Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia.

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.

A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning.

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.

Adaptive toothbrush handle: case report of a Thalidomide patient.

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, case report and review of the literature.

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.

Caudal dysgenesis and sirenomelia-single centre experience suggests common pathogenic basis.

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.

Clusters of sirenomelia in South America.

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.

Experiences of parents of children with congenital limb differences with health care providers: a qualitative study.

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.

Caudal dysplasia syndrome and sirenomelia: are they part of a spectrum?

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.

Asymmetric limb lengthening in the treatment of tibial hemimelia caused by osteomyelitis: A case report.

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.

Sirenomelia and cyclopia cluster in Cali, Colombia.

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.

Beyond the myth: the mermaid syndrome from Homerus to Andersen. A tribute to Hans Christian Andersen's bicentennial of birth.

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.

Etiology and pathogenesis of the cohesinopathies.

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.

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.

Amelia: analysis of its epidemiological and clinical characteristics.

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.

Amniotic band sequence and limb defects: data from a population-based study.

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.

Caudal regression syndrome: etiopathogenesis, prenatal diagnosis, and perinatal management.

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.

Caudal dysplasia sequence: severe phenotype presenting in offspring of patients with gestational and pregestational diabetes.

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.

[Severe anomaly of fetal limbs after early and failed voluntary interruption of pregnancy]. / Severa anomalia degli arti fetali dopo precoce e fallita interruzione volontaria di gravidanza.

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.

Orthopaedic manifestations of Brachmann-de Lange syndrome: a report of 34 patients.

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.