*3.1.1. Holoprosencephaly (HPE)*

Holoprosencephaly (HPE) refers to an anomaly in which the differentiation of the prosencephalon from the neural tube is defective, thus leading to malformations of the forebrain, midface, and occasionally limbs. It can be recognized as early as CS12 or 13.

HPE can be classified into three categories, depending on the degree of defect in the development of prosencephalon: alobar holoprosencephaly, semi lobar holoprosencephaly, and lobar prosencephaly.

Alobar holoprosencephaly is the most severe, which usually associates with cyclopia, ethmocephaly, and cebocephaly. Cyclopia (**Figure 2A**) is characterized by a single eye centered in the middle of the face, caused by the fusion of the optic vesicles due to the lack of midline tissue. The name of this malformation is derived from the cyclops (or cyclopes) in Greek mythology, first mentioned in Homer's epic poem, "Odyssey" in the seventh century B.C. There are cases of cyclopia with incomplete fusion of optic vesicles, but either with the nose absent or complicated further with proboscis located above the orbit [3]. The cyclopic embryo presented in **Figure 1** shows single eye in the center of the face, without any nose.

Ethmocephaly is morphologically similar to cyclopia, except that both eyes exist with distinct orbits, although marked by hypotelorism, with proboscis located between the eyes (**Figure 2B**) [4]. Cebocephaly is also an anomaly that exhibits hypotelorism in the two distinct orbits, characterized by a single nostril, occasionally complicated by cleft lip and/or palate [5].

HPE is one of the most common lethal congenital anomalies that occur at embryonic stages, and the prevalence rate is approximately 1/250. However, most of them cannot survive to develop into a fetus, which makes it a rare anomaly in newborns (1/10,000–20,000) [6].

**Figure 2.** Congenital anomalies in the CNS. (A) Embryo presenting cyclopia, (B) embryo presenting ethmocephaly, with proboscis located between the eyes, (C) exencephaly presenting the opening in the neural tube, (D) spina bifida occulta observed dorsally, and (E) spina bifida occulta observed laterally.

Although it is yet to be proved, four main genes: *SHH*, *ZIC2*, *SIX3*, and *TGIF* are suggested to be associated with the onset of HPE, along with the aneuploidies in chromosomes 13 and 18. The existence of environmental factors is suggested, and a strong positive correlation of the occurrence with maternal age is noted [7, 8].

A significant amount of folic acid is known to prevent spina bifida; early postnatal treatments, including the closure of the spinal lesion within 48 h after birth, and medical management are

Congenital Anomalies in Human Embryos http://dx.doi.org/10.5772/intechopen.72628 29

Cleft lip, often accompanied by cleft palate, is the most common congenital facial anomaly that causes dental defects, yielding defective speech and feeding disorders, and sometimes ear infections. The prevalence among the Asian and American Indian populations is as high as 1 in 500 births, which is relatively higher than that in European-derived or African-derived population, where prevalence rates are at approximately 1/1000 and 1/2500, respectively [15]. The morphological characteristic of cleft lip is the opening in the upper lip to the roof of the mouth, either located in the center (median cleft lip) (**Figure 3A**) or left and/or right side (bilateral/ unilateral cleft lip, **Figure 3B** and **C**), as a result of failed fusion of various processes. Median cleft lip is the rarest, and is commonly associated with mental retardation, attributed

As for lateral cleft lips, 80% of them are unilateral, out of which 70% are left-sided. Cleft lip can be recognized as early as CS 18, and is considered a multifactorial defect, involving genetic factors, environmental factors, teratogens, and maternal conditions. There are over 50 recognized syndromes that include this malformation, often caused by mutant genes [16]. The occurrence of isolated cleft lip is higher in male, whereas the occurrence of isolated cleft

Micrognathia is a facial malformation characterized by an underdeveloped and receded mandible, thus presenting a bird-like face, as shown in **Figure 3D**. It was first mentioned in the

Micrognathia is often a part of chromosomal disorder; it is commonly seen in patients of Pierre Robin syndrome, and is associated with trisomy 13, trisomy18, Treacher-Collins syndrome,

**Figure 3.** Congenital anomalies of face. (A) Median cleft lip, (B) left-sided unilateral cleft lip, (C) right-sided unilateral

essential for life henceforth [14].

to the loss of midline structures.

palate is higher in females [15].

clay tablets of ancient Babylonia, back in 1700 BC [17].

cleft lip, (D) micrognathia from lateral view, and (E) malformed pinna.

*3.2.2. Micrognathia*

**3.2. Facial anomalies**

*3.2.1. Cleft lip*

### *3.1.2. Exencephaly*

The morphological characteristics of exencephaly are exposed brain and absence of the skull and scalp. This condition arises due to the failure to close the cephalic part of the neural tube, occasionally due to the overgrowth of neural tissue [9] (**Figure 2C**). Exencephaly can be recognized at CS 12 at the earliest, much ahead of the stage at which the development of the neural tube completes.

Neural tube defects such as exencephaly, anencephaly, and spina bifida are extremely common lethal congenital anomalies, and the prevalence rate is approximately 1/1000 [10]; most of these survive for only few hours, and all cases lead to death within a few days. Although the understanding remains unclear, folic acid deficiency is a suggested factor for anencephaly, along with the *MTHFD 1* gene, which is significant in folate metabolism [11].
