#186000 SYNDACTYLY, TYPE II
Alternative
titles; symbols
SYNPOLYDACTYLY; SPD
table OF
CONTENTS
Gene Map Locus: 2q31-q32
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TEXT
A number sign (#) is used with this entry
because of evidence that the phenotype is caused by
mutation in the HOXD13 gene (142989)
which maps to 2q31-q32.
In the hands there is usually syndactyly of the
third and fourth fingers associated with
polydactyly of all components or of part of the
fourth finger in the web. In the feet there is
polydactyly of the fifth toe included in a web of
syndactyly of the fourth and fifth toes. The most
extensive pedigree is that described by Thomsen
(1927) showing 31 affected males and 11
affected females in 7 generations. Other kindreds
were reported by Alvord
(1947) and Pipkin and
Pipkin (1946) among others. Cross
et al. (1968) observed a kindred with 27
affected persons. Two persons transmitted the gene
without showing any effects themselves. All persons
with clinically evident malformation in the hand
showed anomalous palmar dermatoglyphics. No linkage
with any of 12 loci was demonstrable. An excess of
affected males has been a consistent feature.
Cross et al. (1968)
found, in the literature and in their kindred, 133
females and 174 males affected. The 'original' case
of Fabry disease (301500)
reported by Anderson
(1898) had this anomaly: 'The fingers of both
hands are contracted at the middle and distal
phalanges of the fourth finger on each hand are
duplicated, the two digits being enclosed in one
cutaneous investment....his mother and sister, and
three out of four of his children, had congenital
deformities like his own.' Merlob
and Grunebaum (1986) found the anomaly in 16
persons in 6 generations of a family.
Camera et al. (1995)
described a family with 8 affected members in 4
generations. There were at least 3 instances of
male-to-male transmission. Aplasia/hypoplasia of
the middle phalanges of the toes was also noted.
Camera et al. (1995)
suggested that this anomaly is a frequent
manifestation of synpolydactyly. No other major
skeletal or extraskeletal manifestations were
present.
In an extensive Turkish kindred, Sayli
et al. (1995) observed (or obtained information
on) 182 persons with synpolydactyly distributed
over 7 generations. Founder effect accounted for
this extensively affected kindred originating from
the village of Derbent, Afyon. The inheritance was
autosomal dominant with variable expressivity and
an estimated penetrance of 96%. Penetrance differed
between the upper (96%) and lower (69.5%) limbs.
The sex ratio was equal. Four different phenotypes
were observed in various branches of the Derbent
kindred: (1) subjects presenting typical features
of SPD; (2) subjects exhibiting both pre- and
post-axial polydactyly; (3) persons manifesting
postaxial polydactyly type A (174200);
and (4) subjects born to 2 affected parents and
apparently homozygous for the mutation resulting in
severe hand and foot deformities previously
described in SPD families. A total of 27 affected
offspring were born to couples of whom both were
affected. In 7 of them the phenotype was very
severe, consistent with homozygosity (Akarsu
et al., 1995).
Akarsu et al. (1995)
described the clinical features of the homozygous
individuals in the kindred reported by Sayli
et al. (1995): (1) short hands with wrinkled
fatty skin and short feet; (2) complete soft tissue
syndactyly involving all 4 limbs; (3) polydactyly
of the preaxial, mesoaxial, and postaxial digits of
the hands; (4) loss of the normal tubular shape of
the carpal, metacarpal, and phalangeal bones,
resulting in polygonal structures; (5) loss of the
typical structure of the cuboid and all 3 cuneiform
bones while the talus calcaneus and navicular bones
remained intact; (6) large bony islands instead of
metatarsals, most probably because of
cuboid-metatarsal and cuneiform-metatarsal fusions;
and (7) severe middle phalangeal hypoplasia/aplasia
as well as fusion of some phalangeal structures
that are associated with the loss of normal
phalangeal pattern. Three subjects with this
phenotype from 3 different branches of the large
SPD pedigree exhibited the same phenotype with
minimal variation. Akarsu et
al. (1995) stated that the polysyndactyly (Ps)
mutation in mice shows a pattern of synpolydactyly
very similar to that of human SPD and may be a
homologous mutation.
Sarfarazi et al.
(1995) used 62 meioses from the kindred
reported by Sayli et al.
(1995) and Akarsu et al.
(1995) to map the SPD locus to 2q31,
approximately 1.7 cM (lod score = 12.96)
centromeric to a HOXD8 (142985)
intragenic marker. They speculated that a mutation
in a member of the HOXD cluster is a likely site
for the SPD mutation. A single recombinant with
HOXD8 excluded the most 3-prime end of the HOXD
cluster as the site for SPD, but a mutation in the
5-prime end of the HOXD cluster, especially in
HOXD13 (142989),
EVX2 (142991),
or DLX2 (126255)/DLX1
(600029)
may still be responsible for this phenotype.
Muragaki et al. (1996)
examined 3 families with manifestations of SPD. In
2 families there were typical manifestations of
SPD. In 1 family, in which the mother and father
were first cousins, the mother had typical
manifestations of SPD, but her daughter showed a
somewhat different and more severe phenotype in
that the hands and feet were very small, the digits
were very short, and fusion of digits 3, 4 and 5
occurred. The metacarpals and metatarsals were very
short and the carpal bones were abnormal. Muragaki
et al. (1996) suggested that this individual
was homozygous and that 1 of her parents was a
nonpenetrant heterozygote. They showed through
linkage analysis that the SPD region is closely
linked to the HOXD region on chromosome 2q31-q32.
They selected 3 possible candidate genes in this
region on the basis of their expression in the
distal limb bud. Sequencing of the homeodomains of
the 3 genes, each of which was located at the
3-prime end of the gene, revealed no abnormalities.
Sequencing of the 5-prime gene regions revealed
that the HOXD13 protein contains 2 serine stretches
and 1 alanine stretch. Amplification of the gene
region encoding the alanine stretch showed an
additional larger band in the affected individuals
in all 3 pedigrees. Muragaki
et al. (1996) noted that the mutation found in
these pedigrees did not disrupt an evolutionarily
conserved domain.
Akarsu et al. (1996)
reported results of analysis of the HOXD13 gene in
the family studied by Sayli
et al. (1995). Through direct comparison of DNA
sequences at the 5-prime end of the HOXD13 gene in
normal and homozygous affected individuals,
Akarsu et al. (1996)
identified a 27-bp duplication (142989.0001)
of the normal sequences that encode for a
polyalanine tract in the affected individuals. In
normal individuals, a stretch of 15 alanine
residues were identified 145 bp downstream from the
initiation codon. Homozygous affected individuals
had a total of 24 polyalanine residues. Akarsu
et al. (1996) identified 2 affected individuals
who had the polyalanine duplication described above
and who were recombinant at the HOXD13 CA repeat.
In these 2 individuals, there was therefore a
recombination event within a 1.5-kb region between
the HOXD13 CA repeat and the HOXD13 polyalanine
duplication. Akarsu et al.
(1996) documented nonpenetrance of this
disorder. In their haplotype analysis of 2 Turkish
families with 169 members (105 affected) they noted
that 164 expressed the disorder phenotypically as
predicted by their genotype. Gene expression was
approximately 97%; 3% of individuals were gene
carriers who did not express the defect.
-
ANIMAL
MODEL
- Zakany and Duboule
(1996) used embryonic stem cells and a
site-specific recombination system to induce a
mutation that eliminates the products of mouse
Hoxd13, Hoxd12 (142988),
and Hoxd11 (142986)
genes simultaneously. They reported that mice
homozygous for this deficiency showed small
digit primordia, a disorganized cartilage
pattern, and impaired skeletal mass. They noted
that these alterations are similar to the
defects seen in human synpolydactyly. Zakany
and Duboule (1996) suggested that this
syndrome, which is associated with a subtle
mutation in human HOXD13, may involve the loss
of function of several HOXD genes. They noted
further that their studies have provided an
animal model to study human digit malformations.
-
SEE ALSO
- Wood (1971)
REFERENCES
- 1. Akarsu, A. N.;
Akhan, O.; Sayli, B. S.; Sayli, U.; Baskaya, G.;
Sarfarazi, M. :
- A large Turkish kindred with
syndactyly type II (synpolydactyly): 2
homozygous phenotype (sic)?. J.
Med. Genet. 32: 435-441, 1995.
PubMed ID : 7666394
- 2. Akarsu, A. N.;
Stoilov, I.; Yilmaz, E.; Sayli, B. S.;
Sarfarazi, M. :
- Genomic structure of HOXD13 gene: a
nine polyalanine duplication causes
synpolydactyly in two unrelated
families. Hum. Mol. Genet. 5:
945-952, 1996.
PubMed ID : 8817328
- 3. Alvord, R. M.
:
- Zygodactyly and associated
variations in a Utah family. J.
Hered. 38: 49-53, 1947.
- 4. Anderson, W.
:
- A case of
'angeio-keratoma.'. Brit. J.
Derm. 10: 113-117, 1898.
- 5. Camera, G.;
Camera, A.; Pozzolo, S.; Costa, M.; Mantero, R.
:
- Synpolydactyly (type II syndactyly)
with aplasia/hypoplasia of the middle phalanges
of the toes: report on a family with eight
affected members in four generations.
Am. J. Med. Genet. 55: 244-246,
1995.
PubMed ID : 7717427
- 6. Cross, H. E.;
Lerberg, D. B.; McKusick, V. A. :
- Type II syndactyly. Am.
J. Hum. Genet. 20: 368-380, 1968.
PubMed ID : 4298538
- 7. Merlob, P.;
Grunebaum, M. :
- Type II syndactyly or
synpolydactyly. J. Med. Genet.
23: 237-241, 1986.
PubMed ID : 3014149
- 8. Muragaki, Y.;
Mundlos, S.; Upton, J.; Olsen, B. R. :
- Altered growth and branching
patterns in synpolydactyly caused by mutations
in HOXD13. Science 272:
548-551, 1996.
PubMed ID : 8614804
- 9. Pipkin, S. B.;
Pipkin, A. C. :
- Two new pedigrees of zygodactyly.
Variation of expression of polydactyly.
J. Hered. 37: 93-96, 1946.
- 10. Sarfarazi, M.;
Akarsu, A. N.; Sayli, B. S. :
- Localization of the syndactyly type
II (synpolydactyly) locus to 2q31 region and
identification of tight linkage to HOXD8
intragenic marker. Hum. Molec.
Genet. 4: 1453-1458, 1995.
PubMed ID : 7581388
- 11. Sayli, B. S.;
Akarsu, A. N.; Sayli, U.; Akhan, O.; Ceylaner,
S.; Sarfarazi, M. :
- A large Turkish kindred with
syndactyly type II (synpolydactyly): 1 field
investigation, clinical and pedigree
data. J. Med. Genet. 32:
421-434, 1995.
PubMed ID : 7666393
- 12. Thomsen, O.
:
- Einige Eigentuemlichkeiten der
erblichen Poly-und Syndaktylie bei
Menschen. Acta Med. Scand. 65:
609-644, 1927.
- 13. Wood, V. E.
:
- Treatment of central
polydactyly. Clin. Orthop. 74:
196-205, 1971.
PubMed ID : 4322173
- 14. Zakany, J.;
Duboule, D. :
- Synpolydactyly in mice with a
targeted deficiency in the HoxD
complex. Nature 384: 69-71,
1996.
PubMed ID : 8900279
CLINICAL
SYNOPSIS
View
Clinical Synopsis Entry
CONTRIBUTORS
Moyra Smith - updated : 11/15/1996
Moyra Smith - updated : 8/8/1996
Moyra Smith - updated : 5/29/1996
Moyra Smith - Updated : 5/11/1996
CREATION DATE
Victor A. McKusick : 6/2/1986
EDIT HISTORY
mark : 5/16/1997
mark : 11/15/1996
mark : 8/29/1996
mark : 8/8/1996
mark : 8/8/1996
mark : 8/8/1996
carol : 7/19/1996
carol : 5/29/1996
carol : 5/15/1996
carol : 5/11/1996
mark : 1/21/1996
mark : 11/6/1995
mimadm : 5/10/1995
carol : 2/9/1995
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989
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