Systematic radiographic evaluation of tibial hemimelia with orthopedic implications.

Tibial hemimelia is a rare lower-extremity pre-axial longitudinal deficiency characterized by complete or partial absence of the tibia. The reported incidence is 1 in 1 million live births. In this pictorial essay, we define tibial hemimelia and describe associated conditions and principles of preoperative imaging assessment for a child with tibial hemimelia. We also indicate the imaging findings that might influence the choice of treatment, describe the most widely used classification systems, and briefly discuss current treatment approaches.

Foetal fibular hemimelia with focal femoral deficiency following prenatal misoprostol use: A case report.

Misoprostol is a well known abortifacient. It can cause teratogenicity like Mobius sequence and terminal transverse limb defects. We report a rare case of proximal focal femoral deficiency with fibular hemimelia in a woman who had attempted abortion with self-administered misoprostol and later continued the pregnancy. Though the absolute risk of congenital malformations with its use is low ∼1%, this should be clearly communicated to the women requesting abortion to help them make fully informed reproductive health decisions.

Sirenomelia: a review on embryogenic enviromental theories, novel three-dimensional ultrasound imaging and first trimester diagnosis in a case of mosaic 69,XXX/46,XX fetus.

PURPOSE: Sirenomelia is caused by atrophy of the lower extremities that is commonly associated with gastrointestinal and urogenital malformations. METHODS: Embryogenic environmental theories and systematic review of the literature are reported. RESULTS: Genetic basis of the condition has been demonstrated in the animal model. In humans, association with de novo balanced translocation has only recently been documented. CONCLUSIONS: A case of triploidy mosaic fetus with sirenomelia and posterior fossa anomaly diagnosed at first trimester using novel three-dimensional ultrasound imaging techniques is presented.

[Sirenomelia apus. Case report]. / Sirenomelia apus: reporte de un caso clínico.

We report a case of Sirenomelia. The mother began prenatal care in the second trimester. Transabdominal ultrasound was determined anhydramnios, cardiac abnormalities and lumbosacral spine. We obtained a single fetus of 21 weeks' gestation with fused lower extremities from the hip to finish in a stump without the presence of feet. Heart with transposition of the great vessels, among other birth defects. It was classified as symelia, Apodi apus, monopodio sirenoide, siren ectropodia, type VI. It is important to diagnose early, because it is a serious and deadly disorder.

Genetic and pathologic aspects of retinoic acid-induced limb malformations in the mouse.

Because all-trans retinoic acid (atRA) is teratogenic in all species tested and many of the specific defects induced are common across the phylogenetic spectrum, it would be logical to predict that murine strain differences in teratology to this agent are minimal. However, for specific defects, strain susceptibilities are vastly different. Studies with atRA have shown stark differences between C57BL/6 and SWV mouse strains in susceptibility to postaxial forelimb ectrodactyly and ectopic hindlimb formation, with the C57 strain being more susceptible for both defects. Various approaches were used to determine why these strains differ in susceptibility, but the mechanisms remain unknown. Hindlimb duplications were hypothesized to be caused by the formation of ectopic posterior body axes. For forelimb ectrodactyly, a locus on chromosome 11, Rafar, has linkage to the strain difference, and mRNA localization has shown that specific genes (Fgf8, Dlx3, Bmp4, and Sp8) in the postaxial preAER (prior to formation of the apical ectodermal ridge) of the developing limb bud (the site of the defect) were downregulated hours after atRA administration more in the susceptible C57 than in the SWV strain. Because both atRA and divalent cadmium induce postaxial forelimb ectrodactyly (right-sided predominance) at a high rate in C57BL/6 and low in the SWV strain, there is debate as to whether they share a common mechanism. These teratogens cause a greater-than-additive level of forelimb ectrodactyly when coadministered at low doses, but cadmium does not induce ectopic hindlimb formation. The hypothesis is that these agents have separate molecular pathologic pathways that converge to perturb a common anatomic structure.

Upper limb phocomelia: A prenatal case of thrombocytopenia-absent radius (TAR) syndrome illustrating the importance of chromosomal microarray in limb reduction defects.

OBJECTIVE: To describe the ultrasonographic, pathologic and molecular findings in a fetus with TAR syndrome, and to illustrate the contribution of chromosomal microarray analysis (CMA) to the etiological investigation of fetal upper limb reduction defects. CASE REPORT: A 35-year-old woman was referred for Genetic Counseling after pregnancy termination for severe upper limb bilateral phocomelia detected in the second trimester. Fetal autopsy showed severe shortening of the arms and forearms. The fetal skeletal survey confirmed the absence of the radii, ulnae and humeri. CMA revealed an interstitial deletion in 1q21 including the RBM8A gene. Subsequent Sanger sequencing of this gene identified a hypomorphic mutant allele, c.-21G > A, confirming the diagnosis of TAR syndrome. CONCLUSION: The differential diagnosis of upper limb defects is broad. Identification of their cause is essential for adequate genetic counseling including prognosis and recurrence risk estimation. CMA should be considered in fetuses with upper limb reduction defects, especially when the thumbs are present.

Prenatal sonographic findings in a fetus with splenogonadal fusion limb defect syndrome.

Splenogonadal fusion limb defect syndrome (SGFLD) is a very rare abnormality. We report on a case with prenatal sonographic findings of a fetus with postnatally diagnosed SGFLD syndrome. This is also the second case of prenatal ultrasonographic diagnosis of gastrointestinal malrotation associated with SGFLD. A 26-year-old primigravid woman was referred to our clinic because of nonvisualization of both fetal femoral bones at 20 weeks of gestation. A detailed sonographic examination showed complete bilateral absence of lower limbs, micrognathia, single umbilical artery and a right-sided stomach. Autopsy confirmed prenatal sonographic findings and additionally showed that the spleen was abnormally connected to the left gonad by a fibrous band. In conclusion, although all limbs and both sides were equally affected in most of the reported cases, SGFLD syndrome should be considered in cases with terminal limb defects of lower limbs.

Caudal dysgenesis, sirenomelia, and situs inversus totalis: a primitive defect in blastogenesis.

Caudal dysgenesis (CD) constitutes a heterogeneous spectrum of congenital caudal anomalies, including varying degrees of agenesis of the vertebral column, as well as anorectal and genitourinary anomalies. Sirenomelia, characterized by a fusion of the lower limbs, could represent the most severe end of this spectrum. The two main debated pathogenic hypotheses are an aberrant vascular supply versus a primary axial mesoderm defect. We present the autopsy findings of two fetuses of non-diabetic mothers, with normal karyotype. Both fetuses presented situs inversus associated with a CD, in one case consisting of sirenomelia, establishing a very rare association profile that might be random. This association also suggests the occurrence of a common pathogenic mechanism, in accordance to recent genetic data, such as displayed in the Kif3A murine mutation phenotype. Some cases of sirenomelia and CD could represent developmental field defects of blastogenesis involving the caudal mesoderm, rather than being related to vascular insufficiency.

Sirenomelia: a case report.

Sirenomelia is a rare and interesting congenital anomaly where there is fusion of the lower limb buds in association with a number of other anomalies, together termed as the caudal regression syndrome. We report this syndrome in a male foetus of 33 weeks gestational age, and review its embryological basis.

Postaxial limb hypoplasia (PALH): the classification, clinical features, and related developmental biology.

Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.

Prenatal diagnosis of a 1.6-Mb 4p16.3 interstitial microdeletion encompassing FGFRL1 and TACC3 associated with bilateral cleft lip and palate of Wolf-Hirschhorn syndrome facial dysmorphism and short long bones.

OBJECTIVE: We present prenatal diagnosis of a 4p16.3 interstitial microdeletion associated with bilateral cleft lip and palate and short long bones on prenatal ultrasound, and we discuss the genotype-phenotype correlation. MATERIALS AND METHODS: A 32-year-old woman underwent amniocentesis at 22 weeks of gestation because of bilateral cleft lip and palate and short limbs on prenatal ultrasound. Conventional cytogenetic analysis was performed on cultured amniocytes and parental bloods. Oligonucleotide array comparative genomic hybridization (aCGH) was performed on the DNAs extracted from uncultured amniocytes, parental bloods and umbilical cord. Metaphase fluorescence in situ hybridization (FISH) was performed on cultured amniocytes. RESULTS: Amniocentesis revealed a karyotype of 46,XY. The parental karyotypes were normal. aCGH analysis on uncultured amniocytes revealed a 1.66-Mb interstitial microdeletion at 4p16.3 encompassing 23 Online Mendelian Inheritance of in Man (OMIM) genes including FGFRL1 and TACC3. The parents did not have such a deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with typical Wolf-Hirschhorn syndrome (WHS) facial appearance and bilateral cleft lip and palate. aCGH analysis of the umbilical cord confirmed the prenatal diagnosis with a result of arr 4p16.3 (72,447-1,742,649) × 1.0 [GRCh37 (hg19)]. Metaphase FISH analysis of cultured amniocytes confirmed a 4p16.3 microdeletion. CONCLUSION: Haploinsufficiency of FGFRL1 and TACC3 at 4p16.3 can be associated with bilateral cleft lip and palate of WHS facial dysmorphism and short long bones. Prenatal diagnosis of facial cleft with short long bones should raise a suspicion of chromosome microdeletion syndromes.

Sirenomelia with agenesis of corpus callosum.

Sirenomelia is a very rare anomaly presented with fusion of the lower limbs. Genitourinary, neural tube, and vertebral anomalies are found in most cases. We report a case of sirenomelia with agenesis of corpus callosum, which has not been reported previously.

Sirenomelia: a review of embryogenic theories and discussion of the differences from caudal regression syndrome.

OBJECTIVE: To discuss the pathological features of sirenomelia in the light of our 10 cases and review the current theories. METHODS: We identified 10 patients with sirenomelia from our hospital database. All clinical details and the autopsy features of 10 cases were noted. RESULTS: Of the 10 children with sirenomelia seven had bilateral renal agenesis, three had bladder agenesis and one had a renal hypoplasia. Single umbilical artery was found in 60% of children with sirenomelia. External genitalia was ambiguous in seven of 10 patients. CONCLUSIONS: Even though the etiology of caudal regression syndrome (CRS) and sirenomelia remains unknown we tend to believe that sirenomelia and CRS might be different entities.

Vascular steal: the pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues.

Dissection of the abdominal vasculature in 11 cases of sirenomelia has demonstrated a pattern of vascular abnormalities that explains the defects usually found in this condition. The common feature is the presence of a single large artery, arising from high in the abdominal cavity, which assumes the function of the umbilical arteries and diverts nutrients from the caudal end of the embryo distal to the level of its origin. The steal vessel derives from the vitelline artery complex, an early embryonic vascular network that supplies the yolk sac. Arteries below the level of this steal vessel are underdeveloped and tissues dependent upon them for nutrient supply fail to develop, are malformed, or arrest in some incomplete stage. In contrast to the prevailing view that sirenomelia arises by posterior fusion of the two developing lower limbs, these studies suggest that the single lower extremity in sirenomelia arises from failure of the lower limb bud field to be cleaved into two lateral masses by an intervening allantois.

Interrelationships of the hemifacial microsomia-VATER, VATER, and sirenomelia phenotypes.

The phenotypes of hemifacial microsomia-VATER, VATER, and sirenomelia patients suggest a sequence of overlapping developmental abnormalities. The malformations of 247 hemifacial microsomia (HFM) patients with one or more anomalies in other body regions were analyzed and compared with those of 255 VATER and 101 sirenomelia patients studied in the same fashion. The HFM patients were analyzed in four subgroups delineated by the number of their concomitant VATER ascertainment abnormalities (VAA). Three or more VAA occurred in 33 HFM patients who were designated to have the HFM-VATER phenotype and while no significant alteration of the HFM phenotype was found, there were notable differences in the analyses of the 20 malformation categories studied. Analyzed in separate heart and blood vessel (BV) categories, occurrences of BV defects in HFM patients with 0-1 VAA were low (4-6%) and due to anomalies other than single umbilical arteries (SUA). The BV abnormalities increased to 20% in the HFM with two VAA, HFM-VATER, and VATER phenotypes with equal occurrences of SUA and other BV anomalies. The incidence of SUA was markedly increased (64%) in the sirenomelia. Heart defects rose from 22% to 40% with the increasing VAA in individual HFM patients but were less in VATER (29%) and sirenomelia (21%) patients and were attributed to complex, conotruncal, and other early embryonic anomalies. Unilateral agenesis of paired organs systems occurred frequently and, possibly, can be attributed to an absent blood supply. Each phenotype of the sequence also had increased VAA, rib/vertebrae hypersegmentation, and monozygotic twinning. The variation in the incidences of malformations in the three phenotypes can be attributed to their relative location in the craniocranial organogenesis sequence of normal human embryologic development.

Long term survival of an infant with sirenomelia.

We report on a 3-month-old infant whose sirenomelia was diagnosed prenatally. The infant is neurologically normal and has "fusion" of the lower limbs with associated renal dysplasia, imperforate anus, pelvic and sacral "dysplasia," and genital abnormalities. In addition she has a preauricular skin tag and rib fusion. The infant's anomalies are compatible with life and surgical separation of the lower limbs is planned.

Möbius sequence: further in vivo support for the subclavian artery supply disruption sequence.

Möbius sequence consists of a congenital bilateral facial nerve palsy and external ophthalmoplegia often associated with malformations of the limbs and orofacial structures. The pathogenesis of the sequence is a subject of debate. However, a new hypothesis proposes that Möbius sequence results from an interruption of embryonic blood supply (subclavian artery supply disruption sequence). Here we present an infant with bilateral facial nerve palsy (VII), external ophthalmoplegia (IV, VI), paresis of cranial nerves V, IX, X, XI, and XII, absence of the pectoralis major muscle (Poland anomaly), terminal transverse limb defects, and absence of the right diaphragm. Also, he was found to have discrete foci of brainstem calcifications in the region of the dorsal respiratory group on both CT scan and the histologic sections with microscopic evidence of diffuse brainstem "injury." The anomalies and histopathology noted in this infant imply that vascular insufficiency prior to the sixth week of gestation involving the proximal sixth intersegmental artery may result in the manifestations presented in this report and lend further support for the existence of a subclavian artery supply disruption sequence.

Sacrococcygeal dysgenesis association.

In the malformation analysis of 445 patients ascertained only for a sacrococcygeal malformation, a new phenotype, the sacrococcygeal dysgenesis association (SDA), was delineated in 34%. In addition, sirenomelia patients were found in 12%, the VATER association in 27%, and 27% could not be classified. Heterogeneity in the patients with sacrococcygeal malformations was identified by the differences found in their associated malformations. SDA patients have a relatively small average number (3.3) of anomalies per patient as compared with 9.3 in sirenomelia and 6.2 in VATER patients. SDA abnormalities occurred to a significant degree only in 6 of 20 designated malformation categories (vertebral, rib, pelvic, lower limb, central nervous system [CNS], renal) in contrast to 17 in VATER and 18 in sirenomelia patients. The SDA vertebral malformation pattern also differed from that of VATER/sirenomelia patients as did the high sacrococcygeal agenesis:dysgenesis ratio and low thoracolumbar vertebrae and/or rib hypersegmentations. Most significantly, SDA patients had a large number of CNS anomalies and CNS-related dysfunctions of the urinary and distal intestinal tracts but no anatomic urinary or intestinal tract malformations. This contrasted sharply with the markedly increased occurrences of anatomic abnormalities in these body regions of the sirenomelia and VATER patients. Demographic data such as patient survival, twinning and, particularly, the high (28%) incidence of maternal diabetes in the SDA further support its differentiation from VATER/sirenomelia patients.

Neural crest defects. A neuroanatomic basis for classification of multiple malformations related to phocomelia.

Skeletal and internal structures are shown to be linked anatomically through segmental levels of innervation, or "neurotomes", and are related embryologically to the neural crest. Congenital abnormalities within the same or adjacent neurotomes would explain the distribution of defects in thalidomide embryopathy and morphologically similar multiple malformation syndromes. Classification of these "neural crest defects" on the basis of the segmental nerve supply is suggested.