POLYMELIA (SUPERNUMERARY LIMBS) IN
Dr Laurence Denholm, DPI NSW
Lisa Martin, District
Veterinarian, New England LHPA
Andrew Denman, Blayney Veterinary Hospital
Whilst sporadic cases of polymelia
in cattle have been reported all around the world in both Bos taurus and Bos indicus
breeds, in recent years the incidence of this congenital defect seems to be increasing in
Angus calves in Australia above the background sporadic level, suggesting the
possibility of an emerging heritable defect in this breed.
At least fifteen cases of the notomelic form of polymelia were
reported in newborn Angus calves in NSW in the last two years. One purebred commercial
Angus herd with a high incidence of two recently recognised but unrelated heritable
defects in Angus (AM and NH) as a result of intense linebreeding to high marbling
American Angus sires has also reported several cases of notomelia and one case of
the dipygus/pygomelic form of polymelia in the last two years. Other recent polymelia
cases in NSW were however more sporadic. Several identical polymelia cases have
been reported in regional newspapers in other Australian states and on national
television, all in the Angus breed (www.geelongadvertiser.com.au/article/2009/08/14/93641_news.html) and (au.news.yahoo.com/thewest/a/-/offbeat/7017620/five-legged-calf-surprises-farmers/).
Wikipedia uses a notomelic Angus steer from northern NSW to illustrate its
webpage on polymelia. There are also numerous press reports on the internet of
polymelia in US beef cattle.
Pedigree investigations of these recent Angus polymelia cases
in NSW are underway to identify the closest common ancestor. Trial breeding of
affected animals is proposed. Some DNA samples were sent to the USA for SNP chip
analysis earlier this year but additional DNA samples are now required for this
research, from cases of polymelia in purebred Angus with at least some pedigree
Although the current evidence suggests an underlying
primary genetic basis to polymelia in these Angus calves, no clear pattern of
inheritance has been identified to date. Trial breeding can identify patterns
of inheritance and hence obtaining further polymelia cases for trial breeding would
be a useful strategy to determine the heritability of this congenital defect,
as proved so useful with contractural arachnodactyly (CA) in Angus calves.
Further polymelia cases are also required for the SNP analysis of DNA now in
progress to identify any causal mutation present in this syndrome.
The project to date has involved a field collaboration of veterinarians
from DTIRIS (Dr Laurence Denholm), New England LHPA (Lisa Martin) and Blayney
Veterinary Hospital (Andrew Denman). The collaborating genomics laboratory, led
by Assoc. Prof. Jonathan Beever of the University of Illinois and AgriGenomics
Inc., has an excellent track record in identifying causal mutations and developing
commercial DNA diagnostic tests for carriers of heritable defects in cattle including
arthrogryposis multiplex (AM), neuropathic hydrocephalus (NH), contractural
arachnodactyly (CA), osteopetrosis (OP), tibial hemimelia (TH), pulmonary
hypoplasia with anasarca (PHA), idiopathic epilepsy (IE) and alpha-mannosidosis
(MA) - all in the last few years.
NSW veterinarians who see polymelia cases in Angus calves where
the owners have at least some pedigree details and are prepared to cooperate in
case investigation are asked to contact their local LHPA veterinarian or Dr
Laurence Denholm (see below). Polymelia cases in other breeds should also be
Variants of polymelia are classified according to the
point of attachment to the body - notomelia
where the attachment is in the region of the embryonic notochord, cephalomelia where the attachment is on
the head, thoracomelia where the
attachment is on the thorax below the dorsal midline (for example, where the
attachment is to the margin of the scapula of the normal limb) and dipygus or pygomelia where the attachment is to the pelvis.
The supernumerary limb will have either a left or a right
sided anatomy and may develop as a forelimb
(cephalomelia, notomelia and thoracomelia) or as a hindlimb (usually as pygomelia).
Pygomelia usually results from a caudal bifurcation of the long axis of the
body. More rarely, a form of pseudopolymelia occurs in ischiopagus conjoined
twins, where the parasitic twin is acephalic.
The majority of bovine polymelia cases are notomelic, with
one or more supernumerary forelimbs attached along the dorsal midline anywhere
from the occiput to the thoraco-lumbar junction. The foot of the supernumerary
limb may be normal or syndactyl. Minor osseous anomalies in these extra limbs are
common, including absence of the proximal diarthrodial joints with fusion of the
adjoining leg bones (see Fig. 2). Thin bands of muscle tissue may or may not be
seen on dissection of the limb, embedded in large amounts of adipose tissue. Some
cases have more than one complete supernumerary limb. Others have a single
additional limb with abnormal bifurcation at a level below the shoulder joint, creating
the appearance of multiple limbs. The limbs may lack innervation.
Losses from dystocia and the significant costs of
veterinary amputation under anaesthesia in affected calves surviving birth constitute
the main economic impacts of the syndrome. After birth, many surviving calves
appear to grow and breed normally regardless of whether the extra limbs are
Developmental anomalies of the limbs are amongst the most
common congenital defects in man and domestic animals and more frequent in the
distal parts of the limbs. True polymelia apparently results from a failure in normal
intercellular inductive signalling during early embryonic development, within
the lateral plate mesoderm or in the reciprocal inductive signalling between
lateral plate mesoderm and overlying apical ridge ectoderm, leading to a failure
of the normal regression of supernumerary primordial limb buds within the
lateral mesoderm and hence the development of one or more supernumerary limbs (or
parts thereof) from ongoing growth of these persistent vestigial limb buds.
The molecular pathogenesis of supernumerary
limbs in mammals remains uncertain, although a genetic basis to this type of
teratogenicity is likely, as clearly demonstrated in Drosophila spp. where loss of function mutations of the slimb gene cause supernumerary limbs as
a result of ectopic activation of pathways regulating transcription of genes
involved in control of the cell cycle during body patterning. The F-Box/WD40
repeat protein slimb is a subunit of
a multi-protein complex that targets proteins for degradation by the
ubiquitin-proteasome pathway, an important mechanism regulating the abundance of
several proteins in eukaryotes involved in embryonic cell cycle regulation. Slimb is thus an important regulator of body
pattern development in Drosophila.
An evolutionarily conserved homolog of the slimb gene called β-TrCP in mammals is
also now known to be the specificity determinant for signal-induced
ubiquitination pathways in mammals, but no congenital abnormality of limb
development has yet been attributed to loss of function mutation in the β-TrCP gene
or to mutation of any related gene in these developmental ubiquitination regulatory
pathways. Nonetheless, supernumerary limbs in mammals could well result from mutations
of one or more of the many genes involved in the signal-induced phosphorylation
pathways that regulate ubiquitination and subsequent degradation of proteins controlling
the nuclear entry of proteins required for activating the transcription of
target genes involved in cell cycle regulation and apoptosis in limb bud regression.
There is certainly some potentially interesting developmental molecular biology
in these bovine polymelia cases.
Despite evidence suggesting the possibility of
a heritable basis to these recent bovine polymelia cases in NSW, alternative mechanisms
of teratogenicity are possible but seem unlikely on epidemiological grounds -
particularly given the apparent breed predisposition and the wide geographic
distribution of these recent Angus polymelia cases. Nonetheless, it is known
that pesticide immunocompromised tadpoles of several frog species develop
supernumerary limbs when infected with any of several parasitic species of the trematode Riberoiia.Moreover, retinol
toxicity and chromosomal defects have also been identified as causes of
polymelia in amphibians.
Karyotype abnormalities have also been described in
polymelic calves, but whether these arise from an environmental teratogen or
from a heritable mutation causing chromosomal instability at a particular locus
The same cellular signalling pathways in early embryonic
development can be impacted by environmental toxins or early embryonic infection
as well as by heritable mutations of genes encoding proteins in the pathway, thereby
producing identical morphological abnormalities from quite different primary
Laurence Denholm BVSc(Hons) PhD,
Trade and Investment NSW
61 2 6365 5482, 0418 641957
Angus calf with notomelia (Photograph – L. Denholm, DTIRIS)
Radiograph of amputated supernumerary limb from calf
shown in Figure 1.
(Radiograph – A. Denman, Blayney Veterinary Hospital)