates sometimes present; and a
question mark (?) indicates unknown.

sibility that mutations in the coding region are causative proband) had findings that are most typical of Ellis–van
of this condition (Ide et al. 1996). Creveld syndrome. The paternal relatives, however, pre-
It has been suggested that isolated postaxial polydac- sented with postaxial polydactyly, short stature relative
tyly, which occurs in these two conditions, may be a to unaffected sibs, and tooth abnormalities segregating
heterozygous manifestation of Ellis–van Creveld syn- in an autosomal dominant manner. These findings are
drome (Fryns 1991; Goldblatt et al. 1992). Another sim- similar to those reported for Weyers acrofacial dysostosis
ilar condition with postaxial polydactyly as a clinical (Curry and Hall 1979; Roubicek and Spranger 1984;
feature is Jeune syndrome (OMIM 208500 [http:// Shapiro et al. 1984). We performed linkage analysis of
www.ncbi.nlm.nih.gov/Omim/]) (Jeune et al. 1955; Pir- this condition and mapped it to chromosome 4p16 in a
nar and Neuhauser 1966; Langer 1969). The pelvis and region that encompasses the locus for Ellis–van Creveld
limbs are similar in Ellis–van Creveld and Jeune syn- syndrome.
dromes, but nail dystrophy, abnormal frenula, and car-
diac abnormalities are not found in the latter condition.
Patients and Methods
In addition, renal involvement is a frequent feature of
Jeune syndrome and is not found in Ellis–van Creveld
syndrome. Postaxial polydactyly also has been observed Patient Population
to segregate as a single trait. Linkage of an autosomal
dominant form of postaxial polydactyly type A to chro- Genomic DNA was isolated from blood samples or
mosome 7p15-q11.23 recently was reported in a five- lymphoblast cultures from 19 available family members,
generation Indian family with no other clinical findings by use of the Blood and Cell Culture DNA kit (Qiagen).
(Radhakrishna et al. 1997). All these family members were examined clinically by
We have studied a family in which one individual (the one of the authors (A.E.G.).
Howard et al.: Polydactyly Maps to Chromosome 4p16 1407

Case Presentation and a first cousin (IV:2) has bilateral fusion of primary
mandibular canine and lateral incisors and several con-
The proband (fig. 1; individual IV:4 in fig. 2) was the ical-shaped primary teeth. The same cousin also has a
7-lb 8-oz male product of an uncomplicated term preg- prominent raphe extending over the middle of her phil-
nancy of a 29-year-old mother and her nonconsanguin- trum, from vermilion border to nasal root. The family
eous 28-year-old husband. The initial physical exami- history includes the proband’s mother (III:9) being 5 feet
nation of the newborn was significant for a narrow chest, 6 inches tall and having a history of urinary reflux. Her
four-extremity postaxial polydactyly type A, short limbs, family’s history is negative for short stature, polydactyly,
and swelling secondary to forceps delivery because of onychodystrophy, congenital heart disease, or dental
face presentation. As this swelling receded, examination abnormalities.
of the upper lip revealed multiple frenula with shallow
sulcus. Neonatal cardiology evaluation demonstrated a
large patent ductus arteriosus that closed spontaneously PCR Amplification and Sequence Analysis
at age 5 d and a small muscular ventricular septal defect.
Radiographs were remarkable for short ribs and a flat For the nine genetic markers listed in table 2, PCR
acetabular roof with pointed pelvic prominence. was performed with DNA from each family member, in
The proband was ventilator dependent for the first 10-ml reactions consisting of 100 ng genomic DNA, 50
month of life but otherwise had an uncomplicated new- mM KCl, 10 mM Tris-HCl, 200 mM each dNTP, 1.5
born course. He remained on oxygen supplementation mM MgCl2, 0.1 mg BSA/ml, 0.6 mmol each primer, 5–10
by nasal cannula until 10 mo of age. At ∼2 mo of age, ng one g[32P]-dATP end-labeled primer, and 1.0 U Taq
the proband developed a hemangioma over the left chest DNA polymerase (Boehringer Mannheim). Amplifica-
that began to involute after his first birthday. By ∼3 years tion parameters were as follows: 3 min at 94⬚C; 10 cycles
of age, his fingernails and toenails had become dys- of 40 s at 94⬚C, 40 s at the annealing temperature, and
trophic. He has decreased range of motion of the distal 40 s at 72⬚C; followed by 15 cycles of 40 s at 92⬚C, 40
interphalangeal joints of his hands, and his thumbs ap- s at the annealing temperature, and 40 s at 72⬚C; and
pear to be mildly digitalized. Dental evaluation has re- a final extension of 3 min at 72⬚C. The annealing tem-
vealed a number of symmetrically absent primary teeth perature for each genetic marker was as described in the
and dental pitting. Renal evaluation demonstrated no Genome Database (http://www.gdb.org/), with the ex-
structural or functional abnormalities. He generally has ceptions that the temperature for D4S827 was increased
enjoyed excellent health and normal development. from 62⬚C to 65⬚C and that for D4S412 was decreased
Height has been at slightly below but paralleling the 5th from 55⬚C to 50⬚C. The PCR products were separated
percentile, weight has been at approximately the 10th on a 6.0% polyacrylamide sequencing gel and were de-
percentile, and head circumference has been at the tected by autoradiography.
25th–50th percentile. The MSX1 gene was sequenced by, first, amplification
The proband’s father has a history of postaxial poly- of both exons with two sets of PCR primers derived
dactyly type A, radial fifth-digit clinodactyly, and ony- from the published sequence (Hewitt et al. 1991). To
chodystrophy, as do at least seven other of the father’s amplify exon 1, the forward primer 5-CTGCTGACA-
relatives (see fig. 2). Chromosome analysis was per- TGACTTCTTTGC-3 and the reverse primer 5-TGG-
formed on the affected father (III:8 in fig. 2) and revealed GTTCTGGCTACTACCTG-3, which amplify a 477-bp
a normal 46,XY karyotype. In the affected individuals, fragment, were used. PCR reactions for exon 1 were
the polydactyly involves all four extremities, with the performed in 50-ml volumes consisting of 100–500 ng
extra digits on the feet usually more fully formed than genomic DNA, 10 mM Tris-HCl (pH 8.3), 50 mM KCl,
those on the hands. The individuals also may be slightly 1.5 mM MgCl2, 200 mM each dNTP, 0.5 mM each pri-
shorter in stature than their sibs. For instance, the pro- mer, 5% dimethyl sulfoxide, and 1.25 U Taq DNA poly-
band’s father (III:8) is 5 feet 9 inches tall, and his affected merase (Boehringer Mannheim). PCR parameters were
brothers are 5 feet 8 inches (III:4) and 5 feet 11 inches 35 cycles of 1 min at 94⬚C, 1 min at 60⬚C, and 1 min
(III:6), whereas their unaffected brothers are 6 feet 2 at 72⬚C. Exon 2 was amplified with the forward primer
inches (III:2) and 6 feet 4 inches (III:3) and their unaf- 5-GGCTGATCATGCTCCAATGCTT-3 and the re-
fected sister (III:1) is 5 feet 11 inches. Some of these verse primer 5-TACAGCACCAGGGCTGGAGG-3,
affected individuals have unusual labial frenula or shal- yielding a 561-bp fragment. PCR reactions were per-
low labial sulci. Several, but not all, of the affected family formed as described for exon 1, with cycling parameters
members have had dental abnormalities: the paternal of 1 min at 95⬚C, 1 min at 66⬚C, and 2 min at 72⬚C.
great-aunt (II:4) is reported to have conical-shaped teeth; PCR products were run on 2% NuSieve gels (FMC
the proband’s father (III:8) has tooth agenesis; a paternal BioProducts) and were extracted. The DNA, isolated
uncle (III:4) had a pear-shaped tooth that was removed; with the Gel Extraction Kit (Qiagen), was directly se-
Figure 1 Clinical photographs of affected family members. A, Proband (IV:4 in fig. 2), front and lateral view. Note the short stature, abnormal configuration of the chest, hands with nail
dysplasia of the thumbs (bottom right), and postaxial polydactyly in infancy (bottom left). B, Father of the proband (III:8 in fig. 2), front and lateral view. Note the proportional stature, normal
chest, and onychodystrophy. His postaxial polydactyly had been surgically removed.
Howard et al.: Polydactyly Maps to Chromosome 4p16 1409

in Weyers acrofacial dysostosis, Ellis–van Creveld syn-

drome, and Jeune syndrome. Of these conditions, the
proband most closely fits Ellis–van Creveld syndrome,
on the basis of his short stature, four-extremity postaxial
polydactyly type A, dystrophic nails, abnormal labial
frenula and sulcus, hypodontia with poor enamel, tho-
racic dysplasia, congenital heart disease, neonatal pelvic
x-ray significant for flat acetabular roof with pointed
pelvic prominence, and survival postinfancy. If one as-
sesses the family when the proband is excluded, however,
the autosomal dominant mild short stature, four-extrem-
ity postaxial polydactyly type A, onychodystrophy, hy-
podontia, and abnormal frenula, with which the affected
members present, closely resemble Weyers acrofacial
dysostosis.

Linkage to Chromosome 4p16 and Haplotype Analysis

The proband in this family has features most consis-
tent with Ellis–van Creveld syndrome. Therefore, we
evaluated this family by using nine genetic markers from
near the Ellis–van Creveld locus on chromosome 4p16.1
(table 2) (Polymeropoulos et al. 1996). Evidence for link-
age to this region was observed, with LOD scores 13.00
and no recombination for two of the markers, D4S827
and D4S2366. The highest two-point LOD score was
Figure 2 Linkage- and haplotype-analysis data for the studied 4.09 with the genetic marker D4S2366. One recombi-
family with features of Weyers acrofacial dysostosis and Ellis–van
Creveld syndrome. For each individual evaluated, the alleles for the
nation event, between the genetic markers D4S2366 and
genetic markers are given below the symbol; individuals without as- D4S3007, was detected in individual III:10 (fig. 2), de-
signed alleles were not available for analysis. The proband is indicated fining the most proximal boundary for the region con-
with an arrow. The boxed areas include the alleles that are either taining the disease locus. Recombinants that would have
certainly or possibly inherited from an affected parent and show the indicated the most distal boundary for the location of
largest possible region in which the disease locus may lie.
the gene were not detected within this 10-cM region.
quenced by the Johns Hopkins Genetic Resources Core Using the LOD score 4.09, we calculated the 95% con-
Facility, by use of the specific PCR primers. fidence interval for the disease locus to be 14 cM prox-
imal and distal of D4S2366. However, the genetic dis-
Linkage and Haplotype Analysis tance between D4S431 and D4S3007, which flank
Nine genetic markers, spanning 10 cM (Polymero- D4S2366, is only 3 cM (Polymeropoulos et al. 1996);
poulos et al. 1996), were used for linkage analysis (table thus, the recombinant (detected in individual III:10) lim-
2). The ILINK and MLINK options of the LINKAGE its the proximal boundary to a maximum of 3 cM from
software package (version 5.1) (Ott 1991) were used to
calculate LOD scores by use of an IBM personal com-
Table 2
puter. The disease was modeled as an autosomal dom-
inant, fully penetrant disorder. The allele frequencies for Linkage Analysis of Postaxial Polydactyly, Nail Dystrophy, and
each marker were set as equal. For the haplotype anal- Dental Abnormalities to Chromosome 4p16
ysis, the order of the genetic markers was determined LOD SCORE AT v⫽
from the publicly available YAC physical map from MARKER .00 .01 .05 .10 .20 .30 .40 Zmax vmax
the Stanford University Genome Center (ftp://
D4S412 2.46 2.44 2.33 2.17 1.77 1.23 .59 2.46 .00
shgc.stanford.edu/pub/hgmc/YAC㛮data) and from the D4S2957 ⫺.04 ⫺.04 ⫺.03 ⫺.03 ⫺.02 ⫺.01 .00 .00 .50
order described elsewhere (Polymeropoulos et al. 1996). D4S432 .25 .25 .25 .24 .20 .15 .08 .25 .04
MSX1 1.14 1.14 1.11 1.06 .90 .68 .38 1.14 .00
Results D4S827 3.22 3.16 2.93 2.63 1.98 1.27 .53 3.22 .00
D4S431 1.62 1.59 1.46 1.29 .92 .52 .16 1.62 .00
Phenotype of Family Members D4S2366 4.09 4.02 3.74 3.37 2.57 1.69 .75 4.09 .00
As table 1 indicates, the proband and a number of his D4S3007 ⫺⬁ .26 .81 .92 .81 .54 .20 .92 .11
D4S394 ⫺⬁ 1.73 2.20 2.19 1.82 1.27 .60 2.22 .07
paternal relatives have features similar to those observed
1410 Am. J. Hum. Genet. 61:1405–1412, 1997

D4S2366. Therefore, the region most likely to contain veld syndrome, or Jeune syndrome inherited from his
the gene is a 17-cM interval. This region encompasses mother.
the 3-cM critical region, between D4S2957 and A final possibility is that the proband has Ellis–van
D4S827, for the Ellis–van Creveld syndrome locus, re- Creveld syndrome and that his “affected” paternal rel-
ported elsewhere (Polymeropoulos et al. 1996). Hap- atives are symptomatic heterozygotes. Although some
lotype analysis provided similar results, with the critical have questioned this interpretation (see OMIM 225500
region found to reside distal to D4S3007 on the basis [http://www.ncbi.nlm.nih.gov/Omim/]) because no het-
of recombination events detected in individual III:10 erozygous effects of Ellis–van Creveld syndrome were
(fig. 2). observed in the Amish population (McKusick et al.
1964), reports exist of several families in which heter-
Sequencing of the MSX1 Candidate Gene ozygotes exhibit findings similar to those in the family
reported here (Fryns 1991; Goldblatt et al. 1992; Spran-
A candidate gene that maps within the critical region ger and Tariverdian 1995). In fact, a similar family, con-
is the homeobox gene MSX1. The mouse homologue, sisting of a proband with Ellis–van Creveld syndrome
Hox-7, is expressed in the neural crest, the developing and her father, who had features of Weyers acrofacial
mandible and teeth, the embryonic heart, and the limb dysostosis (mild short stature, nail dysplasia, and teeth
buds (Robert et al. 1989), all of which are developmental abnormalities but no polydactyly), has been reported
regions affected in Ellis–van Creveld syndrome. In ad- (Spranger and Tariverdian 1995). The features observed
dition, a mutation in MSX1 was recently reported in a in our proband’s paternal relatives could be the phe-
family with selective tooth agenesis (Vastardis et al. notype resulting from one specific allele of the Ellis–van
1996), which may be relevant to the dental abnormalities Creveld syndrome gene, an allele that differs from the
observed in both Ellis–van Creveld syndrome and Wey- allele affected in the Amish population. The proband
ers acrofacial dysostosis. Both exons of MSX1 from the may have inherited this allele from his father and a dif-
proband (IV:4) and his affected paternal uncle (III:6) ferent mutant allele from his mother, leading to the full
were sequenced. No mutations were detected, suggesting Ellis–van Creveld phenotype. Although no mutations
that changes in the MSX1 coding region are not re- were detected in the coding region of MSX1 in the two
sponsible for the clinical phenotype of this family. This members of this family who were tested, it is conceivable
result is consistent with the recent report that no mu- that mutations in the MSX1 regulatory elements may be
tations were detected in either of the two MSX1 exons responsible for the condition in this family and, perhaps,
in patients with Ellis–van Creveld syndrome (Ide et al. for Ellis–van Creveld syndrome. Previous studies, using
1996). deletion analysis of the mouse Msx1 promoter, identified
regions that were important for distinct spatial and tem-
Discussion poral expression patterns (MacKenzie et al. 1997).
Another candidate gene in the critical region for the
We have studied a four-generation family segregating condition in our family is that for fibroblast growth-
a condition with features of both Weyers acrofacial dy- factor receptor 3 (FGFR3). Mutations in FGFR3 have
sostosis and Ellis–van Creveld syndrome. The disorder been reported in patients with achondroplasia (Rousseau
in affected members of this family, including in the pro- et al. 1994; Shiang et al. 1994), hypochondroplasia (Bel-
band, demonstrated linkage to a chromosome 4p16 re- lus et al. 1995), thanatophoric dysplasia (Tavormina et
gion estimated to be 17 cM and defined by recombi- al. 1995; Rousseau et al. 1996), and craniofacial and
nation only proximally between loci D4S3007 and limb abnormalities resembling Crouzon, Pfeiffer, or Sae-
D4S2366. The linkage-analysis data clearly show that, thre-Chotzen syndromes (Meyers et al. 1995; Bellus et
in this family, the candidate region for the condition al. 1996). FGFR3 maps to chromosome 4p16.3
encompasses the Ellis–van Creveld gene. The mapping (Thompson et al. 1991) and is a potential candidate gene
of these two diseases to the same chromosomal region for the condition in this family or for Weyers acrofacial
might represent any one of several phenomena. One pos- dysostosis, but it is distal to the critical region for the
sibility is that all affected members of this family have Ellis–van Creveld locus (Polymeropoulos et al. 1996).
either an unreported autosomal dominant condition or Other genes located on human chromosome 4p16 (those
Weyers acrofacial dysostosis with variable expression, for dopamine receptor D1B [DRD1B], zinc finger pro-
with the proband being the most severely affected. Thus, tein–141 [ZNF-141], dopamine receptor D5 [DRD5],
the proband’s condition would be a genocopy for El- and protein S-100P [S100P]; the myosin light-chain reg-
lis–van Creveld syndrome. A second possibility is that ulatory gene [MYL5]; and homeobox gene H6
the proband is a double heterozygote, with a mutation [HMX1]), identified in the syntenic region of mouse
for the condition inherited from his father and a mu- chromosome 5 (those for phosphodiesterase 6B, cGMP-
tation for Weyers acrofacial dysostosis, Ellis–van Cre- specific, rod, beta [PDEB]; diacylglycerol kinase, delta
Howard et al.: Polydactyly Maps to Chromosome 4p16 1411

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