*3.3.2. Cleft hand/foot*

Cleft hand/foot, also known as split-hand/split-foot malformation (SHFM), is a limb malformation that imparts an appearance resembling a lobster claw, due to the absence of the middle finger and hence an abnormal gap between the second and fourth metacarpal bones and soft tissues (**Figure 4C**). The two fingers on either side of the cleft in a cleft hand may be fused, which would make it appear as if there are only two digits on one hand [26].

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

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 anoma-

Low-set ears refer to malpositioned auricles, located anteriorly to the horizontal line drawn at the level of the inner canthus (**Figure 3E**).The size of a low-set ear is usually smaller compared to that in a normally developed embryo, with the angle posteriorly rotated [22]. Low-set ears accompany a variety of congenital chromosomal defects, including Turner's syndrome, Patau syndrome, Treacher-Collins syndrome, trisomy 18, trisomy 13, Cri du chat syndrome, and

Malformations of the ear can be recognized earliest at CS 18, although it can be estimated earlier by observing the auricle hill. Besides being low-set, the auricles may also be malformed

Polydactyly is a limb malformation, characterized by additional digit(s) in the limbs (**Figure 4A** and **B**) [23]. There can be preaxial, postaxial, or median polydactyly, corresponding to extra digits on the radial or tibial sides, ulnar or fibular sides, or in between medial fingers, respectively [24].This malformation is more likely to occur in the hands than in the feet, and can be estimated at CS 16 [25]. The prevalence varies across races, and occurs more frequently in the right hand than the left, among the Japanese. Its frequency on each finger may also vary; the highest to lowest being in the order: thumb, little finger, middle finger, ring finger, and index finger in the Japanese population. Polydactyly is one of the most common hereditary malformations of the extremities, with *GLI3* and *SHH* genes being responsible [23]. The extra digit in preaxial polydactyly may be surgically treated after 8–12 months of birth, whereas that of

Cleft hand/foot, also known as split-hand/split-foot malformation (SHFM), is a limb malformation that imparts an appearance resembling a lobster claw, due to the absence of the middle finger and hence an abnormal gap between the second and fourth metacarpal bones and soft tissues (**Figure 4C**). The two fingers on either side of the cleft in a cleft hand may be fused,

which would make it appear as if there are only two digits on one hand [26].

lies, breathing problems, and tongue growth defect, which need close observation.

often observed in association with cleft palate [21].

30 Congenital Anomalies - From the Embryo to the Neonate

Down syndrome. It is often observed along with micrognathia.

postaxial polydactyly is dissected shortly after birth.

*3.2.3. Low-set ears*

as shown in **Figure 3E**.

*3.3.1. Polydactyly*

*3.3.2. Cleft hand/foot*

**3.3. Anomalies of extremities**

**Figure 4.** Congenital anomalies of extremities. (A) Polydactyly in hand; (B) polydactyly in foot; (C) cleft hand, (D) sirenomelia, lateral view, and (E) sirenomelia, anterior view.

Ectrodactyly, or oligodactyly refers to malformations of the limb such that there are digits less than 5, arising from either ulnar deficiency, radial deficiency, or median deficiency (cleft hand/foot) [26]. **Figure 4C** shows a cleft hand with four distinct digits, with a large gap in between the second and third digits, presenting a lobster claw-like feature.

The inheritance of cleft hand is autosomal dominant, caused by deletions or mutations in autosomes such as chromosomes 2, 3, 7, and 10. For example, the deletion in chromosome 2 results not only in ectrodactyly, but also in microcephaly, micrognathia, low-set ears, and mental retardation. Although ectrodactyly is often associated with other malformations, a single family has been reported for the inheritance of isolated ectrodactyly resulting from X-linked recessive inheritance [26]. Another well-known syndrome that is associated with this malformation is EEC (ectrodactyly-ectodermal dysplasia-cleft lip/palate) syndrome, which comprises of ectodermal dysplasia and cleft lip, occasionally accompanied by cleft palate, due to an autosomal dominant inheritance [27]. The prevalence is approximately 1 in 18,000 births [28], and can be observed as early as CS 18, at the stage when the finger rays develop. There is no difference between females and males in terms of occurrence, and surgical treatment is scheduled when the child is 1 or 2 years old.

and Gynecology (ISUOG) [43] for performing effective screening of morphological anomalies. Meanwhile, studies conducted during the 1980s–1990s made it clear that soft markers in ultrasonography indicate an elevated risk of chromosomal abnormalities [44–46], even though they may not be directly harmful by themselves. Soft markers combined with mater-

Congenital Anomalies in Human Embryos http://dx.doi.org/10.5772/intechopen.72628 33

Magnetic resonance (MR) microscopy refers to MR imaging for screening small samples. It is significantly useful for the 3D measurement of chemically fixed human embryos, due to the large amount of mobile or NMR responsive protons existing in the preservation fluid (formalin) [48]. Being a non-invasive and non-destructive imaging process, it has been applied to a number of animal models for understanding developmental embryology [49–52]. MR imaging provides highly beneficial features [50, 53, 54], reaching a resolution of 40 μm/pixel or higher when scanning a sample for an extended amount of time. Superconducting magnets with field strength of 1.0–9.4 T [52, 54, 55] have been used for describing human embryo using MR imaging. **Figure 5C**–**D** and **E–F** is obtained with MR microscopes equipped with 7.0 and

X-rays are electromagnetic waves with characteristic amplitude and phase. When X-rays penetrate a sample, its amplitude decreases and the phase gets shifted. Conventional X-ray imaging (radiography) is based on absorption contrast (i.e. amplitude imaging) and represented by the internal mass density distribution within the sample (**Figure 6A** and **B**). Unfortunately, only sensitivity to X-ray distribution is not enough for a detailed analysis of the samples containing biological soft tissues such as embryos, unless it is either combined with contrast agents or performed at higher X-ray doses. Another way of solving this issue is by exploiting the phase information of X-rays. Since lighter elements, such as hydrogen, carbon, nitrogen, and oxygen are 1000 times more sensitive to phase-shift compared to the actual absorption [56], they can be used to detect the phase-shift. To that end, it is essential to convert the phase shift into a change in X-ray intensity, which can be measured easily by current-detecting devices. Conversion methods, such as interferometry and diffractometry, are applied for the

**Figure 5.** The results of MRI from several imaging devices. A, B: 2.34 T super parallel MRM (MR microscope), developed by Prof. Kose et al. in the University of Tsukuba. C, D: Pre-clinical MRI (Bruker BioSpin, 7 T) in the Human Health Sciences, Kyoto University Graduate School of Medicine, Japan. E, F: Clinical MRI (Siemens Magnetom, 3 T) in the Kyoto

nal serum is capable of detecting aneuploidy with high precision [47].

*4.1.2. Magnetic resonance imaging*

2.34 T magnets, respectively.

University Hospital, Japan.

*4.1.3. Phase-contrast X-ray computed tomography*
