A new approach to the diagnosis of short stature.

Growth is the task of children. We review the normal process of linear growth from the fetus through adolescence and note that growth is the result of age- and gender-dependent interactions among key genetic, environmental, dietary, socioeconomic, developmental, behavioral, nutritional, metabolic, biochemical, and hormonal factors. We then define the wide range of normative data at each stage of growth and note that a pattern within this range is generally indicative of good general health and that growth significantly slower than this range may lead to growth faltering and subsequent short stature. Although not often emphasized, we detail how to properly measure infants and children because height velocity is usually determined from two height measurements (both relatively large values) to calculate the actual height velocity (a relatively much smaller number in comparison). Traditionally the physiology of growth has been taught from an endocrine-centric point-of-view. Here we review the hypothalamic-pituitary-end organ axes for the GH/IGF-1 and gonadal steroid hormones (hypothalamic-pituitary-gonadal axis), both during "mini"-puberty as well as at puberty. However, over the past few decades much more emphasis has been placed on the growth plate and its many interactions with the endocrine system but also with its own intrinsic physiology and gene mutations. These latter, whether individually (large effect size) or in combination with many others including endocrine system-based, may account in toto for meaningful differences in adult height. The clinical assessment of children with short stature includes medical, social and family history, physical exam and importantly proper interpretation of the growth curve. This analysis should lead to judicious use of screening laboratory and imaging tests depending on the pre-test probability (Bayesian inference) of a particular diagnosis in that child. In particular for those with no pathological features in the history and physical exam and a low, but normal height velocity, may lead only to a bone age exam and reevaluation (re-measurement), perhaps 6 months later. he next step depends on the comfort level of the primary care physician, the patient, and the parent; that is, whether to continue with the evaluation with more directed, more sophisticated testing, again based on Bayesian inference or to seek consultation with a subspecialist pediatrician based on the data obtained. This is not necessarily an endocrinologist. The newest area and the one most in flux is the role for genetic testing, given that growth is a complex process with large effect size for single genes but smaller effect sizes for multiple other genes which in the aggregate may be relevant to attained adult height. Genetics is a discipline that is rapidly changing, especially as the cost of exome or whole gene sequencing diminishes sharply. Within a decade it is quite likely that a genetic approach to the evaluation of children with short stature will become the standard, truncating the diagnostic odyssey and be cost effective as fewer biochemical and imaging studies are required to make a proper diagnosis.

Effect of a mixture of GOS/FOS® on calcium absorption and retention during recovery from protein malnutrition: experimental model in growing rats.

INTRODUCTION: During growth, protein deprivation impairs epiphyseal growth plate (EGP) height, bone volume (BV) and endochondral ossification. During catch-up growth, Ca availability becomes essential to ensure the extra amount needed to achieve optimal peak bone mass and strength. GOS and FOS improve mineral absorption in the colon. PURPOSE: The effect of a mixture of GOS/FOS® 9:1 added to a 0.5 %Ca (NCa) and a 0.3 %Ca (LCa) diets on Ca, P and Mg absorptions and bone mineralization, density and structure using an experimental model of growing rats recovering from early protein malnutrition was investigated. METHODS: To induce protein malnutrition, rats were fed a low protein diet: 4 % (LPD) during 1 week and then were randomly assigned to recovery groups (R) until day 50 (T = 50) as follows: R0.5 %: NCa; RP0.5 %: NCa + 5.3 % GOS/FOS®; R0.3 %: LCa and RP0.3 %: LCa + 5.3 % GOS/FOS®. Control groups received the 0.5 %Ca or 0.3 %Ca diet from weaning until day 40 or 50. RESULTS: Body weight and length increased in C groups throughout the study; both were arrested in all R during LPD consumption and increased immediately after re-feeding. Independently of dietary Ca content, LS counts, ß-glucosidase and Ca, P and Mg absorption increased, whereas cecum pH, ß-glucuronidase, urease and tryptophanase decreased in RP0.5 %: and RP0.3 %: as compared to the other studied groups (p < 0.01). Prebiotic consumption decreased CTX levels and increased femur Ca, Mg and P contents, total skeleton bone mineral content, proximal tibia and spine BMD, BV, EGP height and hypertrophic zone thickness, stiffness and elastic modulus as compared to recovery groups fed the prebiotic-free diets. CONCLUSION: Under the present experimental conditions, GOS/FOS® mixture induced colonic positive effects, which increased Ca, P and Mg absorption. Thus, consuming the prebiotic-containing diet resulted in an extra amount of minerals that improved bone development in growing rats recovering from protein malnutrition.

Geometrical and mechanical factors that influence slipped capital femoral epiphysis: a finite element study.

Slipped capital femoral epiphysis (SCFE) is an orthopedic pathology in which damage of the growth plate leads to the anterosuperior displacement of the femoral body in respect to the femoral head. Despite being a widely studied disease, its etiology is still unknown. This study was carried out to determine the influence of the physeal-diaphysis angle, body mass, the presence of the perichondrial ring, the type of physical activity, and physeal thickness on SCFE. For this purpose, a finite element analysis of the hip joint and the femur-physis interface was carried out. With the computational model, the Von Mises stresses along the growth plate were calculated and subsequently analyzed statistically to find their correlation with the studied factors. It was found that body mass, the type of physical activity, and the presence of the perichondrial ring had more statistical relevance for the physeal stresses than the physeal-diaphysis angle and the physeal thickness. Thus, our work suggests that changes in growth plate inclination and thickness do not influence the etiology of SCFE.

Growth plate stress distribution implications during bone development: a simple framework computational approach.

Mechanical stimuli play a significant role in the process of long bone development as evidenced by clinical observations and in vivo studies. Up to now approaches to understand stimuli characteristics have been limited to the first stages of epiphyseal development. Furthermore, growth plate mechanical behavior has not been widely studied. In order to better understand mechanical influences on bone growth, we used Carter and Wong biomechanical approximation to analyze growth plate mechanical behavior, and explore stress patterns for different morphological stages of the growth plate. To the best of our knowledge this work is the first attempt to study stress distribution on growth plate during different possible stages of bone development, from gestation to adolescence. Stress distribution analysis on the epiphysis and growth plate was performed using axisymmetric (3D) finite element analysis in a simplified generic epiphyseal geometry using a linear elastic model as the first approximation. We took into account different growth plate locations, morphologies and widths, as well as different epiphyseal developmental stages. We found stress distribution during bone development established osteogenic index patterns that seem to influence locally epiphyseal structures growth and coincide with growth plate histological arrangement.

Computational modeling of the mechanical modulation of the growth plate by sustained loading.

This paper presents a computational model that describes the growth of the bone as a function of the proliferation and hypertrophy of chondrocytes in the growth plate. We have included the effects of the mechanical loads on the sizes of the proliferative and hypertrophic areas, the number of proliferative chondrocytes and the final size of the hypertrophic chondrocytes. The validation of the model was performed with experimental data published on other investigations about proximal tibia of rats, subjected to sustained axial stresses of 0.1 MPa, 0.0 MPa, -0.1 MPa and -0.2 MPa. Growth was simulated during 23 days, obtaining numerical errors between 2.77% and 3.73% with respect to experimental growth rates. The results obtained show that the model adequately simulates the behavior of the growth plate and the effect of mechanical loads over its cellular activity.

Lesiones de ligamento cruzado anterior en niños con cartilagos abiertos: tecnica quirurgica sugerida: investigacion bibliografica / Anterior cruciate ligament injuries in children with open physis: suggested surgical technique: bibliographic survey

Se describe el mecanismo de acción, historia natural, presentación clínica y distintos tipos de tratamiento de las lesiones de LCA en niños con cartílago s abiertos y sus complicaciones. La verdadera incidencia de lesión de LCA en niños con cartílagos abiertos es desconocida en Argentina. En el pasado estas lesiones eran subdiagnosticadas, en los últimos años se ha observado un mayor número de estos pacientes. Este aumento ha sido atribuido a un mejor diagnóstico, mejor comprensión de la patología en este grupo etario y a un incremento en la exigencia y participación de los niños en deportes de riesgo. Es importante establecer el potencial de crecimiento ya que tanto éste como el cierre fisiológico de la fisis es variable y deben ser tenidos en cuenta para una adecuada planificación de la técnica quirúrgica y para determinar los eventuales riesgos del compromiso de la fisis. El diagnóstico de lesión de LCA se basa principalmente en el antecedente traumático previo y el examen fisico. La RMN es de utilidad como estudio complementario sobre todo en casos donde la presentación clínica no es clara. El tratamiento de las lesiones de LCA en pacientes esqueléticamente inmaduros es controvertido. El manejo tradicional de estas lesiones ha sido conservador debido al riesgo de lesión de la fisis y desarrollo de alteraciones del crecimiento (discrepancia de miembros inferiores y deformidades angulares). Sin embargo, la bibliografia actual demuestra que la reconstrucción intraarticular precoz y agresiva, permite restaurar la estabilidad articular, retomar al nivel previo de actividad deportiva, disminuir el riesgo de lesiones meniscales secundarias y patología intraarticular degenerativa, con un riesgo mínimo de daño del cartílago de crecimiento con la técnica adecuada. Las distintas opciones quirúrgicas incluyen reparación primaria del ligamento, reconstrucciones extraarticulares, reconstrucción combinada intra y extra articular y reconstrucciones intraarticulares ...

Lesiones de ligamento cruzado anterior en niños con cartilagos abiertos: tecnica quirurgica sugerida: investigacion bibliografica / Anterior cruciate ligament injuries in children with open physis: suggested surgical technique: bibliographic survey

Se describe el mecanismo de acción, historia natural, presentación clínica y distintos tipos de tratamiento de las lesiones de LCA en niños con cartílago s abiertos y sus complicaciones. La verdadera incidencia de lesión de LCA en niños con cartílagos abiertos es desconocida en Argentina. En el pasado estas lesiones eran subdiagnosticadas, en los últimos años se ha observado un mayor número de estos pacientes. Este aumento ha sido atribuido a un mejor diagnóstico, mejor comprensión de la patología en este grupo etario y a un incremento en la exigencia y participación de los niños en deportes de riesgo. Es importante establecer el potencial de crecimiento ya que tanto éste como el cierre fisiológico de la fisis es variable y deben ser tenidos en cuenta para una adecuada planificación de la técnica quirúrgica y para determinar los eventuales riesgos del compromiso de la fisis. El diagnóstico de lesión de LCA se basa principalmente en el antecedente traumático previo y el examen fisico. La RMN es de utilidad como estudio complementario sobre todo en casos donde la presentación clínica no es clara. El tratamiento de las lesiones de LCA en pacientes esqueléticamente inmaduros es controvertido. El manejo tradicional de estas lesiones ha sido conservador debido al riesgo de lesión de la fisis y desarrollo de alteraciones del crecimiento (discrepancia de miembros inferiores y deformidades angulares). Sin embargo, la bibliografia actual demuestra que la reconstrucción intraarticular precoz y agresiva, permite restaurar la estabilidad articular, retomar al nivel previo de actividad deportiva, disminuir el riesgo de lesiones meniscales secundarias y patología intraarticular degenerativa, con un riesgo mínimo de daño del cartílago de crecimiento con la técnica adecuada. Las distintas opciones quirúrgicas incluyen reparación primaria del ligamento, reconstrucciones extraarticulares, reconstrucción combinada intra y extra articular y reconstrucciones intraarticulares ...(AU)

Does the presence of proximal humerus growth plate changes in young baseball pitchers happen only in symptomatic athletes? An x ray evaluation of 21 young baseball pitchers.

OBJECTIVE: To evaluate the presence of x ray changes in the proximal humerus growth plate of 21 young pitchers. DESIGN: Case series. SETTING: This study was conducted at the Orthopaedic and Traumatology Department of the ABC College of Medicine, Santo André, São Paulo, Brazil, tertiary institution. PATIENTS: 21 male adolescent baseball pitchers, with a mean age of 14.5 years and selected from the Brazilian National Team, were studied. INTERVENTIONS: The patients underwent x ray examinations of the shoulders. MAIN OUTCOME MEASUREMENTS: The x rays of the pitchers' shoulders were studied to determine any changes in the proximal humeral growth plate and correlate them with clinical findings. RESULTS: Fourteen athletes (66%) had radiographic changes in the humerus growth plate but only 5 (36%) had pain complaints. Nine of these 14 cases (64%) whom the observers found radiographic changes did not complain of pain. It was also observed that there was a correlation in only 11 cases between clinical and radiographic evaluations. CONCLUSION: Radiographic changes in the proximal humerus growth plate were found in 66% of the cases, but 64% were asymptomatic. These changes indicate possible evolution, in the future, to a greater degree of retroversion in pitchers' dominant shoulders.

Use of extensible internal device in the femur of young dogs.

An extensible internal device (EID) was developed to preserve growth plate during the treatment of fracture complications or segmental bone loss from tumour resection in children. Since this type of extensible, transphyseal, internal fixation device has only been used in a few paediatric cases; the aim of this study was to evaluate an in vivo canine study, a surgical application of this device, and its interference with longitudinal growth of the non-fractured distal femur. Ten clinically healthy two- to three-month-old poodles weighing 1.5-2.3 kg were used. Following a medial approach to the right distal femur, one extremity of the EID, similar to a T-plate, was fixed in the femoral condyle with two cortical screws placed below the growth plate. The other extremity, consisting of an adaptable brim with two screw holes and a plate guide, was fixed in the third distal of the femoral diaphysis with two cortical screws. The EID was removed 180 days after application. All of the dogs demonstrated full weight-bearing after surgery. The values of thigh and stifle circumferences, and stifle joint motion range did not show any difference between operated and control hindlimbs. The plate slid in the device according to longitudinal bone growth, in all but one dog. In this dog, a 10.5% shortening of the femoral shaft was observed due to a lack of EID sliding. The other dogs had the same longitudinal lengths in both femurs. The EID permits longitudinal bone growth without blocking the distal femur growth plate if appropriately placed.

Growth cartilage calcification and formation of bone trabeculae are late and dissociated events in the endochondral ossification of Rana catesbeiana.

Endochondral ossification in the growth cartilage of long bones from the bullfrog Rana catesbeiana was examined. In stage-46 tadpoles and 1-year-old animals, the hypertrophic cartilage had a smooth contact with the bone marrow and the matrix showed no calcification or endochondral bone formation. In spite of showing no aspects of calcification, the chondrocytes exhibited alkaline phosphatase activity and some of them died by apoptosis. However, matrix calcification and endochondral ossification were observed in 2-year-old bullfrogs. Calcium deposits appeared as isolated or coalesced spherical structures in the extracellular matrix of hypertrophic cartilage. Bone trabeculae were restricted to the central area at the sites where the hypertrophic cartilage surface was exposed to the bone marrow. Cartilage matrix calcification and the formation of bone trabeculae were not dependent on each other. Osteoclasts were involved in calcified matrix resorption. These results demonstrate that the calcification of hypertrophic cartilage and the deposition of bone trabeculae are late events in R. catesbeiana and do not contribute to the development and growth of long bones in adults. These processes may play a role in reinforcing bony structures as the bullfrog gains weight in adulthood. In addition, the deposition of bone trabeculae is not dependent on cartilage matrix calcification.

Activation of the growth plates on three-phase bone scintigraphy: the explanation for the overgrowth of fractured femurs.

Children with an uncomplicated femoral fracture, treated with superimposition of fragments and intentional shortening, usually develop overgrowth of the fractured femur and the ipsilateral tibia which may compensate for the initial shortening and enable the limb in question to reach a length similar to that on the normal side. The overgrowth is evaluated clinically and by scanography. The increased metabolic activity of the growth plates that support this overgrowth has not been documented by any laboratory method. In order to evaluate the metabolic activity of the growth plates, 18 patients (11 males, seven females; mean age 6.1 years) with fractures of the femur were studied at three different time intervals (2-5 months, 6-12 months and 18-24 months). Three-phase bone scintigraphy was performed in all patients. Ten children (five males, five females; mean age 7.5 years) who had had bone imaging for other reasons were used as the control group. Visual analysis of the flow and equilibrium phases was performed for the distal femoral and proximal tibial growth plates. Visual and semi-quantitative analyses of the delayed images were performed for the distal femoral and proximal and distal tibial growth plates. Semi-quantitative analyses yielded the following activity ratios: (a) the distal femoral growth plate of the fractured femur to the contralateral one (FR); (b) the proximal growth plate of the tibia on the side of the fractured femur to the contralateral one (TpR); (c) the distal growth plate of the tibia on the side of the fractured femur to the contralateral one (TdR); and (d) in the control group, the distal growth plates of both femora (FCG) and the proximal (TCGp) and distal (TCGd) growth plates of the tibiae. Visual analysis of the blood flow, equilibrium and delayed images showed increased activity in the distal femoral growth plates during the first and second time intervals, but not during the third. No significant activity changes were found in the proximal and distal tibial growth plates during any of the phases analysed. The mean and standard deviation for FR in the three time intervals were: FRI=1.22+/-0.27, FRII=1.17+/-0.16 and FRIII=1.09+/-0.20. FR values were significantly higher than in the control group (FCG=0.99+/-0.03) (P=0.033). The mean and standard deviation for TpR in the three time intervals were: TpRI=1.08+/-0.18, TpRII=0.94+/-0.09 and TpRIII=0.96+/-0.20. TpR values were not significantly different from those in the control group (TCGp=1.00+/-0.05). However, TpRI was significantly higher than TpRII (P=0.043). The mean and standard deviation for TdR in the three time intervals were: TdRI=1.10+/-0.41, TdRII=1.05+/-0.15 and TdRIII=1.13+/-0.36. TdR values were not significantly higher than in the control group (TCGd=1.00+/-0.04) (P=0.777). These results support the concept that three-phase bone imaging is able to quantify and determine that activation occurs in the distal femoral and proximal tibial growth plates of fractured femora. This phenomenon may explain the overgrowth observed in this injured bone structure.

Aggrecan structure in amphibian cartilage.

The structure of the large proteoglycan present in the bullfrog epiphyseal cartilage was studied by immunochemical and biochemical methods. The isolated monomer showed a polydisperse behavior on Sepharose CL2B, with a peak at Kav = 0.14. Chondroitin sulfate chains were identified by HPLC analysis of the products formed by chondroitinase digestion and mercuric acetate treatment. These chains have approximately 38 disaccharides, a Di45:Di68 ratio of 1.6 and GalNAc4S + GalNAc4,6S are the main non-reducing terminals. Keratan sulfate was identified by the use of two monoclonal antibodies in Western blots after chondroitinase ABC treatment. A keratan sulfate-rich region (approximately 110 kDa) was isolated by sequential treatment with chondroitinase ABC and proteases. We also employed antibodies in Western blotting experiments and showed that the full length deglycosylated core protein is about 300 kDa after SDS-PAGE. Domain-specific antibodies revealed the presence of immunoreactive sites corresponding to G1/G2 and G3 globular domains and the characterization of this large proteoglycan as aggrecan. The results indicate the high conservation of the aggrecan domain structure in this lower vertebrate.

Aggrecan structure in amphibian cartilage

The structure of the large proteoglycan present in the bullfrog epiphyseal cartilage was studied by immunochemical and biochemical methods. The isolated monomer showed a polydisperse behavior on Sepharose CL2B, with a peak at Kav = 0.14. Chondroitin sulfate chains were identified by HPLC analysis of the products formed by chondroitinase digestion and mercuric acetate treatment. These chains have approximately 38 disaccharides, a Di45:Di68 ratio of 1.6 and GalNAc4S + GalNAc4,6S are the main non-reducing terminals. Keratan sulfate was identified by the use of two monoclonal antibodies in Western blots after chondroitinase ABC treatment. A keratan sulfate-rich region (~110 kDa) was isolated by sequential treatment with chondroitinase ABC and proteases. We also employed antibodies in Western blotting experiments and showed that the full length deglycosylated core protein is about 300 kDa after SDS-PAGE. Domain-specific antibodies revealed the presence of immunoreactive sites corresponding to G1/G2 and G3 globular domains and the characterization of this large proteoglycan as aggrecan. The results indicate the high conservation of the aggrecan domain structure in this lower vertebrate

The epiphyseal cartilage and growth of long bones in Rana catesbeiana.

The structure of the epiphyseal cartilage of the bullfrog Rana catesbeiana and its role in the growth of long bones were examined. The epiphyseal cartilage was inserted into the end of a tubular bone shaft, defining three regions: articular cartilage, lateral articular cartilage and growth cartilage. Joining the lateral cartilage to the bone was a fibrous layer of periosteum, rich in blood vessels. Osteoblasts with alkaline phosphatase activity were found on the surface of the periosteal bone, which presented a fibrous non-mineralised tip. The growth cartilage was inside the bone. The proliferative chondrocytes presented perpendicular separation of daughter cells and there was no columnar arrangement of the cells. Furthermore, chondrocyte hypertrophy was not associated with either calcification or endochondral ossification, in apparent contrast to the avian and mammalian models. Finally, there was no reinforcement system capable of directing cell volume increase into longitudinal growth. Since bone extension depends on the intramembranous ossification of the periosteum, the growth cartilage is inside and not at the end of the bone and the cells in the growth cartilage show no columnar arrangement and separate in a direction perpendicular to the long bone axis, we conclude that the growth cartilage mainly contributes to the radial expansion of the bone.

Dolores musculoesquéleticos del crecimiento y desarrollo en niños / Growing pains in children

Se tomó una muestra significativa de 100 pacientes de la consulta externa del Servicio de Ortopedia del Hospital Tacuba, ISSSTE, del mes de julio al mes de octubre de 1998 con un rango de edad entre 3 y 12 años. El objetivo era descubrir la existencia del dolor en miembros inferiores, relacionados con el crecimiento y desarrollo, sin patología agregada suponiendo que se debe a un edema subclínico secundario a fatiga por ejercicio físico y demostrar su mejoría rehabilitación específica. Se tomaron estudios radiológicos (AP pelvis, AP y LAT e rodillas, tobillos, dorsoplantar, oblicua y lateral de ambos pies) del segmento afectado, se realizaron exámenes de laboratorio (biometría hemática, velocidad de sedimentación globular, factor reumatoide, proteína C reactiva, exudado faríngeo) y examen físico para descartar datos de otra patología. Posteriormente se entregó un instructivo de ejercicios de estiramiento y adiestramiento a los padres, para la realización de los mismos a los niños con algún problema ortopédico sencillo tal como pie plano, pie cavo, genu valgo o varo fisiológicos y defectos de la marcha, o clínicamente sanos. Se dió seguimiento para valoración de la mejoría. Se encontró que de los 100 pacientes estudiados 60 por ciento presentaban alteraciones ortopédicas. El 47 por ciento requirieron ortosis (zapatos ortopédico, plantillas, separador para Hallux, etc.); 40 por ciento se encontraban clínicamante sanos. Después de los ejercicios de estiramiento se encontró desaparición de los dolores en un 76 por ciento de los pacientes y disminución en la intensidad y frecuencia en el 24 por ciento restante

Ensaio de cisalhamento sobre a cartilagem de crescimento: estudo comparativo entre duas idades diferentes, a fresco e após congelamento / Shearing load on growth cartilage: comparative study between 2 different ages, freshly and after freezing

O objetivo desta investigaçao foi analisar o comportamento mecânico da placa de crescimento sob algumas condiçoes. Inicialmente, foi determinada a curva de crescimento da tíbia de ratas da raça Norvegicus albinus, do 5 ao 83 dia de vida pós-natal. A partir dessa curva, foram selecionadas as idades de 25 e 65 dias para o ensaio mecânico, em razao de representarem, respectivamente, o máximo e o final de crescimento. Para os ensaios mecânicos foram usados 46 pares de tíbias, 23 para cada idade. Para cada par de tíbias, uma foi aleatoriamente ensaiada a fresco e a outra após 30 dias de congelamento a -18 graus Celsius. Todos os ensaios foram realizados à temperatura ambiente e segundo a mesma técnica. Tíbias isoladas foram adaptadas à máquina universal de ensaio mecânico, que aplicou cargas de cisalhamento na placa de crescimento proximal até que ocorresse ruptura. Foi construiída a curva carga x deformaçao. Com a medida da área da placa de crescimento foi obtida a tensao correspondente. Os seguintes parâmetros foram analisados: limite de proporcionalidade, resiliência e nódulo equivalente de elasticidade. Da análise dos rersultados concluiu-se que o congelamento da cartilagem afetou significativamente as suas propriedades mecânicas, tornando-a mais resistente aos esforços aplicados, e que a resistência mecânica ao cisalhamento foi maior na idade mais próxima do final do crescimento da tíbia.