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Three patients with osteoporosis-pseudoglioma syndrome (OPPG) due to novel splice site mutations in LRP5
Abstracts / Bone 45 (2009) S59–S111
An impaired bone mineral status in children and adolescent may represent an increased risk of osteoporosis in adulthood. It has been demonstrated that quantitative ultrasound (QUS) at phalanxes is a reliable method for the assessment of bone status in growing subjects. In 88 consecutive healthy full-term newborns (37 males and 51 females; gestational age: 39.0 ± 1.4 weeks) QUS parameters were assessed within 3 days of birth at distal diaphysis of humerus using Bone Profiler (IGEA, Italy), after an appropriate modification of calliper and software. After 4 years of life the standard technique was used for children. In all subjects we evaluated: AD-SoS (m/s), the characterizing graphic trace parameters (SDy, FWA and BTT), SoS (m/s), which is the speed of sound calculated on the first peak and hBTT, which is the interval time between the first peak of the ultrasound and when this reaches the speed of 1570 m/s, which is the velocity of ultrasound in the soft tissue. Demographic and anthropometric parameters were collected at birth and at 4 years. All QUS parameters were significantly reduced in children with a birth weight < 3.0 kg with respect to those with a birth weight > 3 kg (p < 0.05). On the contrary there were no differences between children who had a length at birth < 50 cm with respect to those with a length > 50 cm. BTT and AD-SoS measured at 4 years were significantly correlated with weight at birth (r = 0.31; p < 0.01 and r = 0.23; p < 0.05 respectively). BTT and AD-SoS showed a correlation with length at birth without reaching any statistical significance (p < 0.95). At the fourth year of life a significant correlation was found between QUS parameters and shoes size (p < 0.01). The present study demonstrates that weight at birth markedly influences bone status in children aged 4 years. doi:10.1016/j.bone.2009.04.186
PF-41 Three patients with osteoporosis-pseudoglioma syndrome (OPPG) due to novel splice site mutations in LRP5 C.M. Lainea,b, M. Susicc, T.E. Prescottd, C. Netzere, T. Fiskerstrandf, B. Chunge, W.G. Colec, E. Sochettc, O. Mäkitiea,b a The Hospital for Children and Adolescents, Helsinki, Finland b Folkhälsan Institute of Genetics, Helsinki, Finland c The Hospital for Sick Children, Toronto, Canada d Rikshospitalet, Oslo, Norway e Universitätsklinikum zu Köln, Köln, Germany f Haukeland University Hospital, Bergen, Norway Osteoporosis-pseudoglioma syndrome (OPPG, OMIM #259770) is an autosomal recessive disorder with severe early-onset osteoporosis, blindness and, in 25% of the patients, cognitive impairment. OPPG is caused by inactivating mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor involved in the Wnt signalling pathway. Several LRP5 mutations have been described but only few splice site mutations have been reported thus far. Here we present three novel LRP5 splice site mutations and the resulting phenotypes. Patient 1 is congenitally blind and has severe osteoporosis (lumbar spine BMD Z-score − 3.8) and multiple vertebral compression fractures. Her psychomotor development is normal. LRP5 screening revealed that she is compound heterozygous for a missense mutation S356L in exon 6 and a splice acceptor site mutation c.41122A > G. In a heterologous splicing assay, the latter mutation causes complete skipping of exon 20. Patient 2, of consanguineous parents, is congenitally blind with bilateral retrolental masses. He is unable to walk due to multiple femur fractures; his total body BMD Z-score was −3.3 at the age of 10. He is mentally retarded and has epilepsy. Direct sequencing of LRP5 revealed a homozygous splice donor site mutation c.1015 + 1G > T, which causes the deletion of exon 5 in a heterologous splicing assay. Patient 3 is congenitally blind and suffers from
S109
osteoporosis. He is of normal intellect. Direct sequencing of LRP5 showed a homozygous splice donor site mutation c.1585 + 4A > T. The mutation activates a cryptic splice site downstream leading to a 21 amino acid in-frame insertion after exon 7. These LRP5 splice site mutations expand the spectrum of LRP5 mutations in OPPG and underscore the importance of thorough examination of not only the exons but also of intronic sequences when searching for LRP5 mutations in patients with features of OPPG. doi:10.1016/j.bone.2009.04.187
PF-42 Knowledge about bone health and bone health promotion behaviours in school age children P. Dsouza, A. George, R. Geetha Sultan Qaboos University, Muscat, Oman Promotion of bone health throughout the life span has become a significant national and international agenda. Physical and sedentary activity in children and adolescents has immediate health benefits and can also set a pattern that carries over into adulthood, resulting in long-term health benefits. The purpose of the study was to explore the knowledge about bone health and bone health promotion behaviours in school age children between 10 and 16 years. An exploratory survey design was used. Nonprobability quota sampling was used to select 500 adolescents in grades 6–10 who are studying in an Indian school. The data were collected using a structured knowledge questionnaire consisted of 40 items and the validity and reliability was established. Health promotion behaviours were assessed by a semistructured questionnaire. The findings revealed that the children had inadequate knowledge level (<50%) in all the areas related to bone health like nutrition aspects, activity level, factors that promote bone health and inhibit bone health. The other important finding of the study was that female adolescents had a significant increase in bone health promotion behaviours when compared to males. The qualitative data collected also gave valuable information regarding health promotion behaviours. These were elicited through the open ended questionnaire. The detailed results will be presented in the conference. The findings provided valuable information to develop a school based bone health programme. doi:10.1016/j.bone.2009.04.234
PF-43 Application of the 2007 International Society for Clinical Densitometry (ISCD) guidelines for the definition of osteoporosis in children — How do they work in clinical practice? N.J. Crabtreea,b, D. Chapmana, N.J. Shawb a University Hospital Birmingham, Birmingham, UK b Birmingham Children's Hospital, Birmingham, UK The ISCD recently produced guidelines to aid the definition of osteoporosis in children based on routine DXA measurement and clinical fracture history. In brief, a child is defined as having osteoporosis if he has a clinically significant fracture history and a low BMC or BMD adjusted for age, gender and body size as appropriate. However, there are currently no automated methods of size adjustment in the software for the DXA output and no facility to record relevant fracture history. The aim of this audit was to evaluate how these guidelines apply in clinical practice in the identification of children with osteoporosis comparing standard manufacturer's output with new ISCD definition.
An impaired bone mineral status in children and adolescent may represent an increased risk of osteoporosis in adulthood. It has been demonstrated that quantitative ultrasound (QUS) at phalanxes is a reliable method for the assessment of bone status in growing subjects. In 88 consecutive healthy full-term newborns (37 males and 51 females; gestational age: 39.0 ± 1.4 weeks) QUS parameters were assessed within 3 days of birth at distal diaphysis of humerus using Bone Profiler (IGEA, Italy), after an appropriate modification of calliper and software. After 4 years of life the standard technique was used for children. In all subjects we evaluated: AD-SoS (m/s), the characterizing graphic trace parameters (SDy, FWA and BTT), SoS (m/s), which is the speed of sound calculated on the first peak and hBTT, which is the interval time between the first peak of the ultrasound and when this reaches the speed of 1570 m/s, which is the velocity of ultrasound in the soft tissue. Demographic and anthropometric parameters were collected at birth and at 4 years. All QUS parameters were significantly reduced in children with a birth weight < 3.0 kg with respect to those with a birth weight > 3 kg (p < 0.05). On the contrary there were no differences between children who had a length at birth < 50 cm with respect to those with a length > 50 cm. BTT and AD-SoS measured at 4 years were significantly correlated with weight at birth (r = 0.31; p < 0.01 and r = 0.23; p < 0.05 respectively). BTT and AD-SoS showed a correlation with length at birth without reaching any statistical significance (p < 0.95). At the fourth year of life a significant correlation was found between QUS parameters and shoes size (p < 0.01). The present study demonstrates that weight at birth markedly influences bone status in children aged 4 years. doi:10.1016/j.bone.2009.04.186
PF-41 Three patients with osteoporosis-pseudoglioma syndrome (OPPG) due to novel splice site mutations in LRP5 C.M. Lainea,b, M. Susicc, T.E. Prescottd, C. Netzere, T. Fiskerstrandf, B. Chunge, W.G. Colec, E. Sochettc, O. Mäkitiea,b a The Hospital for Children and Adolescents, Helsinki, Finland b Folkhälsan Institute of Genetics, Helsinki, Finland c The Hospital for Sick Children, Toronto, Canada d Rikshospitalet, Oslo, Norway e Universitätsklinikum zu Köln, Köln, Germany f Haukeland University Hospital, Bergen, Norway Osteoporosis-pseudoglioma syndrome (OPPG, OMIM #259770) is an autosomal recessive disorder with severe early-onset osteoporosis, blindness and, in 25% of the patients, cognitive impairment. OPPG is caused by inactivating mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor involved in the Wnt signalling pathway. Several LRP5 mutations have been described but only few splice site mutations have been reported thus far. Here we present three novel LRP5 splice site mutations and the resulting phenotypes. Patient 1 is congenitally blind and has severe osteoporosis (lumbar spine BMD Z-score − 3.8) and multiple vertebral compression fractures. Her psychomotor development is normal. LRP5 screening revealed that she is compound heterozygous for a missense mutation S356L in exon 6 and a splice acceptor site mutation c.41122A > G. In a heterologous splicing assay, the latter mutation causes complete skipping of exon 20. Patient 2, of consanguineous parents, is congenitally blind with bilateral retrolental masses. He is unable to walk due to multiple femur fractures; his total body BMD Z-score was −3.3 at the age of 10. He is mentally retarded and has epilepsy. Direct sequencing of LRP5 revealed a homozygous splice donor site mutation c.1015 + 1G > T, which causes the deletion of exon 5 in a heterologous splicing assay. Patient 3 is congenitally blind and suffers from
S109
osteoporosis. He is of normal intellect. Direct sequencing of LRP5 showed a homozygous splice donor site mutation c.1585 + 4A > T. The mutation activates a cryptic splice site downstream leading to a 21 amino acid in-frame insertion after exon 7. These LRP5 splice site mutations expand the spectrum of LRP5 mutations in OPPG and underscore the importance of thorough examination of not only the exons but also of intronic sequences when searching for LRP5 mutations in patients with features of OPPG. doi:10.1016/j.bone.2009.04.187
PF-42 Knowledge about bone health and bone health promotion behaviours in school age children P. Dsouza, A. George, R. Geetha Sultan Qaboos University, Muscat, Oman Promotion of bone health throughout the life span has become a significant national and international agenda. Physical and sedentary activity in children and adolescents has immediate health benefits and can also set a pattern that carries over into adulthood, resulting in long-term health benefits. The purpose of the study was to explore the knowledge about bone health and bone health promotion behaviours in school age children between 10 and 16 years. An exploratory survey design was used. Nonprobability quota sampling was used to select 500 adolescents in grades 6–10 who are studying in an Indian school. The data were collected using a structured knowledge questionnaire consisted of 40 items and the validity and reliability was established. Health promotion behaviours were assessed by a semistructured questionnaire. The findings revealed that the children had inadequate knowledge level (<50%) in all the areas related to bone health like nutrition aspects, activity level, factors that promote bone health and inhibit bone health. The other important finding of the study was that female adolescents had a significant increase in bone health promotion behaviours when compared to males. The qualitative data collected also gave valuable information regarding health promotion behaviours. These were elicited through the open ended questionnaire. The detailed results will be presented in the conference. The findings provided valuable information to develop a school based bone health programme. doi:10.1016/j.bone.2009.04.234
PF-43 Application of the 2007 International Society for Clinical Densitometry (ISCD) guidelines for the definition of osteoporosis in children — How do they work in clinical practice? N.J. Crabtreea,b, D. Chapmana, N.J. Shawb a University Hospital Birmingham, Birmingham, UK b Birmingham Children's Hospital, Birmingham, UK The ISCD recently produced guidelines to aid the definition of osteoporosis in children based on routine DXA measurement and clinical fracture history. In brief, a child is defined as having osteoporosis if he has a clinically significant fracture history and a low BMC or BMD adjusted for age, gender and body size as appropriate. However, there are currently no automated methods of size adjustment in the software for the DXA output and no facility to record relevant fracture history. The aim of this audit was to evaluate how these guidelines apply in clinical practice in the identification of children with osteoporosis comparing standard manufacturer's output with new ISCD definition.