**5.1.1 Genetic etiology**

In humans, genetic factors are responsible for most dysmorphisms with a known cause (Kumar & Burton, 2008). Considering that mammals in general share most of their genes with humans and that the genes responsible for morphogenesis are highly conserved, the genetic factors must be equally responsible for most of the congenital defects of domestic mammals. These factors are: 1) *dominant autosomal mutations*, such as the fibrillin-1 gene (*FBN 1*), which causes Marfan syndrome in cattle (Singleton et al., 2005). The affected animals have long, thin limbs, laxity of the joints, lens abnormalities, aortic dilation, etc. (Besser et al., 1990); 2) *recessive autosomal mutations*, such as the one that causes anotia, cleft palate and bifid tongue in St. Bernard dogs (Villagómez & Alonso, 1998); 3) *recessive X-linked mutations*, such as the one that occurs in the ectodysplasin A1 and A2 gene isoforms (*EDA-A1* and *EDA-A2*) and causes X-linked hypohidrotic ectodermal dysplasia in dogs (Casal et al. 2005). Affected individuals have imperfect teeth, oligodontia and cutaneous areas with no piloglandular units, as shown in Figure 4 (Moura & Cirio, 2004); 4) *deletions of Y chromosome genes*, such as the one of the sex-determining region Y gene (*SRY*), which determines sex reversal in horses, i.e., it leaves individuals with an male XY karyotype with a female phenotype and ovaries (Raudsepp et al., 2010); 5) *chromosomal aberrations,* such as trysomy of chromosome 30 in horses, which makes them smaller than normal, with a

and hundredth day of pregnancy. The affected calves characteristically have bent extremities and can also have scoliosis, torticollis and cleft palate. Ingestion of toxic plants by farm animals can have a serious economic impact on livestock producers in given geographical areas through death losses, abortions, and birth defects (Lee et al., 2008).

8 It has not been completely established that *N*-nitroso compounds, such as nitrosamine and its precursors (nitrites and nitrates) naturally cause congenital diseases. Studies in animals indicate that they are highly carcinogenic and at higher levels can be teratogenic, but there is a need for further studies (Griesenbeck et al. 2010). Likewise, mycotoxins should also be considered. Fumonisins (frequent contaminants of corn) and ochratoxin-A (often found in stored grains) experimentally cause craniofacial and neural tube defects in mice (Marasas et al., 2004; Ueta et al. 2010).

9 An example of routine use in veterinary medicine is griseofulvin, an antifungal drug for animals with dermatomycosis. Scott et al. (1975) observed multiple congenital defects in newborn cats whose mothers orally received high doses of griseofulvin (500-1000 mg, at weekly intervals). There were cerebral defects, skeletal defects, cleft palate, anophthalmia with absence of optic nerves, anal atresia, lack of atrioventricular valves and other defects.

which results in mycotoxins; 4) excessive levels of nitrogen-containing food preservatives8 in low quality animal feed; 5) medicine9 in the early stages of pregnancy; 6) medicines for continuous use during pregnancy, such as some anticonvulsants; 7) occurrence of certain

The *etiological agents* of dysmorphisms can be divided into three large groups: *genetic, environmental and multifactorial*. Although, presumably, any cause of congenital defect is included in one of these groups, a large number of dysmorphsisms have no identified cause

In humans, genetic factors are responsible for most dysmorphisms with a known cause (Kumar & Burton, 2008). Considering that mammals in general share most of their genes with humans and that the genes responsible for morphogenesis are highly conserved, the genetic factors must be equally responsible for most of the congenital defects of domestic mammals. These factors are: 1) *dominant autosomal mutations*, such as the fibrillin-1 gene (*FBN 1*), which causes Marfan syndrome in cattle (Singleton et al., 2005). The affected animals have long, thin limbs, laxity of the joints, lens abnormalities, aortic dilation, etc. (Besser et al., 1990); 2) *recessive autosomal mutations*, such as the one that causes anotia, cleft palate and bifid tongue in St. Bernard dogs (Villagómez & Alonso, 1998); 3) *recessive X-linked mutations*, such as the one that occurs in the ectodysplasin A1 and A2 gene isoforms (*EDA-A1* and *EDA-A2*) and causes X-linked hypohidrotic ectodermal dysplasia in dogs (Casal et al. 2005). Affected individuals have imperfect teeth, oligodontia and cutaneous areas with no piloglandular units, as shown in Figure 4 (Moura & Cirio, 2004); 4) *deletions of Y chromosome genes*, such as the one of the sex-determining region Y gene (*SRY*), which determines sex reversal in horses, i.e., it leaves individuals with an male XY karyotype with a female phenotype and ovaries (Raudsepp et al., 2010); 5) *chromosomal aberrations,* such as trysomy of chromosome 30 in horses, which makes them smaller than normal, with a

and hundredth day of pregnancy. The affected calves characteristically have bent extremities and can also have scoliosis, torticollis and cleft palate. Ingestion of toxic plants by farm animals can have a serious economic impact on livestock producers in given geographical areas through death losses,

8 It has not been completely established that *N*-nitroso compounds, such as nitrosamine and its precursors (nitrites and nitrates) naturally cause congenital diseases. Studies in animals indicate that they are highly carcinogenic and at higher levels can be teratogenic, but there is a need for further studies (Griesenbeck et al. 2010). Likewise, mycotoxins should also be considered. Fumonisins (frequent contaminants of corn) and ochratoxin-A (often found in stored grains) experimentally cause craniofacial

9 An example of routine use in veterinary medicine is griseofulvin, an antifungal drug for animals with dermatomycosis. Scott et al. (1975) observed multiple congenital defects in newborn cats whose mothers orally received high doses of griseofulvin (500-1000 mg, at weekly intervals). There were cerebral defects, skeletal defects, cleft palate, anophthalmia with absence of optic nerves, anal atresia, lack of

infectious or metabolic diseases during pregnancy.

and are provisionally separated as a group of *unknown etiology*.

**5. Etiopathogenesis of dysmorphisms** 

abortions, and birth defects (Lee et al., 2008).

atrioventricular valves and other defects.

and neural tube defects in mice (Marasas et al., 2004; Ueta et al. 2010).

**5.1 Etiology** 

**5.1.1 Genetic etiology** 

serious angular deviation of the thoracic limbs and polydactyly (Bowling & Millon, 1990); 6) *structural chromosomal aberrations*, such as the translocation between the X chromosome and an autosome described by Schelling et al., (2001) in an intersex Yorkshire terrier.

Fig. 4. X-linked hypohidrotic ectodermal dysplasia: A) Congenital absence of hair (congenital alopecia); B) Dental defects (conical teeth and oligodontia); C) Microphotograph of the skin (from an alopecic area) showing absence of hair follicles, sebaceous glands and sweat glands. Shorr stain, X10 objective. Photograph **C** courtesy of Dr. Silvana M. Cirio, Laboratory of Pathology, Faculty of Veterinary Medicine, FEPAR.

#### **5.1.2 Environmental etiology**

The environment can be a source of numerous potential teratogens, an important cause of congenital defects in both humans and animals because their presence is not always obvious or the harmful effect of certain products is unknown to the public at large, which increases the risk of maternal exposure to them. *Environmental teratogens* are agents in the *environment*  that can negatively impact embryonic development, causing congenital defects. Many chemical products and medicines have been considered potentially teratogenic for decades. Some have been confirmed as such and others have been refused, while the potential of others is doubtful or has been mistakenly confirmed (Koren & Nickel, 2010; 2011). In principle, the risk of a defect is related to the frequency and degree of maternal exposure (Holmes, 2011). Agents that are commonly considered as potentially teratogenic can be separated into four groups: 1) *environmental contaminants,* such as mercury10, lead, polychlorinated biphenyls, organochlorines and dioxins. There is also considerable doubt

<sup>10</sup> Mercury does not cause gross birth defects, but rather lesions in the central nervous system which cause psychomotor retard, convulsions and other neurological signs (Lancaster, 2011). The sad history of *Minamata disease* was first reported in 1953, but its cause was identified only three years later: a chemical plant discharged water containing inorganic mercury into Minamata Bay in Japan, and this was transformed into organic mercury (methylmercury) by marine microorganisms. Contaminated fish and clams with mythylmercury were consumed as food by the inhabitants of the town of Minamata and this was the source of poisoning which, in the case of pregnant women, affected the fetus, causing *congenital Mimata disease* (Moura, 1993). The number of people affected by the disease was officially established as 2,252, of whom 1,043 had already died 36 years later (Harada, 1995).

circulation or non-formation of blood vessels like that caused by antiangiogenic drugs, such as thalidomide and retinoids (Holaday & Berkowitz, 2009). They manifest at the histological level in different ways, such as aplasia, hypoplasia, dysplasia, atrophy, hypertrophy, etc. To follow, we present the fundamental concepts of the developmental field theory, the

Developmental field is, initially, the entire embryo in the early stages of its development and, later, it is a region or part of the body of the embryo which responds as a unit to embryonic induction and gives rise to multiple or complex anatomic structures (Spranger et al., 1982; Opitz et al., 2002). Developmental fields are systems that control the progressive differentiation of the structure and size, and also the temporal and spatial distribution of the complex organ components. To understand better the developmental field concept, it is important to remember the meaning of the terms *blastogenesis*, *organogenesis*, *morphogenesis*, *histogenesis* and *phenogenesis* in the context of dysmorphology. *Blastogenesis* is the set of events of embryonic development from fertilization to the end of gastrulation, i.e., it includes phenomena such as the formation of the morula, blastocyst, ectoderm, endoderm, mesoderm, neural tube and midline, in addition to cardioangiogenesis, mesonephrogenesis and curving of the embryo, which then takes the shape of a C (Opitz et al., 2002). At the end of the gastrulation, *organogenesis* begins. This is the set of events that lead to the formation of the organs and other parts of the body (*morphogenesis*) and includes the differentiation of the cells and tissues (*histogenesis*). On average, the duration of blastogenesis is similar in the majority of mammals, but the duration of the phenomena that follow varies from one species to another, especially the fetal period, which is reflected in the duration of pregnancy. The development that ranges from the fetal period and postnatal period to puberty is called *phenogenesis* (Opitz et al., 2002). During the fetal period, phenogenesis is characterized by growth and maturation, preparing the individual for birth. The *primary developmental field* is the field represented by the entire embryo in the early stages of blastogenesis. The initial phenomena of this period include pattern formation, generating components known as **progenitor fields**, which are the primordia of all final structures (Davidson, 1993; Martínez-Frías et al., 1998), as they give rise to the heart, central nervous system and limb buds (Opitz et al. 2002). When the components of a field remain contiguous, they constitute a *monotopic field*, in other words, a developmental field related to the formation of a single area of the body. However, there are fields in which the components separate from one another to give rise to distant final structures among themselves, which are known as *polytopic fields*. Thus, a polytopic field has to do with the formation of structures situated in different areas of the body (Opitz, 1982). *Secondary developmental fields* are the fields formed by the subdivision of progenitor fields, and each of them originates a determined final structure during organogenesis (Martínez-Frías et al.,

knowledge of which facilitates the understanding of dysmorphogenesis.

**5.2.1 Developmental fields** 

1998).

**5.2.2 Congenital defects and developmental fields** 

Malformations, disruptions and dysplasias are the result of disorders that occur in one of more developmental field. If they result from alterations that occur during blastogenesis, when the progenitor fields are formed, they are *primary field defects;* if they are the result of

concerning their real effect on teratogenic processes. For example, dioxins have been held responsible for a variety of defects. However, that scientific data have so far only confirmed a link to spina bifida (Ngo, 2010); 2) *medicines11* such as phenytoin, valproic acid, coumarins and antibiotics; 3) *physical agents* such as heat and radiation12; 4) *infectious agents* such as viruses, bacteria and protozoa. Thus, teratogens are of a chemical (dioxins, drugs), physical (heat, radiation) and biological nature (microbes). Non-infectious maternal diseases can also cause dysmorphisms: diabetes mellitus, iodine deficiency, uterine myomas, autoimmune diseases, etc. Uterine dysmorphisms and abnormalities in the extra-embryonic membranes can also cause fetus defects.
