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PubMed2001

Spinal neurenteric cysts and their relation to more common aspects of occult spinal dysraphism.

OBJECT: Neurenteric cysts are infrequently reported congenital abnormalities believed to be derived from an abnormal connection between the primitive endoderm and ectoderm. The authors report a series of 13 patients treated over a 50-year period. METHODS: Of the 13 patients, seven were female and six were male. Their ages at presentation ranged widely from 5 weeks to 52 years of age. Children presented more commonly with cutaneous stigmata of occult spinal dysraphism (OSD) whereas adults presented primarily with pain. Neurological deficit as a presenting symptom was less common in our series, a finding that reflects the slow growth of these lesions. In all but one patient some form of vertebral anomaly was associated with the cystic lesions, including two patients with Klippel-Feil abnormalities. There was a high incidence of associated forms of OSD including split cord malformation, lipoma, dermal sinus tract, and tethered spinal cord. In previous reports the authors have suggested that neurenteric cysts are more common in the cervical region and in a position ventral to the cord. In the present series these cysts most commonly occurred as intradural, extramedullary masses in the thoracolumbar region, situated dorsal to the spinal cord. The median follow-up period was 7.5 years, and postoperative outcome reflected a patient's preoperative neurological status; in no patient was outcome worsened due to surgery. CONCLUSIONS: Complete excision of the neurenteric cyst remains the treatment of choice, as subtotal excision is associated with recurrence.

Adolescent↗

PubMed1996

Limb anomalies from evolutionary, developmental, and genetic perspectives.

Coming-on-land by vertebrates during the Devonian was preceded by a 100 million year history of evolution of fins from an early agnathan to a sarcopterygian state with proximal single stylopod bone and probable paired zeugopod bones. There is little disagreement about the homology [Owen, 1837: See Desmond, 1982; Owen, 1849 for a general discussion see Roth, 1988] of these three bones to the corresponding ones of present land vertebrates including those of birds and mammals; or, that the concept of homology in this context may safely be interpreted as meaning structural "identity" by virtue of descent from a common ancestor with a prototypic developmental plan irregardless of the corresponding innervating vertebral segments [qv Roth, 1988]. This extraordinarily conserved body plan in all four classes of tetrapods, including some 4500 living species of mammals, suggests early successful selection, adaptation, and emergence of developmental constraints assuring "proper" succession of proximo-distal epimorphic events and the structural and functional integrity of the autopod. The autopod is the most variable part of the tetrapod limb with humans, in contract to most other primates, retaining its most general form with little modification except for use of the thumb [Ankel-Simons, 1983]. There is also no question about the fact that during the later stages of blastogenesis the limb arises as a prepatterned single morphogenetic field from lateral plate (and somite) mesoderm and overlying ectoderm organizing in concert a single, orthotopic developmentally reactive system of ectoderm-covered mesodermal core with distal apical ectodermal ridge and posterior zone of polarizing activity. This assertion is based on two lines of evidence. First, experimental results [beginning with Harrison and Detweiler in 1918] recognized almost immediately as demonstrating not symmetrical, but "equipotential" fields with identical morphogenetic reaction potential in all vertebrates studied so far. One is tempted to say that these morphological results and interpretations have been, "triumphantly" confirmed by recent molecular work. Second, clinical insights beginning with thalidomide, and then drawing on the acrofacial dysostoses, the associations (VATER), and the discovery of the acrorenal polytopic field defect in humans, which found its explanation in the work of Lash and of Geduspan and Solursh (possibly involving a single molecule, namely, the insulin-like growth factor-I). It is evident that the gross morphological pattern set up in subsequent normal limb development is proximo-distally hierarchical (or at least sequential), and that the complex group of secondary (epimorphic) fields (perhaps as many as 33 as identified by analysis of mendelian mutations) is determined before cellular differentiation of the individual tissue components of the limb. The Anikin [1929] patterns of precartilage condensations, segmentations, and branchings in limb rudiments, while involving a specific type of cell (precartilage mesenchyme) in complex interaction with the extracellular matrix, must be looked at primarily as gross morphogenetic field events rather than as "fine" tissue differentiation sensu stricto. In view of the clinical evidence, the Shubin-Alberch-Oster model of (pre) cartilage events (condensation, segmentation, and branching), while universally valid as such, had best be regarded as events with morphogenetic potential rather than as invariable predictors of final structure.

Animals↗

PubMed2004

BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium.

The neural crest is a multipotent, migratory cell population arising from the border of the neural and surface ectoderm. In mouse, the initial migratory neural crest cells occur at the five-somite stage. Bone morphogenetic proteins (BMPs), particularly BMP2 and BMP4, have been implicated as regulators of neural crest cell induction, maintenance, migration, differentiation and survival. Mouse has three known BMP2/4 type I receptors, of which Bmpr1a is expressed in the neural tube sufficiently early to be involved in neural crest development from the outset; however, earlier roles in other domains obscure its requirement in the neural crest. We have ablated Bmpr1a specifically in the neural crest, beginning at the five-somite stage. We find that most aspects of neural crest development occur normally; suggesting that BMPRIA is unnecessary for many aspects of early neural crest biology. However, mutant embryos display a shortened cardiac outflow tract with defective septation, a process known to require neural crest cells and to be essential for perinatal viability. Surprisingly, these embryos die in mid-gestation from acute heart failure, with reduced proliferation of ventricular myocardium. The myocardial defect may involve reduced BMP signaling in a novel, minor population of neural crest derivatives in the epicardium, a known source of ventricular myocardial proliferation signals. These results demonstrate that BMP2/4 signaling in mammalian neural crest derivatives is essential for outflow tract development and may regulate a crucial proliferation signal for the ventricular myocardium.

Animals↗

PubMedDate not supplied

Rhabdomyosarcoma in a patient with cardio-facio-cutaneous syndrome.

A boy with characteristic facial features, pulmonary valvular stenosis, ectodermal abnormalities, growth failure, and mental retardation was admitted for intestinal occlusion at 20 months of age. Clinical findings were consistent with a diagnosis of cardio-facio-cutaneous syndrome (CFC-s), and a huge abdominal mass was evident on computed tomography scan. A biopsy was performed, and embryonal rhabdomyosarcoma was diagnosed. Molecular analysis was performed by reverse transcription (RT) polymerase chain reaction (PCR) on tumor RNA to seek the chimerical transcript of the most common soft tissue sarcoma translocations and analyze neurofibromatosis 1 (NF1) gene expression. Translocations involving 1;13, 2;13, and 11;22 were not found, and the specific transcripts of the NF1 gene were present. Chemotherapy was implemented, but the child died 7 months later of tumor progression. Few patients with CFC-s have been described, and their follow-up is not well known. The association of CFC-s with rhabdomyosarcoma has not been reported previously, but other neoplasms have been reported in patients with Noonan syndrome, a condition similar to CFC-s. More observations are needed, but this and other reports suggest there could be a higher risk of malignancy in patients with syndromes in the Noonan phenotype category.

Adult↗

PubMed2001

Reparation of a severe case of aplasia cutis congenita with engineered skin.

Aplasia cutis congenita (ACC) is an uncommon congenital malformation. It is characterized by defects of the skin that occur most frequently on the scalp along the midline, but can also be localized on the trunk, face and limbs, usually with a symmetrical distribution. When it is localized in the skull it can extend to the dura mater, leaving only the thin pia mater to protect the brain. The most common complications related to this disorder are infection, hemorrhage, and, in defects localized on the vertex, meningitis and bleeding from the sagittal sinus can occur with dramatic consequences. In those cases some authors suggest the use of local flaps even if this implies a surgical procedure. In this case a 2.540-kg baby was delivered at 40 weeks of gestation by eutocic delivery, and good adaptation to extrauterine life. At birth the baby showed a large cutaneous and osseous defect at the vertex measuring 68 cm(2), equal to almost one third of the calvarial surface, and extended to the dura mater through which it was possible to see the sagittal sinus and the brain surface with its vessels. Skull X-rays showed loss of normal radioopacity of the cranial vault with lack of ossification especially at the parietal level. In our patient we therefore decided to use a composite graft of cultured autologous fibroblasts and keratinocytes to provide coverage, avoiding any surgical procedure and patient morbidity. This technique consists first in an autograft of cultured fibroblasts which has proved to promote the production of type IV collagen, fibronectin and laminin whereby creating an ideal bed for the taking of the graft of cultured keratinocytes, to be put in place a week later. The use of a composite graft with both the derma-like and epithelial components has been also suggested to diminish scarring. Two months after the last graft area was completely closed.

Cell Culture Techniques↗

PubMed2002

An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome.

Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear. Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest. The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene disruption outside the typically deleted region of human chromosome 22 to fully recapitulate the deletion 22q11 phenotype. FGF8 may operate directly in molecular pathways affected by deletions in 22q11 or function in parallel pathways required for normal development of pharyngeal arch and neural crest-derived tissues. In either case, Fgf8 may function as a modifier of the 22q11 deletion and contribute to the phenotypic variability of this syndrome.

Abnormalities, Multiple↗

PubMed1998

The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo.

We have characterized an induced mutation, called embryonic ectoderm development or eed, that disrupts A-P patterning of the mouse embryo during gastrulation. Positional cloning of this gene revealed it to be the highly conserved homologue of the Drosophila gene extra sex combs, which is required for maintenance of long-term transcriptional repression of homeotic gene expression. Mouse embryos homozygous for loss-of-function alleles of eed initiate gastrulation but display abnormal mesoderm production. Very little embryonic mesoderm is produced; in contrast, extraembryonic mesoderm is relatively abundant. These observations, along with mRNA in situ hybridization analyses, suggested a defect in the anterior primitive streak, from which much of the embryonic mesoderm of the wild-type embryo is derived. To analyse this defect, we initiated clonal analysis of the pre-streak epiblast in eed mutant embryos, using the lineage tracer horseradish peroxidase (HRP). The results of these studies indicate that epiblast cells ingress through the anterior streak, but the newly formed mesoderm does not migrate anteriorly and is mislocalized to the extraembryonic compartment. Abnormal localization of mesoderm to the extraembryonic region did not appear to be due to a restriction and alteration of distal epiblast cell fate, since the majority of clones produced from regions fated to ingress through the anterior streak were mixed, displaying descendants in both embryonic and extraembryonic derivatives. eed mutant embryos also fail to display proper epiblast expansion, particularly with respect to the A-P axis. Based on patterns of clonal spread and calculated clone doubling times for the epiblast, this does not appear to be due to decreased epiblast growth. Rather, epiblast, which is normally fated to make a substantial contribution to the axial midline, appears to make mesoderm preferentially. The data are discussed in terms of global morphogenetic movements in the mouse gastrula and a disruption of signalling activity in the anterior primitive streak.

Animals↗

PubMed1997

Congenital lumbosacral lipomas.

Congenital lumbosacral lipomas can be responsible for progressive defects. The general feeling is that tethering of roots, filum, or cord probably explains this evolution, and that untethering of these structures could prevent late deterioration. Like the vast majority of neurosurgeons, we too have routinely and systematically operated on lumbosacral lipomas, even in the absence of neurological deficits. This policy stemmed from our belief that spontaneous neurological deterioration was frequent, recovery from preoperative deficits rare, and surgery both efficient and benign in nature. After 22 years of experience, we felt that it was necessary to review our series of 291 lipomas (38 lipomas of the filum and 253 of the conus) operated on from 1972 to 1994. To reassess the value of prophylactic surgery, we attempted an accurate evaluation of (1) the risk of pathology, (2) the risks involved in surgery, (3) the postoperative outcome with respect to preoperative deficits, and (4) the postoperative outcome in asymptomatic patients at 1 year and at maximum follow-up. Special attention was paid to 93 patients whose postoperative follow-up was more than 5 years (average 8.7, median 8, range 5-23 years). Of these 93 patients, 39 were asymptomatic preoperatively (7 with lipoma of the filum and 32 with lipoma of the conus). Lipomas of the filum and of the conus are entirely different lesions and were studied separately. In 6 cases prenatal diagnosis had been possible. The mean age at surgery was 6.4 years. Low back skin stigmata were present in 89.4% of cases. Preoperative neurological deficits existed in 57% of the patients and were congenital in 22%. Clinical signs and symptoms recorded were pain in 13.3% of the patients and/or neurological deficits affecting sphincter (52%), motor (27.6%) and sensory (22.4%) functions. Deficits were progressive in 22.4% of cases, slowly progressive in 58.8% of these and rapidly progressive in the remaining 41.2%. In 36 patients (13.2%) the lipomas were seen to grow either subcutaneously or intraspinally. Among these patients, 21 were infants, 2 were obese adolescents, and 10 were pregnant women. The metabolism of the fat within the lipomas was studied in 11 patients and found to be similar to that at other sites. Lipomas were associated with various other malformations, either intra- or extraspinal. These associated anomalies were rare in the case of lipomatous filum (5.2%) but frequent with lipomas of the conus, except for intracranial malformations (3.6%). Therapeutic objectives were spinal cord untethering and decompression, sparing of functional neural tissue and prevention of retethering. Procedures used to achieve these goals were subtotal removal of the lipoma, intraoperative monitoring, duroplasty, and sometimes closure of the placode. Histologically, lipomas consisted of normal mature fat. However, 77% of them also included a wide variety of other tissues, originating from ectoderm, mesoderm, or entoderm. This indicates that lipomas are either simple or complex teratomas. The results of the study are as follows. (1) Surgery was easy and safe when performed for treatment of lipomas of the filum (no complications), but difficult and hazardous in the case of lipomas of the conus (20% local, 3.9% neurological complications). (2) All types of deficit could be improved by surgery, which was beneficial in all cases of lipoma of the filum and 50% of cases of lipoma of the conus. (3) In asymptomatic patients long-term surgical results depended on the anatomical type of the lipoma. They were excellent in lipomas of the filum. In lipomas of the conus they were good in the short term but eroded with time. At more than 5 years of follow-up only 53.1% of the patients were still free of symptoms. (4) Reoperations were performed in 16 patients (5.5%), 5 (31.2%) of whom improved postoperatively, while in 7 (43.7%) progression stopped, in 3 (18.7%) deterioration continued and in 1 (6.2%) the condition was wor

Adolescent↗

PubMed1995

Bone marrow failure: pathophysiology and management.

Morphologically, bone marrow is made up of a relatively mature but heterogenous population, fueled by a tiny pool of microscopically unrecognizable stem and progenitor cells. This complex tissue has the responsibility of maintaining our hematopoietic and, to a large extent, immunologic integrity, both of which are indispensable for health and, indeed, survival. Perhaps not surprisingly, bone marrow is the target of genetic, autoimmune, and environmental insults. Although robust, it has only a limited number of responses, one of which is reduction in cellular output, sometimes with superimposed qualitative abnormalities, and this is defined as bone marrow failure. Bone marrow failure is a diverse entity but can be logically explained and classified on a pathophysiologic basis. Thus the major recognizable categories of bone marrow failure are congenital and acquired defects. Each of these is subdivided according to the number of cell lines involved, over and above which the severity of the damage will determine reversibility. In each case, the natural history dictates management, and this ranges from short-term growth factor support to biologic immune response modulation and finally to bone marrow transplantation. In the past, many clinicopathologic variants of bone marrow failure were described, although their etiology was obscure and effective therapy was unavailable. This changed dramatically, however, when experimental hematologists, using radiobiology models, uncovered the dynamic nature of blood formation. Cardinal observations included the way in which spontaneous recovery followed irradiation, the central role played by pluripotential stem cells, and the integral participation of stroma in modulating this entire process. Understanding was refined once bone marrow cultures became available while, in parallel, the use of in-bred mouse strains launched the era of allogeneic transplantation. These approaches were combined, and the broad principles that govern basal or constitutive production emerged. Stem cells, with their characteristic commitment to self-renewal, exist at the apex of a hierarchy and generate a tier of proliferating progenitors that, in turn, give rise to a large postmitotic compartment of precursors that mature into distinctive myeloid and lymphoid lineages. The reserve potential is enormous, and output can be induced to meet even greatly increased demands. These events reflect the interaction of growth factors with a balancing set of negative regulators. The link between such diverse functions resides, to a large extent, in accessory cells and matrix geographically organized in what is now described as the hematopoietic inductive microenvironment. Many details of these meticulously orchestrated processes are obscure.(ABSTRACT TRUNCATED AT 400 WORDS)

Agranulocytosis↗