Current awareness in prenatal diagnosis.
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Adult↗
Biomedical subjects
J Spranger
Publications and source records attributed to J Spranger.
Cerebral spinal fluid flow, venous drainage and spinal cord compression in achondroplastic children: impact of magnetic resonance findings for decompressive surgery at the cranio-cervical junction.
UNLABELLED: In order to investigate the diagnostic properties of MRI of the brain and spine in achondroplastic children with regard to decompressive surgery, 25 patients were examined by conventional morphological and by "functional" imaging of CSF flow and magnetic resonance angiography (MRA) of the veins and sinuses at the cranial base following a special protocol. The results were compared to those from age-matched controls and were correlated with each other and retrospectively with the neurological findings. Measurements of distances and angulations at the cranio-cervical junction (CCJ) from MR scans showed similar values to those from conventional radiographs and CTs and thus can be used without correction for spatial distorsion. Signs of cervical medullary compression, myelomalacia and intramedullary cyst formation were found in six, seven and three children respectively. These alterations correlated significantly with each other (P < 0.05). Semiquantitative evaluation of CSF flow demonstrated interruption of CSF pathways at the CCJ, which correlated with CCJ narrowing (P < 0.05). MRA showed a significant narrowing of the jugular foramina with a variable compensatory enlargement of the emissary veins and a significant reduction of the total outflow area (P < 0.01). There were no significant correlations between these MR changes and neurological deficits. CONCLUSION: Due to this unexpectedly poor correlation between magnetic resonance and clinical findings in achondroplastic children, the present role of magnetic resonance in the clinical setting is limited to the demonstration of spinal cord compression in individual cases. In three of our patients with prominent neurological abnormalities, the severe changes demonstrated by magnetic resonance imaging strongly supported the indication for surgical decompression.
Achondroplasia↗
Changes in clinical practice with the unravelling of diseases: connective-tissue disorders.
Unravelling of diseases is achieved in steps by sequentially describing their phenotype, natural course, aetiology and pathogenesis. Through succinct clinical observation, conglomerates of heterogeneous connective-tissue disorders, such as various forms of disproportionate dwarfism, have been split into well-defined entities. They have often been confirmed by biochemical and molecular analysis. On the other hand, seemingly disparate disorders have been shown to be pathogenetically related and to be variable expressions of common defects. Examples are the mucopolysaccharidoses and type II collagenopathies. Disease recognition through splitting and lumping has improved prevention and prognostication. It is the basic requirement for future therapeutic attempts on a pathogenetic or molecular level.
Connective Tissue Diseases↗
Retinal photocoagulation does not influence intraocular levels of IGF-I, IGF-II and IGF-BP3 in proliferative diabetic retinopathy-evidence for combined treatment of PDR with somatostatin analogues and retinal photocoagulation?
Retinal photocoagulation reduces the incidence of severe visual loss in proliferative diabetic retinopathy (PDR). Reduced levels of VEGF/VPF might result in an improved function of the blood-retina barrier and cause a decrease of blood derived intraocular growth factors such as IGF-I. This study investigates whether retinal photocoagulation is able to normalize the concentrations of IGF-I, IGF-II and IGF-BP3 in the vitreous humor of patients undergoing vitrectomy. Levels of IGFs and the permeability marker, albumin, were measured in serum and vitreous of 52 patients. Three groups were compared: controls without proliferating eye disease (n = 19) and patients with PDR with (PDR+; n = 25) and without (PDR-; n = 8) previous retinal photocoagulation. IGF-I, IGF-II, IGF-BP3 and albumin were determined by immunological methods and were confirmed to be increased in patients with PDR compared to controls. Retinal photocoagulation influenced neither the intraocular concentration of the permeability marker albumin (PDR+: 253.2 +/- 46 mg/dl; PDR-: 256.4 +/- 66.5 mg/dl) nor the levels of IGFs (PDR+: IGF-I: 1.2 +/- 0.1 ng/ml; p = 0.38; IGF-II: 34.8 +/- 2.2 ng/ml; p = 0.1; IGF-BP3: 75.7 +/- 9.7 ng/ml; p = 0.27; PDR-: IGF-I: 1.1 +/- 0.2ng/ml; IGF-II: 29.3 +/- 5.2 ng/ml; IGF-BP3: 61.5 +/- 18.3 ng/ml). Systemic levels of albumin and IGFs were not changed significantly by retinal photocoagulation. These results demonstrate that previous retinal photocoagulation in patients undergoing vitrectomy does not functionally reestablish the blood-retina barrier despite decreases in VEGF/VPF. The lack of influence on intraocular concentrations of the serum-derived growth factors, IGF-I, IGF-II and IGF-BP3, might in part explain the failure of previous photocoagulation in the investigated patients. These results suggest that a combined treatment with retinal photocoagulation and growth hormone-lowering drugs, such as somatostatin analogues, could be a useful treatment, which may prevent further loss of visual acuity in patients with PDR.
Adult↗
New concepts in pathogenesis and treatment of diabetic retinopathy.
Retinal neovascularization is a major feature of proliferative diabetic retinopathy, which represents a major public health problem, being responsible for more irreversible blindness in persons of middle and older age than any other pathology. The societal burden of ocular neovascularization has prompted extensive research into its mechanisms. The aim of this review will be to briefly summarize the current knowledge regarding the clinical and laboratory findings of diabetic retinopathy. From an investigational view, studies of ocular neovascularization provide important informations, often permitting real-time, serial observations of neovascularization in vivo. This allows investigators to analyse the relevance of specific pathogenic concepts regarding the mechanisms of angiogenesis in vivo. This review will additionally describe current concepts regarding the pathogenesis and treatment of diabetic retinopathy.
Animals↗
Ischiospinal dysostosis with rib gaps and nephroblastomatosis.
Rib gaps, vertebral ossification defects, hypoplastic ischial bones and large kidneys were present in a newborn. A renal biopsy showed nephroblastomatosis . The observation links two recently described conditions - 'ischiospinal dysostosis' and 'a new syndrome comprising vertebral anomalies and multicystic kidneys' - and shows that nephroblastomatosis may be a manifestation of ischiospinal dysostosis. Ischiospinal dysostosis with nephroblastomatosis is one of a group of disorders characterized by developmental defects of the axial skeleton. It must be added to the conditions predisposing to Wilms tumor formation.
Biopsy↗
Anauxetic dysplasia, a spondylometaepiphyseal dysplasia with extreme dwarfism.
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Bone Diseases↗
Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease.
Retinal neovascularization characterizes proliferative diabetic retinopathy (PDR). Pigment epithelium-derived factor (PEDF) has been shown to be a major antiangiogenic growth factor in the mammalian eye. PEDF expression is suppressed by hypoxia, and changes in PEDF have been correlated to the development of retinal neovascularization in animal models of hypoxic eye disease. However, whether this concept of a reduced angiogenesis inhibitor holds true in humans is as yet unclear. In this study, we analyzed the in vivo regulation of PEDF in patients with and without hypoxic eye disease. We used immunoblots to measure PEDF in ocular fluids obtained from 64 nondiabetic and diabetic patients. In addition, immunohistochemistry of PEDF was carried out in specimens of normal human retinas and retinas with various degrees of diabetic retinopathy. The PEDF concentrations in patients with PDR (P < 0.001) or extensive nondiabetic retinal neovascularization caused by retinal-vein occlusion (P < 0.001) were lower than in control patients. Levels of PEDF were replenished in PDR patients with previous retinal scatter photocoagulation compared with PDR patients without previous photocoagulation (P = 0.01). Immunohistochemistry revealed an interstitial staining pattern as expected for a secreted protein, with an intense staining in retinas of patients without proliferative eye disease. However, in patients with PDR, little or no staining was detectable. Our data strongly support the concept that retinal angiogenesis is induced by loss of the major angiogenesis inhibitor in the eye, PEDF, in combination with an increased expression of angiogenic growth factors such as vascular endothelial growth factor. Our findings suggest that substitution of angiogenesis inhibitors may be an effective approach in the treatment of PDR.
Aged↗
Spectrum of Schwartz-Jampel syndrome includes micromelic chondrodysplasia, kyphomelic dysplasia, and Burton disease.
Follow-up and re-evaluation of four patients originally described as examples of severe infantile "micromelic chondrodysplasia" resembling Kniest disease, "kyphomelic dysplasia," and "Burton skeletal dysplasia" revealed the diagnosis of Schwartz-Jampel syndrome (SJS, myotonic chondrodysplasia) in all of them. SJS may be suspected in neonates with Kniest-like chondrodysplasia, congenital bowing of shortened femora and tibiae, and facial manifestations consisting of a small mouth, micrognathia, and possibly pursed lips. The disorder must be differentiated from the Stüve-Wiedemann syndrome, a genetically distinct myotonic chondrodysplasia with similar clinical but different skeletal changes and an unfavorable early prognosis. The demise of "kyphomelic dysplasia" as a nosological entity reemphasizes the symptomatic nature of congenital bowing of the long bones.
Abnormalities, Multiple↗
A novel mutation in FGFR-3 disrupts a putative N-glycosylation site and results in hypochondroplasia.
Fibroblast growth factor receptor 3 (FGFR3) is a glycoprotein that belongs to the family of tyrosine kinase receptors. Specific mutations in the FGFR3 gene are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, and thanatophoric dysplasia. Hypochondroplasia (HCH), the mildest form of this group of short-limbed dwarfism disorders, results in approximately 60% of cases from a mutation in the intracellular FGFR3-tyrosine kinase domain. The remaining cases may either be caused by defects in other FGFR gene regions or other yet unidentified genes. We describe a novel HCH mutation, the first found outside the common mutation hot spot of this condition. This point mutation, an N328I exchange in the extracellular Ig domain III of the receptor, seems to be unique as it affects a putative N-glycosylation site that is conserved between different FGFRs and species. The amino acid exchange itself most probably has no impact on the three-dimensional structure of the receptor domain, suggesting that the phenotype is the result of altered receptor glycosylation and its pathophysiological consequences.
Amino Acid Substitution↗
Greenberg dysplasia: first reported case with additional non-skeletal malformations and without consanguinity.
In 1988 Greenberg et al. reported an association of fetal hydrops with irregular calcification and moth-eaten skeletal dysplasia. Here, we report on the first case of this disorder accompanied by additional malformations (omphalocele, intestinal malrotation, disturbed fingernails and toes, hypolobated lungs) in a German couple without consanguinity (karyotype 46,XY). Sonograpically, the fetus was characterised by tetraphokomelia, severe generalised hydrops, pulmonal hypoplasia and hepato-splenomegaly. Greenberg dysplasia should be considered in differential diagnosis in cases with severe fetal hydrops and phokomelia on antenatal sonography.
Abnormalities, Multiple↗
Release of the angiogenesis inhibitor angiostatin in patients with proliferative diabetic retinopathy: association with retinal photocoagulation.
AIMS/HYPOTHESIS: Proliferative diabetic retinopathy is a major debilitating disease causing most cases of blindness in humans in the Western world. Photocoagulation is the established therapy of proliferative diabetic retinopathy, although the molecular mechanisms of its effects are still not known. Recently angiostatin has been characterized as a potent inhibitor of neovascularization. Apart from a possible down-regulation of angiogenic cytokines, release of angiostatin could initiate the anti-angiogenic effects of retinal photocoagulation. METHODS: We investigated the regulation of angiostatin and the angiogenic cytokines vascular endothelial growth factor and basic fibroblast growth factor in vivo by comparing vitreal concentrations of 18 control patients and 34 patients with proliferative diabetic retinopathy with and without previous photocoagulation. Concentrations of basic fibroblast growth factor and angiostatin were additionally measured in serum, while vascular endothelial growth factor is known to be regulated locally in the eye. Cytokines were measured by immunological methods. RESULTS: Angiostatin could be detected in 2 out of 18 control patients and in 25 out of 34 diabetic patients (p < 0.00001). Most importantly, production of angiostatin in human vitreous correlated significantly with previous retinal photocoagulation (p < 0.0001) in patients with proliferative diabetic retinopathy. Only two patients (one control and one diabetic) had detectable serum concentrations of angiostatin. Additionally patients with proliferative diabetic retinopathy and with previous photocoagulation had significantly lower concentrations of vascular endothelial growth factor (0.9 +/- 0.1 ng/ml; p < 0.0001) than diabetic patients without previous photocoagulation (4.0 +/- 0.8 ng/ml). The investigation of vitreal and serum basic fibroblast growth factor concentrations yielded no significant differences between the groups. CONCLUSION/INTERPRETATION: Angiostatin is not a regularly expressed angiogenesis inhibitor in human vitreous. The alterations we observed suggest that local release of angiostatin and down-regulation of vascular endothelial growth factor mediate the therapeutic effects of retinal photocoagulation in proliferative diabetic retinopathy.
Aged↗
Systemic levels contribute significantly to increased intraocular IGF-I, IGF-II and IGF-BP3 [correction of IFG-BP3] in proliferative diabetic retinopathy.
Increased intraocular levels of angiogenic growth factors such as insulin-like growth factor I (IGF-I) have been demonstrated in proliferative diabetic retinopathy (PDR). It is unclear whether increased leakage of the blood retina barrier or local synthesis primarily determine intraocular levels of IGFs in man, which is of special interest regarding possible therapeutic options with somatostatin analogues in PDR. This is the first study investigating parallelly serum and vitreous levels of IGF-I/II, IGF-BP3 and the liver-derived permeability marker albumin to determine in vivo the amount of circulation-derived intraocular IGFs. A control group without retinal proliferation and patients with PDR were compared. Levels of IGF-I/II, IGF-BP3 and albumin were determined by immunological methods. Vitreous levels of albumin were 2.2-fold elevated in patients with PDR (254.1 +/- 37.2mg/dl; n = 27; p = 0.0027) compared to controls (115.7 +/- 36.2mg/dl; n =10), whereas serum levels were slightly decreased in diabetes patients (5049 +/- 196 mg/dl vs. 4330 +/- 186 mg/dl; p = 0.0283). This was comparable to an increase of IGF-I/11 and IGF-BP3 in vitreous from PDR patients (IGF-I: 2.3 +/- 1.1 ng/ml p = 0.005. IGF-II: 37.9 +/- 4.9 ng/ml; p = 0.0003. IGF-BP3: 97.9 +/- 26.9 ng/ml; p = 0.0001; n = 34) compared to controls (IGF-I: 0.7 +/- 0.1 ng/ml. IGF-II: 21.3 +/- 4.2 ng/ml. IGF-BP3: 31.3 +/- 4.9 ng/ml: n = 19). Serum levels did not differ significantly among the groups regarding IGF-I, II and IGF-BP3. Intraocular albumin and IGF-I levels calculated as percentage of the respective serum levels correlated significantly (r = 0.42; p = 0.012). This study demonstrates that influx of IGF-I, II and IGF-BP3 in PDR quantitatively parallels influx of the liver derived serum protein albumin suggesting that leakage of the blood retina barrier and serum levels of IGF primarily determine intravitreal IGF levels rather than local synthesis. Suppression of systemic IGF levels by new, highly effective somatostatin-analogues therefore provides a promising approach to prevent PDR.
Aged↗
Abnormal subcortical somatosensory evoked potentials indicate high cervical myelopathy in achondroplasia.
UNLABELLED: Children with achondroplasia may have high cervical myelopathy due to stenosis of the cranio-cervical junction resulting in neurological disability and an increased rate of sudden death. To detect myelopathy we recorded somatosensory evoked potentials (SEPs) after median nerve stimulation in 30 patients with achondroplasia aged 13 months to 18 years (mean 6 years). In addition to the conventional technique of recording the cortical N20 and the central conduction time (CCT), we employed a noncephalic reference electrode recording the subcortical waveforms N13b and P13. generated near the cranio-cervical junction. The findings were related to the clinical status and MRI results. Eighteen patients had MRI evidence of spinal cord compression with indentation or narrowing of the upper cervical cord, and 13 showed signs of myelomalacia. Seven patients had neurological abnormalities. The sensitivities of the SEPs were 0.89 for cervical cord compression, 0.92 for myelomalacia and 1.0 for the clinically symptomatic patients. There were no false-positive results. The subcortical SEPs were more sensitive than the conventional recordings. However, the conventional SEPs were highly specific in the most severely affected patients; here the specificity was 1.0 for patients with myelomalacia and 0.96 for symptomatic patients. Postoperative SEPs improved after occipital decompression in two children. CONCLUSION: The analysis of somatosensory evoked potentials, in particular of subcortical tracings, is useful in the detection of early cervical myelopathy in children with achondroplasia. Early neurosurgical decompression may prevent irreversible damage.
Achondroplasia↗
Deficient activation and different expression of transforming growth factor-beta isoforms in active proliferative diabetic retinopathy and neovascular eye disease.
An increased expression and secretion of angiogenic growth factors was proposed to occur in proliferative diabetic retinopathy and other neovascularizing retinal diseases. However, a loss of anti-angiogenic factors also might promote retinal neovascularization. Therefore we investigated the active and latent vitreous levels of the subtypes of the endothelial anti-mitogen transforming growth factor-beta in vitreous of 58 patients. Four groups of patients were compared: Controls without retinal hypoxia, patients with quiescent and active proliferative diabetic retinopathy (PDR), and patients with severe retinal hypoxia resulting in rubeosis iridis. Whereas the amount of total TGF-beta in the four groups did not differ significantly, latent TGF-beta isoform expression showed complex alterations in ocular vitreous. Levels of active TGF-beta of patients with active PDR (79.5 +/- 28 pg/ml; n = 8) were decreased to 20% of the control levels (378 +/- 55 pg/ml; n = 12; p = 0.0005) and 25% of the mean concentration in quiescent PDR (346 +/- 64 pg/ml; n = 9; p = 0.0021). Levels in rubeosis (52 +/- 10 pg/ml; n = 10) did not differ significantly from those found in active PDR but were decreased to 15% of those in patients with quiescent PDR (p = 0.0004). Furthermore a highly significant inverse correlation between active TGF-beta and alpha2-antiplasmin, a liver produced inhibitor of the activation of TGF-beta by plasmin was noted (r = -0.59; n = 28; p = 0.001). We conclude that deficient activation of TGF-beta occurs in active proliferative diabetic retinopathy and in hypoxic angiogenesis most likely as a consequence of a blood retina barrier breakdown and influx of alpha2-antiplasmin from serum. The disinhibition of endothelial cell proliferation may be a central component in the process of neovascularization.
Aged↗
Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia.
Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous disorder with marked clinical and radiographic variability. Traditionally, the mild "Ribbing" and severe "Fairbank" types have been used to define a broad phenotypic spectrum. Mutations in the gene encoding cartilage oligomeric-matrix protein have been shown to result in several types of MED, whereas mutations in the gene encoding the alpha2 chain of type IX collagen (COL9A2) have so far been found only in two families with the Fairbank type of MED. Type IX collagen is a heterotrimer of pro-alpha chains derived from three distinct genes-COL9A1, COL9A2, and COL9A3. In this article, we describe two families with distinctive oligo-epiphyseal forms of MED, which are heterozygous for different mutations in the COL9A2 exon 3/intron 3 splice-donor site. Both of these mutations result in the skipping of exon 3 from COL9A2 mRNA, but the position of the mutation in the splice-donor site determines the stability of the mRNA produced from the mutant COL9A2 allele.
Adolescent↗
Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation.
We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.
Adult↗
Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome).
The original patient with the Weissenbacher-Zweymüller syndrome was analyzed for mutations in two candidate genes expressed in cartilage (COL2A1 and COL11A2). No mutations were found in the COL2A1 gene but the COL11A2 gene contained a single-base mutation that converted a codon for an obligate glycine to a codon for glutamate at position alpha 2-955 (G955E). The results here and those published previously indicate that the Weissenbacher-Zweymüller syndrome (heterozygous OSMED), nonocular Stickler syndrome, and homozygous OSMED are all caused by mutations in the COL11A2 gene.
Abnormalities, Multiple↗