*3.2.1. Cleft lip*

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

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 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 anenceph-

Spina bifida is the most common congenital anomaly of the CNS, resulting from the incomplete fusion of the vertebrae and hence exposure of the spinal cord. It can be classified into spina bifida occulta (**Figure 2D** and **E**), and spina bifida cystica (or aperta), which can be further classified into meningocele, meningomyelocele, and myelocele [12]. Spina bifida occulta is the mildest form, caused by the malformation of the bony arch that extends caudally, failing to fuse dorsal midline to the spinal cord. The spinal cord itself, however, is unaffected, extended caudally, or duplicated at the end, with no neurological damage. The bone defect is covered by skin, although sometimes patches of hair or pigment may be observed in the area covering the defect. **Figures 4** and **5** exhibit an embryo with spina bifida occulta, presenting a

On the other hand, spina bifida cystica refers to the malformation of the bony arch as well as the neural tube that has failed to close. Meningocele has a fluid-containing cystic swelling, emerging from a defect in the vertebral arch; the spinal cord is completely confined to the

Meningomyelocele and myelocele also refer to cystic swellings emerging dorsally through a vertebral arch, although the spinal cord (located inside the sac) bears its fundus. Myelocele is different from meningomyelocele in the following aspects: spinal cord is exposed to the external surface, often in the lumbosacral area; neutral folds stay flat, and will not elevate; not only the spinal cord, the brain is also often malformed, which may result in hydrocephalus, Chiari

Although spina bifida can be recognized as early as CS 12, it becomes observable earliest by

aly, along with the *MTHFD 1* gene, which is significant in folate metabolism [11].

malformation of the bony arch, with neither neurological defect nor swelling.

CS 13, when the closure of the neural tube is supposed to be completed.

spinal canal, but may exhibit myelodysplasia.

2 malformation, and other defects [13].

occurrence with maternal age is noted [7, 8].

28 Congenital Anomalies - From the Embryo to the Neonate

*3.1.2. Exencephaly*

neural tube completes.

*3.1.3. Spina bifida*

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 to the loss of midline structures.

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 palate is higher in females [15].

#### *3.2.2. Micrognathia*

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

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

and Nager syndrome [18, 19]. The frequency of Pierre Robin syndrome is approximately 1 in 8500–14,000 births [20], and signs of micrognathia can be observed as early as CS 18. It is also often observed in association with cleft palate [21].

Because of the undersized jaw, most have feeding problems after birth and some may have major respiratory obstruction; however, there is usually no need for surgical treatment, since it can be naturally corrected through growth. However, micrognathia leads to dental anomalies, breathing problems, and tongue growth defect, which need close observation.
