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Katrien Janssens - One of the best experts on this subject based on the ideXlab platform.
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Camurati Engelmann Disease progressive diaphyseal dysplasia in a moroccan family
Osteoporosis International, 2005Co-Authors: S Simsek, Katrien Janssens, W Van Hul, Mei Lan Kwee, J Veenstra, J C NetelenbosAbstract:We report on a 46-year-old mother of Moroccan origin, suffering mainly from painful, swollen legs, and her 26-year-old son who had experienced intense pain in his legs, without fever, for approximately 3 years. They did not have dysmorphic features or abnormal gaits. Radiographic studies of the mother revealed diaphyseal sclerosis of the tibia and spondylosis of the thoracal and lumbar vertebrae. The son had sclerosis of the diaphyses of the metacarpalia of the left hand, the femur and the fibula. The other parts of the skeleton were normal. Several osteosclerotic/hyperostotic disorders, such as melorheostosis (present mostly in sporadic cases and affecting lower extremities) and van Buchem’s Disease (autosomal recessive and commonly affecting the mandible) were considered as a diagnosis in the proposita. However, similar symptoms in the son of the proposita suggested an autosomal dominant inheritance pattern. This brought us to the diagnosis of progressive diaphyseal dysplasia (PDD) or Camurati–Engelmann Disease (CED), an autosomal dominant disorder characterized by limb pain, reduced muscle mass, weakness, a waddling gait, progressive periosteal and endosteal sclerosis of the diaphyses of the long bones and sclerosis of the skull base. Mutations in the transforming growth factor (TGF)-β1 gene on chromosome 19q13.1 have been reported to cause this disorder. The diagnosis of PDD/CED in this family was confirmed at the molecular level by detection of a C-to-T transition at position 466, leading to an arginine-to-cysteine amino acid change (position 156) in exon 2 of the transforming growth factor-β1 (TGFB1) gene.
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Camurati Engelmann Disease review of the clinical radiological and molecular data of 24 families and implications for diagnosis and treatment
Journal of Medical Genetics, 2005Co-Authors: Katrien Janssens, Stuart H. Ralston, Nuria Guanabens, Nicola Migone, Maryse Bonduelle, Lionel Van Maldergem, Filip Vanhoenacker, L Verbruggen, S Wientroub, M T DiviziaAbstract:Camurati-Engelmann Disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) β1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.
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Camurati Engelmann Disease review of radioclinical features
Acta Radiologica, 2003Co-Authors: F M Vanhoenacker, Katrien Janssens, W Van Hul, R Gershonibaruch, R Brik, A M De SchepperAbstract:Abstract Purpose: To present a retrospective overview of the clinical and radiological features of Camurati-Engelmann Disease (CED) in a large family with genetically proven CED. Material and Methods: Clinical features and imaging studies were available in 8 affected patients out of a large Jewish-Iraqi family with 21 affected members in four generations. The patients' ages ranged between 7 and 44 years. Results and Conclusions: The most frequent symptoms were pain and muscle weakness accompanied by waddling gait. Two patients were asymptomatic. Radiologically, the Disease can be classified as a craniotubular hyperostosis. Typically, fusiform thickening of the diaphyseal portions of the long bones was seen in all 8 patients, but in 1 patient, metaphyseal involvement was observed as well. Radioclinical abnormalities were most often detected before the age of 30, and were usually more extensive at older age. Radiological abnormalities may precede the clinical signs. Concomitant broadening of the diaphyse...
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transforming growth factor β1 mutations in Camurati Engelmann Disease lead to increased signaling by altering either activation or secretion of the mutant protein
Journal of Biological Chemistry, 2003Co-Authors: Katrien Janssens, Stuart H. Ralston, Peter Ten Dijke, Carsten Bergmann, Wim Van HulAbstract:Transforming growth factor-β1 (TGF-β1) is secreted as a latent precursor, consisting of a homodimer of the latency-associated peptide and the mature peptide. TGFβ-1 can only exert its many functions after going from this latent to an active state, in which the binding site of the mature peptide for its receptor is no longer shielded by the latency-associated peptide. We and others reported that mutations in TGFB1 cause Camurati-Engelmann Disease, a rare bone disorder. Until now, seven mutations have been published. In this study, we investigate the effect of the LLL12–13ins, Y81H, R218C, H222D, and C225R mutations on the functioning of TGF-β1 in vitro. A luciferase reporter assay specific for TGF-β-induced transcriptional response with wild type and mutant TGF-β1 constructs showed a positive effect of all mutations on TGF-β1 activity. By way of enzyme-linked immunosorbent assay, we found that in the R218C, H222D, and C225R mutant constructs, this effect is caused by an increase in active TGF-β1 in the medium of transfected cells. The LLL12–13ins and Y81H mutations on the contrary have a profound effect on secretion; a decreased amount of TGF-β1 is secreted, but the increased luciferase activity shows that the intracellular accumulation of (aberrant) TGF-β1 can initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-β1 signaling, thus causing Camurati-Engelmann Disease.
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A Mutation Affecting the Latency-Associated Peptide of TGFβ1 in Camurati-Engelmann Disease Enhances Osteoclast Formation in Vitro
The Journal of clinical endocrinology and metabolism, 2003Co-Authors: Neil W. A. Mcgowan, Heather Macpherson, Katrien Janssens, Wim Van Hul, Julie C. Frith, William D. Fraser, Stuart H. Ralston, Miep H. HelfrichAbstract:Camurati-Engelmann Disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFbeta type II receptor. Total serum TGFbeta1 levels were similar in affected and unaffected subjects, but concentrations of active TGFbeta1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFbeta1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.
Wim Van Hul - One of the best experts on this subject based on the ideXlab platform.
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Camurati Engelmann Disease progressive diaphyseal dysplasia reports of an indian kindred
Calcified Tissue International, 2014Co-Authors: Sanjay Kumar Bhadada, Subbiah Sridhar, Ellen Steenackers, Vandana Dhiman, Geert Mortier, Anil Bhansali, Wim Van HulAbstract:Camurati-Engelmann Disease (CED, OMIM 131300), or progressive diaphyseal dysplasia, is a rare autosomal dominant skeletal dysplasia, caused by mutations in the transforming growth factor-β1 (TGFβ1) gene. We describe the first Indian CED family with genetic confirmation and presenting manifestations. The proband is a 17-year-old woman who presented with lower limb pain and proximal muscle weakness. Skeletal radiographs of the long bones revealed cortical, periosteal, and endosteal thickenings, predominantly affecting the diaphyses of the long bones. On detailed evaluation, there was a strong family history of bone disorder with similar symptoms of pain and radiological findings in several family members. Exon sequencing of the TGFβ1 gene was performed in available family members. Based on clinical and radiographic studies and its familial nature, a diagnosis of CED was made and confirmed by mutation analysis. A heterozygous G to A transition in exon 4 of the TGFβ1 gene (R218H) was detected in 5 out of 10 available family members, including 4 affecteds and 1 asymptomatic individual. Many of our affected individuals responded to glucocorticoids and cortical windowing. CED is a rare genetic Disease with variable clinical manifestations and incomplete penetrance. CED needs to be considered in the differential diagnosis of nonspecific limb pain and waddling gait in all young individuals.
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transforming growth factor β1 mutations in Camurati Engelmann Disease lead to increased signaling by altering either activation or secretion of the mutant protein
Journal of Biological Chemistry, 2003Co-Authors: Katrien Janssens, Stuart H. Ralston, Peter Ten Dijke, Carsten Bergmann, Wim Van HulAbstract:Transforming growth factor-β1 (TGF-β1) is secreted as a latent precursor, consisting of a homodimer of the latency-associated peptide and the mature peptide. TGFβ-1 can only exert its many functions after going from this latent to an active state, in which the binding site of the mature peptide for its receptor is no longer shielded by the latency-associated peptide. We and others reported that mutations in TGFB1 cause Camurati-Engelmann Disease, a rare bone disorder. Until now, seven mutations have been published. In this study, we investigate the effect of the LLL12–13ins, Y81H, R218C, H222D, and C225R mutations on the functioning of TGF-β1 in vitro. A luciferase reporter assay specific for TGF-β-induced transcriptional response with wild type and mutant TGF-β1 constructs showed a positive effect of all mutations on TGF-β1 activity. By way of enzyme-linked immunosorbent assay, we found that in the R218C, H222D, and C225R mutant constructs, this effect is caused by an increase in active TGF-β1 in the medium of transfected cells. The LLL12–13ins and Y81H mutations on the contrary have a profound effect on secretion; a decreased amount of TGF-β1 is secreted, but the increased luciferase activity shows that the intracellular accumulation of (aberrant) TGF-β1 can initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-β1 signaling, thus causing Camurati-Engelmann Disease.
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A Mutation Affecting the Latency-Associated Peptide of TGFβ1 in Camurati-Engelmann Disease Enhances Osteoclast Formation in Vitro
The Journal of clinical endocrinology and metabolism, 2003Co-Authors: Neil W. A. Mcgowan, Heather Macpherson, Katrien Janssens, Wim Van Hul, Julie C. Frith, William D. Fraser, Stuart H. Ralston, Miep H. HelfrichAbstract:Camurati-Engelmann Disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFbeta type II receptor. Total serum TGFbeta1 levels were similar in affected and unaffected subjects, but concentrations of active TGFbeta1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFbeta1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.
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Transforming growth factor-β1 mutations in Camurati-Engelmann Disease lead to increased signaling by altering either activation or secretion of the mutant protein
The Journal of biological chemistry, 2002Co-Authors: Katrien Janssens, Stuart H. Ralston, Peter Ten Dijke, Carsten Bergmann, Wim Van HulAbstract:Transforming growth factor-beta1 (TGF-beta1) is secreted as a latent precursor, consisting of a homodimer of the latency-associated peptide and the mature peptide. TGFbeta-1 can only exert its many functions after going from this latent to an active state, in which the binding site of the mature peptide for its receptor is no longer shielded by the latency-associated peptide. We and others reported that mutations in TGFB1 cause Camurati-Engelmann Disease, a rare bone disorder. Until now, seven mutations have been published. In this study, we investigate the effect of the LLL12-13ins, Y81H, R218C, H222D, and C225R mutations on the functioning of TGF-beta1 in vitro. A luciferase reporter assay specific for TGF-beta-induced transcriptional response with wild type and mutant TGF-beta1 constructs showed a positive effect of all mutations on TGF-beta1 activity. By way of enzyme-linked immunosorbent assay, we found that in the R218C, H222D, and C225R mutant constructs, this effect is caused by an increase in active TGF-beta1 in the medium of transfected cells. The LLL12-13ins and Y81H mutations on the contrary have a profound effect on secretion; a decreased amount of TGF-beta1 is secreted, but the increased luciferase activity shows that the intracellular accumulation of (aberrant) TGF-beta1 can initiate an enhanced transcriptional response, suggesting the existence of an alternative signaling pathway. Our data indicate that the mutations in the signal peptide and latency-associated peptide facilitate TGF-beta1 signaling, thus causing Camurati-Engelmann Disease.
Steven Mumm - One of the best experts on this subject based on the ideXlab platform.
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JBMR Camurati-Engelmann Disease: Unique Variant Featuring a Novel Mutation in TGFb1 Encoding Transforming Growth Factor Beta 1 and a Missense Change in TNFSF11 Encoding RANK Ligand
2013Co-Authors: Michael P Whyte, William G Totty, Deborah V Novack, Xiafang Zhang, Deborah Wenkert, Steven MummAbstract:We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann Disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFb1 and TNFSF11 encoding TGFb1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were þ 7.7 and þ 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5 0 11 00 mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplicatio
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Camurati Engelmann Disease unique variant featuring a novel mutation in tgfβ1 encoding transforming growth factor beta 1 and a missense change in tnfsf11 encoding rank ligand
Journal of Bone and Mineral Research, 2011Co-Authors: Michael P Whyte, William G Totty, Deborah V Novack, Xiafang Zhang, Deborah Wenkert, Steven MummAbstract:We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann Disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5′11″ mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (c.27_38dup, p.L10_L13dup) in exon 1 of TGFβ1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity. © 2011 American Society for Bone and Mineral Research.
Yoshio Makita - One of the best experts on this subject based on the ideXlab platform.
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Camurati Engelmann Disease type ii progressive diaphyseal dysplasia with striations of the bones
American Journal of Medical Genetics, 2002Co-Authors: Gen Nishimura, Akira Kinoshita, Shiro Ikegawa, Yoshio Makita, Mohsen Ghadami, Hitoshi Nishimura, Yoko Tanaka, Norio NiikawaAbstract:We recently found mutations of the transforming growth factor beta 1 (TGF-β1) gene (TGFB1) in 9 families, in which progressive diaphyseal dysplasia (Camurati-Engelmann Disease) is segregating [Kinoshita et al., 2000: Nat Genetics 26:19–20]. During the study, we encountered two unrelated girls, aged 17 and 11 years, who had clinical manifestations of the disorder, such as marfanoid habitus, waddling gait, muscular weakness, intense leg pain, flexion contracture of the hip and knee joints, delayed sexual development, increased serum alkaline phosphatase levels, and increased erythrocyte sedimentation rates. Radiographic studies in the two girls demonstrated not only diaphyseal dysplasia (cortical thickening of the diaphyses) resembling that of progressive diaphyseal dysplasia but also metaphyseal expansion of the long bones, coarse and thick trabeculae of the long and short tubular bones, striations in the spinal, pelvic, and long bones, and cranial sclerosis restricted to the petromastoid regions. These radiographic changes were overall identical with those seen in hyperostosis generalisata with striations of the bones rather than those in progressive diaphyseal dysplasia. Polymerase chain reaction–direct sequencing of all exons and their flanking regions of TGFB1 did not detect any mutations. PCR-single strand conformational polymorphism analysis of the TGF-β type 1 receptor gene (TGFBR1) did not demonstrate any aberrant DNA fragments. We concluded from these findings that the two girls we described belong to a unique entity distinct from either of the two disorders. © 2001 Wiley-Liss, Inc.
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scintigraphic evaluation of pamidronate and corticosteroid therapy in a patient with progressive diaphyseal dysplasia Camurati Engelmann Disease
Clinical Nuclear Medicine, 2001Co-Authors: Tsutomu Inaoka, Noriyuki Shuke, Junichi Sato, Yukio Ishikawa, Koji Takahashi, Tamio Aburano, Yoshio MakitaAbstract:A 27-year-old woman with progressive diaphyseal dysplasia (Camurati-Engelmann Disease) received pamidronate and corticosteroid therapy for bone pain. During therapy, Disease activity was assessed serially using bone scintigraphy with Tc-99m HMDP. With pamidronate administration, the bone pain became worse and diaphyseal uptake of Tc-99m HMDP increased, whereas corticosteroid administration improved the bone pain and reduced the diaphyseal uptake. In this case, pamidronate and corticosteroid produced different effects. Bone scintigraphy allowed an objective assessment of the response to these treatments, accurately reflecting clinical symptoms.
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domain specific mutations of a transforming growth factor tgf β1 latency associated peptide cause Camurati Engelmann Disease because of the formation of a constitutively active form of tgf β1
Journal of Biological Chemistry, 2001Co-Authors: Takashi Saito, Akira Kinoshita, Yoshio Makita, Keiko Wakui, Norio Niikawa, Kohichiro Yoshiura, Koichi Honke, Naoyuki TaniguchiAbstract:Transforming growth factor (TGF)-β1 is secreted as a latent form, which consists of its mature form and a latency-associated peptide (β1-LAP) in either the presence or the absence of additional latent TGF-β1-binding protein. We recently reported that three different missense mutations (R218H, R218C, and C225R) of β1-LAP cause the Camurati-Engelmann Disease (CED), an autosomal dominant disorder characterized by hyperosteosis and sclerosis of the diaphysis of the long bones. Pulse-chase experiments using fibroblasts from CED patients and expression experiments of the mutant genes in an insect cell system suggest that these mutations disrupt the association of β1-LAP and TGF-β1 and the subsequent release of the mature TGF-β1. Furthermore, the cell growth of fibroblasts from a CED patient and mutant gene-transfected fibroblasts was suppressed via TGF-β1. The growth suppression observed was attenuated by neutralizing antibody to TGF-β1 or by treatment of dexamethasone. On the other hand, the proliferation of human osteoblastic MG-63 cells was accelerated by coculture with CED fibroblasts. These data suggest that the domain-specific mutations of β1-LAP result in a more facile activation of TGF-β1, thus causing CED.
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domain specific mutations in tgfb1 result in Camurati Engelmann Disease
Nature Genetics, 2000Co-Authors: Akira Kinoshita, Shiro Ikegawa, Takashi Saito, Hiroaki Tomita, Yoshio Makita, Kunihiro Yoshida, Mohsen Ghadami, Koki Yamada, Shinji Kondo, Gen NishimuraAbstract:Camurati-Engelmann Disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.
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genetic mapping of the Camurati Engelmann Disease locus to chromosome 19q13 1 q13 3
American Journal of Human Genetics, 2000Co-Authors: Mohsen Ghadami, Shiro Ikegawa, Yoshio Makita, Kunihiro Yoshida, Koki Yamada, Shinji Kondo, Gen Nishimura, Yoshimitsu Fukushima, Keiko Wakui, Norio NiikawaAbstract:Camurati-Engelmann Disease (CED [MIM 131300]), or progressive diaphyseal dysplasia, is an autosomal dominant sclerosing bone dysplasia characterized by progressive bone formation along the periosteal and endosteal surfaces at the diaphyseal and metaphyseal regions of long bones and cranial hyperostosis, particularly at the skull base. The gene for CED, or its chromosomal localization, has not yet been identified. We performed a genomewide linkage analysis of two unrelated Japanese families with CED, in which a total of 27 members were available for this study; 16 of them were affected with the Disease. Two-point linkage analysis revealed a maximum LOD score of 7.41 (recombination fraction .00; penetrance 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at chromosome 19q13.1-q13.3. These findings, together with a genetic distance among the marker loci, indicate that the CED locus can be assigned to a 15.1-cM segment between D19S881 and D19S606.
Pelin Ozlem Simsekkiper - One of the best experts on this subject based on the ideXlab platform.
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positive effects of an angiotensin ii type 1 receptor antagonist in Camurati Engelmann Disease a single case observation
American Journal of Medical Genetics Part A, 2014Co-Authors: Pelin Ozlem Simsekkiper, Esra Dikoglu, Belinda Camposxavier, Gulen Eda Utine, Luisa Bonafe, Sheila Unger, Koray Boduroglu, Andrea SupertifurgaAbstract:Camurati–Engelmann Disease is characterized by hyperostosis of the long bones and the skull, muscle atrophy, severe limb pain, and progressive joint contractures in some patients. It is caused by heterozygous mutations in the transforming growth factor β1 (TGFβ1) believed to result in improper folding of the latency-associated peptide domain of TGFβ1 and thus in increased or deregulated bioactivity. Losartan, an angiotensin II type 1 receptor antagonist, has been found to downregulate the expression of TGFβ type 1 and 2 receptors. Clinical trials with losartan have shown a benefit in Marfan syndrome, while trials are underway for Duchenne muscular dystrophy and other myopathies associated with TGFβ1 signaling. We hypothesized that due to its anti-TGFβ1 activity, losartan might be beneficial in Camurati–Engelmann Disease. This report concerns a boy who presented at age 13 years with severe limb pain and difficulty in walking. Clinical and radiographic evaluation results were compatible with Camurati–Engelmann Disease and the diagnosis was confirmed by mutation analysis (c.652C > T [p.Arg218Cys]). The boy underwent an experimental treatment with losartan at a dosage of 50 mg/day, orally. During the treatment period of 18 months, the intensity and frequency of limb pain decreased significantly (as shown by a pain diary), and muscle strength improved, allowing the boy to resume walking and climbing stairs. No obvious side effects were observed. We cautiously conclude that TGFβ1 inhibition with losartan deserves further evaluation in the clinical management of Camurati–Engelmann Disease. © 2014 Wiley Periodicals, Inc.