Midline Fusion Defects Research Articles

Surgical management of tethered spinal cord syndrome through biportal endoscopic approach: a novel technical note.

This video article explores a case of tethered cord release through a minimally invasive biportal endoscopic approach. A 24-year-old female with chronic back pain and thigh numbness underwent surgery. The chosen approach involved biportal endoscopic technique, demonstrating precision with minimal bone excision. Preoperative imaging revealed a midline fusion defect at L5 and abnormal conus medullaris termination. The surgical procedure involved one-sided hemilaminectomy, durotomy, and careful filum terminale separation. Postoperatively, radiological exams confirmed success with minimal bone defect. Emphasizing minimal invasiveness, reduced bone excision, and muscle sparing, this technique showcased successful outcomes, enabling the patient's rapid postoperative recovery without complications. The video can be found here: https://stream.cadmore.media/r10.3171/2024.1.FOCVID23228.

Encephalocele: Retrospective Analysis and Our Clinical Experience

Encephalocele is defined as extracranial herniation of the CSF, meninges, or cerebral tissue through a midline fusion defect in the cranium. The aim of this article is to present the clinical experience of the authors on encephalocele management. A total of 19 patients who underwent surgery for encephalocele in our hospital between 2015 and 2021 were included in the study. We reached 7 cases who were diagnosed with encephalocele and underwent pregnancy termination between 2018 and 2020 in our hospital. The patients' demographics, neurological examinations, procedure and anaesthesia data, and postoperative follow-up were all evaluated. 15 of 19 patients were female. 2 mothers used folic acid supplementation, but it was not effective. 7 patients were diagnosed prenatally, whereas the others were not followed up during pregnancy. 9 of the patients had parenchyma inside the sac, while the rest had none. 5 patients required shunts. All of the patients were followed up by the departments of neurosurgery, pediatrics, pediatric neurology, neonatal, pediatric gastroenterology, and genetics for their needs. It was demonstrated that folic acid supplementation before conception greatly reduces the incidence of encephalocele. It would be appropriate to inform the families of babies diagnosed with encephalocele in detail at prenatal follow-up about what problems they can expect in the future. Follow-up of encephalocele patients must be done with a multidisciplinary approach to ensure a quality life throughout their life.

Novel peritoneopericardial diaphragmatic hernia in a dog

A 23-month-old German shepherd dog (GSD) with chronic intermittent gastrointestinal signs presented following acute deterioration compatible with gastrointestinal obstruction and suspected peritoneopericardial diaphragmatic hernia (PPDH). Physical examination revealed depression, abdominal...

Genetic and Molecular Insights Into Genotype-Phenotype Relationships in Osteopathia Striata With Cranial Sclerosis (OSCS) Through the Analysis of Novel Mouse Wtx Mutant Alleles.

The X-linked WTX/AMER1 protein constitutes an important component of the β-catenin destruction complex that can both enhance and suppress canonical β-catenin signaling. Somatic mutations in WTX/AMER1 have been found in a proportion of the pediatric kidney cancer Wilms' tumor. By contrast, germline mutations cause the severe sclerosing bone dysplasia osteopathia striata congenita with cranial sclerosis (OSCS), a condition usually associated with fetal or perinatal lethality in male patients. Here we address the developmental and molecular function of WTX by generating two novel mouse alleles. We show that in addition to the previously reported skeletal abnormalities, loss of Wtx causes severe midline fusion defects including cleft palate and ectopic synostosis at the base of the skull. By contrast, deletion of the C-terminal part of the protein results in only mild developmental abnormalities permitting survival beyond birth. Adult analysis, however, revealed skeletal defects including changed skull morphology and an increased whole-body bone density, resembling a subgroup of male patients carrying a milder, survivable phenotype. Molecular analysis in vitro showed that while β-catenin fails to co-immunoprecipitate with the truncated protein, partial recruitment appears to be achieved in an indirect manner using AXIN/AXIN2 as a molecular bridge. Taken together our analysis provides a novel model for WTX-caused bone diseases and explains on the molecular level how truncation mutations in this gene may retain some of WTX-protein functions. © 2018 American Society for Bone and Mineral Research.

Case of 22q11.2 Deletion Syndrome Not Identified by <i>TBX1</i> Screening with a Positive SCID Newborn Screen

Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an embryological midline fusion defect, which can result in a syndrome including congenital heart disease, cleft palate, hypoparathyroidism, thymic hypoplasia, immunologic abnormalities, and developmental delay. The majority of patients have a 3 megabase deletion, which contains multiple genes, including the T-box transcription factor (TBX1) gene. Definitive diagnosis is made through fluorescent in situ hybridization (FISH) or chromosomal microarray (CMA). Newborn screening (NBS) for severe combined immune deficiency (SCID) via low T-cell receptor excision circles (TRECs) can also identify this population if thymic output is low. Samples from infants who screen positive undergo further testing, which includes a purine profile and TBX1 deletion analysis. Diagnostic follow-up testing is centre-dependent and may not include more definitive testing for 22q11.2DS by FISH or CMA. We report a case of a newborn with 22q11.2DS, detected by low TRECs on the SCID NBS, with a normal screening TBX1 result, who was subsequently found to have a TBX1 gene deletion on follow-up 22q11.2 FISH and CMA. This case highlights the limitations of the TBX1 screening assay and the importance of performing diagnostic testing with FISH and (or) CMA regardless of the initial TBX1 result. It also emphasizes the need for a standardized follow-up testing algorithm across institutions for newborns who screen positive for SCID. Statement of novelty: To our knowledge, this is the first case to be described in the literature where a newborn with 22q11.2DS with a typical deletion encompassing the TBX1 gene was not identified by initial TBX1 screening, highlighting the limitations of this test as a standalone screening assay.

Wolf-Hirschhorn syndrome presenting with cardiac manifestations at birth

Wolf–Hirschhorn syndrome (WHS) is a condition of developmental delay and dysmorphology caused by a deletion of short arm of chromosome 4. The main characteristics of WHS are intra and extrauterine growth retardation, mental retardation with typical facial dysmorphism, microcephaly, and midline fusion defects. The diagnosis is based on clinical features and chromosomal analysis, e.g., microsatellite analysis or molecular cytogenetic techniques and fluorescence in situ hybridization (FISH) to detect the deletion. Prenatal diagnosis is possible by FISH. Though no specific treatment is available, supportive management can be fruitful. Here, we describe a female baby with a 4p deletion, who had the majority of the main phenotypic features of WHS and severe congenital heart disease manifesting at birth. The case emphasized that any fetus with intrauterine growth retardation, dysmorphic features on antenatal scan, and midline defects should raise a suspicion of WHS. Conventional cytogenetic studies can miss the diagnosis; hence, these cases should be further investigated using molecular cytogenetic techniques such as FISH or array-comparative genomic hybridization.

Prevalence and possible causes of hypospadias

Hypospadias is the most common congenital malformation of the male external genitalia. After the heart and circulatory system, it is the second most common developmental disorder in males. It is due to a midline fusion defect of the male urethra, which results in a misplaced urethral meatus. Hypospadias may be distal, medial and proximal. It may occur as an isolated defect or it may develop together with other genital disorders (retention of testes in one or both sides, microphallus, bifid scrotum) or with malformation of other organs. In some cases syndromic forms may also occur. Genetic factors play a crucial role in the occurrence of early developmental defect, but endocrine and environmental factors may also be important in the aetiology of hypospadias. It may be associated with various sex and autosomal chromosomal abnormalities. Monogenic and chromosomal causes of hypospadias accounts for about in 30% of all cases, while genetic factors remain unknown in 70% of cases. The authors summarize the development of the male external genitalia, the prevalence and possible causes of hypospadias. They propose that better understanding of the pathogenesis of the disease may contribute to the prevention and decreased prevalence of the disease.

A point mutation in Myh10 causes major defects in heart development and body wall closure.

The 3 isoforms of nonmuscle myosin (NM) II (NMII-A, NMII-B, and NMII-C) play various roles during mouse embryonic development. Previous work, using knockout and hypomorphic mice, showed that Myh10 encoding myosin heavy chain II-B is critical for cardiac and brain development. Ablating or decreasing NMII-B by 80% results in cardiac (ventricular septal defect, double outlet of the right ventricle) and brain defects but not midline fusion defects. Neither NMII-A nor II-C seems to play roles in early myocardial development. We had previously generated point mutant knock-in mice and now report novel findings as a result of expressing motor-deficient NMII-B at wild-type levels. Homozygous mice die at embryonic day 14.5 in cardiac failure, exhibiting abnormalities not seen in NMII-B null and hypomorphic mice: a failure in midline fusion resulting in a cleft palate, ectopia cordis, and a large omphalocele. Fusion of the sternum and endocardial cushions is impaired in the mutant mice associated with a failure in apoptosis of the mesenchymal cells. Failure to disassemble myocyte cell-cell adhesions during cardiac outflow tract development contributes to impaired outflow tract myocardialization and displacement of the aorta to the right ventricle. Expression of motor-impaired NMII-B disrupts normal ventral body wall closure because of a dominant-negative effect. This is not because of the loss of NMII-B function but rather a gain-of-function resulting from prolonged cross-linking of NMII-B to actin filaments, thereby interfering with the dynamics of actomyosin cytoskeletal structure. Furthermore, impaired NMII-B motor activity inhibits outflow tract myocardialization, leading to mislocalization of the aorta.

Uterine Didelphys With Obstructed Hemivagina and Ipsilateral Renal Agenesis Presenting With Hydronephrosis

Mullerian anomalies are present in 7% of the female population with a multifactorial pathogenesis thought to be associated with a midline fusion defect. OHVIRA (Obstructed Hemivagina and Ipsilateral Renal Anomaly) Syndrome comprises about 2-3% of Mullerian abnormalities. Case reports and small series have reported on this syndrome, which most commonly presents in young females with abdominal pain and a pelvic mass.

Inappropriate surgical interventions for midline fusion defects cause secondary tethered cord symptoms: implications for natural history report of four cases

The causes of tethered spinal cord are various. In order to release the tethering effect of these malformations, the surgical interventions must include removal of all tethering components, reconstruction of the neural tube and sectioning of tight filum terminale as well. The cases reported in this paper have had an operation many years before for various developmental defects. After a certain period of time (5-10years) of the first operation, the patients reapplied to the hospital with various symptoms of spinal cord tethering, either vertical or horizontal. At surgical intervention, it was noted that inappropriate surgical procedures caused retethering of the spinal cord in all patients. Postoperative period of all patients were uneventful. All patients declared relief in their symptoms. We would like to draw attention that untreated (or inappropriately treated) midline developmental defects will invariably cause syndrome of tethered cord. Consequently, prophylactic surgical untethering must be applied to all patients with developmental midline defects as soon as possible. It looks that tethered cord symptoms invariably appear as enough negative influence accumulates as the time passes. Elapsed time may vary but unpleasant end result invariably arrives. While these cases with tethered spinal cord develop progressive neurological symptoms, prophylactic and appropriate surgical intervention should be considered as early as possible. There is no acceptable rationale to wait for the appearance of tethered cord syndrome symptoms to perform surgical untethering of the spinal cord because of the probability of irreversibility of the symptoms (incontinence of urine in particular) of tethered spinal cord syndrome.

392 Quantitative measurement of the androgen receptor in prepuces of boys with and without hypospadias

Abstract Purpose Identifiable causes of hypospadias, a midline fusion defect of the male ventral urethra, are still infrequently well-known. The aim of this study was to quantify the androgen receptor mRNA and androgen receptor protein in prepuces of boys with and without hypospadias. Material and Methods Forty prepuce specimens of circumcised boys, aged between 12 and 14 months, with (n=20) and without hypospadias (n=20), were investigated. Immediately after surgery all probes were fixed in formaldehyde and small parts were deep frozen in liquid nitrogen at -80° C. The total RNA of the specimens was isolated and cDNA was written. With the aid of real time PCR the amount of present androgen receptor mRNA was measured. For quantification of present androgen receptor protein, Western Blot (Bradford method) and immunohistochemistry for androgen receptor using standardized automated procedures (Discovery XT, Ventana) were performed. Statistical analyses using the the Kolmogorov-Smirnov and Mann-Whitney U-test were done. Results Our observations show that the androgen receptor mRNA is significantly increased in the prepuce of hypospadiac boys compared to specimens of boys with phimosis.(p Conclusions Our results provide evidence that the different expression of androgen receptor mRNA indicates the extent of a defect androgen receptor signalling in boys with hypospadias.

Cephalothoracopagus, janiceps, disymmetros, monoomphalian conjoined twins undiagnosed until early second trimester

Cephalothoracopagus is the less common type of conjoined twins (CTs) with an incidence estimated at one in three million births or one in 58 conjoined twins. Maternal gene Vg1, a member of the TGF-beta family of cell-signalling molecules which are implicated in dorsoanterior development, and specific actions of Hox and Pax genes that are implicated in very early embryogenesis may be identified as aetiologic factors. A prenatal diagnosis of cephalothoracopagus CTs diagnosed at 17 weeks in a woman undergoing amniocentesis for advanced maternal age is reported. Although first-trimester diagnosis of CTs is feasible and has been reported as early as 8 weeks's gestation, CTs may be misdiagnosed with monoamniotic twins, lymphangioma, teratoma, and/or neoplasm and may be undiagnosed until early second trimester. Three-dimensional and color Doppler ultrasound enabled precise prenatal visualization of the fusion site. Ultrafast MR imaging should be considered an adjunct to ultrasound for antenatal characterization of structural anomalies and for planning surgical separation in selected cases. Echocardiography is mandatory in all cases of CTs as congenital heart defects are seen in 20-30% and polyhydramnios in 50-75%. Neural tube and midline fusion defects, diaphragmatic hernia, and imperforate anus are the frequently associated abnormalities. Prognosis among survivors is usually poor (44% die in the neonatal period) and is dependent upon the type of conjunction, degree of involvement of the shared organs, and presence or absence of associated anomalies, with the worst prognosis in case of twins sharing liver and heart.

Quantitative Measurement of the Androgen Receptor in Prepuces of Boys with and Without Hypospadias

PURPOSE Identifiable causes of hypospadias, a midline fusion defect of the male ventral urethra, are still infrequently well-known. The aim of this study was to quantify the androgen receptor mRNA and androgen receptor protein in prepuces of boys with and without hypospadias. MATERIAL AND METHODS Forty prepuce specimens of circumcised boys, aged between 12 and 14 months, with (n=20) and without hypospadias (n=20), were investigated. Immediately after surgery all probes were fixed in formaldehyde and small parts were deep frozen in liquid nitrogen at -80° C. The total RNA of the specimens was isolated and cDNA was written. With the aid of real time PCR the amount of present androgen receptor mRNA was measured. For quantification of present androgen receptor protein, Western Blot (Bradford method) and immunohistochemistry for androgen receptor using standardized automated procedures (Discovery XT, Ventana) were performed. Statistical analyses using the the Kolmogorov-Smirnov and Mann-Whitney U-test were done. RESULTS Our observations show that the androgen receptor mRNA is significantly increased in the prepuce of hypospadiac boys compared to specimens of boys with phimosis.(p<0,01) similarly the amount of androgen receptor protein is increased compared to healthy boys. (p<0.01) Our results provide evidence that the rise of androgen receptor mRNA and protein seems to be an indirect expression of a decreased androgen receptor DNA binding capability possibly indicating further missing polypeptide encoding. CONCLUSIONS Our results provide evidence that the different expression of androgen receptor mRNA indicates the extent of a defect androgen receptor signalling in boys with hypospadias.

Smad4 is required to regulate the fate of cranial neural crest cells

Smad4 is the central mediator for TGF-β/BMP signals, which are involved in regulating cranial neural crest (CNC) cell formation, migration, proliferation and fate determination. It is unclear whether TGF-β/BMP signals utilize Smad-dependent or -independent pathways to control the development of CNC cells. To investigate the functional significance of Smad4 in regulating CNC cells, we generated mice with neural crest specific inactivation of the Smad4 gene. Our study shows that Smad4 is not required for the migration of CNC cells, but is required in neural crest cells for the development of the cardiac outflow tract. Smad4 is essential in mediating BMP signaling in the CNC-derived ectomesenchyme during early stages of tooth development because conditional inactivation of Smad4 in neural crest derived cells results in incisor and molar development arrested at the dental lamina stage. Furthermore, Smad-mediated TGF-β/BMP signaling controls the homeobox gene patterning of oral/aboral and proximal/distal domains within the first branchial arch. At the cellular level, a Smad4-mediated downstream target gene(s) is required for the survival of CNC cells in the proximal domain of the first branchial arch. Smad4 mutant mice show underdevelopment of the first branchial arch and midline fusion defects. Taken together, our data show that TGF-β/BMP signals rely on Smad-dependent pathways in the ectomesenchyme to mediate epithelial–mesenchymal interactions that control craniofacial organogenesis.

Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf–Hirschhorn syndrome

The Wolf-Hirschhorn syndrome (WHS (MIM 194190)), which is characterized by growth delay, mental retardation, epilepsy, facial dysmorphisms, and midline fusion defects, shows extensive phenotypic variability. Several of the proposed mutational and epigenetic mechanisms in this and other chromosomal deletion syndromes fail to explain the observed phenotypic variability. To explain the complex phenotype of a patient with WHS and features reminiscent of Wolfram syndrome (WFS (MIM 222300)), we performed extensive clinical evaluation and classical and molecular cytogenetic (GTG banding, FISH and array-CGH) and WFS1 gene mutation analyses. We detected an 8.3 Mb terminal deletion and an adjacent 2.6 Mb inverted duplication in the short arm of chromosome 4, which encompasses a gene associated with WFS (WFS1). In addition, a nonsense mutation in exon 8 of the WFS1 gene was found on the structurally normal chromosome 4. The combination of the 4p deletion with the WFS1 point mutation explains the complex phenotype presented by our patient. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletions represents an additional explanation for the phenotypic variability observed in chromosomal deletion disorders.

Wolf-Hirschhorn Syndrome: Report of two Cases in Bosnia and Herzegovina

Wolf-Hirschhorn Syndrome: Report of two Cases in Bosnia and HerzegovinaWolf-Hirschhorn syndrome (WHS) is a rare developmental disorder caused by a partial deletion of the short arm of chromosome 4 (4p-). The main phenotypic characteristics of WHS are: intrauterine growth retardation, mental retardation, typical facial dysmorphism, microcephaly and midline fusion defects (cleft lip or palate, cardiac septal defects). Other abnormalities, such as agenesis of the corpus callosum, dysplastic kidneys, iris coloboma and skeletal abnormalities have occasionally been described.We describe two female newborn babies with a 4p deletion, who have a majority of the main phenotypic features of WHS. Prenatal diagnosis of the syndrome is very important, because dysmorphologic features are associated with profound mental retardation. Postnatal recognition of the syndrome requires genetic counseling of the parents and supportive multidisciplinary treatment.

Cardiac malformations and midline skeletal defects in mice lacking filamin A

The X-linked gene filamin A (Flna) encodes a widely expressed actin-binding protein that crosslinks actin into orthogonal networks and interacts with a variety of other proteins including membrane proteins, integrins, transmembrane receptor complexes and second messengers, thus forming an important intracellular signalling scaffold. Heterozygous loss of function of human FLNA causes periventricular nodular heterotopia in females and is generally lethal (cause unknown) in hemizygous males. Missense FLNA mutations underlie a spectrum of disorders affecting both sexes that feature skeletal dysplasia accompanied by a variety of other abnormalities. Dilp2 is an X-linked male-lethal mouse mutation that was induced by N-ethyl-N-nitrosourea. We report here that Dilp2 is caused by a T-to-A transversion that converts a tyrosine codon to a stop codon in the Flna gene (Y2388X), leading to absence of the Flna protein and male lethality because of incomplete septation of the outflow tract of the heart, which produces common arterial trunk. A proportion of both male and female mutant mice have other cardiac defects including ventricular septal defect. In addition, mutant males have midline fusion defects manifesting as sternum and palate abnormalities. Carrier females exhibit milder sternum and palate defects and misshapen pupils. These results define crucial roles for Flna in development, demonstrate that X-linked male lethal mutations can be recovered from ENU mutagenesis screens and suggest possible explanations for lethality of human males hemizygous for null alleles of FLNA.

Genetic and Molecular Aspects of Hypospadias

Hypospadias, a midline fusion defect of the male ventral urethra, is a relatively common genital anomaly occurring in 0.3 - 7 of 1000 live male births. The anatomical location of the misplaced urethral meatus determines the severity of this anomaly with the severity increasing from distal to proximal. Glandular and penile hypospadias, the most common forms, often appear as an isolated anomaly and account for the majority of hypospadias, whereas about 20 % are classified as scrotal and perineal types. These latter forms frequently occur in association with other genital anomalies such as microphallus, bifid scrotum, penoscrotal transposition, and cryptorchidism, and may represent an intersex phenotype. Besides a higher incidence in consanguineous families and a suggested recessive inheritance, in other families a dominant transmission is likely. The recurrence risk in the next generation seems to be correlated with the severity of hypospadias. Only 30 % of severe hypospadias can be attributed to defects in the synthesis of testosterone or adrenal steroid hormones, receptor defects, syndrome-associated hypospadias, chromosomal anomalies, defects in other genetic factors, or exogenous forms. To identify the underlying causes of the remaining 70 % "idiopathic" hypospadias, familial and twin studies were performed. Familial studies can help identify gene loci and, subsequently, candidate genes by mutational analysis. Either linkage analysis in large families with many affected individuals suspicious for a monogenic trait or association studies in cases of a complex inheritance in many families with a few affected individuals can be performed. Microarrays and proteomics can help detect gene expression or protein differences. Furthermore, genetically modified animal models can be used to detect phylogenetically homologous genes in man. In addition to an optimal documentation and acquisition of blood and tissue samples this requires a close cooperation between clinicians in the operative and non-operative specialties as well as geneticists.

Ultrasonographic Findings In Pentalogy Of Cantrell With Midline Cleft Lip And Cleft Palate: A Report Of Two Cases

We report two cases of Cantrell's Pentalogy detected by ultrasonography at 24 and 25.5 weeks of gestation, respectively and confirmed at autopsy. Cantrell's Pentalogy consists of defects of the lower sternum, anterior diaphragm, midline supraumbilical abdominal wall and diaphragmatic pericardium with ectopia cordis. Our cases showed all these defects along with a bilateral cleft lip and cleft palate in the 24 week fetus. Association of cleft lip and cleft palate with Pentalogy of Cantrell may represent an extension of the basic defect in the migration of mesodermal primordial structures that involve the abdominal and thoracic midline fusion defects of the syndrome to also involve the facial structures, which must therefore be thoroughly looked for in all such cases.

Association of Wilms Tumor with Spinal Dysraphism

Previous data suggested an association of vertebral anomalies with Wilms tumor. At the same time, vertebral midline fusion defects are often indicated by dermal anomalies over the spine. In the present study the prevalence of both occult spina bifida and cutaneous signs of spinal dysraphism was significantly higher in 50 Wilms patients than in 180 control children (18.0 versus 4.4%, p < .01, and 35.9 versus 17.5%, p < .02, respectively). Family investigations are needed to answer the question whether signs of spinal dysraphism in parents and sibs of patients may be regarded as indicators of an increased risk of Wilms tumor in the family.