RESUMEN
Collagen X marker (CXM) is a degradation fragment of collagen type X. It is a real-time biomarker of height velocity with established norms. Plasma C-type natriuretic peptide (CNP) and NTproCNP levels have also been found to correlate with growth velocity in the general population and are elevated in individuals with achondroplasia compared with age- and sex-matched controls. Collagen X marker levels in people with fibroblast growth factor receptor 3 (FGFR3)-opathies have never been systematically measured. The objective of this study was to measure CXM in a population of dwarfism caused by FGFR3-opathies. Using the same cohort in which CNP and NTproCNP levels were previously measured, archived serum aliquots from 63 children with achondroplasia, six with hypochondroplasia, and two with thanatophoric dysplasia had CXM concentrations measured. Results were plotted against age- and sex-specific norms, and standard deviation scores were plotted for comparison between clinical diagnoses. CXM levels were significantly decreased (p < 0.0001) in children with achondroplasia compared with age- and sex-matched controls. Temporal patterns of change in CXM levels were sex-dependent. As the FGFR3 pathway was more constitutively active, CXM levels decreased. New tools are emerging to study impact of skeletal dysplasia on growth plate regulation and function.
Asunto(s)
Acondroplasia , Deformidades Congénitas de las Extremidades , Displasia Tanatofórica , Biomarcadores , Niño , Colágeno Tipo X , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: C-type natriuretic peptide (CNP) and its aminoterminal propeptide (NTproCNP) are potential biomarkers of recombinant human growth hormone (rhGH) efficacy. The objective of this study was to describe the pharmacodynamics of plasma CNP and NTproCNP levels in response to rhGH treatment and to identify the optimal time of sampling after starting rhGH. DESIGN: This was a prospective, observational study. Subjects were treated with rhGH for 1 year, with blood sampled at regular intervals. PATIENTS: Eighteen prepubertal children, eight with low levels of GH on biochemical testing and ten with idiopathic short stature, completed the study. MEASUREMENTS: Blood levels of CNP, NTproCNP, GH, insulin-like growth factor-I, leptin and bone-specific alkaline phosphatase were measured. Anthropometrics were obtained. RESULTS: Plasma levels of both CNP and NTproCNP reached peak levels 7-28 days after starting rhGH treatment and then declined to intermediate levels through the first year. Plasma NTproCNP levels after 14 days trended towards a correlation with height velocity after 6 and 12 months of treatment. Unexpectedly, serum GH levels measured 2 and 28 days after starting rhGH correlated strongly with height velocity after 6 and 12 months of treatment. CONCLUSIONS: This study identified 14 days after starting rhGH treatment as the optimal time for assessing CNP and NTproCNP levels as biomarkers of rhGH efficacy. Additionally, we identified GH levels as a potential biomarker. Larger, prospective studies are now needed to test the clinical utility of these biomarkers.
Asunto(s)
Enanismo/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Péptido Natriurético Tipo-C/sangre , Biomarcadores/sangre , Pesos y Medidas Corporales , Niño , Femenino , Humanos , Masculino , Péptido Natriurético Tipo-C/farmacocinética , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Factores de TiempoRESUMEN
Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss-of-function mutations in short individuals and one gain-of-function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.
Asunto(s)
Enanismo/diagnóstico , Enanismo/genética , Heterocigoto , Mutación , Fenotipo , Receptores del Factor Natriurético Atrial/genética , Alelos , Niño , Preescolar , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Variación Genética , Humanos , Masculino , Linaje , Receptores del Factor Natriurético Atrial/metabolismo , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: C-type natriuretic peptide (CNP) is a paracrine growth factor critical in endochondral bone growth. Amino-terminal CNP (NTproCNP), measurable in plasma, correlates with growth-plate activity and can be used as a biomarker of growth velocity in children. Because severe inflammation in adults increases CNP, we studied CNP peptides and inflammatory markers in children with acute illness. METHODS: Forty-two children aged 2 mo to 5 y with acute illness warranting admission to an acute assessment unit were studied. Fifteen age-matched healthy children attending an outpatient clinic served as controls. Venous CNP concentrations were measured at admission, along with markers of acute inflammation (body temperature, C-reactive protein (CRP), and white blood cell count) in children with acute illness. RESULTS: NTproCNP and CNP SD scores (SDSs) in the acutely ill group were significantly suppressed (P < 0.001) as compared with those of healthy children or healthy population norms. NTproCNP SDS was significantly inversely related to body temperature (r = -0.42, P < 0.01) and CRP (r = -0.56, P < 0.001). CONCLUSION: Acute inflammation in young children potently reduces CNP production, which needs to be considered when screening for growth disorders. Our data raise the possibility that the adverse effects of inflammatory cytokines on skeletal growth may be mediated in part by reduced CNP.
Asunto(s)
Inflamación/sangre , Péptido Natriurético Tipo-C/biosíntesis , Temperatura Corporal , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Preescolar , Humanos , Lactante , Recuento de Leucocitos , Péptido Natriurético Tipo-C/sangreRESUMEN
OBJECTIVE: C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate and plays a key role in endochondral growth. Its amino-terminal propeptide (NTproCNP) is an equimolar product of CNP biosynthesis and is easily measured in plasma. Preliminary studies suggest that NTproCNP levels correlate with height velocity in sheep and children. The objectives of the study were to correlate NTproCNP levels with height velocity and to define the reference range for plasma CNP and NTproCNP across childhood. DESIGN: This was a prospective, cross-sectional, observational study of healthy children. PATIENTS: Participants were 258 healthy children between 2 months and 20 years of age. MEASUREMENTS: Anthropometrics were obtained and CNP and NTproCNP levels were determined by radioimmunoassay. RESULTS: For both sexes, CNP and NTproCNP levels were high in infancy, lower in early childhood, rising during puberty, then falling to low adult levels. Levels of NTproCNP peaked at 14·1 years in boys and 11·9 years in girls, coincident with the age of peak height velocity. Levels of NTproCNP varied with pubertal status, peaking at genital Tanner stage IV in boys and III in girls. There was a highly significant correlation between NTproCNP and height velocity. CONCLUSIONS: C-type natriuretic peptide plays an integral role in endochondral growth. We show here that CNP synthesis (as measured by NTproCNP levels in plasma) is closely related to linear growth in healthy children at all ages. We propose NTproCNP as a biomarker of linear growth.
Asunto(s)
Estatura/fisiología , Desarrollo Infantil/fisiología , Péptido Natriurético Tipo-C/sangre , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Pubertad/sangre , Radioinmunoensayo , Adulto JovenRESUMEN
CONTEXT: Plasma C-type natriuretic peptide (CNP) forms correlate with linear growth velocity in juveniles. In hyperthyroid children, plasma CNP products fall in parallel with height velocity and thyroid hormones (TH) as euthyroidism is restored. The effect of TH on CNP forms after completion of endochondral growth is unknown. OBJECTIVE: To determine the effect of restoring euthyroidism on plasma CNP forms and bone turnover markers (BTMs) in hyperthyroid adults. DESIGN AND SETTING: We performed a prospective observational study in 20 adults (19 women) with acquired hyperthyroidism before and during carbimazole treatment. INTERVENTION AND MAIN OUTCOMES: Blood levels of CNP, amino-terminal propeptide of CNP (NTproCNP), TH and BTMs - bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 amino-terminal propeptide and type 1 collagen C-telopeptide (CTx) - were measured before and during the first 6 months of carbimazole treatment and correlations determined. RESULTS: Both CNP and NTproCNP were significantly correlated with TH at baseline. As in children, decreases in CNP forms were closely associated with fall in TH. Significant associations were found between CNP forms and CTx. CONCLUSIONS: CNP production from tissues other than endochondral cartilage is responsive to TH. Strong temporal links with markers of bone resorption suggest that CNP may also participate in bone remodelling in the adult skeleton.
Asunto(s)
Huesos/metabolismo , Hipertiroidismo/sangre , Péptido Natriurético Tipo-C/sangre , Hormonas Tiroideas/sangre , Adulto , Anciano , Fosfatasa Alcalina/sangre , Carbimazol/uso terapéutico , Colágeno Tipo I/sangre , Femenino , Humanos , Hipertiroidismo/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Osteocalcina/sangre , Estudios Prospectivos , Adulto JovenRESUMEN
CONTEXT: Maternally inherited STX16 deletions that cause loss of methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol once parathyroid hormone (PTH) levels increase, thereby preventing hypocalcemia and associated complications. OBJECTIVE: This study aimed to determine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally. METHODS: Forty-four children of affected (n = 7) or unaffected (n = 7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and thyrotropin (TSH) was advised. RESULTS: The STX16 deletion that causes AD-PHP1B was identified in 25 children. Pretreatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age, and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about 5 years of age. TSH levels showed no consistent rise over time. CONCLUSION: Establishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased, thereby establishing the onset of PTH resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered in order to prevent hypocalcemia and associated sequelae.
Asunto(s)
Herencia Materna , Hormona Paratiroidea/sangre , Seudohipoparatiroidismo/diagnóstico , Sintaxina 16/genética , Calcio/sangre , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Eliminación de Gen , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Masculino , Estudios Prospectivos , Seudohipoparatiroidismo/sangre , Seudohipoparatiroidismo/genética , Índice de Severidad de la Enfermedad , SeudohipoparatiroidismoRESUMEN
CONTEXT: Height velocity (HV) is difficult to assess because growth is very slow. The current practice of calculating it from measurements taken at several-month intervals is insufficient for managing children with growth disorders. We identified a bone growth by-product (collagen X biomarker, CXM) in blood that in preliminary analysis in healthy children correlated strongly with conventionally determined HV and displayed a pattern resembling published norms for HV vs age. OBJECTIVE: The goal was to confirm our initial observations supporting the utility of CXM as an HV biomarker in a larger number of individuals and establish working reference ranges for future studies. DESIGN, SETTINGS, AND PARTICIPANTS: CXM was assessed in archived blood samples from 302 healthy children and 10 healthy adults yielding 961 CXM measurements. A total of 432 measurements were plotted by age, and sex-specific reference ranges were calculated. Serial values from 116 participants were plotted against observed HV. Matched plasma, serum, and dried blood spot readings were compared. RESULTS: A correlation of blood CXM with conventional HV was confirmed. Scatter plots of CXM vs age showed a similar pattern to current HV norms, and CXM levels demarcated the pubertal growth spurt both in girls and boys. CXM levels differed little in matched serum, plasma, and dried blood spot samples. CONCLUSIONS: Blood CXM offers a potential means to estimate HV in real time. Our results establish sex-specific, working reference ranges for assessing skeletal growth, especially over time. CXM stability in stored samples makes it well suited for retrospective studies.
Asunto(s)
Estatura/fisiología , Desarrollo Infantil/fisiología , Colágeno Tipo X/sangre , Adolescente , Biomarcadores/análisis , Biomarcadores/sangre , Desarrollo Óseo/fisiología , Niño , Preescolar , Colágeno Tipo X/análisis , Endocrinología/métodos , Endocrinología/normas , Femenino , Gráficos de Crecimiento , Humanos , Lactante , Masculino , Pautas de la Práctica en Medicina/normas , Estándares de Referencia , Valores de Referencia , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Long-term treatment with high-dose glucocorticoids (GCs) has profound effects on bone metabolism and linear growth. Bone metabolism is a balance between bone resorption by osteoclasts and new bone formation by osteoblasts. Systemically, GC treatment reduces circulating levels of estrogen and modestly increases parathyroid hormone levels. At the local level, GCs decrease insulin-like growth factor I (IGF-I) production, induce IGF-I resistance and increase nuclear factor kappaB ligand production by osteoblasts. These alterations inhibit new bone formation and stimulate bone resorption, with a net loss of bone over time. Clinically, this results in decreased bone mineral density, osteoporosis and increased risk for fracture. Local effects of GCs at the growth plate include reduction of IGF-I production, inducing IGF-I resistance and reducing production of C-type natriuretic peptide, which results in a reduction of chondrocyte proliferation, matrix synthesis and hypertrophy. These reductions in chondrocyte function result in decreased linear growth. CONCLUSIONS: The effects of GCs on bone metabolism and linear growth are sensitive and specific and represent an evolutionary adaptation to redirect resources during times of physiologic stress. Since many of these effects result from alterations in IGF-I production, growth hormone therapy is a potential approach to ameliorate these problems.
Asunto(s)
Huesos/efectos de los fármacos , Cartílago/efectos de los fármacos , Glucocorticoides/efectos adversos , Crecimiento/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Huesos/fisiopatología , Cartílago/fisiopatología , Niño , Humanos , Factor I del Crecimiento Similar a la Insulina/fisiología , Osteoblastos/efectos de los fármacos , Osteoblastos/fisiología , Osteoclastos/efectos de los fármacos , Osteoclastos/fisiología , Osteogénesis/fisiología , OsteoporosisRESUMEN
Reports suggesting that vitamin D may have extraskeletal roles have renewed interest in vitamin D research and stimulated publication of an increasing number of new studies each year. These studies typically assess vitamin D status by measuring the blood concentration of 25-hydroxyvitamin D [25(OH)D], the principal circulating metabolite of vitamin D. Unfortunately, variations in assay format, inconsistency in interpreting 25(OH)D concentrations, cohort bias (age, body mass index, race, season of measurements etc.) and failure to measure critical variables needed to interpret study results, makes interpreting results and comparing studies difficult. Further, variation in reporting results (reporting mean values vs. percent of the cohort that is deficient, no clear statement as to clinical relevance of effect size, etc.) further limits interstudy analyses. In this paper, we discuss many common pitfalls in vitamin D research. We also provide recommendations on avoiding these pitfalls and suggest guidelines to enhance consistency in reporting results.
Asunto(s)
Biomarcadores/sangre , Enfermedades Musculoesqueléticas/sangre , Deficiencia de Vitamina D/complicaciones , Vitamina D/sangre , Vitaminas/sangre , Humanos , Enfermedades Musculoesqueléticas/diagnóstico , Enfermedades Musculoesqueléticas/etiología , Enfermedades Musculoesqueléticas/prevención & controlRESUMEN
CONTEXT: C-type natriuretic peptide (CNP), a paracrine factor of the growth plate, plays a key role in stimulating bone growth. The amino-terminal propeptide of CNP (NTproCNP) is produced in equimolar amounts with CNP and is measurable in plasma, providing a potential biomarker for growth plate activity and, hence, linear growth. OBJECTIVE: We explored the effects of puberty, testosterone, and GH treatment on NTproCNP levels in normal and short-statured children. DESIGN: This was a retrospective analysis of samples obtained during previous studies. SETTING: The study was conducted at a pediatric clinical research center. SUBJECTS: Children with short stature due to GH deficiency, idiopathic short stature (ISS), or constitutional delay of growth and maturation (CDGM) were studied (n = 37). A cohort of normal-statured adolescent boys was also studied (n = 23). INTERVENTIONS: Children with GH deficiency and ISS were studied before and during testosterone and/or GH treatment. Boys with CDGM and healthy controls were studied once. MAIN OUTCOME MEASURES: The main outcomes were NTproCNP levels before and during growth-promoting therapy and during pubertal growth. RESULTS: Children with short stature due to GH deficiency, ISS, or CDGM had comparable baseline levels of NTproCNP, and levels increased markedly in response to GH or testosterone treatment. In boys with CDGM, levels were comparable with height-matched controls but were less than those from age-matched controls. In healthy boys, NTproCNP appears to peak with the pubertal growth spurt. CONCLUSIONS: NTproCNP levels increase during growth-promoting therapy and are increased during puberty in boys. This novel biomarker of growth may have clinical utility in the evaluation of children with short stature and for monitoring growth-promoting therapy.
Asunto(s)
Hormona del Crecimiento/uso terapéutico , Crecimiento/fisiología , Péptido Natriurético Tipo-C/sangre , Pubertad/sangre , Testosterona/uso terapéutico , Adolescente , Antropometría , Composición Corporal/efectos de los fármacos , Composición Corporal/fisiología , Estatura/fisiología , Estudios de Cohortes , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Genitales Masculinos/crecimiento & desarrollo , Hormona del Crecimiento/efectos adversos , Hormona de Crecimiento Humana/deficiencia , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Fragmentos de Péptidos/sangre , Proteínas/metabolismo , Caracteres Sexuales , Testosterona/efectos adversosRESUMEN
CONTEXT: C-type natriuretic peptide (CNP) is an important regulator of skeletal growth. Loss-of-function mutations affecting the CNP receptor natriuretic peptide receptor-B (gene NPR2) cause the autosomal recessive skeletal dysplasia, acromesomelic dysplasia, Maroteaux type (AMDM). The phenotype of heterozygous carriers of NPR2 mutations is less clear. OBJECTIVE: The objective of the study was to determine the phenotypic features of heterozygous carriers of NPR2 mutations. DESIGN AND SETTING: This was a case-control study from the general community. SUBJECTS: Thirty-nine members of a family in which one member has AMDM were studied. INTERVENTION: This was an observational study. MAIN OUTCOME MEASURE: The primary measure was stature, with the hypothesis that carriers have reduced stature compared with noncarriers. RESULTS: Sixteen family members were NPR2 mutation carriers. Height z-scores of these carriers were -1.8 +/- 1.1 (mean +/- sd), which was significantly less than the 23 noncarrier family members (-0.4 +/- 0.8, P < 0.0005) and the general population (P < 0.0005). However, there was no difference in body proportion between carriers and noncarriers. The proband with AMDM had low IGF-I levels and evidence of GH resistance, as well as very high plasma levels of CNP and its amino-terminal propeptide. Levels of these peptides were normal in the heterozygous carriers. CONCLUSIONS: We have shown that heterozygous mutations in NPR2 are associated with short stature. Assuming one in 700 people unknowingly carry an NPR2 mutation, our data suggest that approximately one in 30 individuals with idiopathic short stature are carriers of NPR2 mutations.
Asunto(s)
Estatura/fisiología , Guanilato Ciclasa/genética , Mutación/fisiología , Receptores del Factor Natriurético Atrial/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antropometría , Peso Corporal/genética , Estudios de Casos y Controles , Niño , Preescolar , ADN/genética , Femenino , Genotipo , Heterocigoto , Humanos , Inmunoensayo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
C-type natriuretic peptide (CNP), acting through its receptor, natriuretic peptide receptor-B (NPR-B), plays a critical role in linear growth. Knockout mice for CNP and NPR-B are dwarfed, and transgenic mice overexpressing CNP are overgrown. CNP has a direct regulatory effect on growth plate chondrocytes, acting primarily to promote terminal differentiation and hypertrophy. In humans, homozygous NPR-B mutations are the cause of acromesomelic dysplasia, Maroteaux type (AMDM), a severe form of disproportionate dwarfism. A patient with AMDM and the NPR-B knockout mouse both have low insulin-like growth factor I (IGF-I) levels, suggesting an interaction between these regulatory systems. Heterozygous carriers of NPR-B mutations also have reduced stature, but no other abnormalities. Hence, heterozygous NPR-B mutations are another cause of "idiopathic" short stature. The CNP-NPR-B system has only recently been found to be an important regulator of human growth, and abnormalities in this system have clinical implications. Considerable work is needed to further understand this new paradigm of human growth regulation.
Asunto(s)
Placa de Crecimiento/metabolismo , Crecimiento y Desarrollo/fisiología , Péptido Natriurético Tipo-C/fisiología , Animales , Humanos , Modelos Biológicos , Péptido Natriurético Tipo-C/químicaRESUMEN
CONTEXT: C-type natriuretic peptide (CNP) is a crucial regulator of endochondral bone growth. In a previous report of a child with acromesomelic dysplasia, Maroteaux type (AMDM), caused by loss-of-function of the CNP receptor (natriuretic peptide receptor-B [NPR-B]), plasma levels of CNP were elevated. In vitro studies have shown that activation of the MAPK kinase (MEK)/ERK MAPK pathway causes functional inhibition of NPR-B. Achondroplasia, hypochondroplasia, and thanatophoric dysplasia are syndromes of short-limbed dwarfism caused by activating mutations of fibroblast growth factor receptor-3, which result in overactivation of the MEK/ERK MAPK pathway. OBJECTIVE: The purpose of this study was to determine whether these syndromes exhibit evidence of CNP resistance as reflected by increases in plasma CNP and its amino-terminal propeptide (NTproCNP). DESIGN: This was a prospective, observational study. SUBJECTS: Participants were 63 children and 20 adults with achondroplasia, 6 children with hypochondroplasia, 2 children with thanatophoric dysplasia, and 4 children and 1 adult with AMDM. RESULTS: Plasma levels of CNP and NTproCNP were higher in children with achondroplasia with CNP SD scores (SDSs) of 1.0 (0.3-1.4) (median [interquartile range]) and NTproCNP SDSs of 1.4 (0.4-1.8; P < .0005). NTproCNP levels correlated with height velocity. Levels were also elevated in adults with achondroplasia (CNP SDSs of 1.5 [0.7-2.1] and NTproCNP SDSs of 0.5 [0.1-1.0], P < .005). In children with hypochondroplasia, CNP SDSs were 1.3 (0.7-1.5) (P = .08) and NTproCNP SDSs were 1.9 (1.8-2.3) (P < .05). In children with AMDM, CNP SDSs were 1.6 (1.4-3.3) and NTproCNP SDSs were 4.2 (2.7-6.2) (P < .01). CONCLUSIONS: In these skeletal dysplasias, elevated plasma levels of proCNP products suggest the presence of tissue resistance to CNP.
Asunto(s)
Acondroplasia/sangre , Huesos/anomalías , Enanismo/sangre , Deformidades Congénitas de las Extremidades/sangre , Lordosis/sangre , Péptido Natriurético Tipo-C/sangre , Displasia Tanatofórica/sangre , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The most common cause of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency. The molecular genetics of this disease are such that genotyping is a potentially useful tool in its diagnosis. An assay was developed using real-time, quantitative PCR to detect deletions of the steroid 21-hydroxylase gene (CYP21A2). This assay was able to detect heterozygous gene deletions with an alpha error rate of less than 5%, with a power greater than 95%. When combined with allele-specific PCR, genotyping for the nine most common mutations can be completed within hours of blood sampling. This technique was used to study subjects with 21-hydroxylase deficiency in North Florida. Twenty-eight subjects with congenital adrenal hyperplasia, seven first-degree relatives and thirteen normal subjects, were characterized. Of 96 chromosomes, 69 abnormal alleles were identified. Among unrelated abnormal alleles, the frequency of specific mutations was 28% for a gene deletion, 24% for the intron 2 splice mutation, 10% for ile172asn, 8% each for val281leu and the exon 6 cluster, and 6% for gln318x mutations. These frequencies, as well as the genotype/phenotype correlation, were similar to those found in comparable populations. The utility of genotyping in the diagnosis of 21-hydroxylase deficiency is increased by the rapidity of the analysis. With quantitative PCR, the need for more expensive and time consuming Southern blot analysis is reduced and limited to the clarification of certain genotypes. Faster results will allow for more timely initiation of appropriate therapy and limit the exposure of potentially unnecessary therapy.
Asunto(s)
Sistemas de Computación , Reacción en Cadena de la Polimerasa/métodos , Esteroide 21-Hidroxilasa/genética , Conservación de la Sangre , Niño , ADN/sangre , ADN/genética , Femenino , Eliminación de Gen , Genotipo , Humanos , Recién Nacido , Masculino , Fenotipo , Mutación Puntual , Valores de ReferenciaRESUMEN
CONTEXT: B-type natriuretic peptide (BNP) expression in vitro is up-regulated by the protein coded by the short stature homeobox gene (SHOX). C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate that plays a key role in endochondral growth and shares clearance pathways with BNP. We explored the possibility that alterations in natriuretic peptide regulation may play a role in the overgrowth of boys with Klinefelter syndrome. OBJECTIVE: The objectives of the study were to document the blood levels of amino-terminal propeptide of B-type natriuretic peptide (NTproBNP), CNP, and its amino-terminal propeptide (NTproCNP) in boys with Klinefelter syndrome and compare values with age- and height-matched control subjects. DESIGN: This was a prospective, case-controlled, observational study. SUBJECTS: Participants were 24 healthy boys with Klinefelter syndrome between 4 and 14 yr of age. Data from sex-, age-, and height-matched healthy controls were obtained from subjects participating in a previously described study. RESULTS: Plasma levels of NTproBNP and CNP were lower, whereas levels of NTproCNP were higher in boys with Klinefelter syndrome compared with published reference ranges. In addition, CNP levels were lower and NTproCNP levels higher than in sex-, age-, and height-matched controls. CONCLUSIONS: In contrast to plasma NTproBNP, CNP production and clearance are increased in boys with Klinefelter syndrome. Together these findings argue against an interaction between BNP with CNP in the growth plate. Why CNP peptide levels are altered in Klinefelter syndrome remains to be explored.
Asunto(s)
Síndrome de Klinefelter/sangre , Péptido Natriurético Tipo-C/sangre , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Humanos , Masculino , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Estudios ProspectivosRESUMEN
OBJECTIVE: We performed a case-control study to determine whether occult bone disease is associated with a history of frequent fractures in children. METHODS: Healthy children with > or = 2 incidences of low-energy fractures were recruited (n = 68). Children with no history of fractures served as control subjects (n = 57). Food logs, activity surveys, physical examinations, laboratory tests, and dual-energy radiographic absorptiometry were used. RESULTS: Bone mineral density z scores were significantly reduced in case subjects, compared with control subjects. Three case subjects (4.3%) and 1 control subject (1.8%) had bone mineral density z scores below the expected range. Of those 4 subjects, 2 had dairy avoidance and 2 had delayed puberty. An additional case subject had evidence of vitamin D deficiency. A significant number of subjects (20% of case subjects and 23% of control subjects) had idiopathic hypercalcuria, based on 24-hour urine collections. Among the case subjects, bone mineral density z scores were significantly lower for those with idiopathic hypercalcuria. Among the control subjects, the presence of idiopathic hypercalcuria did not affect bone mineral density. The case subjects with idiopathic hypercalcuria accounted for virtually all of the differences in bone mineral density between the case and control groups. Analysis of parathyroid hormone and 1,25-dihydroxy-vitamin D levels showed that children with frequent fractures and hypercalcuria had renal hypercalcuria, whereas children with no fractures and hypercalcuria had absorptive hypercalcuria. CONCLUSIONS: We identified a significant association between a history of frequent fractures and hypercalcuria in children. We propose that the appropriate screening evaluation for children who present with a history of frequent fractures consists of a dietary history targeted at calcium and vitamin D intakes, a physical examination to assess for pubertal delay, and urinary calcium concentration/creatinine ratio determination to assess for hypercalcuria. Children with abnormalities in this screening should undergo dual-energy radiographic absorptiometry and appropriate evaluation.
Asunto(s)
Enfermedades Óseas Metabólicas/diagnóstico , Fracturas Óseas/etiología , Absorciometría de Fotón , Adolescente , Densidad Ósea , Enfermedades Óseas Metabólicas/complicaciones , Calcio/orina , Niño , Preescolar , Dieta , Ejercicio Físico , Femenino , Humanos , Masculino , Deficiencia de Vitamina DRESUMEN
A unique heterozygous 3-kb microdeletion within STX16, a closely linked gene centromeric of GNAS, was previously identified in multiple unrelated kindreds as a cause of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib). We now report a novel heterozygous 4.4-kb microdeletion in a large kindred with AD-PHP-Ib. Affected individuals from this kindred share an epigenetic defect that is indistinguishable from that observed in patients with AD-PHP-Ib who carry the 3-kb microdeletion in the STX16 region (i.e., an isolated loss of methylation at GNAS exon A/B). The novel 4.4-kb microdeletion overlaps with the previously identified deletion by 1,286 bp and, similar to the latter deletion, removes several exons of STX16 (encoding syntaxin-16). Because these microdeletions lead to AD-PHP-Ib only after maternal transmission, we analyzed expression of this gene in lymphoblastoid cells of affected individuals with the 3-kb or the 4.4-kb microdeletion, an individual with a NESP55 deletion, and a healthy control. We found that STX16 mRNA was expressed in all cases from both parental alleles. Thus, STX16 is apparently not imprinted, and a loss-of-function mutation in one allele is therefore unlikely to be responsible for this disorder. Instead, the region of overlap between the two microdeletions likely harbors a cis-acting imprinting control element that is necessary for establishing and/or maintaining methylation at GNAS exon A/B, thus allowing normal G alpha(s) expression in the proximal renal tubules. In the presence of either of the two microdeletions, parathyroid hormone resistance appears to develop over time, as documented in an affected individual who was diagnosed at birth with the 4.4-kb deletion of STX16 and who had normal serum parathyroid hormone levels until the age of 21 mo.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Seudohipoparatiroidismo/genética , Proteínas de Transporte Vesicular/genética , Cromograninas , Metilación de ADN , Femenino , Eliminación de Gen , Genes Dominantes , Impresión Genómica , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Sintaxina 16RESUMEN
Growth hormone (GH) is a peptide hormone secreted from the pituitary gland under the control of the hypothalamus. It has a many actions in the body, including regulating a number of metabolic pathways. Some, but not all, of its effects are mediated through insulin-like growth factor-I (IGF-I). Both GH and IGF-I play significant roles in the regulation of growth and bone metabolism and hence are regulators of bone mass. Bone mass increases steadily through childhood, peaking in the mid 20s. Subsequently, there is a slow decline that accelerates in late life. During childhood, the accumulation in bone mass is a combination of bone growth and bone remodeling. Bone remodeling is the process of new bone formation by osteoblasts and bone resorption by osteoclasts. GH directly and through IGF-I stimulates osteoblast proliferation and activity, promoting bone formation. It also stimulates osteoclast differentiation and activity, promoting bone resorption. The result is an increase in the overall rate of bone remodeling, with a net effect of bone accumulation. The absence of GH results in a reduced rate of bone remodeling and a gradual loss of bone mineral density. Bone growth primarily occurs at the epiphyseal growth plates and is the result of the proliferation and differentiation of chondrocytes. GH has direct effects on these chondrocytes, but primarily regulates this function through IGF-I, which stimulates the proliferation of and matrix production by these cells. GH deficiency severely limits bone growth and hence the accumulation of bone mass. GH deficiency is not an uncommon complication in oncology and has long-term effects on bone health.
Asunto(s)
Densidad Ósea , Desarrollo Óseo/fisiología , Hormona de Crecimiento Humana/fisiología , Animales , Curación de Fractura/fisiología , Hormona de Crecimiento Humana/farmacología , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismoRESUMEN
Linear growth occurs as the result of growth plate chondrocytes undergoing proliferative and hypertrophic phases. Paracrine feedback loops that regulate the entry of chondrocytes into the hypertrophic phase have been shown and similar pathways likely exist for the proliferative phase. Human long-bone growth plate chondrocytes were cultured in vitro. The proliferative effects of a variety of factors were determined by [3H]thymidine uptake and the gene expression profile of these cells was determined by DNA microarray analysis. Serum, insulin-like growth factor (IGF)-I and -II, transforming growth factor-beta (TGF-beta, fibroblast growth factor (FGF)-1, -2, and -18, and platelet-derived growth factor (PDGF)-BB were potent stimulators of proliferation. FGF-10, testosterone, and bone morphogenetic proteins (BMP)-2, -4, and -6 inhibited proliferation. Microarray analysis showed that the genes for multiple members of the IGF-I, TGF-beta, FGF, and BMP pathways were expressed, suggesting the presence of autocrine/paracrine pathways that regulate the proliferative phase of growth plate-mediated growth.