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1.
Front Endocrinol (Lausanne) ; 12: 707283, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34721288

RESUMEN

Objective: Vitamin D is critical for calcium and bone metabolism. Vitamin D insufficiency impairs skeletal mineralization and bone growth rate during childhood, thus affecting height and health. Vitamin D status in children with short stature is sparsely reported. The purpose of the current study was to investigate various vitamin D components by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to better explore vitamin D storage of short-stature children in vivo. Methods: Serum circulating levels of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3], and 3-epi-25-hydroxyvitamin D3 [3-epi-25(OH)D3, C3-epi] were accurately computed using the LC-MS/MS method. Total 25(OH)D [t-25(OH)D] and ratios of 25(OH)D2/25(OH)D3 and C3-epi/25(OH)D3 were then respectively calculated. Free 25(OH)D [f-25(OH)D] was also measured. Results: 25(OH)D3 and f-25(OH)D levels in short-stature subgroups 2 (school age: 7~12 years old) and 3 (adolescence: 13~18 years old) were significantly lower compared with those of healthy controls. By contrast, C3-epi levels and C3-epi/25(OH)D3 ratios in all the three short-stature subgroups were markedly higher than the corresponding healthy cases. Based on cutoff values developed by Endocrine Society Recommendation (but not suitable for methods 2 and 3), sufficient storage capacities of vitamin D in short-stature subgroups 1, 2, and 3 were 42.8%, 23.8%, and 9.0% as determined by Method 3 [25(OH)D2/3+25(OH)D3], which were lower than those of 57.1%, 28.6%, and 18.2% as determined by Method 1 [25(OH)D2+25(OH)D3+C3-epi] and 45.7%, 28.5%, and 13.6% as determined by Method 2 [25(OH)D2/3+25(OH)D3+C3-epi]. Levels of 25(OH)D2 were found to be weakly negatively correlated with those of 25(OH)D3, and higher 25(OH)D3 levels were positively correlated with higher levels of C3-epi in both short-stature and healthy control cohorts. Furthermore, f-25(OH)D levels were positively associated with 25(OH)D3 and C3-epi levels in children. Conclusions: The current LC-MS/MS technique can not only separate 25(OH)D2 from 25(OH)D3 but also distinguish C3-epi from 25(OH)D3. Measurement of t-25(OH)D [25(OH)D2+25(OH)D3] alone may overestimate vitamin D storage in children, and short-stature children had lower vitamin D levels compared with healthy subjects. Ratios of C3-epi/25(OH)D3 and 25(OH)D2/25(OH)D3 might be alternative markers for vitamin D catabolism/storage in short-stature children. Further studies are needed to explore the relationships and physiological roles of various vitamin D metabolites.


Asunto(s)
Biomarcadores/sangre , Cromatografía Líquida de Alta Presión/métodos , Enanismo/patología , Trastornos del Crecimiento/patología , Espectrometría de Masas en Tándem/métodos , Deficiencia de Vitamina D/fisiopatología , Vitamina D/sangre , 25-Hidroxivitamina D 2/sangre , Adolescente , Estatura , Calcifediol/sangre , Estudios de Casos y Controles , Niño , Enanismo/sangre , Femenino , Estudios de Seguimiento , Trastornos del Crecimiento/sangre , Humanos , Masculino , Pronóstico , Deficiencia de Vitamina D/sangre , Vitaminas/sangre
2.
Clin Genet ; 100(5): 601-606, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34272725

RESUMEN

In 2016 a new syndrome with postnatal short stature and low IGF1 bioavailability caused by biallelic loss-of-function mutations in the gene encoding the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) was described in two families. Here we report two siblings of a third family from Saudi Arabia with postnatal growth retardation and decreased IGF1 availability due to a new homozygous nonsense mutation (p.Glu886* in exon 7) in PAPPA2. The two affected males showed progressively severe short stature starting around 8 years of age, moderate microcephaly, decreased bone mineral density, and high circulating levels of total IGF1, IGFBP3, and the IGF acid-labile subunit (IGFALS), with decreased free IGF1 concentrations. Interestingly, circulating IGF2 and IGFBP5 were not increased. An increase in growth velocity and height was seen in the prepuberal patient in response to rhIGF1. These patients contribute to the confirmation of the clinical picture associated with PAPP-A2 deficiency and that the PAPPA2 gene should be studied in all patients with short stature with this characteristic phenotype. Hence, pediatric endocrinologists should measure circulating PAPP-A2 levels in the study of short stature as very low or undetectable levels of this protein can help to focus the diagnosis and treatment.


Asunto(s)
Enanismo/diagnóstico , Enanismo/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Factor I del Crecimiento Similar a la Insulina/metabolismo , Fenotipo , Proteína Plasmática A Asociada al Embarazo/deficiencia , Adolescente , Biomarcadores , Enanismo/sangre , Familia , Femenino , Estudios de Asociación Genética/métodos , Humanos , Mutación con Pérdida de Función , Masculino , Radiografía , Arabia Saudita , Hermanos
3.
BMC Endocr Disord ; 20(1): 119, 2020 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-32746834

RESUMEN

BACKGROUND: The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is critical for the regulation of children's growth and development. Serum IGF-1 concentrations are usually low in individuals with idiopathic short stature (ISS) despite normal endogenous GH levels, and the associated underlying factors are unknown. This study aimed to explore the relationship between IGF-1 and hemoglobin (Hb) in children with ISS. METHODS: A cross-sectional analysis was performed including 178 children and adolescents with ISS who were enrolled from March 2013 to February 2019. The related clinical and biochemical parameters were evaluated for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were performed. RESULT: The mean levels of IGF-1 standard deviation scores (SDS) and Hb were - 0.99 (- 1.60 - -0.09) and 131.81 ± 9.36 g/L, respectively. Univariate analysis displayed a significant positive association between Hb and IGF-1 SDS (P < 0.001). After adjusting for potential confounding factors, the positive relationship between Hb and IGF-1 SDS remained (P = 0.001). Furthermore, there was an inflection point for Hb in the curve. In a multivariate piecewise linear regression model, IGF-1 SDS was significantly positively associated with Hb when Hb concentrations were lower than 145 g/L (B 0.05; 95% CI 0.02, 0.07; P < 0.001). However, IGF-1 SDS decreased with increasing Hb levels when Hb concentrations were greater than 145 g/L (B -0.15; 95% CI -0.23, - 0.06; P = 0.001). CONCLUSION: This study demonstrated that Hb is associated with IGF-1 in Chinese children and adolescents with ISS. The levels of IGF-1 increased with the elevation of Hb, but when the concentration of Hb exceeded a certain range, with the increase of Hb, IGF-1 decreased instead.


Asunto(s)
Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/epidemiología , Hemoglobinas/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Adolescente , Estatura , Niño , China/epidemiología , Estudios Transversales , Enanismo/sangre , Enanismo/epidemiología , Femenino , Hemoglobinas/análisis , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino
4.
Genes Genomics ; 42(8): 847-854, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32506268

RESUMEN

BACKGROUND: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare skeletal dysplasia following autosomal recessive mode of inheritance and characterized by abnormal growth plates, short and abnormal bones in the extremities and spine. OBJECTIVE: Present study was designed to report the molecular basis of AMDM in enrolled consanguineous family from Pakistan. METHODS: A consanguineous family from Vehari District in Pakistan having multiple siblings suffering from AMDM was enrolled in present study. Whole exome sequencing (WES) approach was adopted to identify causative agent of AMDM. Human full length NPR2 gene and sequence with nonsense mutation was amplified by using Myc-tagged pXN vector and transformed in E. coli DH5α cells to confirm mutation. SDS-PAGE and Western blotting were done to confirm the production of truncated protein. Computational three dimensional structure generation through homology modeling approach was done to compare protein structure between patients and controls. RESULTS: WES reveled a nonsense mutation (c.613 C>T, p.R205X) in exon 1 of NPR2 gene leading to premature termination codon in mRNA of NPR2 gene resulting in a truncated protein with 204 amino acid residues that was confirmed by SDS-PAGE and Western blotting. Sanger sequencing confirmed that mutation in all subjects and mutation followed Mendalian pattern of inheritance. Multiple sequence alignment by ClustalW revealed that mutated domain of NPR2 is conserved region. Proetin structure comparison revealed a significant structural part of NPR2 was missing in truncated protein as compared to control. CONCLUSION: We are reporting that a novel nonsense mutation (c.613 C>T, p.R205X) in exon 1 of NPR2 gene is causing AMDM in a consanguineous Pakistani family.


Asunto(s)
Codón sin Sentido , Enanismo/genética , Osteocondrodisplasias/genética , Receptores del Factor Natriurético Atrial/genética , Consanguinidad , Enanismo/sangre , Escherichia coli , Femenino , Células HEK293 , Humanos , Masculino , Osteocondrodisplasias/sangre , Pakistán , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa/métodos , Receptores del Factor Natriurético Atrial/sangre , Secuenciación del Exoma/métodos
5.
J Hum Genet ; 65(9): 743-750, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32313197

RESUMEN

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Enanismo/genética , Discapacidad Intelectual/genética , Proteínas de Transporte de Monosacáridos/genética , Alelos , Preescolar , Cromatografía Liquida , Trastornos Congénitos de Glicosilación/sangre , Trastornos Congénitos de Glicosilación/complicaciones , Enanismo/sangre , Enanismo/complicaciones , Enanismo/fisiopatología , Femenino , Estudios de Asociación Genética , Glicómica , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Proteínas de Transporte de Monosacáridos/química , Mutación Missense , Plasma/química , Plasma/inmunología , Plasma/metabolismo , Estudios Retrospectivos , Alineación de Secuencia , Espectrometría de Masas en Tándem , Secuenciación del Exoma
6.
PLoS One ; 14(10): e0224103, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31648221

RESUMEN

BACKGROUND: Midkine (MDK), one of the heparin-binding growth factors, is highly expressed in multiple organs during embryogenesis. Plasma concentrations have been reported to be elevated in patients with a variety of malignancies, in adults with obesity, and in children with short stature, diabetes, and obesity. However, the concentrations in healthy children and their relationships to age, nutrition, and linear growth have not been well studied. SUBJECTS AND METHODS: Plasma MDK was measured by immunoassay in 222 healthy, normal-weight children (age 0-18 yrs, 101 boys), 206 healthy adults (age 18-91 yrs, 60 males), 61 children with BMI ≥ 95th percentile (age 4-18 yrs, 20 boys), 20 girls and young women with anorexia nervosa (age 14-23 yrs), and 75 children with idiopathic short stature (age 3-18 yrs, 42 boys). Body fat was evaluated by dual-energy X-ray absorptiometry (DXA) in a subset of subjects. The associations of MDK with age, sex, adiposity, race/ethnicity and stature were evaluated. RESULTS: In healthy children, plasma MDK concentrations declined with age (r = -0.54, P < 0.001) with values highest in infants. The decline occurred primarily during the first year of life. Plasma MDK did not significantly differ between males and females or between race/ethnic groups. MDK concentrations were not correlated with BMI SDS, fat mass (kg) or percent total body fat, and no difference in MDK was found between children with anorexia nervosa, healthy weight and obesity. For children with idiopathic short stature, MDK concentrations did not differ significantly from normal height subjects, or according to height SDS or IGF-1 SDS. CONCLUSIONS: In healthy children, plasma MDK concentrations declined with age and were not significantly associated with sex, adiposity, or stature-for-age. These findings provide useful reference data for studies of plasma MDK in children with malignancies and other pathological conditions.


Asunto(s)
Adiposidad , Biomarcadores/sangre , Enanismo/diagnóstico , Trastornos del Crecimiento/diagnóstico , Midkina/sangre , Obesidad/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Enanismo/sangre , Femenino , Trastornos del Crecimiento/sangre , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Obesidad/sangre , Adulto Joven
7.
Biomed Res Int ; 2019: 5939372, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31073528

RESUMEN

OBJECTIVE: This study aimed to examine the relationship between serum alanine aminotransferase (ALT) and growth hormone (GH) in children and adolescents with short stature. METHODS: In this retrospective cohort study, 670 Chinese children and adolescents with short stature were included, and 253 of them received recombinant human GH (rhGH) therapy. Anthropometric and biochemical indicators were measured. GH peak levels were assessed after provocation tests with L-dopa and insulin. The subjects were divided into 3 groups according to the GH peak level. The association between the GH peak and ALT was analyzed. The change of ALT during rhGH therapy was assessed by a generalized additive mixed model. RESULTS: Serum ALT and incidence of ALT elevation were both decreased across the GH tertiles (P = 0.002, 0.012, respectively). A univariate analysis showed that the GH peak was negatively associated with ALT (ß: -0.12; 95%CI: -0.22, -0.02; P = 0.023). Furthermore, multiple linear stepwise regression analysis demonstrated that the GH peak was independently related to ALT after adjusting for other confounding variables (ß: -0.12; 95%CI: -0.24, -0.00; P = 0.042). Besides, mean values of the change in ALT from baseline displayed that, during the early stages of rhGH treatment, serum ALT level indicated a temporary upward trend, but it subsequently gradually decreased (ß: -0.16; 95%CI: -0.23, -0.09; P < 0.001). CONCLUSIONS: GH secretion level was strongly negatively correlated with ALT in short children and adolescents. And rhGH therapy could reduce ALT level over time.


Asunto(s)
Alanina Transaminasa/sangre , Enanismo/sangre , Hormona del Crecimiento/sangre , Proteínas Recombinantes/administración & dosificación , Adolescente , Antropometría , Estatura , Niño , China , Enanismo/tratamiento farmacológico , Enanismo/fisiopatología , Femenino , Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/genética , Humanos , Insulina/sangre , Levodopa/sangre , Masculino , Proteínas Recombinantes/genética
8.
Growth Factors ; 36(3-4): 172-177, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30304969

RESUMEN

Fibroblast growth factor 21 (FGF21) is mainly secreted by the liver. It is a factor that is not fully understood in relation to growth. Sirtuin 1 (SIRT1) is a deacetylase protein. It is thought that may have an effect on the release and function of GH and IGF-1. Visfatin is synthesized from adipose tissue as primary. It may be prognostic marker associated with growth factors. As a result of our work, FGF21 is not associated with short stature but levels of SIRT1 and visfatin are associated with short stature. The decrease in visfatin value in the short-stature group is thought to be due to an insufficient amount of adipose tissue, which is important for growth and development. SIRT1 might decrease GH effect by increasing STAT5 deacetylation in the liver and we think that the result of this reduction of SIRT1 would negatively impact IGF-1 and IGFBP-3 production.


Asunto(s)
Estatura , Enanismo/sangre , Factores de Crecimiento de Fibroblastos/sangre , Nicotinamida Fosforribosiltransferasa/sangre , Sirtuina 1/sangre , Biomarcadores/sangre , Niño , Humanos , Masculino
9.
Endocrinol Diabetes Nutr (Engl Ed) ; 65(10): 584-591, 2018 Dec.
Artículo en Inglés, Español | MEDLINE | ID: mdl-30143447

RESUMEN

INTRODUCTION AND OBJECTIVES: Growth hormone (rhGH) is used in children with intrauterine growth retardation without catch-up growth. The Advisory Committee of Castilla y León was implemented in 2010 to watch for consistent application of the criteria for using rhGH. The aim is to assess anthropometric and clinical changes in children treated with growth hormone. PATIENTS AND METHODS: A retrospective, longitudinal study of patients diagnosed with intrauterine growth retardation without catch-up growth in Castilla y León since 2010 who have received treatment for at least 3 years. Changes in anthropometric, clinical, and laboratory parameters were assessed. RESULTS: Forty-three children with a mean age of 6.06 years (58.14%<5 years) were enrolled and treated with a mean dose of 0.038mg/kg/day. A significant increase was seen in height (-3.05 to -1.58SD). Both weight and BMI (14.51 to 15.80kg/m2) increased throughout the study. Growth rate peaked during the first year of treatment (0.74SD). IGF-1 levels increased throughout the study (99.96 to 392.88ng/mL). There were significant increases in glycosylated hemoglobin levels in the first year, and in basal blood glucose and insulin levels during the second year. The LDL/HDL ratio decreased during the study period (1.70 to 1.50). CONCLUSION: Treatment with rhGH promotes growth in children with intrauterine growth retardation. Peak effect occurs in the first 12 months of treatment, and is greater when growth hormone is started before the age of 5 years.


Asunto(s)
Enanismo/tratamiento farmacológico , Retardo del Crecimiento Fetal , Hormona del Crecimiento/uso terapéutico , Glucemia/análisis , Estatura/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Niño , Preescolar , Esquema de Medicación , Resistencia a Medicamentos , Enanismo/sangre , Enanismo/embriología , Estudios de Seguimiento , Edad Gestacional , Hemoglobina Glucada/análisis , Humanos , Recien Nacido Prematuro , Enfermedades del Prematuro/tratamiento farmacológico , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Lípidos/sangre , Lipoproteínas/sangre , Estudios Retrospectivos , España , Resultado del Tratamiento
10.
Growth Horm IGF Res ; 40: 17-19, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29653372

RESUMEN

As a result of our publication of the first patients with short stature due to a mutation in the gene for PAPP-A2 the question, "Why did you continue to study these patients when they were not more than 2 SDS below normal?" has been proposed surprisingly frequently. We would like to communicate our opinions on why these patients were studied and share the experience on how this process took place. In addition, the choice of treatment is also discussed. We believe that this discovery process is a good example of good clinical practice and international collaboration.


Asunto(s)
Biomarcadores/análisis , Enanismo/diagnóstico , Factor I del Crecimiento Similar a la Insulina/análisis , Mutación , Proteína Plasmática A Asociada al Embarazo/genética , Niño , Enanismo/sangre , Enanismo/genética , Femenino , Humanos , Pronóstico
11.
J Endocrinol Invest ; 41(8): 977-983, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29423542

RESUMEN

PURPOSE: To describe the course of growth hormone response to growth hormone releasing hormone (GHRH) plus arginine provocative test in children with idiopathic short stature (ISS) and to evaluate the role of peak time. METHODS: A retrospective study was performed analyzing 344 GHRH plus arginine provocative tests performed in children and adolescents with short stature. Serum GH levels were measured at four-time points (T0', T30', T45' and T60') and GH peak was defined as the maximum value at any time point. Mean (T30'-T60') GH value and area under the curve (AUC) were calculated. RESULTS: When analyzing the time of peak at the provocative test, the most frequent peak time was T45' (53.8%) in the ISS group, with no differences in gender, age, and pubertal stage. Analyzing GHD subjects, the most frequent time of peak was T30 (50%). Analyzing the whole population, the GH T0' levels were significantly lower in subjects with the GH peak at T45' than those with the GH peak at T30' (1.7 ± 2.0 vs. 3.2 ± 4.0, p < 0.001). In subjects with GH peak at T45', the value of GH peak, AUC and mean GH were significantly higher than in those with GH peak at T30' and T60'. A direct correlation was found between the value of GH peak and growth velocity SDS (r = 0.127, p = 0.04) and a negative one between GH peak and GH level at T0' (r = - 0.111, p = 0.04), even when adjusted for gender, age, pubertal stage and BMI Z score. CONCLUSIONS: The time peak at 45 min seems to be associated with a better response to the test considering GH peak, mean and AUC. Patients with a GH peak at 30 min more probably could have a derangement in GH secretion showing worst growth pattern and/or a GH deficiency and should be carefully observed.


Asunto(s)
Arginina/administración & dosificación , Enanismo/sangre , Enanismo/tratamiento farmacológico , Hormona Liberadora de Hormona del Crecimiento/administración & dosificación , Hormona de Crecimiento Humana/sangre , Inmunoensayo/métodos , Adolescente , Niño , Preescolar , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Estudios Retrospectivos
12.
J Int Med Res ; 46(2): 761-772, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28974136

RESUMEN

Objective To investigate the basal amino acid metabolism and impact of growth hormone (GH) therapy in short-stature children born small for gestational age (short SGA children). Methods In this age-matched case-control study, the basal blood levels of amino acids, asymmetric dimethylarginine (ADMA), and nitrite/nitrate (NOx) were compared between 24 short SGA children and 25 age-matched normal children. Changes in these parameters were assessed for 12 months in 12 short SGA children initiating GH therapy (Group A) and 12 age-matched short SGA children without GH therapy (Group B). Results The arginine levels were significantly lower in the short SGA than in normal children. The ADMA levels were significantly higher and NOx levels were significantly lower in the short SGA than normal children. In Group A, the ADMA level was significantly lower and NOx level was significantly higher at 6 months than at baseline. At 12 months, the ADMA level in Group A began to increase, but the NOx level remained the same. Group B showed no significant changes. Conclusions This study is the first to show that ADMA is promoted and nitric oxide is suppressed in short SGA children and that GH therapy affects the production of ADMA and nitric oxide.


Asunto(s)
Arginina/análogos & derivados , Enanismo/tratamiento farmacológico , Hormona del Crecimiento/uso terapéutico , Nitratos/sangre , Nitritos/sangre , Arginina/sangre , Biomarcadores/sangre , Estatura/efectos de los fármacos , Estudios de Casos y Controles , Niño , Preescolar , Enanismo/sangre , Enanismo/diagnóstico , Enanismo/fisiopatología , Femenino , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional/sangre , Recién Nacido Pequeño para la Edad Gestacional/crecimiento & desarrollo , Estudios Longitudinales , Masculino
13.
J Pediatr Endocrinol Metab ; 30(4): 427-430, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28301320

RESUMEN

BACKGROUND: The majority of children who present for evaluation of tall stature fall under the diagnosis of constitutional tall stature (CTS). METHODS: To investigate mechanisms of tall stature, we evaluated serum IGF-I values and the expression of the GHR gene in the peripheral blood cells of 46 subjects with normal height, 38 with tall stature and 30 healthy children with short stature. RESULTS: Our results showed significantly lower IGF-I levels in children with short stature (-0.57±0.18 SDS) compared to control children (0.056±0.19 SDS; p<0.0001) and to subjects with tall stature (0.594±0.17; p=0.00067). Furthermore, we found significantly higher GHR gene expression levels in tall children (321.84±90.04 agGHR/5×105agGAPDH) compared with other groups of subjects (short children: 30.13±7.5 agGHR/5×105agGAPDH, p<0.0001; controls: 86.81ag±19.5 GHR/5×105agGAPDH, p=0.035). The GHR gene expression level in short children was significantly lower compared with control subjects (p=0.0068). CONCLUSIONS: Significantly higher GHR gene expression levels in tall subjects suggests a sensitization of the GHR-IGF system leading to overgrowth in CTS.


Asunto(s)
Estatura , Enanismo/sangre , Trastornos del Crecimiento/sangre , Hormona de Crecimiento Humana/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Receptores de Somatotropina/sangre , Estudios de Casos y Controles , Niño , Enanismo/patología , Femenino , Estudios de Seguimiento , Trastornos del Crecimiento/patología , Humanos , Masculino , Pronóstico
14.
Sci Rep ; 6: 38803, 2016 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-27934915

RESUMEN

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder.


Asunto(s)
Anomalías Múltiples/genética , Adenosina Trifosfatasas/genética , Enfermedades del Desarrollo Óseo/genética , Metilación de ADN , Enanismo/genética , Cara/anomalías , Trastornos del Desarrollo del Lenguaje/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , Anomalías Múltiples/sangre , Adenosina Trifosfatasas/sangre , Adenosina Trifosfatasas/deficiencia , Adenosina Trifosfatasas/fisiología , Adolescente , Adulto , Niño , Preescolar , Ensamble y Desensamble de Cromatina , Codón sin Sentido , Islas de CpG/genética , ADN/sangre , ADN/genética , Enanismo/sangre , Femenino , Genes Dominantes , Humanos , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular/genética , Trastornos del Desarrollo del Lenguaje/sangre , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Miosina Tipo I/genética , Síndrome
15.
Endocr Res ; 41(2): 81-8, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26726735

RESUMEN

OBJECTIVE: to assess the growth and pubertal development among a group of patients with ß-Thalassemia Major (ß-TM) and to evaluate the role of the pituitary gland and liver MRI signal intensity (SI) reduction in assessing and predicting the clinical severity of growth and pubertal dysfunctions. METHODS: Thirty-eight patients with ß-TM were examined and divided into two groups: Group I patients were of normal height and puberty and Group II patients had short statures and hypogonadism. Laboratory investigations included serum ferritin, LH, FSH, prolactin, TSH, and basal and dynamic growth hormones. Pituitary and liver MRIs were performed to assess the pituitary to fat (P/F) and liver to muscle (L/M) signal intensities (SI), respectively. Fifteen healthy and sex- and age-matched subjects were included as controls. RESULTS: Both patient groups had significantly elevated serum ferritin and significantly decreased prolactin and IGF1 compared to control subjects. Group II showed a significant reduction in LH, FSH, and IGF1 and a significant increase in ferritin in comparison with Group I and the control group, and it had a highly significant reduction in both P/F and L/M SI in comparison with Group I (p<0.001 and 0.008, respectively). The reduced P/F ratio was significantly correlated with FSH and LH, and a cutoff for a P/F ratio ≥0.94 was obtained to differentiate between Group I and II. CONCLUSION: MRI in conjunction with the P/F signal intensity ratio is a useful and noninvasive tool for the early diagnosis of pituitary iron overload.


Asunto(s)
Enanismo/diagnóstico , Hipogonadismo/diagnóstico , Sobrecarga de Hierro/diagnóstico , Hígado/diagnóstico por imagen , Hipófisis/diagnóstico por imagen , Talasemia beta/diagnóstico , Adolescente , Adulto , Enanismo/sangre , Enanismo/diagnóstico por imagen , Enanismo/etiología , Femenino , Humanos , Hipogonadismo/sangre , Hipogonadismo/diagnóstico por imagen , Hipogonadismo/etiología , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/diagnóstico por imagen , Sobrecarga de Hierro/etiología , Imagen por Resonancia Magnética , Masculino , Adulto Joven , Talasemia beta/sangre , Talasemia beta/complicaciones , Talasemia beta/diagnóstico por imagen
16.
Am J Hum Genet ; 97(6): 894-903, 2015 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-26637979

RESUMEN

SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably ß-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.


Asunto(s)
Proteínas de Transporte de Catión/genética , Trastornos Congénitos de Glicosilación/genética , Enanismo/genética , Manganeso/sangre , Espasmos Infantiles/genética , Secuencia de Aminoácidos , Secuencia de Carbohidratos , Proteínas de Transporte de Catión/deficiencia , Cationes Bivalentes , Trastornos Congénitos de Glicosilación/sangre , Trastornos Congénitos de Glicosilación/complicaciones , Trastornos Congénitos de Glicosilación/dietoterapia , Enanismo/sangre , Enanismo/complicaciones , Enanismo/dietoterapia , Femenino , Galactosa/uso terapéutico , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Transporte Iónico , Manganeso/deficiencia , Datos de Secuencia Molecular , Mutación , Linaje , Alineación de Secuencia , Espasmos Infantiles/sangre , Espasmos Infantiles/complicaciones , Espasmos Infantiles/dietoterapia
17.
Am J Hum Genet ; 97(6): 886-93, 2015 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-26637978

RESUMEN

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.


Asunto(s)
Proteínas de Transporte de Catión/genética , Enfermedades Cerebelosas/genética , Enanismo/genética , Genes Recesivos , Discapacidad Intelectual/genética , Manganeso/sangre , Zinc/sangre , Adolescente , Proteínas de Transporte de Catión/metabolismo , Cationes Bivalentes , Enfermedades Cerebelosas/sangre , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/etnología , Niño , Enanismo/sangre , Enanismo/complicaciones , Enanismo/etnología , Etnicidad , Exoma , Femenino , Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/etnología , Transporte Iónico , Masculino , Manganeso/orina , Población Blanca , Adulto Joven , Zinc/orina
18.
Exp Clin Endocrinol Diabetes ; 123(7): 405-10, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26069077

RESUMEN

AIM: It has recently been suggested that prolactin (Prl) level above the upper limit of normal range, recorded in a single measurement in serum is enough to diagnose hyperprolactinemia (HPrl). The aim of the study was the analysis of the circadian rhythm of Prl secretion in children with an increased morning Prl concentration in order to establish whether it is a real hyperprolactinemic state or not. MATERIAL AND METHODS: The analysis comprised a group of 44 children (32 boys and 12 girls, aged from 4.2 to 14.1 years, mean±SD: 10.4±3.5 years) with either short stature or precocious puberty, with an elevated Prl concentration at 8:00 a.m., suggesting hyperprolactinemic state. In all patients the circadian Prl secretion profile was assessed on the basis of Prl concentrations in 9 blood samples, collected in 3-h intervals. An analysis of the circadian Prl rhythm was performed. Depending on the medical history and the magnetic resonance imaging result, the children were divided into the following groups: A - congenital disorders of hypothalamic-pituitary region (n=10); B - acquired disorders of hypothalamic-pituitary region (other than pituitary adenomas) (n=15), C - pituitary adenomas (n=19). The control group consisted of 14 healthy children (9 boys and 5 girls), aged from 5.2 to 14.3 years, mean±SD: 10.8±3.2 years. RESULTS: In only 18 children (41%), apart from a higher morning Prl concentration, an elevated Prl concentration at other time points was observed and the circadian rhythm was disturbed, implying hyperprolactinemic state (2 children from Group A, 8 from Group B and 8 form Group C). In the remaining 26 children (59%), higher morning Prl concentrations were not accompanied by elevated Prl concentrations at other time points of the circadian profile. CONCLUSIONS: In children with elevated Prl concentrations in the morning, a circadian Prl secretion profile should be performed in order to avoid overdiagnosing of continuous HPrl. In children with the presence of pituitary adenoma and increased morning Prl concentrations, the diagnosis of Prl-secreting adenoma is not completely obvious.


Asunto(s)
Ritmo Circadiano/fisiología , Enanismo/sangre , Hiperprolactinemia/sangre , Enfermedades de la Hipófisis/sangre , Prolactina/sangre , Pubertad Precoz/sangre , Adolescente , Niño , Preescolar , Enanismo Hipofisario/sangre , Femenino , Humanos , Masculino
19.
J Clin Endocrinol Metab ; 100(2): E355-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25387261

RESUMEN

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 Prospectivos
20.
J Clin Res Pediatr Endocrinol ; 7(4): 301-6, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26777041

RESUMEN

OBJECTIVE: Idiopathic short stature (ISS) constitutes a heterogeneous group of short stature which is not associated with an endocrine or other identifiable cause. Some ISS patients may have varying degrees of insulin-like growth factor-1 (IGF-1) deficiency. Recombinant growth hormone (rGH) treatment has been used by some authors with variable results. Reports on long-term rGH treatment are limited. METHODS: In this study, 21 slowly growing, non-GH-deficient ISS children who received rGH treatment for 3.62±0.92 years were evaluated at the end of a 5.42±1.67-year follow-up period. The study group included patients with low IGF-1 levels who also responded well to an IGF generation test. The patients were divided into two groups as good responders [height increment >1 standard deviation (SD)] and poor responders (height increment <1 SD) at the end of the follow-up period. RESULTS: The height of the patients improved from -3.16±0.46 SD score (SDS) to -1.9±0.66 SDS. At the end of the follow-up period, mean height SDS was -1.72. Eleven of the patients showed a good response to treatment. Clinical parameters were essentially similar in the good responders and the poor responders groups. A female preponderance was noted in the good responders group. CONCLUSION: rGH treatment can safely be used in ISS children. Long-term GH treatment will ameliorate the height deficit and almost 40% of patients may reach their target height.


Asunto(s)
Estatura/efectos de los fármacos , Enanismo/sangre , Enanismo/tratamiento farmacológico , Hormona del Crecimiento/farmacología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Adolescente , Niño , Femenino , Estudios de Seguimiento , Hormona del Crecimiento/administración & dosificación , Humanos , Factor I del Crecimiento Similar a la Insulina/deficiencia , Masculino , Proteínas Recombinantes , Resultado del Tratamiento
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