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The Veterinary Journal 177 (2008) 324–333

TheVeterinary Journal

Review

Inherited abnormalities of skeletal development in sheep

K.G. Thompson *, S.A. Piripi, K.E. Dittmer

Institute of Veterinary, Animal and Biomedical Sciences, Massey University, P.O. Box 11222, Palmerston North, New Zealand

Accepted 12 August 2007

Abstract

Inherited diseases of the skeleton are reported less often in sheep than in most other domestic animal species but are likely to occurmore frequently than the veterinary literature would suggest. Although most are lethal or semi-lethal, the gene frequency for some ofthese diseases has reached surprisingly high levels in defined populations, presumably due either to the founder effect or the presenceof a selective advantage of heterozygous individuals. This article reviews the clinical characteristics, pathology, mode of inheritanceand molecular basis of skeletal diseases known to have a genetic aetiology in sheep. Inherited skeletal diseases of sheep are potentialmodels for studying the treatment of similar diseases in humans.� 2007 Elsevier Ltd. All rights reserved.

Keywords: Sheep; Genetic disease; Skeleton; Animal model

Introduction

Inherited abnormalities of skeletal development are welldocumented in humans and some domestic animals, partic-ularly dogs, horses and cattle, but published reports insheep are relatively uncommon. Rather than indicating areduced incidence in sheep, this probably reflects the lowereconomic or social value of this species in some countries(e.g. New Zealand, Australia and South Africa), the expec-tation of a small percentage of natural losses, and the reluc-tance of farmers to face the cost of investigation,particularly if only a small number of lambs are affected.

Many reports of skeletal disease in lambs involve eitherisolated cases, or clusters on individual properties andoften there is insufficient information to determine thecause or else the pedigree data are unavailable. It is impor-tant to recognise that not all skeletal defects are genetic inorigin. Exposure of developing fetuses to certain toxins,infectious agents or nutritional deficiencies at appropriatestages of gestation can induce skeletal lesions virtuallyidentical to those caused by defective genes. This must be

1090-0233/$ - see front matter � 2007 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tvjl.2007.08.015

* Corresponding author. Tel.: +64 6 350 4525; fax: +64 6 350 5636.E-mail address: K.G.Thompson@massey.ac.nz (K.G. Thompson).

considered when offering advice to the owner in order toavoid inappropriate culling of rams or the possibility of lit-igation by a disaffected breeder.

In this paper, we present a review of inherited diseases ofthe skeleton in sheep, including brief mention of severalskeletal abnormalities for which a genetic aetiologyremains in doubt.

Overview of inherited abnormalities in skeletal development

Because of the complexity of bone development andremodelling, and the number of genes involved, it is not sur-prising that the range of skeletal defects in humans anddomestic animals is broad. Major advances in moleculargenetics in recent years have led to a greater understandingof skeletal development. A variety of transcription andgrowth factors have been identified and have providedinsight into the molecular basis of many skeletal defects,as well as enhancing their classification (for review, see Kor-nak and Mundlos, 2003).

In general, the term osteochondrodysplasia (or skeletaldysplasia) includes generalised abnormalities in chondro-osseous tissues while dysostosis refers to a localised malfor-mation of an individual bone, or group of bones (Mundlos

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and Olsen, 1997b; Superti-Furga et al., 2001; Kornak andMundlos, 2003). The osteochondrodysplasias are now clas-sified according to the underlying defect (InternationalWorking Group on Constitutional Diseases of Bone,1998; Superti-Furga et al., 2001), although many of theolder terms remain entrenched in the literature.

Skeletal dysplasias may be caused either by a defect incartilage formation, or in the formation or remodelling ofbone tissue. Since much of the skeleton develops by endo-chondral ossification, a defect in cartilage formation islikely have a substantial and generalised effect on the skel-eton. Such diseases are referred to as chondrodysplasias,although the less appropriate term ‘‘achondroplasia’’ (liter-ally meaning absence of cartilage development) is widelyused in the medical literature.

Disproportionate dwarfism and/or limb deformity arethe most characteristic manifestations of chondrodyspla-sias in all species. A defect in the formation of bone matrixis usually characterised by bone fragility, the best exampleof which is osteogenesis imperfecta, a group of diseasesassociated with abnormal type I collagen synthesis (Byersand Cole, 2002). Defective osteoclastic bone resorption isthe basis of the osteopetroses, a group of inherited skeletaldiseases characterised by the presence of diffusely scleroticbones and, in some cases, increased bone fragility (Whyte,2002). Inherited forms of osteopetrosis have been reportedin cattle, deer, horses, dogs and cats (Thompson, 2007), aswell as laboratory mice and humans, but not to our knowl-edge in sheep. It is highly likely that the disease does occurin some sheep breeds but detailed examination of the bonesof stillborn lambs, as would be required for diagnosis, isseldom practiced.

Although most skeletal dysplasias in animals are eitherlethal or semi-lethal, the gene frequency of some disordersin some breeds has reached much higher levels than wouldbe expected for a disease where homozygous affectedindividuals die before they reach breeding age. This mostlikely reflects either inbreeding or excessive use of a ramcarrying a defective gene. The latter has clearly beenresponsible for the very high prevalence reached by certaingenetic diseases in cattle, where artificial breeding is widelypracticed, or where a new breed has been introduced to acountry and bred up from relatively few purebred founderanimals. This so-called founder effect is a major factor inthe emergence and establishment of genetic diseases innew animal populations (Jolly, 1977; Jolly et al., 2004)and partly explains why some of the diseases discussed herehave only been reported in New Zealand, where certainsheep breeds have been established from a relatively smallgene pool. A mutant gene may also reach a high prevalenceon individual properties if the owner purchases replace-ment sires from the same breeder over an extended periodof time.

Because of their comparable size and ease of manage-ment, sheep may be used as models for studying humanskeletal disorders or surgical techniques. Some of the ovineinherited diseases discussed here are potential models for

investigating various forms of therapy in analogous humandiseases and for advancing our understanding of bonedevelopment and metabolism.

Inherited skeletal diseases of sheep

Chondrodysplasias

An ovine chondrodysplasia, termed the Ancon or Ottermutation, was recognised in Merino sheep in the New Eng-land region of the USA towards the end of the 18th cen-tury, and is considered the earliest recorded genetic defectin domestic animals (Landauer and Chang, 1949). Sincethen the mutation, or a similar one, reappeared twice (inNorway and Texas) during the 20th Century, but is nowbelieved to be extinct (Shelton, 1968). Ancon sheep hadshort limbs with varus and valgus deformities of the elbowand carpus, respectively, but a normal skull and axial skel-eton (Landauer and Chang, 1949). They were initiallyfavoured due to ease of containment, being unable to jumplow stone walls as readily as normal sheep. Inheritance ofthe defect was believed to be autosomal recessive.

The most common inherited chondrodysplasia of sheepis ‘‘spider lamb syndrome’’ (SLS), a semi-lethal disease ofthe Suffolk and Hampshire breeds (Vanek et al., 1986,1989; Rook et al., 1988). The disease was first recognisedin North America in the late 1970s and was diagnosed withincreasing frequency during the 1980s and early 1990s. Itwas subsequently introduced to the Suffolk populationsin Australia and New Zealand with imported genetic mate-rial (Phillips et al., 1993; West et al., 1995). Unlike all othernaturally-occurring chondrodysplasias of animals andhumans, SLS is characterised by increased length of longbones, in addition to various deformities of the limbs andaxial skeleton. The mechanism for this was outlined byBeever et al. (2006), who identified a single-base changein the tyrosine kinase II domain of fibroblast growth factorreceptor 3 (FGFR3) as the underlying defect in SLS.

FGFR3 is a negative regulator of bone growth andplays an important role in chondrocyte proliferation anddifferentiation during endochondral ossification (Denget al., 1996; Ornitz and Marie, 2002). Mutations in thetransmembrane domain of FGFR3 are responsible for sev-eral important chondrodysplasias of humans, includingachondroplasia (Shiang et al., 1994; Rousseau et al.,1994), thanatophoric dysplasia and hypochondrodysplasia(McKusick et al., 1996; Naski et al., 1996). The FGFR3mutations in each of these diseases result in receptor activa-tion and suppression of chondrocyte growth, resulting indwarfism (Kornak and Mundlos, 2003). In SLS, theFGFR3 mutation induces elongation of bones forming byendochondral ossification by removing the FGFR3-induced inhibition of chondrocyte proliferation (Beeveret al., 2006). A similar effect has been observed in trans-genic mice homozygous for targeted disruption of the fgfr3gene (Colvin et al., 1996). A mutation causing partial lossof function mutation of FGFR3 in humans results in

Fig. 2. Distal scapula of a lamb with ‘‘spider lamb syndrome’’. Thesupraglenoid tubercle contains persistent bands and islands of cartilage(arrows) surrounding multiple small ossification centres.

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camptodactyly, tall stature, scoliosis and hearing loss(Toydemir et al., 2006).

Lambs with SLS may be aborted or stillborn, but mostare born alive and have skeletal deformities of varyingseverity. Some appear clinically normal at birth butdevelop typical signs of the disease within their first monthof life, including disproportionately long limbs and neck(Fig. 1), shallow body, scoliosis and/or kyphosis, sternaldeformity, and valgus deformity of the forelimbs belowthe carpus, creating a ‘‘knock-kneed’’ appearance (Vaneket al., 1986; Rook et al., 1988). Hind limb deformitiesmay also be present, but are less severe than those involv-ing the forelimbs. Facial deformities, including ‘‘Romannose’’, deviated nasal septum and shortening of the maxillaare common, but not consistent. The deformities of thelimbs and spinal column become progressively more severewith age. Radiographic changes are usually present in theelbow, sternum, shoulder and spine, and are characterisedby irregular islands of ossification in epiphyseal regions inaddition to malalignment and displacement of sternebrae(Vanek et al., 1989).

Gross lesions of SLS at necropsy may include elonga-tion of occipital condyles in a cranio-caudal direction,sometimes with erosion of cartilage on articular surfaces,and an excess of disorganised cartilage in misshapen orasymmetric cervical and thoracic vertebral bodies. Sterne-brae may also be asymmetric, fail to fuse across the midlineand be displaced dorsally. The olecranon and the supragle-noid tubercle of the scapula typically contain an excess ofcartilage surrounding the multiple, irregular-shaped islandsof ossification (Fig. 2). Severe degenerative joint disease,particularly involving the atlanto-occipital, elbow and car-

Fig. 1. Suffolk lambs with ‘‘spider lamb syndrome’’. Note the long legsand neck, lumbar kyphosis, and the Roman nose in one lamb.

pal joints, is present in lambs that survive to 3 months(Rook et al., 1988), presumably as a result of weight-bear-ing stress on abnormal articular surfaces and underlyingepiphyses. Microscopic changes in SLS reflect abnormaldevelopment of ossification centres, particularly those thatdevelop around the time of birth (Thompson, 2007). Inaffected epiphyses, multiple small ossification centres aresurrounded by hypertrophic cartilage but fail to coalesceand expand normally towards articular surfaces. Prolifera-tive and hypertrophic zones of growth plates in vertebraeand long bones are irregularly thickened and tongues ofcartilage extend into metaphyses and/or epiphyses.

Suffolk sheep heterozygous for the SLS genotype have aslightly greater bone length and frame size than homozy-gous normal sheep of the same breed (Smith et al., 2006)but no advantage in bodyweight. In fact, heterozygouslambs took an average of 11 days longer to reach the har-vest body-weight of 60 kg. This partial expression of thegenotype in heterozygous individuals has led to the sugges-tion that inheritance of SLS be considered co-dominantrather than simple recessive (Beever et al., 2006). Selectionfor increased frame size within the Suffolk breed was pre-sumably responsible for the high gene frequency attainedby this defect in North America. However, the develop-ment of a genetic test for SLS based on the FGFR3 muta-tion, and its widespread commercial use, has resulted in asubstantial reduction in the genotype in the USA, Australiaand New Zealand.

Another form of chondrodysplasia, characterised by dis-proportionate dwarfism and autosomal recessive inheri-tance, has recently been described in Texel sheep in NewZealand (Thompson et al., 2005). Affected lambs areclinically normal at birth but show evidence of dwarfism,

Fig. 5. Photomicrograph of articular cartilage from a Texel lamb withchondrodysplasia. Chondrocytes are surrounded by concentric rings ofabnormal fibrillar material (arrows) and the matrix in one area hasundergone rarefaction. Toluidine blue stain, Bar = 10 lm.

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wide-based stance and exercise intolerance as early as 1 weekof age. Most develop bilateral varus deformity of the fore-limbs (Fig. 3) and often die within the first 3 months of life.Some lambs develop respiratory distress and die acutely fol-lowing exercise, due to tracheal collapse. The severity ofexpression varies, with mildly affected sheep sometimes sur-viving to breeding age, but possessing a short, blocky stature.

Gross lesions in Texel lambs with this form of chondro-dysplasia include erosion of articular cartilage from majorweight-bearing surfaces in severe cases, and a flaccid,abnormally kinked trachea with thickened tracheal ringsand a narrow lumen (Fig. 4). Microscopically, chondro-cytes throughout the body are disorganised, surroundedby concentric rings of abnormal fibrillar material, and thematrix often contains focal to coalescing areas of chondrol-ysis (Fig. 5).

The underlying defect in Texel chondrodysplasia has yetto be determined, but affected lambs have reduced sulph-

Fig. 3. Texel lamb with chondrodysplasia. Note the short legs and wide-based stance.

Fig. 4. Abnormally thickened tracheal rings and attenuated lumen in achondrodysplastic Texel lamb that developed respiratory distress follow-ing exercise.

ation of proteoglycans in their cartilage matrix indicatinga likely abnormality in cellular transport of sulphate, asoccurs in human achondrogenesis type 1B and diastrophicdysplasia (Superti-Furga et al., 2001). The prevalence ofthe defect in New Zealand’s Texel sheep population isnot known but the disease has been recognised on morethan one property. The Texel breed in New Zealand wasestablished following importation of embryos from Den-mark and Finland in 1985 and subsequent amplificationusing embryo transfer technology during a 5-year quaran-tine period. Inadvertent but excessive use of a heterozygousram or ewe during this period could have led to a relativelyhigh frequency of the defective gene at the time of releasethrough founder effect.

A chondrodysplasia distinct from ‘‘spider lamb syn-drome’’ has been recognised in New Zealand in Suffolksheep of North American origin (West et al., 2005).Affected lambs have short legs, mandibles and maxillae,but a relatively long neck, leading the authors to proposethe term ‘‘llama syndrome’’. The disease was reproducedthrough matings of putative carrier ewes to an affectedram, indicating probable autosomal recessive inheritance,although the nature of the defect has not been established;nor have the gross and microscopic lesions been character-ised. None of the heterozygous or affected homozygoussheep tested positive for the FGFR3 mutation of SLS(D.M. West, personal communication).

A syndrome referred to as achondroplasia was reportedin South Country Cheviot sheep (Wray et al., 1971) but thedescription of the disease did not adequately support thisclassification and there was inadequate data to support agenetic aetiology.

Osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heterogeneous groupof diseases characterised by bone fragility and caused by

Fig. 6. Newborn lamb with osteogenesis imperfecta. Note the domed headand brachygnathia inferior.

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mutations in either COL1A1 or COL1A2, the genes encod-ing the two chains of type I collagen, the major protein ofbone matrix (Byers and Cole, 2002). Four major types ofOI are recognised in human patients and it is one of themost commonly encountered inherited connective tissuedisorders (Byers and Cole, 2002). Codons for glycine, themajor amino acid of collagen, are highly mutable, and ofthe amino acids that could potentially replace it as a resultof mutation none are functionally silent in the formation ofthe triple helix of collagen fibrils.

The disease is usually inherited as an autosomal domi-nant trait secondary to a new mutation in germ cell lines.As such, it may occur in ‘‘outbreak’’ form in the progenyof a clinically normal ram (Arthur et al., 1992). The sireis likely to be producing both normal and mutant sperma-tozoa and the percentage of his offspring with the diseasewill depend on the stage of gametogenesis at which themutation occurred (i.e. the degree of gonadal mosaicism).It is important to recognise that clinically normal lambssired by the same ram will not be carrying the defectivegene, and if each disease occurrence is caused by a newmutation, the defect is no more likely to be present in theflock of the ram breeder than any other flock. Further-more, this form of the disease is not breed-specific and isjust as likely to occur in cross-bred as in purebred lambs.

Severe forms of OI analogous to the neonatal lethalhuman type II form have been diagnosed in sheep flocksin New Zealand and the United Kingdom (Holmes et al.,1964; Arthur et al., 1992). Affected lambs usually eitherdie during parturition or soon after, and in addition to evi-dence of bone fragility, often have a range of abnormali-ties, including a domed head, brachygnathia inferior(Fig. 6), poorly erupted pink teeth, blue sclera (Fig. 7)and marked joint laxity. This distribution of lesions reflectsthe predominance of type I collagen in dentine, sclera andtendons as well as in bone matrix. Bones may fracture dur-ing parturition but intra-uterine fractures also occur asindicated by the presence of healing fractures in some new-born lambs. Long bones are soft and may have a thickened

Fig. 7. Enucleated eye from a control lamb (left) and a lamb with osteo

diaphyseal region with an indistinct marrow cavity (Fig. 8).Unlike OI in other species, skin fragility is a feature of thissevere form of the disease in sheep. Microscopically, thereis persistence of the primary spongiosa in long bones andmarrow cavities are filled with delicate trabeculae consist-ing of calcified cartilage lined by a thin layer of abnormallybasophilic bone. Infractions and trabecular microfracturesare common. Cortices are thick but porous and the bonematrix is highly basophilic.

OI is probably much more common in sheep than theliterature would suggest, but only cases where significantnumbers of lambs are affected, and the breeder is suffi-ciently concerned to seek advice, are likely to receive veter-inary attention. Milder forms of OI may also exist in sheepbut are difficult to diagnose as they may not be accompa-nied by abnormalities in teeth, sclera and joints, and mustbe differentiated from other causes of bone fragility, suchas copper deficiency and osteoporosis. A mild form of OI

genesis imperfecta. The sclera from the affected lamb is dark blue.

Fig. 8. Sagittal sections of femur from a control newborn lamb (left) and alamb with osteogenesis imperfecta. The bone from the affected lamb isshorter than normal and has a thickened diaphysis due to markedthickening of the cortex. The marrow cavity is almost obliterated bycortical bone and persistent trabecular bone. In spite of their increasedthickness, the long bones from affected lambs could be broken with littleeffort.

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is reported in Barbados blackbelly lambs that were bornalive and could walk in spite of joint laxity and intra-uter-ine fractures (Thompson, 2007). In this breed the teethwere normal and autosomal recessive inheritance wassuspected.

Fig. 9. Sagittal sections of humeri from an 8-month-old Corriedale sheepwith inherited rickets. The shape of both humeral heads is irregular due tocollapse of subchondral bone. Also note the thickened cortices andoccasional coarse trabeculae traversing the marrow cavity.

Inherited rickets

Rickets is a classic metabolic bone disease of domesticanimals caused by a deficiency of either vitamin D or phos-phorus. Although uncommon in sheep, the disease mayoccur in young animals receiving inadequate exposure tosolar irradiation during the winter, especially if they aregrazing green cereal crops or lush pasture with high concen-trations of carotenes, which have an anti-vitamin D effect(Fitch, 1943; Grant and O’Hara, 1957). Recently, an inher-ited form of rickets has been recognised in Corriedale sheepin New Zealand (Thompson et al., 2007). Although onlydetected in one flock, the disease was diagnosed in approx-imately 20 lambs per year over a 2-year period. Affectedlambs were shown to have been sired by four different rams,all sourced from the same breeder, suggesting that thedefective gene may also be present in several other Corrie-dale flocks in New Zealand. The disease has been repro-duced in embryo transfer-derived offspring derived from

affected ewes and an affected ram that survived to breedingage, thus confirming a genetic aetiology. Autosomal reces-sive inheritance is likely but confirmation awaits the resultsof a breeding trial to be completed in late 2007.

Most affected lambs appear normal at birth but developsigns of reduced growth rate, varus and valgus limb defor-mities and, in many cases, thoracic lordosis within a fewmonths, but there is variation in severity. Some lambsrequire euthanasia on humane grounds during the first 12months of life, while others have survived to breedingage. Evidence of bone fragility and intra-uterine fracturesin newborn lambs derived from embryo transfer has indi-cated that the disease is present at birth (Dittmer, unpub-lished data), thus supporting evidence that ovine foetusesare dependent on 1,25 dihydroxyvitamin D for mainte-nance of the transplacental calcium gradient during preg-nancy (Ross et al., 1980).

Gross skeletal lesions are typical of rickets and includeenlarged costochondral junctions, bilateral irregularity ofarticular surfaces on humeral heads due to collapse of sub-chondral bone (Fig. 9), thickened cortices in long bonesand irregular thickening of physeal cartilages (Fig. 10).Histologically, tongues of hypertrophic chondrocytesextend from physes into metaphyseal regions. Metaphysealtrabeculae are thick, disorganised and often lined by wideosteoid seams. Osteoclastic activity is excessive as indicted

Fig. 11. Peromelia in a newborn lamb. Both hind limbs and the leftforelimb are affected. The right forelimb is normal.

Fig. 10. Distal radius from a 12-month-old Corriedale sheep withinherited rickets showing irregular thickening of the physeal cartilage(arrows).

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by resorption cavities within many trabeculae. Affectedlambs have persistent hypocalcaemia, hypophosphataemiaand increased concentrations of 1,25 dihydroxyvitamin D,but normal serum 25 hydroxyvitamin D concentrations,suggesting a defect in end-organ responsiveness to 1,25dihydroxyvitamin D as the likely mechanism. This diseaseof Corriedale sheep appears to be analogous to humanvitamin D-resistant rickets (Malloy et al., 1999).

Dysostoses

Several localised skeletal abnormalities have beenreported as possible inherited defects in sheep, but a geneticaetiology is usually difficult to prove, especially when thenumber of cases is small. In many cases, abnormalities ina skeletal element are combined with other malformations(Dennis and Leipold, 1972a).

Syndactyly, a defect characterised by partial or completefusion of the functional digits is well recognised in severalbreeds of cattle, where it is inherited as an autosomal reces-sive trait (Ojo et al., 1975; Leipold et al., 1998; Drogemulleret al., 2007). There are only isolated reports of syndactylyin sheep (Dennis and Leipold, 1970, 1972a; Yeruhamet al., 2005) and although a genetic cause is likely, it hasnot been proven. In one report (Yeruham et al., 2005) anaffected lamb also had epitheliogenesis imperfecta, but thiswas probably a chance occurrence in an inbred flock ratherthan indicating any linkage between the two defects. Differ-ent mutations of the LRP4 gene have been demonstrated inHolstein and Angus cattle with syndactyly (Duchesneet al., 2006; Johnson et al., 2006), thus providing a likelycandidate gene for the defect in sheep.

Diseases characterised by partial or complete absence ofdistal parts of limbs, and with a suspected genetic basis, arethe subject of several reports in sheep (Dennis and Leipold,1972a; Leipold et al., 1972; Hawkins et al., 1983; Allenet al., 1983). The terms ectrodactyly, adactyly, peromeliaand hemimelia have been used, but because of the similar-ity in clinical appearance between these syndromes, the ori-ginal classification may not always have been appropriate.It most cases there were insufficient data to confirm agenetic aetiology, although this has been suggested foradactyly in Southdown lambs (Leipold et al., 1972). Out-breaks of hemimelia reported in lambs in Western Austra-lia (Hawkins et al., 1983; Allen et al., 1983) were consideredmore likely to be caused by ingestion of lupins by ewes dur-ing early pregnancy, but lupins have yet to be shown tocause this defect. In fact, the syndrome described and illus-trated by Hawkins et al. (1983) more closely resemblesperomelia, where there is failure of part of a limb todevelop. Autosomal recessive inheritance is reported forperomelia in Angora goats (Agerholm et al., 1997) andshould also be considered for sheep. In lamb, as in goatswith peromelia, the hindlimbs are usually more severelyaffected than the forelimbs (Fig. 11).

Polydactyly is reported only occasionally in lambs (Den-nis and Leipold, 1972a, 1979) but is likely to be much morecommon than the literature would suggest as sporadiccases in sheep flocks are unlikely to be of sufficient concernto warrant veterinary investigation. Inherited forms arerecognised in several other species (Thompson, 2007) andprobably exist in sheep.

Mandibulofacial malformations of varying severityappear to be more common in sheep than other domesticanimals. Agnathia was the most common abnormality ina survey of malformed lambs in one study, occurring in74/401 (18%) malformed lambs (Dennis and Leipold,1972b). In another survey of 4408 newly born dead lambs,agnathia was also the most commonly encountered con-genital abnormality (Hughes et al., 1972). In neither studywas it possible to determine the aetiology, but agnathia has

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been reported as a probable genetic defect in the DorsetDown breed (Smith, 1968). Teratogenic agents, particu-larly plant toxins, have also been incriminated but not pro-ven, and must always be considered. Agnathia is essentiallyan extreme form of micrognathia and the terms are oftenused interchangeably. Other cranial defects, includingatelostomia, microglossia or aglossia, and synotia arealmost inevitable in lambs with severe forms of agnathia(Dennis and Leipold, 1972b). Less severe forms arereferred to as either micrognathia or brachygnathia infe-rior, the latter representing a relatively mild mandibularlesion known colloquially as ‘‘undershot jaw’’ or ‘‘parrotmouth’’. This is common in sheep and other domestic ani-mals, and, although not life-threatening, is usually consid-ered an important defect if detected during soundnessexaminations.

Although not all cases are likely to be genetic in origin,the risk of passing the defect on to future generations is toogreat to encourage use of an affected animal for breedingpurposes, especially a ram capable of generating a largenumber of offspring. Micrognathia is a feature of lambswith osteogenesis imperfecta (Arthur et al., 1992) and issometimes present in conjunction with other defects suchas adactyly (Dennis and Leipold, 1972a). Palatoschisis isoccasionally seen in newborn lambs, sometimes in associa-tion with agnathia (Dennis and Leipold, 1972b), but thereis no evidence for a genetic aetiology in sheep and terato-gens should always be considered. In goats, palatoschisisand arthrogryposis are known to be associated with inges-tion of certain plants, including poison hemlock (Coniummaculatum) and lupins (Lupinus formosus) during earlypregnancy (Panter et al., 1990).

A syndrome characterised by shortening of the vertebralcolumn was reported in 22 Perendale lambs in a flock of1000 ewes in New Zealand over a 5-year period (Clarkand Twine, 1983). Post mortem examination of an affectedlamb revealed 4 cervical, 10 thoracic, 4 lumbar, 3 sacraland 8 coccygeal vertebrae, compared with the expected 7,13, 6, 5 and 16–18, respectively, in normal lambs. Althoughbreeding records were unavailable, the epidemiology sup-

Fig. 12. (a) Rambouillet ram lamb with valgus deformity of the left forelimb.consistent with osteochondrosis. Such lesions may have caused impaired grow

ported inheritance as an autosomal recessive trait. Theskeletal manifestations of this disease in Perendale lambsare similar to those of complex vertebral malformation inHolstein calves, which is known to have autosomal reces-sive inheritance (Agerholm et al., 2001).

Perosomus elumbis, a rare congenital defect character-ised by agenesis of the lumbosacral spinal cord and verte-brae, has been reported in sheep (Dennis, 1975). A similarsyndrome, characterised by vertebral malformationrestricted to the tail, was reported in a commercial flockof Romney-Southdown cross-breds in New Zealand (Car-ter, 1978). The defect varied from complete absence of a tailto a short, often kinked, tail due to variable hypoplasia ofcoccygeal vertebrae. Breeding experiments suggested domi-nant inheritance with homozygous tailless embryos degen-erating and dying within the first 3–4 weeks of gestation.

Studies in humans and mice have identified a range ofdyostoses associated with abnormalities in the homeoboxand paired-box transcription factor families, and membersof the transforming growth factor superfamily (e.g. bonemorphogenic proteins), all of which are required for nor-mal condensation of mesenchyme and osseous differentia-tion during embryogenesis (Mundlos and Olsen, 1997a;Kornak and Mundlos, 2003). Although some of thesedefects no doubt have a genetic basis, exposure to certainteratogenic agents at an appropriate stage of embryogene-sis has the potential to damage developing somites andinduce similar abnormalities.

Osteochondrosis

Osteochondrosis is a well recognised skeletal disease ofrapidly growing young animals of several species, includinghorses, pigs, cattle, deer and dogs (Thompson, 2007), buthas also been reported as a cause of lameness in young,rapidly growing Suffolk ram lambs (Doherty et al., 1996;Scott et al., 1996). The aetiology has yet to be resolvedbut appears to be multifactorial and most likely involvesan interaction of genetic, nutritional and mechanical fac-tors. In sheep, as in pigs, the elbow joint appears to be a

(b) Distal radius of the same ram showing residual physeal abnormalitiesth on one side of the physis, leading to angular deformity.

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predilection site for lesions. Focal thickening of articularcartilage on the medial condyle of the distal humerus isdescribed in affected lambs (Doherty et al., 1996; Scottet al., 1996). Physeal lesions typical of osteochondrosisare also described in the long bones of young lambs (Duff,1986) and may predispose to angular limb deformity bycausing localised impairment of endochondral ossification.This is supported by the detection of residual lesions in thedistal radial physics of many young rams with valgus orvarus deformities of the forelimb (Figs. 12a and b).

Conclusions

The inherited skeletal abnormalities in sheep describedhere almost certainly represent the tip of an iceberg. Newmutations are occurring all the time but only a small per-centage of these ‘‘experiments of nature’’ are ever likely tobecome manifest phenotypically. Of those that do, manyare never published. Successful recognition and reportingof such diseases depends on the observational skills of farm-ers and the enthusiasm and investigative skills of veterinaryclinicians and pathologists, but due to time and financialconstraints field observations often do not progress beyondthe farm gate. Few inherited defects ever become economi-cally significant but they may reach a high prevalence onindividual properties or in specific breeds. Furthermore,such defects often provide an opportunity to generate newscientific knowledge or create animal models of human dis-ease. Perhaps this review will encourage veterinarians whobecome aware of possible inherited skeletal defects in sheepto make them known to colleagues in diagnostic laborato-ries or universities who may be keen to pursue them further.

Acknowledgement

We are grateful to Professor R.D. Jolly for his sugges-tions and advice during the preparation of manuscript,and for his encouragement and enthusiastic support ofour research over many years.

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