Epidemiological survey of 214 families with bladder exstrophy-epispadias complex

PURPOSE: We sought to identify causative nongenetic and genetic risk factors for the bladder exstrophy-epispadias complex. MATERIALS AND METHODS: A total of 237 families with the bladder exstrophy-epispadias complex were invited to participate in the study, and information was obtained from 214 families, mainly from European countries. RESULTS: Two families showed familial occurrence. Male predominance was found among all subgroups comprising epispadias, classic bladder exstrophy and cloacal exstrophy, with male-to-female ratios of 1.4:1, 2.8:1 and 2.0:1, respectively (p = 0.001). No association with parental age, maternal reproductive history or periconceptional maternal exposure to alcohol, drugs, chemical noxae, radiation or infections was found. However, periconceptional maternal exposure to smoking was significantly more common in patients with cloacal exstrophy than in the combined group of patients with epispadias/classic bladder exstrophy (p = 0.009). Only 16.8% of mothers followed the current recommendations of periconceptional folic acid supplementation, and 17.6% had started supplementation before 10 weeks of gestation. Interestingly, in the latter group mothers of patients with cloacal exstrophy were more compliant with folic acid supplementation than were mothers of the combined group of patients with epispadias/classic bladder exstrophy (p = 0.037). Furthermore, mothers of children with cloacal exstrophy knew significantly more often prenatally that their child would have a congenital malformation than did mothers of children with epispadias/classic bladder exstrophy (p <0.0001). CONCLUSIONS: Our study corroborates the hypothesis that epispadias, classic bladder exstrophy and cloacal exstrophy are causally related, representing a spectrum of the same developmental defect, with a small risk of recurrence within families. Embryonic exposure to maternal smoking appears to enforce the severity, whereas periconceptional folic acid supplementation does not seem to alleviate it. There is a disproportional prenatal ultrasound detection rate between severe and mild phenotypes, possibly due to the neglect of imaging of full bladders with a focus on neural tube defects.

Physical long-term health problems and mental comorbidity: evidence from Vietnam

OBJECTIVE: The mental health of children living in low-income countries remains a neglected research area despite the high burden of disease. This study is one of the first that examines the effects of long-term physical health problems on child mental health disorders in a low-income country and investigates whether this association is modified by the socio-economic status of the child's family. METHODS: Community-based cross-sectional survey of 975 eight-year-old children from 20 sites in Vietnam. Long-term physical health problems were measured by a caregiver report and included conditions such as anaemia, congenital malformation, physical disability and skin problems. Child mental disorders were assessed using the strengths and difficulties questionnaire (SDQ). Generalised estimating equations models were fitted to explore the association between long-term physical health problems and child mental disorders. RESULTS: Vietnamese children who suffer from long-term physical health problems have odds 2:1 times greater than children without long-term physical health problems of having a mental disorder (95% CI 1.2 to 3.6, p = 0.006). No significant interaction with socio-economic status was found. CONCLUSIONS: This study showed a high burden of mental disorders among physically ill children, re-enforcing the idea that there is "no health without mental health". While this association needs to be explored longitudinally, children with long-term health problems may be a visible group for targeted mental-health interventions.

Quality of life of grown-up congenital heart disease patients after congenital cardiac surgery

BACKGROUND: Due to better early and long-term outcome, the increasing population of grown-ups with congenital heart disease (GUCH) brings up unexpected quality of life (QoL) issues. The cardiac lesion by itself is not always the major problem for these patients, since issues pertaining to QoL and psychosocial aspects often predominate. This study analyses the QoL of GUCH patients after cardiac surgery and the possible impact of medical and psychosocial complications. PATIENTS AND METHODS: A questionnaire package containing the SF-36 health survey (health related QoL), the HADS test (anxiety/depression aspects) and an additional disease specific questionnaire was sent to 345 patients (mean 26+/-11 years) operated for isolated transposition of the great arteries (TGA), tetralogy of Fallot (TOF), and ventricular septal defect (VSD). The scores were compared with age- and gender-matched standard population data and in relation to the underlying congenital heart disease (CHD). RESULTS: In all SF-36 and HADS health dimensions the GUCH patients showed excellent scores (116+/-20), which are comparable to the standard population (100+/-15), regardless of the initial CHD (p=0.12). Eighty-two percent of the patients were found to be in NYHA class I and 83% patients declared that they do not consider their QoL to be limited by their malformation. Complications like reoperations (p=0.21) and arrhythmias (p=0.10) do not show significant impact on the QoL. The additional questionnaire revealed that 76% of adult patients have a fulltime job, 18% receive a full or partial disability pension, 21% reported problems with insurances, most of them regarding health insurances (67%), and 4.4% of adult patients declared to have renounced the idea of having children due to their cardiac malformation. CONCLUSION: QoL in GUCH patients following surgical repair of isolated TOF, TGA and VSD is excellent and comparable to standard population, this without significant difference between the diagnosis groups. However, these patients are exposed to a high rate of complications and special psychosocial problems, which are not assessed by standardized questionnaires, such as the SF-36 and HADS. These findings highlight the great importance for a multidisciplinary and specialized follow-up for an adequate management of these complex patients.

[Dens invaginatus. Review of the literature and diagnostic and therapeutic guidelines]

Dens invaginatus is a clinically relevant malformation of teeth resulting from an infolding of enamel and dentine into the dental structure during tooth formation, hence the former denomination "dens in dente". The dens invaginatus shows multiple morphological variations of crown and root formation. This frequently leads to caries, pulpal and periodontal involvement with necrosis and loss of attachment. Therefore, early diagnosis and prevention are of utmost importance. Due to the complexity of the malformation, treatment options in former days were limited. This article presents a profound review of the literature regarding etiology, epidemiology and histology. It discusses clinical appearance and diagnosis and it provides guidelines for decision-making and treatment of invaginated teeth.

The umbilical cord in Cantrell: Pentalogy or Hexalogy?

Objective: Pentalogy of Cantrell (PC) is a rare congenital defect associated with five midline anomalies. The type of cardiac malformation and the size of the abdominal wall defect is often responsible for the high mortality. Of interest, the embryonic period in which PC develops is similar to that of the umbilical cord’s (UC) formation. The aim of the following study was to investigate the relationship between UC anomalies and PC. Methods: Charts of four cases with PC from 2002–08 were retrospectively reviewed for associated UC anomalies. UC anomalies were defined as single umbilical artery (SUA), short cord (during 1st trimester less than CRL or less than 30cm at term) or atypical UC coiling pattern. Results: We identified four cases: 3 singletons and one monochorionic diamniotic twin pregnancy with TRAP sequence. All cases showed a normal karyotype. All but one demonstrated the classical pulsatile omphalocele with ectopia cordis and all others anomalies of PC. One case was characterized by a major cranial omphalocele without ectopia cordis and no UC anomaly. This fetus was delivered by Cesarean at term and successfully operated on d1. In all other cases the parents requested ToP. Among the three cases with ectopia cordis, two had a short UC with SUA and one a short three-vessel cord; all these three UC were markedly uncoiled. Conclusions: Our data suggest a strong association between Cantrell and the development of the UC, in particular in cases with ectopia cordis. One might speculate that hemodynamic alterations of the feto-placental blood flow because of the cardiac malformation or structural changes at the umbilical ring (omphalocele) influence the development of the UC. More observations are needed to decide if Cantrell is a ‘‘hexalogy’’ instead of pentalogy.

Chronic intervertebral disk herniation associated with fused vertebrae treated by vertebral lateral corpectomy in a cat

A 10-year-old Domestic Shorthair cat was admitted for chronic ambulatory paraparesis and a spinal malformation. The clinical examination revealed paraparesis accentuated on the left side. Thoracolumbar radiographs revealed a spinal malformation with a narrowed intervertebral space between L1 and L2, and a dorsal fusion at the level of L2-L3 with a common dorsal process. Magnetic resonance imaging (MRI) revealed an intervertebral disk herniation with a ventral compression of the spinal cord at the level of L1/2. A standard vertebral lateral corpectomy with a foraminotomy was performed with a good outcome.

The etiology of cleft palate formation in BMP7-deficient mice

Palatogenesis is a complex process implying growth, elevation and fusion of the two lateral palatal shelves during embryogenesis. This process is tightly controlled by genetic and mechanistic cues that also coordinate the growth of other orofacial structures. Failure at any of these steps can result in cleft palate, which is a frequent craniofacial malformation in humans. To understand the etiology of cleft palate linked to the BMP signaling pathway, we studied palatogenesis in Bmp7-deficient mouse embryos. Bmp7 expression was found in several orofacial structures including the edges of the palatal shelves prior and during their fusion. Bmp7 deletion resulted in a general alteration of oral cavity morphology, unpaired palatal shelf elevation, delayed shelf approximation, and subsequent lack of fusion. Cell proliferation and expression of specific genes involved in palatogenesis were not altered in Bmp7-deficient embryos. Conditional ablation of Bmp7 with Keratin14-Cre or Wnt1-Cre revealed that neither epithelial nor neural crest-specific loss of Bmp7 alone could recapitulate the cleft palate phenotype. Palatal shelves from mutant embryos were able to fuse when cultured in vitro as isolated shelves in proximity, but not when cultured as whole upper jaw explants. Thus, deformations in the oral cavity of Bmp7-deficient embryos such as the shorter and wider mandible were not solely responsible for cleft palate formation. These findings indicate a requirement for Bmp7 for the coordination of both developmental and mechanistic aspects of palatogenesis.

P450 oxidoreductase deficiency: a new disorder of steroidogenesis

Microsomal P450 enzymes, which metabolize drugs and catalyze steroid biosynthesis require electron donation from NADPH via P450 oxidoreductase (POR). POR knockout mice are embryonically lethal, but we found recessive human POR missense mutations causing disordered steroidogenesis and Antley-Bixler syndrome (ABS), a skeletal malformation syndrome featuring craniosynostosis. Dominant mutations in exons 8 and 10 of fibroblast growth factor receptor 2 (FGFR2) cause phenotypically related craniosynostosis syndromes and were reported in patients with ABS and normal steroidogenesis. Sequencing POR and FGFR2 exons in 32 patients with ABS and/or hormonal findings suggesting POR deficiency showed complete genetic segregation of POR and FGFR2 mutations. Fifteen patients carried POR mutations on both alleles, four carried POR mutations on 1 allele, nine carried FGFR2/3 mutations on one allele and no mutation was found in three patients. The 34 affected POR alleles included 10 with A287P, 7 with R457H, 9 other missense mutations and 7 frameshifts. These 11 missense mutations and 10 others identified by database mining were expressed in E. coli, purified to apparent homogeneity, and their catalytic capacities were measured in four assays: reduction of cytochrome c, oxidation of NADPH, and support of the 17alpha-hydroxylase and 17,20 lyase activities of human P450c17. As assessed by Vmax/Km, 17,20 lyase activity provided the best correlation with clinical findings. Modeling human POR on the X-ray crystal structure of rat POR shows that these mutant activities correlate well with their locations in the structure. POR deficiency is a new disease, distinct from the craniosynostosis syndromes caused by FGFR mutations.

Blood vessel anomalities in the oral cavity of two calves

Two calves were presented with a congenital mass in the rostral mandibular gingiva. In both cases the masses relapsed after surgical removal. Histologically, the two masses were composed of irregularly arranged vascular cavities, embedded in loosely arranged stroma and alcian-blue PAS positive ground substance. Radiologically, a destruction of the alveolar cavity was recognized in both cases, which was in case 1 histologically compatible with bone resorption and remodeling associated with the infiltration of abundant granulation tissue. A literature survey revealed that no consistent criteria for a correct classification for vascular tumours exists, resulting in the fact that comparable lesions were named differently in the past. We therefore propose to classify such lesions as congential vascular malformation until distinct morphological, immunohistochemical and molecular genetic analysis criteria will exist.

Analysis of Variation in Clubfoot Candidate Genes

Isolated clubfoot, a common birth defect occurring in more than 135,000 livebirths worldwide each year, is associated with significant health care and financial burdens. Clubfoot is defined by forefoot adduction, hindfoot varus, midfoot cavus and hindfoot equinus. Isolated clubfoot, which is the focus of these studies, is distinct from syndromic clubfoot because there are no other associated malformations. Population, family, twin and segregation analysis studies provide evidence that genetic and environmental factors play an etiologic role in isolated clubfoot. The studies described in this thesis were performed to define the role of genetic variation in isolated clubfoot. Interrogation of a deletion region associated with syndromic clubfoot, suggested that CASP8 and CASP10, two apoptotic genes, play a role in isolated clubfoot. To explore the role of apoptotic genes in clubfoot, SNPs spanning genes involved in the apoptotic pathway in the six chromosomal deletion regions, and limb patterning genes, HOXD and HOXA, were interrogated. SNPs in mitochondrial mediated apoptotic genes and several SNPs in HOXA and HOXD genes were modestly associated with clubfoot with the most significant SNP, rs3801776, located in the basal promoter of HOXA9. Several significant associations were found with SNPs in NFAT2 and TNIP2. Significant gene interactions were detected between SNPs in HOX and apoptotic genes. These findings suggest a model for clubfoot in which variation in one gene is not sufficient to cause the malformation but requires variation several genes to perturb protein expression sufficiently to alter muscle and foot development. These results significantly impact our knowledge base by delineating underlying mechanisms causing clubfoot.

Analysis of Band 4.1B in Integrin-Mediated Cell Adhesion and Signaling

Band 4.1B is a cytoskeletal adaptor protein that regulates various cellular behavior; however, the mechanisms by which Band 4.1B contributes to intracellular signaling are unclear. This project addresses in vivo and in vitro functions for Band 4.1B in integrin-mediated cell adhesion and signaling. Band 4.1B has been shown to bind to β8 integrin, although cooperative functions of these two proteins have not been determined. Here, functional links between β8 integrin and Band 4.1B were investigated using gene knockout strategies. Ablation of β8 integrin and Band 4.1B genes resulted in impaired cardiac morphogenesis, leading to embryonic lethality by E11.5. These embryos displayed malformation of the outflow tract that was likely linked to abnormal regulation of cardiac neural crest migration. These data indicate the importance of cooperative signaling between β8 integrin and Band 4.1B in cardiac development. The involvement of Band 4.1B in integrin-mediated cell adhesion and signaling was further demonstrated by studying its functional roles in vitro. Band 4.1B is highly expressed in the brain, but its signaling in astrocytes is not understood. Here, Band 4.1B was shown to promote cell spreading likely by interacting with β1 integrin via its band 4.1, ezrin, radixin, and moesin (FERM) domain in cell adhesions. In astrocytes, both Band 4.1B and β1 integrin were expressed in cell-ECM contact sites during early cell spreading. Exogenous expression of Band 4.1B, especially its FERM domain, enhanced cell spreading on fibronectin, an ECM ligand for β1 integrin. However, the increased cell spreading was prohibited by blocking β1 integrin. These findings suggest that Band 4.1B is crucial for early adhesion assembly and/or signaling that are mediated by β1 integrin. Collectively, this study was the first to establish Band 4.1B as a modulator of integrin-mediated adhesion and signaling.

Genetic analysis of factors regulating mesenchymal cell fates

Formation of cartilage and bone involves sequential processes in which undifferentiated mesenchyme aggregates into primordial condensations which subsequently grow and differentiate, resulting in morphogenesis of the adult skeleton. While much has been learned about the structural molecules which comprise cartilage and bone, little is known about the nuclear factors which regulate chondrogenesis and osteogenesis. MHox is a homeobox-containing gene which is expressed in the mesenchyme of facial, limb, and vertebral skeletal precursors during mouse embryogenesis. MHox expression has been shown to require epithelial-derived signals, suggesting that MHox may regulate the epithelial-mesenchymal interactions required for skeletal organogenesis. To determine the functions of MHox, we generated a loss-of-function mutation in the MHox gene. Mice homozygous for a mutant MHox allele exhibit defects of skeletogenesis, involving the loss or malformation of craniofacial, limb and vertebral skeletal structures. The affected skeletal elements are derived from the cranial neural crest, as well as somitic and lateral mesoderm. Analysis of the mutant phenotype during ontogeny demonstrated a defect in the formation or growth of chondrogenic and osteogenic precursors. These findings provide evidence that MHox regulates the formation of preskeletal condensations from undifferentiated mesenchyme. In addition, generation of mice doubly mutant for the MHox and S8 homeobox genes reveal that these two genes interact to control formation of the limb and craniofacial skeleton. Mice carrying mutant alleles for S8 and MHox exhibit an exaggeration of the craniofacial and limb phenotypes observed in the MHox mutant mouse. Thus, MHox and S8 are components of a combinatorial genetic code controlling generation of the skeleton of the skull and limbs. ^

Diagnosis and Treatment of Venous Malformations Consensus Document of the International Union of Phlebology (IUP): updated 2013

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects) . These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/persistence rates, high morbidity following non-specific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular sub-types of VMs. This incorporated the embryological origin, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustrated as a separate topic to differentiate from isolated VMs and to rectify the existing confusion with name-based eponyms such as Klippel-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndrome-based VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

Congenital cervical kyphosis in two young sighthounds

Introduction: Cervical vertebral (C) malformation is rarely reported in large breed dogs. Congenital cervical kyphosis (CCK) may result from defects of vertebral segmentation, failure of formation or both. This report describes two cases of C3-C4 CCK in young sighthounds, treated surgically. Case description: An 18-month-old female Deerhound and a six-week-old female Borzoi dog were presented because of the complaints of reluctance to exercise and signs of of neck pain. Both dogs were neurologically normal. Diagnostic imaging revealed C3-C4 deformity, moderate kyphosis, and spinal canal stenosis associated with chronic spinal cord pressure atrophy. Both dogs underwent surgical treatment. Results: A staged two-step surgery starting with dorsal decompression was elected in the Deerhound. After the first surgical procedure, the dog developed focal myelomalacia and phrenic nerve paralysis and was euthanatized. A ventral distraction-fusion technique with two locking plates was performed in the Borzoi. This patient recovered uneventfully and long-term follow-up computed tomography revealed complete spondylodesis. Clinical significance: Until now, CCK has only been described in sighthounds. Congenital cervical kyphosis might be considered a differential diagnosis in these breeds that are presented with signs of cervical pain. Ventral realignment-fusion and bone grafting may be considered for surgical treatment, although the earliest age at which this procedure can and should be performed remains unclear.

Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.

Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.