Overview of Congenital and Inherited Anomalies
Embryonic and fetal development are the result of a complex series of well orchestrated events. When properly accomplished, the outcome is a healthy neonate. Errors in the sequential steps of development may be followed by embryonic loss, fetal death, fetal mummification, abortion, stillbirth, birth of nonviable neonates, or birth of viable offspring with defects. When a developmental disruption results in a deviation from normal that is present or apparent at birth, the defect is said to be congenital. Other developmental defects may not become apparent until later in life, and although the disruptive event occurred before birth, the defect is not strictly classified as congenital. Although the event or agent resulting in disrupted development remains undefined for many recognizable congenital conditions, technologic advances in the field of teratology have identified an increasing number of specific genetic, environmental, and infectious agents as etiologic determinants of certain cases of defective fetal development.
Teratogens are agents or factors that cause development of physical defects in the embryo or fetus. The timing of teratogenic exposure influences the eventual outcome. Although zygotes, the cells resulting from the union of gametes, are relatively resistant to the effects of most teratogens, they may be affected by chromosomal alterations or aberrations that occur during the process of gametogenesis or fertilization, as well as by genetic mutations that may be passed from one or both parents. As the zygote develops into the embryo and organogenesis progresses, susceptibility to environmental teratogens and teratogenic infectious agents increases. As the conceptus ages further, the fetus becomes increasingly resistant to environmental teratogens. Late-differentiating structures such as the palate, cerebellum, and urogenital system remain at risk well into the fetal period.
Similar, and perhaps indistinguishable, defects may be induced by more than one agent. Exposure to toxic or infectious agents at critical phases of embryonic or fetal development may induce congenital anomalies that closely resemble heritable conditions. With increased awareness of the importance of inherited anomalies by breeders and breed associations, practitioners and diagnosticians must be thorough in investigating cases, to avoid failing to recognize conditions that may be heritable and to avert improperly implicating breeding lines as a cause.
Structural and functional congenital defects have been described in all domestic species. Although congenital defects are often classified or described by the body system or part primarily involved, such classification systems are complicated by frequent simultaneous involvement of multiple body systems. Even so, descriptive classifications provide a basis for comparison and allow for estimation of the time of the disruptive event relative to fetal development, and sometimes etiology (see Table: Some Common Congenital Defects of Domesticated Animals).
Some Common Congenital Defects of Domesticated Animals
Identification of molecular signals that guide sequential development of organs and organ systems, coupled with molecular diagnostic tools and genomic testing, allow a more detailed understanding of many observed congenital anomalies. It is likely that as these technologies improve, the etiology of other conditions will be clarified.
Chromosomal abnormalities occurring during gametogenesis or fertilization may result in embryo lethal anomalies or occasionally in abnormal but viable offspring. Errors in oogenesis can be associated with increased maternal age in several species and may result in failure of fertilization, reduced embryo viability, or in deficiencies expressed during fetal development. Chromosomal errors such as trisomy, in which there are three instances of a particular chromosome instead of the normal two, have been reported in veterinary medicine, and increasing availability of karyotyping and ancillary chromosomal analysis have increased recognition of these defects. Aging of gametes after suboptimal timing of insemination represents another source of chromosomal abnormality leading to errors in embryonic and fetal development. All cells of the defective embryo may be aneuploid (the presence of an abnormal number of chromosomes in a cell) or various degrees of mosaicism (the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg) may exist.
Chromosomal and epigenetic abnormalities may occur during assisted reproductive techniques that involve oocyte collection, culture, and fertilization. Bovine pregnancies resulting from somatic cell nuclear transfer or, to a lesser extent, from in vitro fertilization, are at increased risk of development of abnormal offspring syndrome due to failures in physiologic mechanisms necessary for proper fetal and placental development. These errors in development and placentation can result in fetal death, abortion, abnormally large or small birth weights, or birth of defective neonates, and are often associated with dystocia.
Inherited defects resulting from mutant genes present in breeding lines or families have been seen in all breeds. They may be expressed in typical patterns of inheritance such as the common simple autosomal recessive pattern typified by the recently described arthrogryposis multiplex anomaly of Angus cattle. Dominant defect traits are inherited as well and are sometimes selected for.
Some polygenetic defects require inclusion of more than one interacting gene. Rat tail syndrome, a congenital form of hypotrichosis in cattle, is controlled by genes at two interacting loci.
Because animals heterozygous for undesirable or lethal recessive traits often cannot be detected by visual examination, and sometimes exhibit a phenotype that is thought to be desirable, inadvertent selection may help spread genetic defects in a particular breed. For example, cattle heterozygous for tibial hemimelia reportedly have rear limb conformation and hair coat characteristics preferred by some breeders, and phenotypic selection of certain sires may have increased the allele frequency in the population. Similarly, while the Overo color pattern is attractive to some horse breeders, animals homozygous for this color pattern are often affected with a lethal congenital anomaly due to failure of intestinal tract innervation secondary to ileocolonic agangliosis. It is recommended to include only one Overo parent in a mating. The dominant inheritance of polledness in dairy goats is associated with coinheritance of a recessive allele that results in masculinization of homozygous females (the so-called polled intersex goat). Restrictive breeding programs that ensure at least one member of the breeding pair has horns are recommended to avoid this defect.
Heritable defects in metabolic function may result in embryonic or fetal death, birth of nonviable neonates, or birth of compromised offspring that survive. Such defects may be lethal in utero or early in the postnatal period, or animals may survive in a compromised form. Careful observation and diagnostic evaluation are required to properly identify these conditions and link them to pedigree information.
Deficiency of monophosphate synthase (DUMPS) is a lethal autosomal recessive trait formerly widely dispersed in Holstein cattle. When breeding of two DUMPS carriers results in a homozygous embryo, apparently normal fertilization and embryonic development is followed by death of the fetus in early gestation. Screening of sires destined for use in artificial insemination has successfully reduced the incidence of DUMPS.
Citrullinemia in cattle results in disruption of the urea cycle due to arginosuccinate synthetase deficiency and is lethal in the homozygous state. Affected calves appear healthy at birth but develop increased blood ammonia concentrations and die within a few days.
Defects found on the X chromosome, such as the one responsible for canine X-linked muscular dystrophy in Golden Retrievers, Labrador Retrievers, and other breeds, are expressed in males carrying only a single copy of a defective allele. Both parents are unaffected, with the dam carrying a single copy of the defective gene on an X chromosome.
For a partial list of inherited disorders with a known molecular basis, see Table: Congenital Disorders with a Known Molecular Basis.
Congenital Disorders with a Known Molecular Basis
Use of elite genetic lines in domestic species increased with the rapid and widespread adoption of reproductive technologies, particularly artificial insemination, embryo transfer, and in vitro fertilization. Dissemination of undetected genetic recessives to a large portion of the population domestically and internationally has been an inadvertent and unintended consequence. As the percentage of animals carrying undesirable recessive traits grows, an increased opportunity for breeding genetically related individuals is followed by the expression of the undesirable phenotype. Complex vertebral malformation in Holstein-Friesian dairy cattle was spread internationally primarily due to the influence of a single Holstein sire from the USA and his offspring. Similarly, arthrogryposis multiplex in Angus cattle received international attention due to the influence of a popular bull, his offspring, and descendants. In both cases, genetic testing developed after description of the condition provided breed associations and breeders opportunities to minimize the effects or eliminate the conditions.
By the time detrimental genetic conditions are recognized in a population or breed, the abnormal allele is often widely distributed. Early recognition and detection are desirable to minimize this possibility. All congenital anomalies should be investigated, and when a condition appears to have an underlying genetic component, appropriate techniques to assess pedigree information and identify the mutated homozygous phenotype should be explored. A structured system of reporting and recording, beginning with accurate clinical and pathologic descriptions, is necessary to centralize data and focus attention on physical and physiologic abnormalities that may be genetic in origin. Pedigree analysis and test mating of closely related animals coupled with recently developed DNA-based testing have the potential to identify specific genetic aberrations, in some cases relatively rapidly after recognition of the defect. Most breed associations have procedures to report congenital anomalies and work with pathologists, geneticists, and molecular biologists to identify emerging genetic defects.
Once known genetic recessive conditions are identified, several options exist to minimize their occurrence. For complex vertebral malformation, testing of all Holstein sires entering artificial insemination programs was chosen. Bulls were identified as being either carriers or free of the defect. The resulting decline in use of semen from carrier bulls led to a decrease in the occurrence of the condition and the allelic frequency within the breed. Other genetic recessive conditions in the same breed, including bovine leukocyte adhesion deficiency and DUMPS were handled similarly, and the recently identified brachyspina syndrome will likely be managed in the same manner. The extensive use of artificial insemination in dairy cattle allows this strategy to have a rapid impact.
In breeds or species with less use of artificial insemination, a more aggressive approach may be required. After recognition of arthrogryposis multiplex, the American Angus Association mandated testing and identification of all sires in active artificial insemination programs. They also required genetic testing to determine carrier status of all animals with suspect pedigrees submitted for registration. No certificate of registration will be issued to carrier animals born after a specified date. Similar requirements for animals with pedigrees tracing to carriers of neurogenic hydrocephalus have been put in place by this breed association. Extensive testing and identification of carrier individuals is used by the American Quarter Horse Association to minimize the incidence of hyperkalemic periodic paralysis.
As new genetic recessive abnormalities are identified and characterized, genetic tests to determine carrier status can be developed. Breed associations and breeders will adopt testing and identification strategies similar to those mentioned above. However, implementation of testing strategies will be more complicated for nonlethal defects and for conditions in which heterozygotes have a phenotype perceived as desirable.
Environmental teratogens include plant toxins, viruses, drugs, trace elements, nutritional deficiencies, and physical agents such as irradiation, hyperthermia, uterine positioning, and perhaps pressure during rectal examination for pregnancy. Although the defects produced in the neonate may resemble or mimic heritable defects, they do not follow a familial pattern. Specific causes may be difficult to identify but often follow seasonal patterns associated with growth characteristics of toxic plants or availability of suitable vectors of arthropodborne viruses. Although congenital anomalies may follow maternal disease due to plant intoxication or viral infection, teratogenic effects sometimes occur in the absence of observed clinical signs in the dam.
Biologically active products produced by many plants are known to be teratogens. (See also Poisonous Plants.) Ingestion may result in abortion, birth of nonviable neonates, or production of neonates that are abnormal at birth. Production losses can be significant if large numbers of animals gain access to affected plants at critical times in embryonic or fetal development. Veratrum californicum (skunk cabbage) has been implicated as a cause of fetal gigantism, prolonged gestation, and craniofacial deformities in sheep grazing rangelands containing the plant. Cyclopamine, a steroidal alkaloidal compound produced by the plant, is the teratogenic agent. Experimental dosing with this toxin in ewes on day 13–15 of pregnancy can cause a variety of congenital anomalies. Ingestion on day 14 specifically induces synophthalmia or cyclopean defect. Ewes exposed later in gestation may deliver healthy lambs, illustrating the critical interaction of time of exposure and gestational age.
In cattle, ingestion of several species of lupines (Lupinus laxiflorus, L caudatus, L sericeus, or L nootkatensis) has resulted in “crooked calf disease,” characterized by joint contractures, torticollis, scoliosis or kyphosis, cleft palate, or combinations of these defects. The quinolizidine alkaloid anagyrine is identified as the teratogen, and the critical window for exposure is 40–70 days gestational age. Ingestion of L formosus causes similar skeletal defects and cleft palate in cattle and goats; the teratogen is the alkaloid piperidine. With either toxin, defects are thought to be related to an alkaloidal toxin–induced inhibition of fetal movement during critical gestational periods. Periodic losses due to lupine-induced crooked calf disease occur in the western USA after ingestion by cattle on rangeland.
Conium maculatum (poison hemlock) causes contracture defects and occasionally cleft palate in cattle, goats, sheep, and pigs. Both the plant and seed contain the teratogenic alkaloidal toxin coniine.
Ingestion of Nicotiana tabacum (cultivated tobacco) produces skeletal defects in pigs similar to those induced in cattle and pigs by Lupinus spp and C maculatum. Congenital amelia and hemimelia in piglets that occurred when pregnant sows were allowed access to tobacco stalks are seldom seen today due to changes in swine management. Nicotiana glauca (tree tobacco) also induces contracture defects and cleft palate in cattle, sheep, and goats.
Other plants suspected of causing similar defects in calves include Senecio spp, Cycadales, Blighia, Papaveraceae, Colchicum, Vinca spp, and Indigofera spicata and related plants. Sudan grass (Sorghum vulgare) has been incriminated as a cause of congenital joint contracture in horses, and S sudanense may cause arthrogryposis in calves.
Pregnant mares consuming fescue pasture or fescue hay infected with the fungal endophyte Neotyphodium coenophialum are at risk of abortion, prolonged gestation, hypogalactia, and delivery of weak or dysmature foals (see Fescue Poisoning). Ergovaline and other ergot alkaloids produced by the endophyte are the cause of fescue toxicosis. Endophyte-free fescue and fescue infected by nontoxic strains of endophyte reportedly can be grazed safely by pregnant mares.
Congenital hypothyroidism in foals has been linked to increases of dietary nitrate concentrations in pregnant mares in western Canada and to dietary exposure of late gestation mares to N coenophialum–infected fescue.
Pesticides, herbicides, pharmaceutical agents, and other chemicals have been incriminated as teratogenic agents. Currently, drugs and chemicals undergoing approval processes in the USA, Canada, and many other countries must be tested for teratogenic potential before commercial licensing. Products may be labeled with instructions to specifically avoid use in animals that are pregnant or may be pregnant. Other products may be labeled as safe for pregnant animals once the fetus exceeds a specified gestational age. When using some herbicides, it may be necessary to withhold animals from pasture for specified periods after application. Extra-label use of pharmaceutical agents in pregnant animals and inadvertent exposure to pesticides and other chemicals carries inherent risks, including adverse effects on the developing fetus. Practitioners and producers should be aware of the potential for pregnancy loss or development of congenital anomalies after administration of therapeutic agents or exposure to pesticides and chemicals and should exercise appropriate caution when using such products.
Prenatal viral infections may be teratogenic in cattle, sheep, goats, pigs, dogs, and cats but have rarely been incriminated in congenital defects in horses. The stage of fetal or embryonic development at the time of exposure determines the type and extent of the anomalies observed. Viral infection in late gestation may result in fetal infection and seroconversion without observed clinical signs, while exposure during earlier stages may induce pregnancy loss or induce congenital defects.
Production of neonates with congenital anomalies after in utero infection may follow observable clinical disease in the dam; however, anomalies are also seen without history of disease during pregnancy. On occasion, use of modified-live virus vaccines in pregnant animals has produced congenital defects; such use is discouraged.
Pestivirus infections are teratogenic in many species. Bovine viral diarrhea virus (BVDV) is among the most economically significant infectious agents affecting cattle worldwide, and prenatal infection can cause a variety of congenital defects in survivors, including cerebellar hypoplasia, brachygnathia, alopecia, ocular defects, internal hydrocephalus, and impaired immunocompetence. Immunotolerant, persistently infected animals may result from fetal infection with noncytopathic BVDV before gestational day 120. These animals serve as a major reservoir of infection.
Pestivirus infections in other species also result in congenital defects. Infection of pregnant ewes with border disease virus (see Border Disease) may manifest as embryonic and fetal death or congenital defects involving the integumentary, nervous, skeletal, endocrine, and immune systems. Defects include tremors, ataxia, abnormal hair coat, low birth weight, facial and ocular abnormalities, depressed immune response, and birth of small, weak lambs with poor growth and viability. Infection of pregnant ewes with BVDV from cattle has produced identical congenital anomalies in sheep.
Classical swine fever (see Classical Swine Fever), a pestivirus infection of swine, was once known as hog cholera. The virus has been eradicated in the USA but remains a major cause of swine disease in some areas. Prenatal infection can result in congenital defects similar to those seen in cattle infected with BVDV.
Cache Valley virus infection of pregnant ewes may result in anomalies in their lambs, including arthrogryposis, torticollis, scoliosis, lordosis, hydranencephaly, microcephaly, porencephaly, and cerebellar and muscular hypoplasia. This bunyavirus is spread by mosquitoes and is found in the USA, Canada, and Mexico. Other ruminant species may be affected, and other bunyaviruses have been reported to cause similar congenital defects.
Bluetongue virus, an orbivirus endemic in many areas of North America, South America, Africa, and parts of Asia, has recently expanded its range in Europe. In utero exposure may induce hydranencephaly, porencephaly, and arthrogryposis in sheep, and it can result in abortion, stillbirths, arthrogryposis, campylognathia, prognathia, hydranencephaly, and “dummy calf” syndrome in cattle. Other orbiviruses such as Chuzan virus and perhaps epizootic hemorrhagic disease may cause abortion, congenital defects, and neonatal losses similar to bluetongue virus.
Akabane virus (see Akabane Virus Infection), an orbivirus present in many tropical and subtropical areas, is spread by Culicoides spp (biting midges). Infection of naive animals can be followed by transplacental infection of the fetus and may produce deformities similar to those seen with viruses such as bluetongue and Cache Valley virus.
Congenital cerebellar hypoplasia in kittens has long been recognized as a result of infection of pregnant queens with feline panleukopenia virus. Infection of pregnant ferrets with feline panleukopenia virus also can result in congenital cerebellar hypoplasia.
Deficiency of one or more nutrients during pregnancy may result in congenital defects in the newborn. Microminerals and vitamins are implicated in a variety of developmental defects. Severe deficiencies may interrupt pregnancy or result in weak or nonviable young.
Iodine deficiency may cause congenital goiter or cretinism in all species. Copper deficiency is a cause of enzootic ataxia in lambs. Manganese deficiency can result in congenital limb deformities in calves. Vitamin D deficiency may cause neonatal rickets, and vitamin A deficiency may cause eye defects or harelip. Experimentally, teratogenic effects have been induced by deficiencies of choline, riboflavin, pantothenic acid, cobalamin, and folic acid, and by hypervitaminosis A.
Congenital joint contracture after birth of relatively large calves or foals, or associated with cases of twin pregnancy in these normally monotocous species, is a result of restricted motion due to uterine crowding. Many cases are mild and potentially self-correcting after birth.
Torticollis, scoliosis, and limb abnormalities in foals have been associated with intrauterine fetal positioning after transverse or caudal presentation. Pervious urachus in foals is reportedly associated with umbilical cord twisting.
In cattle, aggressive transrectal palpation of the amnionic vesicle before day 42 of gestation (eg, during pregnancy diagnosis) may disrupt vascular supply to the intestinal tract and induce atresia coli. Most cases of this malformation are seen in Holstein cattle, and a genetic predisposition may exist. At least one report suggests an autosomal recessive inheritance pattern for atresia coli.
In many cases of congenital anomalies, the etiology or predisposing factors remain unknown. Some specific anomalies of unknown etiology occur frequently enough to be readily recognized by veterinarians in the field.
Perosomus elumbis is a congenital anomaly that occurs primarily in cattle but also in small ruminants and swine. Affected calves have agenesis of segments of the lumbosacral spinal cord and vertebral column, with secondary hypoplasia, arthrogryposis, and ankylosis of the pelvic limbs. Other anomalies associated with development of the GI and urogenital systems accompany this condition. The body, limbs, and organs cranial to the developmental defect in the spinal cord appear normal. The condition is fatal, resulting in stillbirth or requiring euthanasia on humane grounds. Dystocia is a frequent complication. Although there are suggestions of inheritance, no definitive cause is recognized. Aberrations in the homeobox gene family, responsible for cranial to caudal patterning, may be involved.
Schistosomus reflexus, a fatal congenital disorder seen in ruminants, is characterized by severe retroflexion of the spinal column, resulting in positioning of the hindlimbs adjacent to the skull, ankylosis of appendicular joints, and failure of closure of the abdominal wall with consequential presence of abdominal viscera outside the body. Other anomalies, including thoracoschisis, may accompany the condition. The presence of an affected fetus results in dystocia, frequently requiring surgical intervention or fetotomy. Some reports utilizing pedigree analysis suggest a genetic etiology, but no specific defect or mode of inheritance has been found. Interestingly, cases involving one affected calf and a healthy co-twin have been reported.
Fetal anasarca is a fatal anomaly seen in several breeds of dogs. The cause remains unknown and may vary from breed to breed. This condition frequently results in dystocia due to the disproportionately large fetus at term. Single or multiple pups within a litter may be affected.