Midline Defects Research Articles

The Mutation in Chd7 Causes Misexpression of Bmp4 and Developmental Defects in Telencephalic Midline

Mutations in chromosome-helicase-DNA-binding protein 7 (CHD7) are identified as the main cause for CHARGE syndrome (coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies). Most patients (55% to 85%) with CHARGE syndrome display developmental defects in the central nervous system (CNS), of which pathology and molecular mechanisms remain unclear. In this study, we report a novel mutant mouse strain carrying a nonsense mutation, COA1, in exon4 of Chd7 gene. Chd7(COA1/+) mice phenocopied human CHARGE syndrome and displayed developmental defects in the telencephalic midline, including dilated third and lateral ventricles, reduced cerebral cortex, and corpus callosum crossing failure. Programed cell death in the telencephalic midline zone of Chd7(COA1/+) embryos was impaired, consistent with the incomplete telencephalic medial invagination in Chd7(COA1/+) embryos. Interestingly, expression of Bmp4, a signal well known to induce forebrain midline cell fate and apoptosis, was down-regulated and also expanded in the forebrain of Chd7(COA1/+) embryos. Furthermore, in vitro studies suggested that CHD7 may directly regulate Bmp4 expression by binding with an enhancer element downstream of the Bmp4 locus. These studies provide novel insight into pathogenesis of CNS anomalies in CHARGE syndrome.

Frizzled-3a and slit2 genetically interact to modulate midline axon crossing in the telencephalon

The anterior commissure forms the first axon connections between the two sides of the embryonic telencephalon. We investigated the role of the transmembrane receptor Frizzled-3a in the development of this commissure using zebrafish as an experimental model. Knock down of Frizzled-3a resulted in complete loss of the anterior commissure. This defect was accompanied by a loss of the glial bridge, expansion of the slit2 expression domain and perturbation of the midline telencephalic–diencephalic boundary. Blocking Slit2 activity following knock down of Frizzled-3a effectively rescued the anterior commissure defect which suggested that Frizzled-3a was indirectly controlling the growth of axons across the rostral midline. We have shown here that Frizzled-3a is essential for normal development of the commissural plate and that loss-of-function causes Slit2-dependent defects in axon midline crossing in the embryonic vertebrate forebrain. These data supports a model whereby Wnt signaling through Frizzled-3a attenuates expression of Slit2 in the rostral midline of the forebrain. The absence of Slit2 facilitates the formation of a midline bridge of glial cells which is used as a substrate for commissural axons. In the absence of this platform of glia, commissural axons fail to cross the rostral midline of the forebrain.

Genetic Overlap between Holoprosencephaly and Kallmann Syndrome

Patients with Kallmann syndrome (KS; congenital hypogonadotropic hypogonadism and decreased/absent sense of smell), septo-optic dysplasia (SOD), or holoprosencephaly (HPE) reportedly have midline defects. In this study, we investigate a genetic overlap between KS, SOD, and HPE. Nineteen subjects (18 males, 1 female) with KS and without mutations in the known KS genes were screened for mutations in SOX2, SHH, SIX3,TGIF1,TDGF1,FOXH1,GLI2, and GLI3. One male carried 2 heterozygous missense changes, one in SIX3 (c.428G>A, p.G143D) and the other in GLI2 (c.2509G>A, p.E837K). Both of these genes have been implicated in the etiology of HPE and neither of these changes were present in 200 control subjects. Other variants found among the subjects were known polymorphisms. KS and HPE may display a genetic overlap. The involvement of genes implicated in the etiology of midline defects in patients with KS warrants further studies.

OTX2 mutations contribute to the otocephaly-dysgnathia complex

BackgroundOtocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans.Methods and resultsThis study reports...

Rhombencephalosynapsis: new findings in a larger study

Rhombencephalosynapsis is a developmental midline defect affecting the cerebellar vermis. The absence of the vermis in rhombencephalosynapsis may be compared to the other condition in which the vermis is largely absent. In Joubert syndrome, the cerebellar hemispheres are close to normal in volume; the intervening vermis is small and much shortened, leaving a gap between the cerebellar hemispheres. Although the vermis may also be totally absent in rhombencephalosynapsis, remnants such as the nodule may often be found in their normal place with respect to the adjoining hemispheres. Allowing a simplification, one can describe the vermis in Joubert syndrome as shortened and in rhombencephalosynapsis as narrowed. The debut of the rhombencephalosynapsis story is credited to Obersteiner in 1916 with a detailed case report entitled ‘Ein Kleinhirn ohne Wurm’ (‘A cerebellum without vermis’) describing the autopsy findings in a 31-year old male. The original study is still worth reading for its wealth of detail such as absence of the mesencephalic trigeminal nucleus and misrouting of tracts at the lower mesencephalic level. Over 100 cases have since been published, mostly as case reports or small series. A review lists 58 published cases before …

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.

Cdon and Boc: Two transmembrane proteins implicated in cell–cell communication

Cdon and Boc, and their Drosophila homologues Ihog and Boi, are evolutionary conserved transmembrane glycoproteins belonging to a subgroup of the Immunoglobulin superfamily of cell adhesion molecules (CAMs). Initially isolated in vertebrates as CAMs that link cadherin function with MAPK signaling in myoblast differentiation, they have thereafter been shown to act as essential receptors for the Hedgehog (Hh) family of secreted proteins. They associate with both ligand and other Hh receptor components, including Ptch and Gas1, thus forming homo- and heteromeric complexes. In Drosophila, they are also involved in ligand processing and release from Hh producing cells. Cdon/Boc and Ihog/Boi can substitute one another and play redundant functions is some contexts. In addition, Boc, but not Cdon, mediates axon guidance information provided by Hh in specific neuronal populations, whereas mutations in the CDON cause holoprosencephaly, a human congenital anomaly defined by forebrain midline defects prominently associated with diminished Hh pathway activity.

Accidental Finding on Bone Scan

Cleft sternum is an extremely rare anomaly of development. It results from failure of fusion of midline structures that contribute to the formation of the sternum. The defect may affect the upper sternum, the lower sternum, or the whole sternum. Most cases are diagnosed in childhood when it is associated with serious midline defects. We present a case of an isolated upper sternal cleft in a 55-year-old adult, found accidentally on bone scan. To our knowledge, no bone scan image of cleft sternum could be found in the literature.

Panhypopituitarism Presenting as Life-Threatening Heart Failure Caused by an Inherited Microdeletion in 1q25 Including LHX4

Clinical presentation of hypopituitarism in the neonate may be variable, ranging from absent to severe nonspecific symptoms and may be life-threatening in patients with adrenocorticotropic hormone deficiency. The LIM homeobox gene 4 (LHX4) transcription factor regulates early embryonic development of the anterior pituitary gland. Autosomal dominant mutations in LHX4 cause congenital hypopituitarism with variable combined pituitary hormone deficiency (CPHD). We report on a neonate with unexplained heart failure and minor physical anomalies, suggesting a midline defect. She was diagnosed with complete CPHD. Cardiac function was rescued by replacement with hydrocortisone and thyroxine; hypoglycaemia stopped under growth hormone therapy. Magnetic resonance imaging revealed a dysgenetic pituitary gland suggesting an early developmental defect. Array comparative genomic hybridization showed a maternally inherited 1.5-megabase microdeletion in 1q25.2q25.3, including the LHX4 gene. Haploinsufficiency of LHX4 likely explains the predominant pituitary phenotype in the proposita and we suggest variable intrafamilial penetrance of the inherited microdeletion. To the best of our knowledge, we are the first to report on heart failure as a rare nonspecific symptom of treatable CPHD in the newborn. Variably penetrant pituitary insufficiency, including this severe and atypical presentation, can be correlated with LHX4 insufficiency and highlights the role of LHX4 for pituitary development.

Fryns Anophthalmia-Plus Syndrome in an 18-Week-Old Fetus

Fryns anophthalmia-plus syndrome is a very rare condition initially described by Fryns and colleagues in 1995 in a pair of siblings of nonconsanguineous parents. Since that time, only a few cases have been reported, most of them in newborns and young children. Clinical presentation is variable and includes anophthalmia/microphthalmia, cleft lip/palate, and other facial deformities. Furthermore, skeletal, central nervous system, and endocrine anomalies have been described. We report the case of a male fetus of 18 weeks of gestation with normal karyotype and findings matching Fryns anophthalmia-plus syndrome. Pregnancy was terminated because of sonographically proven facial midline defects and a marked cerebral ventriculomegaly. Macroscopic and histological findings obtained at autopsy showed extreme bilateral microphthalmia, unilateral cleft palate, unilateral nasal deformity, and low-set ears. Skeletal anomalies included 13 pairs of ribs, premature ossification of the calcaneus, and talipes.

Endocrine and anatomical findings in a case of Solitary Median Maxillary Central Incisor Syndrome

Solitary Median Maxillary Central Incisor Syndrome (SMMCI) is a rare malformation syndrome consisting of multiple, mainly midline defects. Some authors suggest that it is a mild manifestation of the wide spectrum of holoprosencephaly, others classify it rather as a distinct entity. Authors report a case of SMMCI presenting with growth retardation, mild intellectual disability and absence of puberty. Cytogenetic and molecular cytogenetic investigations could identify no abnormalities. The presence of a single maxillary incisor called for further investigations to clarify hidden anomalies, these were empty sella, panhypopituitarism, hypothyroidism, and hypoplasia of the inner genitals. Based on the above findings, growth hormone, estrogen, and L-thyroxine substitution was introduced, which resulted in satisfactory longitudinal growth and onset of sexual maturation. We suggest genetic counselling and if needed, invasive investigations in female patients with short stature and absent/delayed puberty, with or without sex chromosomal anomalies, as the adequate therapy and even the quality of life of patient depends largely on the knowledge of their anatomical and endocrine status.

Presenting features and long-term effects of growth hormone treatment of children with optic nerve hypoplasia/septo-optic dysplasia

BackgroundOptic nerve hypoplasia (ONH) with/or without septo-optic dysplasia (SOD) is a known concomitant of congenital growth hormone deficiency (CGHD).MethodsDemographic and longitudinal data from KIGS, the Pfizer International Growth Database, were compared between 395 subjects with ONH/SOD and CGHD and 158 controls with CGHD without midline pathology.ResultsONH/SOD subjects had higher birth length/weight, and mid-parental height SDS. At GH start, height, weight, and BMI SDS were higher in the ONH/SOD group. After 1 year of GH, both groups showed similar changes in height SDS, while weight and BMI SDS remained higher in the ONH/SOD group. The initial height responses of the two groups were similar to those predicted using the KIGS-derived prediction model for children with idiopathic GHD. At near-adult height, ONH/SOD and controls had similar height, weight, and BMI SDS.ConclusionsCompared to children with CGHD without midline defects, those with ONH/SOD presented with greater height, weight, and BMI SDS. These differences persisted at 1 year of GH therapy, but appeared to be overcome by long-term GH treatment.

3D analysis of cystoceles using magnetic resonance imaging assessing midline, paravaginal, and apical defects

This study assesses relative contributions of "midline defects" (widening of the vagina) and "paravaginal defects" (separation of the lateral vagina from the pelvic sidewall). Ten women with anterior predominant prolapse and ten with normal support underwent pelvic MR imaging. 3-D models of the anterior vaginal wall (AVW) were generated to determine locations of the lateral AVW margin, vaginal width, and apical position. The lateral AVW margin was farther from its normal position in cases than controls throughout most of the vaginal length, most pronounced midvagina (effect sizes, 2.2-2.8). Vaginal widths differed in the midvagina with an effect size of 1.0. Strong correlations between apical and paravaginal support were evident in mid- and upper vagina (r = 0.77-0.93). Changes in lateral AVW location were considerably greater than changes in vaginal width in cases vs controls, both in number of sites affected and effect sizes. These "paravaginal defects" are highly correlated with apical descent.

The Cerebellum, a Small Brain with a Big Outcome

The simple three-layered cortex, the well-defined connectivity, the anatomical accessibility as well as genetical tools available to manipulate cell-type specific gene expression made the cerebellum a favourable model system, in which basic mechanisms of central nervous system development can be investigated. The fundamental knowledge about cerebellar structure and development improved our understanding of clinical symptoms. The definition of compartments, migrational paths of neurons and neuronal differentiation are topics which will be discussed in this context. As the cerebellum develops out of the mid-hindbrain junction, it is clearly divided into a vermal and hemispheric region. The mechanistic basis of the setup and maintenance of this division is of major importance, not only for the spatially organized connectivity of the cerebellum to afferent and efferent projection fields, but also for answering questions about the origin of medulloblastomas, the regional differences in the sensitivity towards neurodegeneration or midline defects. The cells of the cerebellum migrate along distinct paths either in a radial or transverse direction. Mechanisms guiding neural cells to their final destination are considered causative for many neuronal heterotopias. And finally, the differentiation of neurons is essential for proper neurotransmission and neuronal communication. The Purkinje cells provide a historical, but still suitable attractive and often used model cell to investigate neuronal differentiation and maturation. Our knowledge about neuronal differentiation helped to understand neuropsychiatric disorders of adult, but also of newborns and tottlers.

Bladder exstrophy and extreme genital anomaly in a patient with pure terminal 1q deletion: Expansion of phenotypic spectrum

We describe a 5 2/12 years old male patient with a de novo deletion 1q43q44 of approximately 10.4 Mb in size. The boy presented with the classic features of chromosome 1q43q44 deletion syndrome including growth and psychomotor retardation, microcephaly, distinct facial features and various midline defects as agenesis of corpus callosum, cardiac and urogenital anomalies. Fronto-parietal simplified gyral pattern was an additional neuroimaging finding. The urogenital anomalies in our patient were remarkable in form of bladder exstrophy and severe hypogenitalism with a marked hypoplastic scrotum, small sized retractile testis and absent phallus. To the best of our knowledge, bladder exstrophy and absence phallus have not been previously reported in terminal deletion 1q43q44 syndrome. This report provides further evidence of phenotype–genotype correlation and expands the phenotypic spectrum of midline defects described with this syndrome.

Transport distraction along the mandibular midline

Background Reconstruction of mandibular continuity defect is a challenging task. Transport distraction osteogenesis is a novel reconstructive modality that has been added to the armamentarium of maxillofacial reconstructive surgeons. The difficulties faced for the reconstruction of mandibular midline defects also remain problematic for this recent reconstructive modality.

Bladder exstrophy: reconstructed female patients achieving normal pregnancy and delivering normal babies

Bladder exstrophy (BE) is an anterior midline defect that causes a series of genitourinary and muscular malformations, which demands surgical intervention for correction. Women with BE are fertile and able to have children without this disease. The purpose of this study is to assess the sexual function and quality of life of women treated for BE. All patients in our institution treated for BE from 1987 to 2007 were recruited to answer a questionnaire about their quality of life and pregnancies. Fourteen women were submitted to surgical treatment for BE and had 22 pregnancies during the studied period. From those, 17 pregnancies (77.2%) resulted in healthy babies, while four patients (18.1%) had a spontaneous abortion due to genital prolapse, and there was one case (4.7%) of death due to a pneumopathy one week after delivery. There was also one case (5.8%) of premature birth without greater repercussions. During pregnancy, three patients (21.4%) had urinary tract infections and one patient (7.14%) presented urinary retention. After delivery, three patients (21.4%) presented temporary urinary incontinence; one patient (7.14%) had a vesicocutaneous fistula and seven patients (50%) had genital prolapsed. All patients confirmed to have achieved urinary continence, a regular sexual life and normal pregnancies. All patients got married and pregnant older than the general population. BE is a severe condition that demands medical and family assistance. Nevertheless, it is possible for the bearers of this condition to have a satisfactory and productive lifestyle.

Posterior pituitary (PP) evaluation in patients with anterior pituitary defect associated with ectopic PP and septo-optic dysplasia

Controversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction. The study was conducted in a single Pediatric Endocrinology Research Unit. Forty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed. Mean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, P<0.0001). Group 5 showed higher mean Posm and lower mean AVP at all time points (P<0.0001). Mean thirst score did not show a significantly different trend between the groups 1 and 2. Urine osmolality was above 750 mosm/kg in all but seven patients after osmotic challenge. Patients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.

Airway management for occipital encephalocele in neonatal patients: A review of 17 cases

Introduction:Encephalocele, midline defect of cranial bone fusion, occurs most frequently in the occipital region. Airway management in pediatric patients with craniofacial disorders poses many challenges to the anesthesiologist. The purpose of this study is to describe the airway problems encountered for such cases, and describe how these problems were managed.Materials and Methods:We reviewed the charts of occipital encephalocele newborn that were treated by surgical correction in Harran University Hospital during 2006–2008. The collected data were categorized into preoperative, intraoperative, and postoperative data.Results:The mean age of the patients was 5.17 days. Of these 17 patients, eight patients (47.1%) had hydrocephaly, one patient (5.8%) with Dandy Walker syndrome. Micrognathia, macroglossia, restriction in neck movements were recorded as the reasons in six cases each. No major anesthetic complication was found.Conclusions:We reported perioperative management in 17 occipital encephalocele infant. Comprehensive care during peroperative period is essential for successful outcome.

Heparan sulfate proteoglycan specificity during axon pathway formation in the Drosophila embryo

Axon guidance is influenced by the presence of heparan sulfate (HS) proteoglycans (HSPGs) on the surface of axons and growth cones (Hu, [2001]: Nat Neurosci 4:695-701; Irie et al. [2002]: Development 129:61-70; Inatani et al. [2003]: Science 302:1044-1046; Johnson et al. [2004]: Curr Biol 14:499-504; Steigemann et al. [2004]: Curr Biol 14:225-230). Multiple HSPGs, including Syndecans, Glypicans and Perlecans, carry the same carbohydrate polymer backbones, raising the question of how these molecules display functional specificity during nervous system development. Here we use the Drosophila central nervous system (CNS) as a model to compare the impact of eliminating Syndecan (Sdc) and/or the Glypican Dally-like (Dlp). We show that Dlp and Sdc share a role in promoting accurate patterns of axon fasciculation in the lateral longitudinal neuropil; however, unlike mutations in sdc, which disrupt the ability of the secreted repellent Slit to prevent inappropriate passage of axons across the midline, mutations in dlp show neither midline defects nor genetic interactions with Slit and its Roundabout (Robo) receptors at the midline. Dlp mutants do show genetic interactions with Slit and Robo in lateral fascicle formation. In addition, simultaneous loss of Dlp and Sdc demonstrates an important role for Dlp in midline repulsion, reminiscent of the functional overlap between Robo receptors. A comparison of HSPG distribution reveals a pattern that leaves midline proximal axons with relatively little Dlp. Finally, the loss of Dlp alters Slit distribution distal but not proximal to the midline, suggesting that distinct yet overlapping pattern of HSPG expression provides a spatial system that regulates axon guidance decisions.