**5.2.3 Heterogeneity, pleiotropy and sequence**

Developmental fields are embryonic morphogenetic units and, thus, respond to an inductive stimulus as an epimorphically hierarchical self-organizing unit that is temporally synchronized and spatially coordinated (Opitz, 1982). Consequently, a given abnormal phenotype can originate as a response of a field to different causes. This becomes clearer if we remember that different fields can share parts of the same cell signaling pathway involved in embryonic development. For example, the *Sonic hedgehog cell signaling pathway* is composed of genes that codify proteins that act as intercellular signals in many development processes. Mutations in these genes can result in malformations such as holoprosencephaly, syndactyly, polydactyly, heart defects, kidney defects and anal atresia, or even in neoplasias such as meningioma and squamous cell carcinoma (Cohen Jr, 2004). A congenital defect can be the result of mutations in different genes, chromosomal aberrations or the action of mutagenic agents or teratogens, i.e., it is *causally heterogeneous*. Evidently, the meaning of this is that defects that are clinically the same can have a genetic or environmental cause (Fig. 5). A defect caused by an environmental factor, but which is the same as another caused genetically, is known as a *phenocopy*.

Fig. 5. Cleft lip and palate in dogs are phenotypically and etiologically heterogeneous. They can be unilateral (A) or bilateral (B). They can affect the entire extension of the palate or only the primary palate (C). They can have a multifactorial origin or a monogenic autosomal recessive origin, or be caused by environmental factors (phenocopy).

On the other hand, the same gene can give rise to a series of morphogenetic events that are necessary for the formation of different final structures. This genetic phenomenon in which a gene is responsible for several different phenotypic characteristics is known as *pleiotropy* and is also one of the phenomena that can occur in dysmorphogenesis. For example, a mutation in the gene that codifies ectodysplasin, a protein that regulates the initial

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

Developmental fields are embryonic morphogenetic units and, thus, respond to an inductive stimulus as an epimorphically hierarchical self-organizing unit that is temporally synchronized and spatially coordinated (Opitz, 1982). Consequently, a given abnormal phenotype can originate as a response of a field to different causes. This becomes clearer if we remember that different fields can share parts of the same cell signaling pathway involved in embryonic development. For example, the *Sonic hedgehog cell signaling pathway* is composed of genes that codify proteins that act as intercellular signals in many development processes. Mutations in these genes can result in malformations such as holoprosencephaly, syndactyly, polydactyly, heart defects, kidney defects and anal atresia, or even in neoplasias such as meningioma and squamous cell carcinoma (Cohen Jr, 2004). A congenital defect can be the result of mutations in different genes, chromosomal aberrations or the action of mutagenic agents or teratogens, i.e., it is *causally heterogeneous*. Evidently, the meaning of this is that defects that are clinically the same can have a genetic or environmental cause (Fig. 5). A defect caused by an environmental factor, but which is the same as another

Fig. 5. Cleft lip and palate in dogs are phenotypically and etiologically heterogeneous. They can be unilateral (A) or bilateral (B). They can affect the entire extension of the palate or only the primary palate (C). They can have a multifactorial origin or a monogenic autosomal

On the other hand, the same gene can give rise to a series of morphogenetic events that are necessary for the formation of different final structures. This genetic phenomenon in which a gene is responsible for several different phenotypic characteristics is known as *pleiotropy* and is also one of the phenomena that can occur in dysmorphogenesis. For example, a mutation in the gene that codifies ectodysplasin, a protein that regulates the initial

recessive origin, or be caused by environmental factors (phenocopy).

originate in the early stages of blastogenesis (Martínez-Frías, 1998).

**5.2.3 Heterogeneity, pleiotropy and sequence** 

caused genetically, is known as a *phenocopy*.

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).
