**3.1 Concept**

72 A Bird's-Eye View of Veterinary Medicine

In veterinary medicine, dysmorphology is still a neglected field of knowledge, but has begun to take shape in line with the advances in veterinary medical genetics. Its basis is derived from human dysmorphology due to current knowledge of the genomic similarities between man and other vertebrates, especially mammals, showing that morphogenesis is evolutionarily conserved throughout the zoological scale. The inductive molecular mechanisms that form the embryonic pattern are identical in all vertebrates (Opitz et al., 2002). Furthermore, veterinary medicine and human medicine share most of the same methods and techniques, both in terms of diagnosis and therapy. However, in the current stage of the development of veterinary dysmorphology, some minute criteria used in human dysmorphology, especially those concerning the extension of concepts, could not always be

The meaning of dysmorphology in veterinary medicine becomes clear when one considers that congenital defects in animals cause different types of impact: 1) the obvious suffering of the affected individual; 2) the psychological stress for the owners, who are more affectionate towards animals; 3) the abandonment of affected animals by many owners; and 4) the economic loss suffered by breeders, both of companion and production animals. All of these situations are directly linked to the professional work of the veterinarian, meaning different

The main objectives of veterinary dysmorphology are humanitarian, professional, scientific, preventive and educational. The goal in humanitarian terms is to strive to minimize the suffering of affected individuals and have to do with the perception that animals are sentient beings, i.e., they can feel pain, discomfort, a number of difficulties and other feelings when they are affected by a defect or illness and, consequently, they suffer. The professional goals are to offer qualified assistance to clients who seek guidance and a solution to the congenital health problems of their animals. With these aims in mind more and more people are seeking veterinary clinics and hospitals, especially those dedicated to small animals. The scientific goals have to do with producing knowledge that will result in benefits for the animals themselves and also human beings. The study of spontaneous animal models of human diseases generates knowledge that could not be obtained from human patients for legal and ethical reasons. There are a great number of these animal models recognized today. New medical and molecular biology technology greatly facilitate these studies. The preventive goals are to attempt to advise owners and breeders of animals to help them make decisions and prevent the birth of new individuals with congenital defects. Scientifically based advice is an important step to avoiding the perpetuation of abnormalities, be they of a genetic nature or caused by environmental factors. The educational objectives include raising awareness that veterinarians, like any other professional, should contribute to the development of a better society in every way possible, encouraging ethical values and respect for human beings, animals, nature and life in

**2. Dysmorphology in veterinary medicine** 

adopted here.

**2.1 Importance** 

**2.2 Objectives** 

general.

goals in terms of intervention.

Dysmorphism2 is the generic name for abnormalities of the form and structure of an animal's body, being used especially for congenital abnormalities, thus constituting an *inborn error of development*. It is important to remember that the adjective "congenital" means born with the individual, independent of the cause. However, it is not synonymous with either "genetic" or "hereditary". Therefore, there are congenital defects that have a genetic cause (the majority) while others have an environmental cause. The word dysmorphism has a broad meaning and can also refer to alterations that are expressed in deviations of size, position, number and even the coloring of one or more parts of the body. Thus, all of the following examples are dysmorphisms: cleft lip and palate (*cheilopalatoschisis*); absence of the cranial vault and cerebral hemispheres (*anencephaly*); very small jaw (*micrognathia*); heart with the apex to the right-hand side (*dextrocardia*); an out of place kidney (*renal ectopia*); one or two missing eyes (*anophthalmia*); extra toes (*polydactyly*); two heads (*dicephaly*); a simple and hyperplasic congenital stain on the skin (*congenital nevus*). Some are extremely serious and lead to death in early life, such as anencephaly; others cause little or no harm to the animal, such as polydactyly (Fig.1).

Fig. 1. Examples of dysmorphisms in dogs: A) Anencephaly; B) Anophthalmia; C) Polydactyly.

#### **3.2 Classification**

According to the nature of the alteration that causes the dysmorphism and the stage at which it manifests, the phenomenon can be divided into three categories: *malformation, disruption and deformation.* Malformations begin earlier, during the embryonic period, while disruptions appear later. Most deformations begin during the fetal stage, which is when the conceptus grows more rapidly (Kumar & Burton, 2008). If subjacent histological alterations are also considered, a fourth category can be added: *dysplasia*.

<sup>2</sup> Dysmorphism should not be confused with dimorphism, which means the existence of "two different and normal forms" of a given characteristic (from the Greek *di*, two; *morphé*, form), commonly used in the expression "sexual dimorphism" to indicate the natural differences between male and female in a given species.

hydranencephaly in cats (Résibois et al., 2007); 3) The intrauterine infection caused by the blue tongue virus (BTV serotype 8) causes hydranencephaly in cattle (Wouda et al., 2009); 4) A well known cause of disruption in human beings and which has also been found in the rhesus monkey (Tarantal & Hendrickx, 1987), are amniotic bands that can cause constriction of body structures, leading to facial clefts, amputation of fingers and toes or limbs and other

This is a defect of the shape or position of part of the body caused by mechanical forces (Spranger, 1982). These forces may be of internal or external origin and are most evident in the bones, cartilage and joints, as soft tissues tend to return to their original form as soon as the force ceases. Deformations set in during the fetal stage and are normally caused by forces that act late in pregnancy (Epstein, 2004). A large number of deformations have a spontaneous resolution after birth, although this normally takes place slowly. Sometimes, however, treatment is necessary to correct a deformation (Aase, 1990). Like disruptions, although later on, deformations also cause damage to previously intact developed structures with no intrinsic tissue abnormality (Kumar & Burton, 2008). Examples: 1) Club foot as a result of too little space in the uterus and muscular hypotonia or joint laxity, impeding movement of the extremities. Among the factors that reduce uterine space are a very large fetus and a reduction in amniotic fluid, a condition known as oligohydramnios; 2) Increased cephalic perimeter in the hydrocephaly5 due to pressure from the accumulation of cerebrospinal fluid. The first example is caused by an external force (pressure from the uterus) whereas the second one is caused by an internal force (pressure from the cerebrospinal fluid). It is worth bearing in mind, however, that not all deformations are congenital. They can also develop in postnatal life. For example, bones can be bent because of a lack of calcium or the joints can lose alignment because of the laxity of the joints or lack of calcium. These structures become deformed because of the

Dysplasia is a morphological defect that results from a disorganization of cells (Spranger, 1982) and other components of a tissue, which, in turn, does not have normal architecture. Therefore, dysplasias are disorders of histogenesis and the alterations occur on a microscopic level and are reflected in the imperfect appearance of the organ or other affected regions of the body. Examples: 1) Congenital alopecia and dental abnormalities in dogs with X-linked hypohidrotic ectodermal dysplasia. There is also absence of piloglandular units in the areas of alopecia (Moura & Cirio, 2004). 2) Thoracic and pelvic limbs are short and bent in dogs affected by chondrodysplasia as can be seen in Great Pyrenees dogs (Bingel & Sande, 1994) or in Labrador retrievers (Smit et al., 2011). Figure 2 shows a visual comparison between normal development and the four types of inborn

5 The cause of hydrocephaly is a malformation or disruption that blocks the drainage of cerebrospinal fluid which, in turn, dilates the cerebral ventricles and separates the cranial bones, *deforming* the head.

errors of development (malformation, disruption, deformation and dysplasia).

abnormalities.

**3.2.3 Deformation** 

weight of the body.

**3.2.4 Dysplasia** 

#### **3.2.1 Malformation**

This is a morphological defect of an organ, part of an organ, or a larger region of the body, resulting from an intrinsically abnormal developmental process (Spranger, 1982)3. This definition highlights that malformations are disorders in the formation of organs and manifest early, i.e., they are *abnormal processes since the time of their origin*. The affected organ can show varying degrees of imperfection or simply not exist. Malformations arise during blastogenesis or organogenesis and are causally heterogeneous and those that appear earlier (blastogenesis) tend to affect more than one region of the body (Opitz et al., 2002). Although they can be induced by environmental factors, they are commonly caused by gene mutations, chromosomal aberrations or a combination of genetic and environmental factors (Kumar & Burton, 2008). Examples: 1) A nonsyndromic cleft lip and palate can be caused by a recessive autosomal mutation in Brittany spaniels (Richtsmeier et al., 1994), Pyrenees shepherds (Kemp et al., 2009) and boxers (Moura et al., 2011); 2) In Rocky Mountain horses ciliary body cysts, iridal hypoplasia, iridocorneal adhesions and megalocornea are caused by codominant autosomal mutation, with cysts expressed in the heterozygotes and multiple ocular anomalies expressed in the homozygotes (Ewart et al., 2000), whose locus was mapped to the long arm of chromosome 6 (Andersson et al. 2008); 3) The trisomy 18 in cattle causes brachygnathia and is lethal (Herzog, 1974); 4) Cardiac malformations usually have a multifactorial etiology, such as a patent ductus arteriosus in poodles (Buchanan & Patterson, 2003); 5) Neural tube closure defects, such as spina bifida and anencephaly, also have a multifactorial etiology, including mutations in genes involved in folate metabolism (De Marco et al., 2011).

#### **3.2.2 Disruption**

A disruption is a morphological defect of an organ, part of an organ or a larger region of the body, resulting from a disturbance in an originally normal developmental process (Spranger, 1982)4. This definition highlights that the *formation process of the organs was initially normal, but suffered negative interference during its development*, having affected the organ during the embryonic or fetal stage. In a disruption there is damage to structures of the conceptus because of interference in the blood supply, anoxia, infection or mechanical force (Epstein, 2004), affecting several different tissues and the defect does not respect the boundaries imposed by embryonic developmental process (Aase, 1990). In general, disruptions are caused by environmental factors, but genetic factors can predispose to the development of a disruption (Kumar & Burton, 2008). Examples: 1) A number of therapeutic drugs can cause damage to the embryo when used during pregnancy, especially drugs for continuous use, such as the anticonvulsant valproic acid (Jentink et al., 2010); 2) The feline panleukopenia virus has long been known to cause cerebellar hypoplasia and eventually

<sup>3</sup> In the early 1980s, due to divergences and mistaken nomenclature at that time, specialists in congenital defects formed an International Work Group (IWG) to classify and define terms and expressions for morphogenesis disorders. Their recommendations were published in 1982 (Spranger et al., 1982) and adopted by most dysmorphologists and are still in use today, with very few modifications.

<sup>4</sup> The definitions of malformation and disruption used here correspond, respectively, to the *primary malformation* and *secondary malformation* that were previously in use in dysmorphology. In 1982, the IWG restricted the use of malformation to intrinsically abnormal or primary defects (Opitz, 1984).

This is a morphological defect of an organ, part of an organ, or a larger region of the body, resulting from an intrinsically abnormal developmental process (Spranger, 1982)3. This definition highlights that malformations are disorders in the formation of organs and manifest early, i.e., they are *abnormal processes since the time of their origin*. The affected organ can show varying degrees of imperfection or simply not exist. Malformations arise during blastogenesis or organogenesis and are causally heterogeneous and those that appear earlier (blastogenesis) tend to affect more than one region of the body (Opitz et al., 2002). Although they can be induced by environmental factors, they are commonly caused by gene mutations, chromosomal aberrations or a combination of genetic and environmental factors (Kumar & Burton, 2008). Examples: 1) A nonsyndromic cleft lip and palate can be caused by a recessive autosomal mutation in Brittany spaniels (Richtsmeier et al., 1994), Pyrenees shepherds (Kemp et al., 2009) and boxers (Moura et al., 2011); 2) In Rocky Mountain horses ciliary body cysts, iridal hypoplasia, iridocorneal adhesions and megalocornea are caused by codominant autosomal mutation, with cysts expressed in the heterozygotes and multiple ocular anomalies expressed in the homozygotes (Ewart et al., 2000), whose locus was mapped to the long arm of chromosome 6 (Andersson et al. 2008); 3) The trisomy 18 in cattle causes brachygnathia and is lethal (Herzog, 1974); 4) Cardiac malformations usually have a multifactorial etiology, such as a patent ductus arteriosus in poodles (Buchanan & Patterson, 2003); 5) Neural tube closure defects, such as spina bifida and anencephaly, also have a multifactorial etiology, including mutations in genes involved in folate metabolism (De

A disruption is a morphological defect of an organ, part of an organ or a larger region of the body, resulting from a disturbance in an originally normal developmental process (Spranger, 1982)4. This definition highlights that the *formation process of the organs was initially normal, but suffered negative interference during its development*, having affected the organ during the embryonic or fetal stage. In a disruption there is damage to structures of the conceptus because of interference in the blood supply, anoxia, infection or mechanical force (Epstein, 2004), affecting several different tissues and the defect does not respect the boundaries imposed by embryonic developmental process (Aase, 1990). In general, disruptions are caused by environmental factors, but genetic factors can predispose to the development of a disruption (Kumar & Burton, 2008). Examples: 1) A number of therapeutic drugs can cause damage to the embryo when used during pregnancy, especially drugs for continuous use, such as the anticonvulsant valproic acid (Jentink et al., 2010); 2) The feline panleukopenia virus has long been known to cause cerebellar hypoplasia and eventually

3 In the early 1980s, due to divergences and mistaken nomenclature at that time, specialists in congenital defects formed an International Work Group (IWG) to classify and define terms and expressions for morphogenesis disorders. Their recommendations were published in 1982 (Spranger et al., 1982) and

4 The definitions of malformation and disruption used here correspond, respectively, to the *primary malformation* and *secondary malformation* that were previously in use in dysmorphology. In 1982, the IWG

adopted by most dysmorphologists and are still in use today, with very few modifications.

restricted the use of malformation to intrinsically abnormal or primary defects (Opitz, 1984).

**3.2.1 Malformation** 

Marco et al., 2011).

**3.2.2 Disruption** 

hydranencephaly in cats (Résibois et al., 2007); 3) The intrauterine infection caused by the blue tongue virus (BTV serotype 8) causes hydranencephaly in cattle (Wouda et al., 2009); 4) A well known cause of disruption in human beings and which has also been found in the rhesus monkey (Tarantal & Hendrickx, 1987), are amniotic bands that can cause constriction of body structures, leading to facial clefts, amputation of fingers and toes or limbs and other abnormalities.

#### **3.2.3 Deformation**

This is a defect of the shape or position of part of the body caused by mechanical forces (Spranger, 1982). These forces may be of internal or external origin and are most evident in the bones, cartilage and joints, as soft tissues tend to return to their original form as soon as the force ceases. Deformations set in during the fetal stage and are normally caused by forces that act late in pregnancy (Epstein, 2004). A large number of deformations have a spontaneous resolution after birth, although this normally takes place slowly. Sometimes, however, treatment is necessary to correct a deformation (Aase, 1990). Like disruptions, although later on, deformations also cause damage to previously intact developed structures with no intrinsic tissue abnormality (Kumar & Burton, 2008). Examples: 1) Club foot as a result of too little space in the uterus and muscular hypotonia or joint laxity, impeding movement of the extremities. Among the factors that reduce uterine space are a very large fetus and a reduction in amniotic fluid, a condition known as oligohydramnios; 2) Increased cephalic perimeter in the hydrocephaly5 due to pressure from the accumulation of cerebrospinal fluid. The first example is caused by an external force (pressure from the uterus) whereas the second one is caused by an internal force (pressure from the cerebrospinal fluid). It is worth bearing in mind, however, that not all deformations are congenital. They can also develop in postnatal life. For example, bones can be bent because of a lack of calcium or the joints can lose alignment because of the laxity of the joints or lack of calcium. These structures become deformed because of the weight of the body.

#### **3.2.4 Dysplasia**

Dysplasia is a morphological defect that results from a disorganization of cells (Spranger, 1982) and other components of a tissue, which, in turn, does not have normal architecture. Therefore, dysplasias are disorders of histogenesis and the alterations occur on a microscopic level and are reflected in the imperfect appearance of the organ or other affected regions of the body. Examples: 1) Congenital alopecia and dental abnormalities in dogs with X-linked hypohidrotic ectodermal dysplasia. There is also absence of piloglandular units in the areas of alopecia (Moura & Cirio, 2004). 2) Thoracic and pelvic limbs are short and bent in dogs affected by chondrodysplasia as can be seen in Great Pyrenees dogs (Bingel & Sande, 1994) or in Labrador retrievers (Smit et al., 2011). Figure 2 shows a visual comparison between normal development and the four types of inborn errors of development (malformation, disruption, deformation and dysplasia).

<sup>5</sup> The cause of hydrocephaly is a malformation or disruption that blocks the drainage of cerebrospinal fluid which, in turn, dilates the cerebral ventricles and separates the cranial bones, *deforming* the head.

On its own, a certain type of congenital defect may be rare, but congenital defects as a whole are relatively common in all domestic species and their different breeds and are a significant cause of neonatal and infant mortality and morbidity. Preliminary data suggest that the frequency of dysmorphisms is greater in pigs, followed in descending order by dogs, horses,

The *frequency* of major dysmorphisms in humans is estimated at 3% of live births (Marden et al, 1964). This number practically doubles by the end of the first year of life, with the identification of defects that manifest later (Kumar & Burton, 2008). In domestic animals, these numbers must be similar or even higher because inbreeding is common in selective breeding both for companion animals and for farm animals, increasing the coefficient of consanguinity. One study (Priester et al, 1970), which included all domestic species, analyzed almost 138,000 individuals and found a rate of 4.68%. However, minor dysmorphisms are not always identified and are seldom included in statistics. The same may occur in the case of major dysmorphisms when they affect internal structures and cause intrauterine or neonatal death and are not always reported. Rates of occurrence vary according to each abnormality and can also vary according to species, breed and geographical location. *Mortality* varies a great deal from one dysmorphism to another. Some are so serious that they cause intrauterine or perinatal death, such as combined heart-lung defects; others are incompatible with life and the affected individual dies soon after birth, as is the case with anencephaly. However, a large number of major dysmorphisms can be corrected surgically or be given some form of treatment, making life viable. Furthermore, minor dysmorphisms have no meaning in terms of mortality. Like mortality, *morbidity* also varies according to the dysmorphism. In many cases, treatment definitively cures the defect and the individual goes on to live a normal life; in other cases, treatment can improve the quality of life, but the individual will have chronic difficulties until the end of his days.

The artificial selection in breeding to obtain animals with a new or better appearance or for financial gain often means consanguineous unions, increasing the risk of the recurrence of a given defect in future generations. The environment also poses many risk factors during pregnancy, such as: 1) residue from pesticides in water, pasture and other foods; 2) certain toxic plants7 in the pasture; 3) inadequate conservation of animal feed and other foodstuff

6 Cats are generally under-represented in samples involving several species. However, veterinarians of small animals often come across congenital defects in purebred cats, which are suggestive of a relatively high rate of dysmorphisms in this species, which is not always reported in journals. They have seen conjoined twins, poliotia, radial agenesis, frontonasal dysplasia, cyclopia, diprosopia, meningocele, anencephaly, spina bifida, hydrocephaly, polydactyly, syndactyly, anal atresia, hypospadias, true

7 Examples include certain species of the genus *Lupinus* (lupines) that contain teratogenic alkaloids (anagyrine, ammodendrine) that cause a form of congenital arthrogryposis in calves, known as "crooked calf disease". This disease occurs when pregnant cows ingest the plants between the fortieth

**4. Epidemiological aspects of dysmorphisms** 

cattle and cats6 (Hámori, 1983).

**4.2 Risk factors** 

hermaphroditism, pseudohermaphroditism and others.

**4.1 Frequency, mortality and morbidity** 

Fig. 2. Types of dysmorphisms compared with normal development.

### **3.3 Further considerations**

Dysmorphisms can also be classified based on criteria other than those presented above. When the medical consequences are considered, they are divided into major and minor dysmorphisms. The former have a significant effect on the quality of life of the affected individual, such as oral clefts, or even impede survival (lethal dysmorphisms), such as anencephaly. The latter have little or no effect on the quality of life of the affected individual and do not require treatment or can be easily treated, such as polydactyly. Dysmorphisms can occur due to increased size or number of body parts and are known as excess dysmorphisms, e.g., extra fingers and toes (polydactyly), duplication of the face (diprosopia) and two heads (dicephaly); or missing body parts, known as reduction dysmorphisms, such as unilateral or bilateral absence of the radius (radial agenesis), missing pinna (anotia) and missing tail (anury). Figure 3 shows some of these defects.

Fig. 3. A) Dicephaly (excess dysmorphism) in extreme premature calf); B) Bilateral radial agenesis in a dog (reduction dysmorphism); C) Anotia in a dog (reduction dysmorphism). Photograph **A** courtesy of Dr. Antonia M. R. B. do Prado and Dr. Joséli Maria Büchele, Laboratory of Anatomy, Faculty of Veterinary Medicine, Pontíficia Universidade Católica do Paraná

Dysmorphisms can also be classified based on criteria other than those presented above. When the medical consequences are considered, they are divided into major and minor dysmorphisms. The former have a significant effect on the quality of life of the affected individual, such as oral clefts, or even impede survival (lethal dysmorphisms), such as anencephaly. The latter have little or no effect on the quality of life of the affected individual and do not require treatment or can be easily treated, such as polydactyly. Dysmorphisms can occur due to increased size or number of body parts and are known as excess dysmorphisms, e.g., extra fingers and toes (polydactyly), duplication of the face (diprosopia) and two heads (dicephaly); or missing body parts, known as reduction dysmorphisms, such as unilateral or bilateral absence of the radius (radial agenesis), missing pinna (anotia) and

Fig. 3. A) Dicephaly (excess dysmorphism) in extreme premature calf); B) Bilateral radial agenesis in a dog (reduction dysmorphism); C) Anotia in a dog (reduction dysmorphism). Photograph **A** courtesy of Dr. Antonia M. R. B. do Prado and Dr. Joséli Maria Büchele, Laboratory of Anatomy, Faculty of Veterinary Medicine, Pontíficia Universidade Católica

Fig. 2. Types of dysmorphisms compared with normal development.

missing tail (anury). Figure 3 shows some of these defects.

**3.3 Further considerations** 

do Paraná
