**2. The phenotype**

The typical phenotype of SML is characterized by a partial or complete merging of the lower extremities into one single limb. The deformity, which gives the mermaid appearance to the syndrome, is invariably associated with smooth perineum, malformed or absent perineal structures, and in most instances, Potter facies (**Figure 1**). The classic Sirenomelia sequence consists of a uniform spectrum

**169**

**3. Pathogenesis**

(Bmp) signaling [11].

**3.1 Non-genetic theories**

*3.1.1 Vascular steal hypothesis*

*Genetics of Sirenomelia, the Mermaid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97555*

of visceral malformations involving urogenital and gastrointestinal systems, pelvic and lumbosacral spinal defects, and a single aberrant umbilical artery. Renal agenesis or severe renal malformation are almost invariably present and lead to oligohydramnios and consequent pulmonary hypoplasia. Other commonly observed abnormalities in SML are sacral agenesis, abnormal vertebrae, hemivertebrae, meningomyelocele, and less frequently, cleft palate, cardiac defects omphalocele, and pentalogy of Cantrell [1, 11]. It is hypothesized that a defect in blastogenesis leads to impaired angiogenesis in the embryonic caudal region, and the resultant vascular compromise causes anomalous development of the area structures. The lower extremity phenotype is evidenced to occur due to merger and not by fusion of the two bilaterally positioned fetal hind limb buds as suggested by the histopathological persistence of epithelial linings in the conjoined limb fields. [1] The merged lower extremities are abnormally rotated by 180 degrees to the normal position of legs (**Figure 1**). Normally, during development, the hind limb buds rotate medially, and the original ventral surface turns to become dorsal [12] In SML, due to the early midline posterior fusion of the embryonic hind limbs, this rotation does not occur, as a result of which, the soles of the affected fetus face anteriorly, and the fibulae end up being placed medially between the tibiae. [1] Some researchers believe that the typical phenotype in SML is secondary and not a primary defect. As the developing leg fields in the fetus normally lie along the lateral body wall, it is thought that a developmental failure of caudal midline structures, such as ventrally positioned cloaca and urogenital sinus, and dorsally positioned somites and neural tube, results in the approximation and final merging of the two analgen of fetal limb buds [12, 13]. In SML, kidneys are almost always affected, and although the gonads may be spared, the urethra is undeveloped and external genitalia either absent or represented by abnormal tissue tags [14]. Other almost invariably present anomalies involve the gastrointestinal tract and are represented by a blind-ending colon, rectal atresia, and imperforate anus [15]. In the classic form, SML is fatal during the perinatal period, whereas, in the minor forms, reconstructive pelvic and limb surgery may prolong the life if the renal function is compatible with survival. [16] Notably, the neurodevelopment of the surviving babies is reported to be normal.

Although unsubstantiated, it is believed that SML is an autosomal-dominant genetic condition in humans, and each case is the result of a new spontaneous mutation. It is speculated that the syndrome is induced by a combination of genetic and environmental influences. The most accepted non-genetic hypotheses for the pathogenesis of SML are the vascular steal phenomenon and defective blastogenesis. These two theories are not mutually exclusive as any deficiency in blastogenesis could potentially lead to fetal vascular and visceral maldevelopment. Genetically, SML phenotype has been demonstrated in mutant mice with both gain-of-function of retinoic acid (RA) signaling and loss-of-function of bone morphogenetic protein

SML is characterized by an anomalous single umbilical artery that diverts blood away from the caudal fetal limb buds to the placenta, thereby compromising the regional blood supply during the early developmental period. In the early fetal

#### *Genetics of Sirenomelia, the Mermaid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97555*

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

of the genetic aspect of the anomaly. [1] SML occurs sporadically, and even though not recognized as familial, it is documented to be more common in twin monozygotic pregnancies, among whom the relative risk is stated to be increased by 100-fold. About 9–15% of all cases of SML are products of twin gestation. Environmental and teratogenic factors, such as cocaine, retinoic acid, heavy metals, cyclophosphamide, and certain antibiotics, have been linked to SML in humans and animal models [1, 9]. In addition, nicotine, alcohol, radionuclides, diethylpropion- an appetite suppressor, organic solvents of fats, and even air pollution have been associated with SML and caudal regression syndrome, which is controversially considered as its minor form [4, 9]. Other authors have reported fetal exposure to cadmium, lithium, phenytoin, sodium valproate, carbamazepine, warfarin, methylergonovine, diethylpropion, trimethoprim, and ochratoxin-a type of fungus as possible triggers for the anomaly. [7–9] Some of the maternal complications, such as diabetes mellitus, hyperthermia during the 1st trimester of pregnancy, amniotic bands, and age below 20 years or over 40 years at conception, have also been implicated in the pathogenesis of SML. [1, 9]. Recently a case report tentatively associated persistent early gestational maternal Chlamydia trachomatis (CT) infection with SML. CT is an obligate intracellular pathogen that is recognized for its cytopathogenic effects like cellular disruption, tissue dysgenesis, and genomic instability and is known to invade the placenta and cause fetal demise. [10] SML has no ethnic or geographical preferences, and a gender preponderance with a male to female ratio of 2.7:1 has been described. [1] The prevalence of SML is reported to be between 1.1 and 4.2 per 100,000 births [1, 6].

*Sirenomelia in a newborn infant showing merged hind extremities and Potter facies.*

The molecular basis of the defects in SML is yet to be defined.

The typical phenotype of SML is characterized by a partial or complete merg-

ing of the lower extremities into one single limb. The deformity, which gives the mermaid appearance to the syndrome, is invariably associated with smooth perineum, malformed or absent perineal structures, and in most instances, Potter facies (**Figure 1**). The classic Sirenomelia sequence consists of a uniform spectrum

**168**

**2. The phenotype**

**Figure 1.**

of visceral malformations involving urogenital and gastrointestinal systems, pelvic and lumbosacral spinal defects, and a single aberrant umbilical artery. Renal agenesis or severe renal malformation are almost invariably present and lead to oligohydramnios and consequent pulmonary hypoplasia. Other commonly observed abnormalities in SML are sacral agenesis, abnormal vertebrae, hemivertebrae, meningomyelocele, and less frequently, cleft palate, cardiac defects omphalocele, and pentalogy of Cantrell [1, 11]. It is hypothesized that a defect in blastogenesis leads to impaired angiogenesis in the embryonic caudal region, and the resultant vascular compromise causes anomalous development of the area structures. The lower extremity phenotype is evidenced to occur due to merger and not by fusion of the two bilaterally positioned fetal hind limb buds as suggested by the histopathological persistence of epithelial linings in the conjoined limb fields. [1] The merged lower extremities are abnormally rotated by 180 degrees to the normal position of legs (**Figure 1**). Normally, during development, the hind limb buds rotate medially, and the original ventral surface turns to become dorsal [12] In SML, due to the early midline posterior fusion of the embryonic hind limbs, this rotation does not occur, as a result of which, the soles of the affected fetus face anteriorly, and the fibulae end up being placed medially between the tibiae. [1] Some researchers believe that the typical phenotype in SML is secondary and not a primary defect. As the developing leg fields in the fetus normally lie along the lateral body wall, it is thought that a developmental failure of caudal midline structures, such as ventrally positioned cloaca and urogenital sinus, and dorsally positioned somites and neural tube, results in the approximation and final merging of the two analgen of fetal limb buds [12, 13]. In SML, kidneys are almost always affected, and although the gonads may be spared, the urethra is undeveloped and external genitalia either absent or represented by abnormal tissue tags [14]. Other almost invariably present anomalies involve the gastrointestinal tract and are represented by a blind-ending colon, rectal atresia, and imperforate anus [15]. In the classic form, SML is fatal during the perinatal period, whereas, in the minor forms, reconstructive pelvic and limb surgery may prolong the life if the renal function is compatible with survival. [16] Notably, the neurodevelopment of the surviving babies is reported to be normal.
