**5.1.3 Multifactorial etiology**

The joint action of several genes (polygenic inheritance) can also play a significant role in the occurrence of dysmorphisms. Deleterious alleles of the different genes play an additive effect until they reach a threshold at which the defect occurs. Environmental factors usually add to this mechanism. Thus, an individual with a given genotype becomes more susceptible to developing a defect, which can be unleashed when environmental forces are at play (multifactorial inheritance). Neural tube closure defects (anencephaly, spina bifida) and conotruncal defects (truncus arteriosus, tetralogy of Fallot) generally have a multifactorial etiology.

#### **5.2 Pathogenesis**

The process that gives rise to an abnormal form is a *morphogenetic disturbance* and is known as dysmorphogenesis. The mechanisms involved in dysmorphogenesis are complex, compromising a number of the embryonic developmental phenomena (division of cells, cellular migration, cell adhesion, differentiation, etc.), including cell signaling pathways, e.g., the Sonic hedgehog pathway. They can also include hypoxia resulting from blocked

<sup>11</sup> The tragic history of thalidomide is a warning that the use of medicine during pregnancy should be strictly limited to what is absolutely necessary and should be taken only with medical advice. Thalidomide was launched in 1956, initially as a sedative. By the early 1960s it had become a popular medicine to control morning sickness during pregnancy and could be purchased without a prescription. The following year, Australian obstetrician *William McBride* and German pediatrician *Widukind Lenz* independently saw the link between thalidomide in the early stages of pregnancy and *phocomelia*. The children born with this defect had short limbs close to their bodies and malformed fingers and toes. The abnormality could affect one limb, both arms or all four limbs and often affected internal organs such as the heart and duodenum, constituting a pattern of abnormalities that became known as *thalidomide embryopathy*. It is estimated that there were 8,000 to 10,000 cases worldwide (von Moos et al. 2003). However, thalidomide has been used successfully to treat diseases such as cancer, leprosy and autoimmune diseases.

<sup>12</sup> The *Chernobyl nuclear accident* (Ukraine), in 1986, is a blatant and relatively recent example of the catastrophic effect of *ionizing radiation* on living beings. A number of disorders, including a variety of *malformations*, were registered in animals, from fish to mammals, and even in invertebrates. Congenital defects of the mouth, anus, legs and head were reported in domestic animals. Until today, in animal populations of the contaminated region, there is *transgenerational genomic instability* and *gene mutation rates* are significantly high. In some areas of Europe, the radionuclide levels remain high in mammals, birds, amphibians and fish (Yablokov, 2009).

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

The joint action of several genes (polygenic inheritance) can also play a significant role in the occurrence of dysmorphisms. Deleterious alleles of the different genes play an additive effect until they reach a threshold at which the defect occurs. Environmental factors usually add to this mechanism. Thus, an individual with a given genotype becomes more susceptible to developing a defect, which can be unleashed when environmental forces are at play (multifactorial inheritance). Neural tube closure defects (anencephaly, spina bifida) and conotruncal defects (truncus arteriosus, tetralogy of Fallot) generally have a

The process that gives rise to an abnormal form is a *morphogenetic disturbance* and is known as dysmorphogenesis. The mechanisms involved in dysmorphogenesis are complex, compromising a number of the embryonic developmental phenomena (division of cells, cellular migration, cell adhesion, differentiation, etc.), including cell signaling pathways, e.g., the Sonic hedgehog pathway. They can also include hypoxia resulting from blocked

11 The tragic history of thalidomide is a warning that the use of medicine during pregnancy should be strictly limited to what is absolutely necessary and should be taken only with medical advice. Thalidomide was launched in 1956, initially as a sedative. By the early 1960s it had become a popular medicine to control morning sickness during pregnancy and could be purchased without a prescription. The following year, Australian obstetrician *William McBride* and German pediatrician *Widukind Lenz* independently saw the link between thalidomide in the early stages of pregnancy and *phocomelia*. The children born with this defect had short limbs close to their bodies and malformed fingers and toes. The abnormality could affect one limb, both arms or all four limbs and often affected internal organs such as the heart and duodenum, constituting a pattern of abnormalities that became known as *thalidomide embryopathy*. It is estimated that there were 8,000 to 10,000 cases worldwide (von Moos et al. 2003). However, thalidomide has been used successfully to treat diseases such as cancer, leprosy and auto-

12 The *Chernobyl nuclear accident* (Ukraine), in 1986, is a blatant and relatively recent example of the catastrophic effect of *ionizing radiation* on living beings. A number of disorders, including a variety of *malformations*, were registered in animals, from fish to mammals, and even in invertebrates. Congenital defects of the mouth, anus, legs and head were reported in domestic animals. Until today, in animal populations of the contaminated region, there is *transgenerational genomic instability* and *gene mutation rates* are significantly high. In some areas of Europe, the radionuclide levels remain high in mammals,

can also cause fetus defects.

**5.1.3 Multifactorial etiology** 

multifactorial etiology.

**5.2 Pathogenesis** 

immune diseases.

birds, amphibians and fish (Yablokov, 2009).

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 knowledge of which facilitates the understanding of dysmorphogenesis.

#### **5.2.1 Developmental fields**

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., 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

epithelial-mesenchymal interaction necessary for the formation of ectodermal derivatives, causes X-linked hypohidrotic ectodermal dysplasia, which occurs in humans, cattle, mice and dogs, and is characterized by defects in the teeth and in the skin (absence of piloglandular units) and other ectodermal derivatives (Moura & Cirio, 2004). In addition to heterogeneity and pleiotropy, another phenomenon may be behind multiple abnormalities: they may be the consequence of only one initial defect that provokes the occurrence of new events in a chain reaction, characterizing a *dysmorphogenetic sequence*. For instance, micrognathia can unleash retroglossoptosis which, in turn, causes cleft palate and

respiratory distress, a condition known as Pierre Robin sequence (Mackay, 2011).

and coronary arteries, forming a common arterial trunk (*truncus arteriosus*).

**5.2.4 More frequently affected systems and selected examples of abnormalities** 

*Cardiovascular system*: communication between the pulmonary trunk and the aorta artery (*patent ductus arteriosus,* Fig. 6-A); communication between the atria (*atrial septal defect*) or between the ventricles (*ventricular septal defect*); combination of pulmonary stenosis with a ventricular septal defect, hypertrophy of the right ventricle and an overriding aorta, i.e., the aorta is positioned directly over a ventricular septal defect (*tetratology of Fallot*); imperfect mitral valve and support structures (*mitral dysplasia*); imperfect tricuspid valve and support structures (*tricuspid dysplasia);* right or left atrium divided by a membrane, leaving it with two chambers (*cor triatriatum*); absence of communication between the right atrium and ventricle (*tricuspid atresia*); lack of differentiation of the origins of the pulmonary trunk, aorta

Fig. 6. Examples of abnormalities of the cardiovascular system: A) Patent ductus arteriosus (arrow); B) Abnormality of the caudal vena cava in a dachshund dog with Caroli disease. Note that this vein (raised by forceps) does not have normal morphology. Photograph **B** courtesy of Dr. Marconi R. de Farias, Companion Animal Veterinary Hospital, Faculty of

*Musculoskeletal system*: missing jaw (*agnathia*); shorter-than-normal jaw (*brachygnathia*); abnormally small jaw (*micrognathia*); incompletely formed vertebra (*hemivertebra,* Fig. 7-A and B); missing vertebrae in the lumbar and sacral region (*lumbosacral agenesis*); absence of

Veterinary Medicine, Pontifícia Universidade Católica do Paraná.

alterations that occur during organogenesis, after the formation of the progenitor fields, they are *secondary field defects*. Those that are localized, i.e., the affect only one structure or part of the body, which was differentiated during organogenesis, are *monotopic field defects*; those affecting structures situated in different parts of the body are *polytopic field defects* and originate in the early stages of blastogenesis (Martínez-Frías, 1998).
