Why does sirenomelia happen

They may require multiple surgeries, both for their lower body and for any other genetic abnormalities, such as kidney disorders. Sadly, because mermaid syndrome often causes other organ abnormalities, including those of the heart and lungs, mermaid syndrome is typically fatal in the newborn stage. However, if mermaid syndrome mostly affects the legs and not other parts of the body especially the kidneys , some babies may survive for a longer period.

Mermaid syndrome is a severe and often fatal congenital abnormality. Doctors emphasize getting regular prenatal care to enhance diagnosis and detection. If you are concerned about this condition, your doctor can talk with you about medications and substances that can cause congenital abnormalities, including mermaid syndrome.

Ideally, this can help to prevent congenital conditions whenever possible. Phocomelia is an extremely rare birth defect. In more serious cases, the limbs might be completely…. Caudal regression syndrome, or sacral agenesis, is a rare condition where the lower spine doesn't fully form before birth. Here's what you should know. According to an observational study in , couples, there was a 35 percent increase in the chance of birth defects in newborns if the father…. Krabbe disease is a rare and life threatening disorder of the nervous system.

Sturge-Weber syndrome is a rare neurological disorder present at birth. Learn about its symptoms, causes, diagnosis, and treatment. Alkaptonuria is a rare genetic disorder that causes homogentisic acid to build up in your body. Learn about the symptoms, causes, and treatment. Hemochromatosis is when too much iron builds up in the body.

It can result from external factors, such as diet, or genetic factors. Treatment will…. Cellulitis is a common bacterial skin infection. Learn more about its symptoms, how it's treated, and how you can prevent it in the first place. Health Conditions Discover Plan Connect. The caudal curved parts of the dorsal aortas are called the recurved distal portions, although they are also referred to as the primary umbilical arteries Fig.

By E8. Subsequently, the vitelline artery discontinues its connection with the umbilical artery while connecting dorsally with the abdominal aorta Monie and Khemmani, ; Garcia-Porrero et al. Consequently, the umbilical artery pumps blood from the embryo to the placenta while the vitelline artery carries blood from the embryo to the yolk sac and eventually becomes remodeled to form the intestinal arteries.

The presence of an SUA of vitelline origin has been considered as characteristic or even pathognomonic of sirenomelia and was proposed to be used for the differential diagnosis of other malformations of the lower body such as caudal dysgenesis CD; see Box 2 Heifetz, ; Stevenson et al.

However, there are occasional cases of sirenomelia with two symmetrical umbilical arteries, although they are of abnormal origin Opitz et al. Reciprocally, aberrant umbilical arteries have also been described in individuals with CD Duesterhoeft et al. Among other abnormalities that are commonly observed in sirenomelia are lumbosacral and pelvic malformations, including sacral agenesis, malformed vertebrae and hemivertebrae Fig.

Finally, it should be mentioned that, albeit at a much lower frequency, sirenomelia is also associated with malformations of the upper part of the body, including cleft palate, upper thoracic and cervical vertebral abnormalities, pulmonary hypoplasia, and cardiac defects Kallen and Winberg, ; Rodriguez et al. In summary, sirenomelia comprises a variable combination of malformations, predominantly of the lower body. In the remainder of this article, we discuss experimental evidence that provides insight into the still-uncertain causes and mechanisms of this malformation, which collectively suggest a global defect in the development of the caudal end of the embryo.

Vascular pattern in a normal versus sirenomelia fetus. A Schematic drawing of the fetal umbilical cord vasculature in a normal and a sirenomelia fetus. Note the abnormally high origin of the SUA in sirenomelia and the hypoplasia of the aorta caudal to its origin. B Left two panels: schematic of transverse sections at the caudal level of an early normal and sirenomelia embryo. Below each section, the corresponding vascular pattern is shown in red. Right panel: a schematic lateral view of an embryo in which the great caudal vessels are shown in red and the hindgut in yellow.

The broken red line indicates the level of the sections shown in the two panels to the left. Although the primary molecular defect underlying sirenomelia remains unknown, clinical studies have given rise to several hypotheses to explain the causal mechanisms. The two main pathogenic hypotheses are the vascular steal hypothesis and the defective blastogenesis hypothesis.

Other mechanical hypotheses that have been proposed to cause sirenomelia, such as lateral compression of the caudal body by amniotic folds and medial compression by overdistension of the neural tube, are not considered here Gardner, ; Orr et al. The vascular steal hypothesis is based on the aberrant vasculature pattern of the caudal body present in most individuals with sirenomelia Kampmeier, ; Kallen and Winberg, ; Stevenson et al.

This hypothesis posits a vascular origin for the defect: it proposes that the SUA of vitelline origin diverts blood flow to the placenta, leaving the lower part of the body with a severely deficient circulation Fig. It is unknown how the abnormal vasculature is established in sirenomelia, but it seems reasonable to assume that the aberrant SUA of apparent vitelline origin derives from the original connection between the vitelline and umbilical vasculature Fig.

This pattern might be favored in the remodeling of the very early capillary plexus if there is a defect in the formation of the caudal part of the aortas. According to the vascular steal hypothesis, fusion of the limbs results from a deficient blood flow and nutrient supply to the caudal mesoderm, which in turn would result in agenesis of midline structures and subsequent abnormal approximation of both lower limb fields.

In this view, the variable lower limb phenotype depends on the variable development of the sciatic artery, a branch of the recurved distal portions of the dorsal aorta that initially supplies the leg bud and that, with variable development, is normally present in sirenomelia.

Vascular mechanisms have been proposed to underlie the pathogenesis of several other defects as well as sirenomelia Sadler and Rasmussen, However, in most cases, including sirenomelia, the evidence gathered is not sufficient to unequivocally establish the abnormal vasculature pattern as the primary cause, and the possibility of an earlier interference with a basic developmental event cannot be ruled out.

Caudal dysgenesis CD; OMIM ; formerly referred to as caudal regression syndrome describes a heterogeneous variable association of malformations of the lower body that always include some degree of sacral agenesis Duhamel, ; Boulas, CD is characterized by, in variable proportions, lumbosacral vertebral, cardiac, anorectal and genitourinary malformations, as well as some type of dysgenesis of the lower limbs.

The easily recognizable VACTERL association is found in many clinical entities and syndromes of known causal factors, reflecting a heterogeneous etiology Martinez-Frias et al. The considerable degree of overlap in the abnormalities present in CD, VACTERL association and sirenomelia, together with the poorly understood etiology of each, has led to debate about whether these three entities might in fact be different manifestations of a common pathogenic process Stocker and Heifetz, ; Duncan et al.

It is conceivable that a defect during blastogenesis, regardless of its nature, could result in abnormal development of caudal structures ranging from mild forms of CD to sirenomelia — the two ends of the same malformative spectrum. It should be stressed that disruption of various different factors that function in the same pathway could result in identical or very similar alterations in blastogenesis, therefore explaining why VACTERL association can be found in entities with different etiologies.

This hypothesis was initially shaped in the 19th century, when several investigators noted the overall abnormal caudal body in individuals with sirenomelia and correlated its origin with defective development of the caudal somites and tailbud [see Stocker and Heifetz Stocker and Heifetz, and references therein]. Later, Duhamel identified the frequent and nonrandom association between different types of malformations of the lower body, affecting the hindgut and other systems, and he introduced the notion of caudal regression syndrome to refer to a variable combination of defects of the caudal part of the body Duhamel, Caudal regression syndrome is presently designated by the more accurate term of CD Opitz et al.

The vertebrate body plan goes through a series of events during gastrulation. In amniotes, this involves massive movements of epiblast cells through the primitive streak, transforming a two-layered blastocyst into an embryo consisting of three germ layers, with the formation of the endomesoderm in a rostrocaudal sequence Voiculescu et al. At late gastrulation, after massive ingression movements terminate, the remnant of the regressing primitive streak forms the caudal eminence, or tailbud, posterior to the site of the former neurenteric canal [ Fig.

The caudal eminence has a bulb-like appearance and consists of a mass of loose mesenchyme covered by the ectoderm [ Fig. As a consequence of the growth and elongation of the tailbud, the remnants of the primitive streak progressively involute towards the ventral region of the embryo [see figure 5 from Mills and Bellairs Mills and Bellairs, ]. This morphogenetic process is accompanied by the formation of a thickened ectodermal area on the ventral distal side called the ventral ectodermal ridge VER Gruneberg, Fig.

The VER is considered the continuation of the posterior primitive streak. In fact, mesoderm precursors on the surface continue to internalize and to contribute to tail elongation and formation of caudal structures Wilson and Beddington, ; Knezevic et al.

This continuity has been confirmed in both chick and mouse embryos through the analysis of molecular markers whose expression is continuous from the primitive streak cells into subpopulations of cells in the tailbud region Gofflot et al.

The VER has been compared to another ectodermal thickening, the apical ectodermal ridge of the developing limb Gruneberg, , and has attracted much attention as a putative signaling center responsible for tail elongation by controlling cell proliferation in the underlying mesoderm.

Although experiments of VER ablation in mice did not confirm a role for the VER in promoting proliferation, studies in chick reported that VER cells undergo an epithelial-mesenchymal transition process, accounting for the accumulation of mesoderm in the lateral and ventral tailbud region Gofflot et al.

Diagrams summarizing the normal development of the caudal region of the vertebrate embryo before, during and after tailbud formation. For each stage [before A , during B and after C tailbud formation] a dorsal representation of the caudal end of the embryo is shown on the left; the structures that would be seen underneath the ectoderm are shown.

Adapted from Mills and Bellairs Mills and Bellairs, , with permission. According to the defective blastogenesis hypothesis, sirenomelia is a primary defect of blastogenesis that occurs during the final stages of gastrulation at the tailbud stage, corresponding to the third gestational week in humans Opitz et al.

The phenotypic variability depends on the intensity, time of initiation and duration of the underlying event. In this view, sirenomelia can be considered a particular manifestation of CD, in contrast to the still persistent debate in the clinic regarding whether sirenomelia is a distinct entity. Debate has been based on the observation that sirenomelia presents with characteristics that are distinct from CD: these characteristics include the nearly constant presence of an SUA of vitelline origin, the occurrence of cases without dorsal defects of the neural tube and spine, and the lack of a clear association with maternal insulin-dependent diabetes mellitus, as is observed for CD see Boxes 2 , 3 Passarge and Lenz, ; Stocker and Heifetz, ; Duncan and Shapiro, ; Lynch and Wright, Although the vascular steal hypothesis and the deficient blastogenesis hypothesis do not exclude one other, it is reasonable to assume that deficient blastogenesis would concomitantly affect organ and vessel development.

Although sirenomelia has been known to occur in humans since ancient times Saint-Hilaire, ; Stocker and Heifetz, , this malformation was only recently documented in other animals, including mice Gluecksohn-Schoenheimer and Dunn, Interestingly, and in marked contrast to the human condition in which all the cases reported so far have been sporadic, sirenomelia in the mouse has been shown to have a genetic basis.

The first cases of mouse sirenomelia were reported in the progeny of mice carrying different mutations at or near the T locus [in the brachyury gene short-tail strain and in the axin1 gene fused strain ] Gluecksohn-Schoenheimer and Dunn, The mutations in these mice were known to affect tail and caudal body development.

Although, at the time of this study, the genotypes could not be fully established, it was clear that at least one copy of the short-tail allele was involved in the phenotype. A spontaneous mutation called sirenomelia srn was also identified but it was unfortunately lost Hoornbeek, Remarkably, all of these mice exhibited the combination of malformations typical of human sirenomelia.

More recently, a sirenomelia-like phenotype has been observed in several genetically modified mouse strains with either gain-of-function of retinoic acid RA signaling or loss-of-function of bone morphogenetic protein Bmp signaling. Cyp26a1 is an enzyme that degrades RA the active metabolite of vitamin A and that is expressed in the caudal region of the embryo and transiently in the developing vascular network Abu-Abed et al. Consistently, disruption of Cdx2 , which encodes a transcription factor that activates the Cyp26a1 promoter, or the disruption of Por , which encodes an enzyme that is required for the function of the Cyp26 family of enzymes, both cause sirenomelia Ribes et al.

A decrease in the production of RA by reducing the level of the enzyme that synthesizes it haploinsufficiency of Raldh2 is sufficient to rescue the Cyp26a1 phenotype Niederreither et al. Kochhar Kochhar, and Yasuda et al. Yasuda et al. Therefore, in mice, sirenomelia is clearly associated with excess RA signaling in the caudal region of the embryo.

An important discovery was the finding that sirenomelia was an invariable phenotypic trait in the double Bmp7;Tsg Twisted gastrulation mutant mouse Zakin et al. Tsg, which can function as an activator or inhibitor of Bmp signaling, depending on the context, acts as a positive modulator in the caudal embryonic region Larrain et al.

The mermaid phenotype in the Bmp7;Tsg double mutant results from a reduction in Bmp signaling in the ventral caudal mesoderm; this reduction is more marked than that caused by the loss of Bmp7 alone, because the single Bmp7 mutant does not exhibit a mermaid phenotype Zakin et al.

The contribution of reduced Bmp signaling to the malformation has been confirmed in loss-of-function experiments Bmp7 -morpholino and Tsg -morpholino injections in Xenopus laevis Zakin et al. In zebrafish, deficient Bmp signaling after the mid-gastrula stage similarly causes deficient ventral mesoderm formation, with defects in kidney and excretory system morphogenesis e. Therefore, the association between reduced Bmp signaling at the caudal level and the occurrence of sirenomelia seems to be conserved across species.

In humans, a genetic etiology for congenital caudal anomalies has only been confirmed for the Currarino syndrome Currarino et al. By contrast, to date, all reported incidences of sirenomelia in humans have been sporadic cases Castilla et al. This is in marked contrast to the well-established genetic basis for sirenomelia-like phenotypes in mice.

Although it is possible that, in humans, sirenomelia is an autosomal-dominant genetic condition, with every single case caused by a new spontaneous mutation, it seems more likely that it has a combined genetic and environmental component. The absence of familial cases might rely, at least in part, on insufficient documentation and classification of spontaneous or induced abortions Castilla et al. However, it should be noted that there are two reported cases of diabetic mothers that had children with sirenomelia and CD, or children with sirenomelia and VACTERL Assimakopoulos et al.

RA, maternal diabetes and heavy metals have been described as important environmental risk factors for caudal malformations. The involvement of RA signaling in the genesis of sirenomelia is well established in experimental models and represents a potentially interesting connection to the environment, because RA levels can be modified by genetic, nutritional and iatrogenic causes. However, to date, sirenomelia has not been reported among the malformations of RA-exposed human fetuses.

However, this association remains controversial for sirenomelia because only 0. Finally, exposure to heavy metals is associated with CD and sirenomelia in both experimental models Ferm and Carpenter, ; Hilbelink and Kaplan, and in humans Castilla et al. Out of the mutant mice that have been characterized to date, the Cyp26a1 and Bmp7;Tsg engineered mouse mutants exhibit a phenotype that is most similar to the human condition, making them the most suitable models for studying and understanding the pathogenesis of this human malformation.

Sirenomelia, as well as other malformations that affect multiple organs, arises very early during development and could therefore result from disturbances of a basic developmental event that would later have a broad impact in different systems. For example, a single pathophysiological mechanism affecting the formation of the caudal mesoderm could explain the abnormal vascular pattern as well as the variable organ hypoplasia Duesterhoeft et al.

The alternative possibility that several pathological mechanisms, acting independently on different biological functions, lead to the sirenomelia phenotype seems less likely.

Clinical data suggest that sirenomelia might result from a defect, at the late gastrula stage, in the formation or remodeling of the early embryonic vasculature or in the generation of the mesodermal precursors.

In both situations, the resulting development of the caudal region would be impaired. Experimental data suggest that sirenomelia has a genetic basis resulting from a defect in RA or Bmp signaling in the caudal embryonic region Abu-Abed et al.

Therefore, it seems plausible that there is a connection between the cellular mechanisms identified in the clinic and the molecular signals identified in animal studies. As such, the use of new and existing animal models will be of great value in elucidating the definite cause of sirenomelia. Bmp signaling performs multiple important roles during early embryogenesis, including the control of gastrulation. During late gastrulation, several Bmp ligands and their extracellular antagonists and modulators are concomitantly expressed in dynamic and partially overlapping domains Winnier et al.

Although this makes it difficult to assign a specific role to each particular factor, a role for Bmp signaling in the growth of the tailbud and in promoting the formation of caudal mesoderm in the VER has been shown Ohta et al. Consistently, in the chick, termination of cell movements through the VER coincides with the attenuation of Bmp signaling at this level Goldman et al.

Furthermore, the sirenomelia phenotype of the double Bmp7;Tsg mutant strongly supports the involvement of Bmp signaling in caudal development Zakin et al.

Bmp signaling also plays a crucial role in angiogenesis and vasculogenesis by promoting endothelial cell activation, migration and proliferation, three processes that are central to the establishment and remodeling of the vasculature. Bmp signaling also directs maturation of the primitive capillary plexus into the mature vasculature Park et al.

Therefore, defective Bmp signaling is a solid candidate cause for sirenomelia, given that this pathway is important for the normal formation of the mesoderm and the differentiation of hematopoietic and endothelial precursor cells. Similar to Bmp, RA signaling also plays crucial roles during early embryogenesis, particularly in influencing the development of caudal structures. The spatiotemporal distribution of RA in the early embryo is tightly controlled by the balanced expression of its synthesizing and catabolizing enzymes Duester, ; Niederreither and Dolle, A multitude of experiments that modified the level of RA signaling by genetic and nutritional means have demonstrated that the embryo is particularly sensitive to deviations from normal levels of RA during gastrulation Fujii et al.

The expression of Cyp26a1 , which occurs at the early gastrula stage in the primitive streak and its newly formed mesoderm, shifts to the open neuropore, hindgut endoderm and tailbud mesoderm at the late gastrula stage Fujii et al.

The elongation of the trunk is controlled by a balance between the amount of fibroblast growth factor 8 Fgf8 produced at the tail tip and RA signaling generated by Raldh2 in the somites Diez del Corral et al.

Fgf8 maintains an undifferentiated zone of precursor cells Akai et al. The primary characteristic is a partial or complete fusion of the lower limbs, which may mean a baby having only one femur — the long bone at the front of the thigh. Babies may also have one or no feet, or they might have two rotated feet. A team of specialist healthcare professionals will need to care for people with mermaid syndrome because of the seriousness of the condition and how it can affect different organs and structures in the body.

Surgery has proved successful in separating the legs of some people with this condition. Surgeons insert expanders similar to balloons under the skin and gradually fill them with a solution of salt.

The skin stretches and grows, and the surgeons use the excess to cover the legs after separating them. Mermaid syndrome, although very rare, is often fatal. Most babies with this condition are stillborn or die within a few days of birth, despite treatment. Worldwide, only a few babies have survived beyond the newborn stage. It is sometimes possible to detect mermaid syndrome as early as 13 weeks of pregnancy, and some people may choose a termination in these circumstances.

In , the BBC reported that Milagros Cerron, a 2-year-old girl with mermaid syndrome, had taken her first steps after surgery. The same report said that the only other person to have survived years after surgery was the then year-old Tiffany Yorks.

However, both of these survivors have now died due to complications of mermaid syndrome. Mermaid syndrome is a very rare condition in which a baby is born with their legs partially or totally fused.

They may also have a range of major problems with other organs, including the heart, lungs, kidneys, and urogenital system. The condition might also affect their spine and skeletal structures. There have been a few cases of surgical separation of the legs. A team of doctors from different specialties will help plan and provide the treatment and care of babies with mermaid syndrome, as well as supporting the family.

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