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We present a case of sirenomelia diagnosed in the first trimester of pregnancy. The ultrasound examination showed fused lower extremities and an anechoic structure in the lower abdomen that is clue in the early diagnosis. The postmortem study showed the existence of a single umbilical artery (vitelline artery), with an origin in the abdominal aorta. This finding not only explained the presence of a vascular steal with subsequent underdeveloped of pelvic organs, but also differentiated this condition from caudal regression syndrome.

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113 ∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113 ∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Rationale: Tibial hemimelia is known as a rare congenital lower limb deficiency. It has been classified into different types based on Jones classification, and the traditional treatment of tibial hemimelia is amputation. Here we present a variant and unclassified case of tibial hemimelia, which was caused by osteomyelitis. And the lower limb with tibial hemimelia was salvaged by asymmetric limb lengthening., Patient Concerns: 19-year-old girl had the shortened and curved left lower extremity with walking abnormalities., Diagnosis: The patient's deformity was caused by osteomyelitis of tibia occurred when she was 18 month old. The tibial shaft was absent, while the proximal and distal tibia was present but was hypoplastic with radiographic analysis. The fibula was hypertrophied and curved like the capital letter C. The leg length discrepancy (LLD), mostly coming from the left lower leg, was 22 cm., Interventions: We were able to salvage the limb successfully by 5 operations, including releasing soft tissue, fusing the proximal tibiofibular joint, fibular osteotomy, femur lengthening, and fibular lengthening., Outcomes: The whole treatment time for the patient was 3 years and 2 months, and she was followed up for 5 years afterward. The length of femur lengthening and fibula lengthening during the reconstruction were 7.8 cm and 11 cm, respectively. Most of the deformities were corrected, except that the left lower limb was still 2 cm shorter than the contralateral limb, and the 34 mm of mechanical axis deviation (MAD) of left lower limb remained. The reason why the patient's lower limbs were asymmetric was that the femur and fibular lengthening were performed within the affected limb only. Overall, the patient was very satisfied with her asymmetric limbs and its function after surgeries., Lessons: The LLD in this case mainly came from tibial hemimelia. However, the fibula was unable to be lengthened to 22 cm during the lower leg distraction process because of blood flow disturbance. We could only lengthen the femur to salvage the limb in this situation. Even though the patient still had a few residual deformities and a pair of asymmetric lower limbs, she was satisfied with the function and appearance of the reconstructed limb. Therefore, the lower limb with tibial hemimelia can be salvaged by asymmetric limb lengthening in special cases.

Cohesin is a chromosome-associated protein complex that plays many important roles in chromosome function. Genetic screens in yeast originally identified cohesin as a key regulator of chromosome segregation. Subsequently, work by various groups has identified cohesin as critical for additional processes such as DNA damage repair, insulator function, gene regulation, and chromosome condensation. Mutations in the genes encoding cohesin and its accessory factors result in a group of developmental and intellectual impairment diseases termed 'cohesinopathies.' How mutations in cohesin genes cause disease is not well understood as precocious chromosome segregation is not a common feature in cells derived from patients with these syndromes. In this review, the latest findings concerning cohesin's function in the organization of chromosome structure and gene regulation are discussed. We propose that the cohesinopathies are caused by changes in gene expression that can negatively impact translation. The similarities and differences between cohesinopathies and ribosomopathies, diseases caused by defects in ribosome biogenesis, are discussed. The contribution of cohesin and its accessory proteins to gene expression programs that support translation suggests that cohesin provides a means of coupling chromosome structure with the translational output of cells., (© 2015 The Authors. WIREs Developmental Biology published by Wiley Periodicals, Inc.)

Congenital malformations represent approximately 3 in 100 live births within the human population. Understanding their pathogenesis and ultimately formulating effective treatments are underpinned by knowledge of the events and factors that regulate normal embryonic development. Studies in model organisms, primarily in the mouse, the most prominent genetically tractable mammalian model, have equipped us with a rudimentary understanding of mammalian development from early lineage commitment to morphogenetic processes. In this way, information provided by studies in the mouse can, in some cases, be used to draw parallels with other mammals, including human. Here, we provide an overview of our current understanding of the general sequence of developmental events from early cell cleavages to gastrulation and axis extension occurring in human embryos. We will also review some of the rare birth defects occurring at these stages, in particular those resulting in conjoined twinning or caudal dysgenesis., (Copyright © 2012 Wiley Periodicals, Inc.)

Chromosome cohesion, mediated by the cohesin complex, is essential for the process of chromosome segregation. Mutations in cohesin and its regulators are associated with a group of human diseases known as the cohesinopathies. These diseases are characterized by defects in head, face, limb, and heart development, mental retardation, and poor growth. The developmental features of the diseases are not well explained by defects in chromosome segregation, but instead are consistent with changes in gene expression during embryogenesis. Thus a central question to understanding the cohesinopathies is how mutations in cohesin lead to changes in gene expression. One of the prevailing models is that cohesin binding to promoters and enhancers directly regulates transcription. I propose that in addition cohesin may influence gene expression via translational mechanisms. If true, cohesinopathies may be related in etiology to another group of human diseases known as ribosomopathies, diseases caused by defects in ribosome biogenesis. By considering this possibility we can more fully evaluate causes and treatments for the cohesinopathies.

We present 2 cases of sirenomelia and highlight the recent theories about its pathogenesis. Both cases had a large aberrant abdominal umbilical artery (AAUA) arising from the aorta, suggesting vascular steal as the pathophysiology. However, the bilateral upper limb defects noted in 1 case, the reported 10% association of holoprosencephaly and anencephaly, and the reports of sirenomelia with normal umbilical arteries point to the alternative caudal dysgenesis (CD) theory. This proposes that an insult at the early blastogenic stage interferes with the formation of the notochord, resulting in abnormal development of caudal structures, an AAUA, and occasional neural tube defects. We have also analyzed the implications of the similarities between sirenomelia/CD and the VATER association; the increased risk of CD but not sirenomelia in infants of diabetic mothers; the fact that sirenomelia, holoprosencephaly, and the VATER association are all more common in monozygotic twins; the experimental production of sirenomelia in mice; and the possible genetic implications of the co-occurrence of sirenomelia and CD.

Thalidomide poisoning can result in malformation of limbs, specifically upper limbs, compromising manual dexterity. Although Thalidomide has long since been withdrawn for use in pregnant patients, its affects on those exposed pose significant challenges for patients' oral hygiene maintenance. This case reports a novel technique of adaptation to facilitate a Thalidomide poisoned patient in maintenance of oral hygiene via an adaptive toothbrush handle.

Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the lower body characterized by fusion of the legs and a variable combination of visceral abnormalities. The causes of this malformation remain unknown, although the discovery that it can have a genetic basis in mice represents an important step towards the understanding of its pathogenesis. Sirenomelia occurs in mice lacking Cyp26a1, an enzyme that degrades retinoic acid (RA), and in mice that develop with reduced bone morphogenetic protein (Bmp) signaling in the caudal embryonic region. The phenotypes of these mutant mice suggest that sirenomelia in humans is associated with an excess of RA signaling and a deficit in Bmp signaling in the caudal body. Clinical studies of sirenomelia have given rise to two main pathogenic hypotheses. The first hypothesis, based on the aberrant abdominal and umbilical vascular pattern of affected individuals, postulates a primary vascular defect that leaves the caudal part of the embryo hypoperfused. The second hypothesis, based on the overall malformation of the caudal body, postulates a primary defect in the generation of the mesoderm. This review gathers experimental and clinical information on sirenomelia together with the necessary background to understand how deviations from normal development of the caudal part of the embryo might lead to this multisystemic malformation.

Abnormally formed lower limbs with varying degrees of fusion are the major feature of sirenomelia whereas maldeveloped lower limbs without fusion are found in association with caudal dysgenesis (CD). The relationship between these two entities has been a topic of debate for many years. The presence of a single umbilical artery originating from the abdominal aorta was considered a major feature distinguishing sirenomelia from CD. Based on this finding, the vascular steal theory was put forward as the causative mechanism of sirenomelia. CD and sirenomelia were considered to be two entirely different entities with distinct pathogenic mechanisms. However, it is now clear that a single umbilical artery can be found in some patients of CD and normal umbilical arteries in some patients of sirenomelia. The hypothesis of primary deficiency of caudal mesoderm caused by early developmental disruption suggests that sirenomelia and CD are two ends of a spectrum of maldevelopment of caudal mesoderm. In this paper we report on the clinical and pathological features of 16 patients of CD and 9 patients of sirenomelia from our institution and review the literature. This series of cases is notable for the significant association with neural tube defects, refining the renal and urogenital pathology associated with these conditions, and supporting the concept of a continuum of the disease spectrum., (Copyright © 2010 Wiley-Liss, Inc.)

Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation. Both X-irradiation and thalidomide-induced phocomelia have been interpreted as patterning defects in the context of the progress zone model, which states that a cell's proximodistal identity is determined by the length of time spent in a distal limb region termed the 'progress zone'. Indeed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal patterning is unaffected after X-irradiation does not support the predictions of the progress zone model.

Unlabelled: This article describes a qualitative, participatory action research study based in grounded theory, in which an online survey was developed and utilized to explore and generate suggestions for further research about the needs and health care experiences of parents of children with congenital limb differences (CLD) during the first year of the child's life., Participants: Fifty parents completed an online survey that was developed through review of themes in the literature and input from people with CLD and their families. Primarily with open-ended questions, the survey targeted the respondents' perceptions of the attitudes and approaches of health care providers., Results and Discussion: Results indicate that parents consistently commented on three main areas of interaction with health care providers: attitudes, information, and emotional or psychological support. Research hypotheses generated from the data are presented. Implications and suggestions for future directions are discussed., ((PsycINFO Database Record (c) 2009 APA, all rights reserved).)

Background: One hospital in the city of Cali, Colombia, of the ECLAMC (Latin-American Collaborative Study of Congenital Malformations) network, reported the unusual occurrence of four cases of sirenomelia within a 55-day period., Methods: An ECLAMC routine for cluster evaluation (RUMOR) was followed that included: calculations of observed/expected ratios, site visits, comparison with comprehensively collected local, South American, and worldwide data, cluster analysis, and search for risk factors., Results: All four Cali sirenomelia cases were born to mothers living in a 2 km(2) area, in neighboring communes, within the municipality of Cali. Considering the total births of the city of Cali as the denominator, and based on ECLAMC baseline birth prevalence rates (per 100,000) for sirenomelia (2.25, 95% CI: 2.66, 3.80), the cluster for this congenital abnormality was unlikely to have occurred by chance (observed/expected ratio = 5.77; 95% CI: 1.57-14.78; p = .002). No consistent common factor was identified, but vicinity to an open landfill as the cause could not be rejected. Another ECLAMC hospital in San Justo, Buenos Aires, Argentina, reported three further cases but these did not seem to constitute a nonrandom cluster., Conclusions: The methodology used to evaluate the two possible clusters of sirenomelia determined that the Cali sirenomelia cluster was unlikely to have occurred by chance whereas the sirenomelia cluster from San Justo seemed to be random., (. (c) 2008 Wiley-Liss, Inc.)

Caudal dysplasia syndrome (CDS) is associated with hypoplastic lower extremities, caudal vertebrae, sacrum, neural tube, and urogenital organs. Sirenomelia is characterized by a single lower extremity, absent sacrum, urogenital anomalies, and imperforate anus. There is controversy in the medical literature about whether sirenomelia and CDS are part of the spectrum of the same malformation. Patients with CDS and sirenomelia were identified from our pathology files from 1991 to 2006. Maternal history, pathologic examination, and radiographs were collected and tabulated. We found 9 cases with CDS and 6 with sirenomelia. Fully 7 of 9 patients with CDS (77.7%) versus none of sirenomelic babies were infants of diabetic mothers. Congenital heart disease was present in 5 patients with CDS (55.5%) and none of the infants with sirenomelia. Of 9 children with CDS 2 (22.2%) had bilateral renal agenesis versus 66% of sirenomelics. Single umbilical artery was found in 33% of cases with CDS and 100% of children with sirenomelia. External genitalia were ambiguous in 2 of 9 patients (22.2%) with CDS and in all patients with sirenomelia. Imperforate anus was found in 10 cases (66.6%) divided as 4 of 9 babies with CDS (44.4%) and all patients with sirenomelia. Three patients with CDS had concomitant maternal diabetes mellitus and chronic hypertension. These babies also had cleft lip and palate. Congenital heart disease was found in 55.5% of cases with CDS and none of the children with sirenomelia. We conclude that although CDS and sirenomelia share many similar features, they are two different entities.

Sirenomelia and cyclopia share etiologic and pathogenic characteristics. A cluster of these two patterns of malformation in the city of Cali, Colombia, is described. Four sirenomelia and four cyclopia cases were born within a 165 days period in one hospital in Cali. The lapse between conception dates of first and last cases was shorter for sirenomelia (53 days) than for cyclopia (231 days). Based on ECLAMC (Latin American Collaborative Study of Congenital Malformations) published data, the observed/expected ratio (5.7) for both defects is statistically significant (P < 0.001). Mother's residence during the first trimester of pregnancy is concentrated in a same city quarter for four of the eight cases, close to a know polluting active landfill, and the other four cases, along the Cauca river, downstream from this landfill. Birth prevalence rates for two sentinel anomalies, that is, anal and esophageal atresia for sirenomelia and oral clefts for DeMyer holoprosencephaly spectra, were not higher in Cali than in the rest of ECLAMC material. The Computer Assisted Telephone Interviewing was applied to mothers of the 8 patients, and 32 matched controls. Seven of 295 variables were associated with sirenomelia, 3 of them related to house tap water, one to exposure to street drugs, one to physical injury, and 2 secondary to abnormal pregnancy outcome. None was associated with cyclopia. Results from hair dosage of heavy metals in the 8 patient's mothers were inconsistent. The time-space cluster is nonrandom for sirenomelia, and possibly random for cyclopia. The polluting landfill remains as a possible etiological factor., (2008 Wiley-Liss, Inc.)

Mermaid or sirens have been part of the cultural tradition of the sailors during the first expeditions in the western world. The Siren's Myth appeared for a first time with Homer, who described in the Odyssey some singing creatures that lured the enchanted sailors to death. More frequently described with a bird body and a female head, sometimes the female part was extended to torso, with arms prolonged in sturdy claws. In the Latin literature Publius Ovidius Naso presented in the Métamorphoses these creatures. Proposed ethymology for the word "siren" seems to confirm the prerogatives of these creatures, related to magnetism, seduction, charm. The first figuration of Sirens resembling to fish-women was in the second century bc. Hans Christian Andersen provided to leave us the strongest legend of Siren in the well-known fairy tale "The Little Mermaid". Following this story, Sirens are definitely considered as beautiful half-fish women who lived in the bottom of the sea, having a lovely voice to be used when they rise up to allow sweeter the agony of the wrecked sailors. Beyond the Myth, may the Siren really exist? It can be hypothesized that these creatures probably were individuals affected by sirenomelia. In our literature and medical review, we describe the etiology of the disease, and we illustrated the anatomical features of fetuses affected by this pathology using MDCT 3D reconstructions. Syrenomelia is a condition not compatible with the normal life, however nine cases of "mermaid" survived to reconstructive surgery have been reported until now. In our report we also presented a case of survival baby girl affected by sirenomelia, before and after surgery, with correlative radiologic imaging findings. The most important characteristic that seems to allow survival of the affected individuals is the presence of one functional kidney, displaced in pelvis. As so dramatically tragic was the history of the Andersen Little Mermaid, so unattended pleasant would be the destiny of a modern mermaid, who can hope to finally marry her prince, without the risk to "loose her head", as the Copenhagen City's Symbol did in the past years, for a story beyond the Myth.

Asymmetrical conjoined twins or heteropagus twins are extremely rare. They are characterized by an incomplete component (parasite) that is normally smaller and dependent on the host (autosite). In cases of an epigastric heteropagus twin, the insertion occurs in the epigastrium. There are few reports of epigastric heteropagus twinning in the English-language literature. The authors report an extremely rare case of epigastric heteropagus twinning in which the parasite presented with head, thorax, and a rudimentary heart.

Brachmann-de Lange syndrome (BDLS) is a disorder of unknown cause that is recognized on the basis of characteristic facies in association with growth retardation, mental retardation and, in many cases, upper limb anomalies. Because of its association with skeletal anomalies, patients with the syndrome are often referred to the paediatric orthopaedic surgeon. Thirty-four patients with Brachmann-de Lange syndrome were evaluated for the prevalence and pattern of musculoskeletal involvement. The average age of the patients was 10.2 years (range, 1 month to 44 years). Both sexes were affected equally. The common orthopaedic manifestation affected the hand (100%), elbow (47%), and the heel cord (26%). Severe bony anomalies included complete absence of the hand in one case, and ulna hemimelia in two cases. In two patients bilateral Legg-Perthes-like changes were noted. Scoliosis presented in four cases, all before the age of 10 years. Surgery was performed in two patients with severe bilateral equinovarus feet. Despite the constellation of musculoskeletal findings, most of the patients did not have surgical intervention for their deformities.

The association of maternal diabetes mellitus and congenital anomalies is well established. Children of insulin-dependent diabetic women have an increased risk of congenital malformations, especially major multiorgan defects. The cardiovascular, central nervous, gastrointestinal, genitourinary and musculoskeletal are the most affected body systems. Studies also show that offspring of women with gestational diabetes (specially those with fasting hyperglycaemia) tend to have higher rates of congenital anomalies. We report two cases of infants born to unrelated mothers: one with diabetes mellitus first detected during pregnancy (gestational diabetes) and the other with pregestational diabetes. Both infants had amelia of the lower limbs (suggestive of caudal dysplasia sequence), together with cardiovascular, skeletal, urinary and gastrointestinal defects. While pregestational diabetes seems to leave no doubt about its teratogenicity, the association of gestational diabetes and fetal/newborn malformations is still under discussion. Complete absence of the lower limbs has not been reported in association with gestational diabetes, but it may represent a spectrum of the caudal dysplasia sequence. The presentation of two cases with the same clinical phenotype of mothers with gestational and pregestational diabetes supports the evidence that gestational diabetes can be responsible for the development of the most severe form of the caudal dysplasia sequence.

The authors report a case of a surviving infant with sirenomelia (Mermaid syndrome). The child is now 4 years of age. The authors believe that this is only the fourth reported case of an infant with sirenomelia surviving beyond the neonatal period and the first associated with absent bladder. The abnormal distal aorta shown in this case supports the theory that sirenomelia is an extreme form of caudal dysgenesis rather than occurring secondary to vascular steal.

The sirenomelia sequence with fusion, rotation, hypotrophy or atrophy of the lower limbs in combination with severe urogenital and gastrointestinal malformations is a rare and usually lethal disorder. We present the case of a 28-year-old woman, who was referred to our department because of an intraabdominal cystic structure in the 9th week of gestation. Subsequent scans confirmed the diagnosis of a sirenomelia sequence with the fusion of the lower extremities without fusion of the bones according to Stocker I classification. The size of the intraabdominal cyst decreased during follow-up. After counseling, termination of pregnancy was induced. The postmortem X-ray confirmed the ultrasound diagnosis. The exact etiological mechanism of this malformation is still unknown. An early alteration of the embryological vascular network damaging the caudal mesoderm is thought to lead to arrested development of the lower limbs and other affected organs. The cyst we saw in the 9th week might fit with this theory, either as an expression of the complex malformation of the lower abdomen or as the sonographic appearance of necrosis., (Copyright 2003 John Wiley & Sons, Ltd.)

An association of Amniotic Band Disruption Sequence and Mermaid Syndrome in a newborn having multiple congenital anomalies is being reported. The newborn had aberrant string like tissues attached to the amputed fingers and toes. Adhesions of amniotic bands had disrupted the fetal parts especially anteriorly in the midline, causing multiple anomalies. Apart from these features of Amniotic Band Disruption Sequence, the newborn had complete fusion of the lower limbs by cutaneous tissue, a characteristic of Mermaid Syndrome (Sirenomelia). Associated malformations were anal stenosis, rectal atresia, small horseshoe kidney, hypoplastic urinary bladder and a bicomuate uterus. The single umbilical artery had a high origin, arising directly from the aorta just distal to the celiac axis, which is unique to sirenomelia. Theories put forward regarding the etiopathogenesis of both the conditions are discussed.

Background: Phocomelia, which is primarily due to a disruption in the proximodistal axis, is found in virtually all mouse embryos exposed to high doses of retinoic acid (RA) on 11 days post coitum (dpc)., Methods: To identify genes that potentially mediate the effects of retinoic acid (RA) on limb development, we have examined the expression of 9,000 clones from the IMAGE consortium by microarray analysis of RNA isolated from 11 dpc mouse forelimbs exposed to RA or vehicle for 6 hr. Eight genes that demonstrated altered expression were chosen for further study of their mRNA levels using RT-PCR. Protein levels were determined by Western blot analysis., Results: Of the 9,000 genes examined in the microarray, approximately 111 demonstrated altered expression (33 known genes and 78 ESTs). Of the eight known genes chosen for further study using RT-PCR, four mRNAs (PBX1a, PBX1b, IGF-Ia, and IGF-Ib) demonstrated consistent elevation ( approximately 3-fold) in their levels after RA treatment in both the forelimbs and hindlimbs as early as 3 hr after RA treatment. In addition to the two PBX1 isoforms, the mRNA level of the other two subtypes (PBX2 and PBX3) and the level of PBX1/2/3 protein were also found to be elevated in limb buds after RA treatment. Finally, we examined the expression of MEIS1, MEIS2, and MEIS3 because these proteins are necessary for PBX nuclear localization. The mRNA level of all three subtypes of MEIS were elevated approximately three- to four-fold in both the forelimbs and hindlimbs after RA treatment., Conclusions: Because both PBX and MEIS (and their orthologs) are believed to be involved in the control of proximodistal axis formation in mouse and fly limbs and IGFs in the development of limbs, we suggest that increases in PBX, MEIS and IGF-1 mRNA levels may contribute to proximodistal limb reduction defects caused by teratogenic doses of RA., (Copyright 2002 Wiley-Liss, Inc.)

Fibrous dysplasia is an uncommon condition characterized by the presence of mesenchymatous tissue in bone. There are various risks. We describe the clinical and radiological features observed in a patient with fibrous polyostotic fibrous dysplasia and discuss risks. A 37-year-old man suffered from bone pain and multiple fractures without endocrine disorder since the age of 10 years. At admission in 1998, he presented limb deformities and hyperchromic spots on the thorax. Calciuria was low and alkaline phosphatase was 1274 IU/ml. Endocrine tests were normal. Radiographs showed polyostotic defects in the right hemibody and in the skull. They also showed a right subtrochanteric fissure. CT scan of the face and skull did not demonstrate nerve compression. Histology analysis identified fibrous dysplasia. Vitamin and calcium supplementation and preventive measures were instituted. No deformity led to surgical correction despite the early beginning. Polyostotic fibrous dysplasia is a congenital disease. Radiological aspects are variable. There is a risk of deformities, fractures, osteomalacia (as in our case), neurological compression, and finally a risk of sarcomatous transformation. Recently introduced biphosphonate therapy appears to provide effective pain relief and probably satisfactory prevention of fractures.

We report a case of a dizygotic twin with complex abnormalities of head, body, and limbs. The anomalies include the following: lateral and midline cleft upper lip, ectopic palatal pituitary, natal teeth, bilateral nasal proboscides with an absent nose, left microphthalmia with conjunctival-lined cyst, right ocular dysgenesis, bilateral retinal dysplasia, platybasia with skull asymmetry, hydrocephalus secondary to aqueductal atresia, brain hemispheric asymmetry with a parietal-occipital cortical flap, agenesis of posterior corpus callosum, absence of the olfactory nerves and left anterior cerebral artery, leptomeningeal and intraventricular heterotopias, right radial longitudinal terminal meromelia with constriction rings of fingers, partial syndactyly of the third and fourth left fingers, dorsiflexed great toes and pes equinovarus bilaterally, and multiple skin tags with a sacral appendage. Additionally, this twin's placental disc and extraplacental membranes were devoid of amnion. We regard these anomalies as a possible expression of the human homologue of the disorganization phenotype or another gene mutation. Nevertheless, an abnormality of blastogenesis with early damage to organizing tissues of the frontonasal region and limbs, or a vascular disruption, cannot be excluded. Early amnion rupture sequence (possible extraamniotic pregnancy with amniotic bands, limb reduction defects with Streeter bands, and multiple skin tags tapering into amniotic bands) was also present in this case, and may have acted as a contributing factor.

Dichorionic placentation is observed in both monozygotic (MZ) and dizygotic (DZ) twinning, while monochorionic placentation is unique to MZ twinning. Examinations of monochorionic twin placentas frequently reveal the presence of vascular anastomoses between the two fetal circulations; such anastomoses rarely occur in dichorionic placentas. Consequently, abnormalities resulting from placental vascular communications are almost exclusively observed in MZ twin pairs with monochorionic placentas. We report opposite-sex DZ twins in which vascular anastomoses occurred within a fused dichorionic placenta and were associated with vascular disruptions in one twin. The liveborn male twin had amelia, cutis aplasia, and XX/XY blood chimerism; the female twin died in utero.

Eighteen cases of amelia in the Spanish Collaborative Study of Congenital Malformations (ECEMC) were analyzed epidemiologically. Prevalence at birth was 0.15 per 10,000 newborn infants, which is not different from that reported by other authors. Affected females outnumbered males. When compared with the control group, a lower birth weight, shorter gestation, lower placental weight, greater frequency of single umbilical artery, noncephalic presentation at birth, and more frequent maternal vaginal bleeding were observed in amelia cases. There were no significant variations of parental age. None of these patients was exposed to known teratogens, apart from 1 born to a diabetic mother; 3 patients had a genetic condition. Comparison of these variables with other studies is difficult because there is only one study that specifically analyzed amelia. Our data together with previous observations suggest that the genetic basis of amelia might be more important than has been considered previously.

Sirenomelia is an uncommon congenital malformation of unknown etiology characterized by all degrees of severity in merning, malrotation, and dysgenesis of the lower limbs, combining as it does malformation with several anomalies of the external and internal organs, specially of the urogenital and gastrointestinal systems and other lumbosacral vertebral abnormalities; the severity of the associated malformations are not compatible with life. A genetic mechanism leading to sirenomelia is unlikely, due to the absence of the familial cases.

Caudal regression syndrome represents a continuum of congenital malformations ranging from agenesis of the lumbosacral spine to the most severe cases of sirenomelia with lower extremities fusion and major visceral anomalies. The etiology of this syndrome is not well known. Maternal diabetes, genetic predisposition, and vascular hypoperfusion have been suggested as possible causative factors. The degree of associated anomalies usually parallels the severity of the primary defect. Ultrasonography is the diagnostic tool of choice revealing the absent distal vertebrae of the fetal spine. Amnioinfusion and magnetic resonance imaging (MRI) are of help in better evaluation of the fetal anatomy in cases with oligohydramnios. Perinatal management depends mainly on gestational age at diagnosis and severity of the lesion. It should include genetic counseling and serial sonography to assess interval growth and amniotic fluid volume. Surviving infants have usually a normal mental function and they require extensive urologic and orthopedic assistance. Their long-term morbidity consists mostly of neurogenic bladder dysfunction resulting in progressive renal damage and disabling neuromuscular deficits of the lower extremities. Neurosurgical and orthopedic intervention with physical rehabilitation is indicated to improve the quality of their lives.

The authors report the case of a patient who underwent a failed legal abortion at the 7th week of pregnancy via vacuum aspiration. A follow-up ultrasound survey done at the 14th week demonstrated the continuance of pregnancy and the presence of a serious fetal deformity consisting of the amelia of the two upper limbs, complete phocomelia of the right lower limb and distal phocomelia of the left lower limb. In the light of recent findings of a high incidence of fetal limb abnormalities in women subjected to chorionic villus sampling, before the 9th week of gestation, the Authors hypothesize that chorionic villus sampling, occurring during the abortion attempt, could probably be the cause of the fetal limb abnormalities in the present case study.

A case of combined pentalogy of Cantrell with sirenomelia in a monozygotic twin is described. Similar cases from the world literature are reviewed. Current concepts on the etiology of anterior midline ventral wall defects and sirenomelia are detailed. It has been proposed that anterior midline ventral wall defects may be caused by either monozygotic twinning or vascular dysplasia. Likewise, a vascular steal phenomenon causes sirenomelia. A common etiology for these defects, an alteration in vascular development, is proposed.

Cases with amniotic bands were analysed separately as part of an ongoing study of limb defects occurring among 1,213,913 liveborn infants in British Columbia during the years 1952 to 1984. A total of 24 cases with this specific condition was identified among 659 cases with limb defects. The calculated incidence for amniotic band sequence with significant limb involvement was 0.19 in 10,000 livebirths. This is a minimal incidence, as cases without defects of the limbs, but with constriction rings were not identified with this approach. Familial cases and cases with additional anomalies were found.

Several malformations and malformation complexes have been alleged to be associated with maternal type 1 diabetes mellitus: in particular, sacral dysplasia, caudal regression/sirenomelia, femoral dysplasia, and holoprosencephaly. For some of the malformations the claim rests on case material, and for others on theoretical considerations. The history and evolution of these ideas are presented.

We report a case of fetal amelia (limb deficiency). The causes of this anomaly include amniocentesis, amniotic band syndrome, teratogen exposure, or a vascular accident. Recently, chorionic villus sampling has also been implicated in the amputation of an extremity. Although chorionic villus sampling (CVS) was not performed in our case, this possible association suggests subsequent sonographic scanning following CVS should include precise delineation of all fetal limbs.

A population-based and validated data set of 14 cases with isolated proximal intercalary type of congenital limb deficiency born in Hungary between 1975-84 was evaluated. Two cases had phocomelia of upper limbs, while 12 cases were affected with classical intercalary defects mainly in femurs. Of 14 cases, 13 had unimelic manifestation and both sexes were equally affected. The intrauterine growth retardation, the excess of second birth order, a higher rate of acute maternal disorder of the respiratory system and the lack of familial cluster are noteworthy. The vascular disruption hypothesis seems to be the most plausible explanation for the origin of isolated proximal intercalary defects.

A complex study (roentgenographic, arteriographic, anatomic, anthrometric and microscopic) of 16 upper extremities of stillborn and deceased infants with aplasia and hypoplasia of the radius has been carried out. The etiologic factors of the defect were chromosomal and monogenic mutations and multifactor causes. It has been demonstrated that: 1) in cases of reduction of the radius the structure of the arteries, nerves and muscles in destroyed mostly in the radial border of the forearm and hand; 2) the severity of the changes in the anatomic depends on the type of the defect; 3) the pathomorphologic manifestations of the forms of the defect characterized by the same severity are mostly similar. The mechanisms of deformations of the hand in aplasia (hypoplasia of the radius) are discussed.

Amelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 was studied using the records of a population-based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.

Two babies with sirenomelia are described. Case 1, one of twins, showed the full sirenomelia sequence in conjunction with atelencephaly and cebocephaly. Case 2 had malformations consistent with a diagnosis of the VATER association. Review of the literature indicates that the basic defect in sirenomelia and the VATER association lies in the formation and differentiation of mesodermal tissue and that sirenomelia, the VATER association, and monozygotic twinning show a complex etiological interrelationship.

Prenatal sonographic findings of sirenomelia (or mermaid fetus) were retrospectively reviewed in eleven proven cases. Sonography showed oligohydramnios in all the cases, five (45%) of which had severe oligohydramnios that limited prenatal diagnosis by poor visibility. In five cases (45%), sirenomelia was correctly diagnosed by ultrasound; in the remainder, only bilateral renal agenesis was identified. All eleven fetuses had other associated malformations: congenital heart defects (4), skeletal deformities (10), and abdominal wall defects (4). Death resulted from termination of pregnancy in six cases and stillbirth in three cases. Two newborns died at 24 and 36 hours of neonatal life, respectively. We concluded that some cases of sirenomelia can be detected on prenatal sonograms by demonstration of a single lower extremity, oligohydramnios, and bilateral renal agenesis. Sirenomelia is a lethal condition and can be detectable in the second trimester of pregnancy, allowing for termination of pregnancy.

Four cases of congenital diaphragmatic hernia associated with homolateral upper limb reduction deformities are presented and are analyzed in terms of their pathogenesis. Diaphragm and upper limb are supplied by adjacent segments of cervical neural crest, and the sensitive period for upper limb formation occurs during early neural crest development. The evidence supports the possibility of cervical neural crest injury as the underlying pathogenesis.