El crecimiento es un fenómeno biológico continuo resultante del equilibrio entre la cantidad, calidad y función de la materia, que permite adquirir de forma paulatina una conformación estable y un desempeño maduro, que se debe expresar en forma plena y óptima en todos los humanos. Su expresión debe considerarse un signo de salud y por ello debe ser analizado por todos los médicos en la vigilancia de cada paciente desde el nacimiento hasta el término de la pubertad, ya que al ser un indicador objetivo nos permite cuantificar y calificar las variaciones en las dimensiones físicas y la composición corporal a las diferentes edades, y refleja el equilibrio entre la expresión de las condiciones genéticas y los factores permisivos o restrictivos del medio ambiente. El método más recomendable es comparar las medidas auxológicas de una población con la expresión individual, aunque debe considerarse que los estudios poblacionales señalan solo lo que es “habitual” en una población, lo que no forzosamente es sinónimo de normal ni de óptimo, ya que: varones y mujeres muestran diferencias en la edad e intensidad del crecimiento, el crecimiento prenatal puede afectar al crecimiento posnatal, existen variaciones étnicas o raciales en la expresión del crecimiento posnatal, hay variaciones entre familias de la misma etnia en el crecimiento posnatal, y existen variaciones en la velocidad de maduración incluso dentro de miembros de la misma familia. Se describen las principales medidas antropométricas, las características de los instrumentos que las cuantifican y cómo se debe analizar el resultado. PALABRAS CLAVE: Crecimiento, antropometría, talla, peso, índice de masa corporal, proporcionescorporales, velocidad de crecimiento

Objective: To investigate the occurrence of abnormally elevated values of biomarkers of growth hormone (GH) action in short children on recombinant human GH (rhGH) therapy. Methods: Sixty-three prepubertal short children were examined: 31 with GH deficiency (GHD), 25 small for gestational age (SGA), and 9 with Turner syndrome (TS). The main outcomes were the following: standard deviation score (SDS) values of IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio before, at the 1st and at the 2nd year on rhGH and Δheight (Ht)-SDS to evaluate GH treatment efficacy (adequate 1st-year ΔHt SDS: >0.4 SDS for GHD and >0.3 SDS for non-GHD). Results: Seventy-eight percent of GHD, 78% of SGA and 55% of TS children had adequate 1st-year ΔHt SDS. In GHD, 88% of IGF-I SDS and IGFBP-3 SDS that were ≤–2.0 SDS at baseline normalized on treatment. Abnormal IGF-I values >+2.0 SDS were observed in 52% of SGA and in 55% of TS patients on rhGH. Within each group, the IGF-I/IGFBP-3 molar ratio increased significantly from pretreatment and throughout therapy, remaining within normal range for most patients. ΔIGF-I/IGFBP-3 molar ratio SDS were significantly higher in children with an adequate response (p < 0.01). Conclusion: Non-GHD groups presented markedly elevated concentrations of GH biomarkers on rhGH and normal IGF-I/IGFBP-3 molar ratio in most patients. Since there is a lack of consensus regarding the molar ratio usefulness, we think that interventions towards a more physiological IGF-I serum profile should be implemented.

Los niños con restricción del crecimiento intrauterino (RCIU) presentan en la vida posnatal una serie de alteraciones metabólicas y hormonales, y tienen predisposición al desarrollo de obesidad, hipertensión arterial, enfermedad cardiovascular, resistencia a la insulina y diabetes tipo2. La exposición a un ambiente intrauterino desfavorable en fases críticas del desarrollo puede tener un efecto deletéreo sobre la gónada en formación.

Background: In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system. Patients and Methods: In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined. Results: In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers. Conclusions: These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.

OBJECTIVE:To investigate the possible association of circulating components of GH-IGFs-IGFBPs system with the GHR-exon 3 genotype in normal and idiopathic short stature (ISS) children. DESIGN:Descriptive, cross-sectional study in normal and ISS children. SUBJECTS AND METHODS:192 normal and 81 ISS children (age: 5-17 years) were included. Serum IGF-I, IGFBP3, ALS and GHBP levels were measured. GHR-exon 3 polymorphism (GHRd3) was analyzed by multiplex PCR assay. Normal and ISS children were divided according to GHR-exon 3 genotype: homozygous for the full-length GHR isoform (GHRfl) and carriers of one or two copies of the GHRd3 allele. RESULTS:GHRd3 genotype distribution (fl:fl/fl:d3/d3:d3,%) in normal (60:34:6) and ISS (64:32:4) was similar and reached Hardy-Weinberg equilibrium. ISS children had significantly reduced levels of GHBP and GH-dependent factors as compared to controls (p<0.0001). Within the normal group, homozygous carriers of the GHRfl allele had significantly higher GHBP serum levels than those with one or two copies of the GHRd3 allele (Mean ± SEM; GHRfl: 3.2 ± 0.2 vs GHRd3: 2.7 ± 0.2 nmol/L, p = 0.04). No other significant association with GHR exon 3 polymorphism was found in either the normal or the ISS groups. CONCLUSIONS:GHR exon 3 polymorphism is distributed similarly in normal and ISS children, however only normal homozygous children for GHRfl allele showed higher GHBP levels. The lack of association between GHBP and GHR polymorphism in ISS children might be related to the heterogeneity of this group, where potential defects in GH receptor action may result in partial GH insensitivity.

CONTEXT:Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function.PATIENT:The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD.RESULTS:Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the βD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription.CONCLUSION:A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 βD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.

Resistance to thyroid hormone (RTH) is characterized by elevated levels of thyroid hormones, normal or slightly increased TSH levels respondent to TRH, resistance to thyroid hormone administration, and variable clinical expression. To describe the diverse clinical and biochemical findings of six children from five unrelated families with molecular diagnosis of RTH (0.5–12.7 years) and their follow-up (3–20 years). All RTH patients and 4 affected parents’ harbored mutations in exons 9 or 10 of the thyroid receptor β gene: p.M313T (de novo), pN331D, p.L341P, p.L346F, and p.P453L. At consultation 5/6 had goiter, 4/6 tachycardia, and 3/5 learning disabilities. Median hormone levels were: T4 257.4 nmol/l (NR: 77.2–180.2); FreeT4 39.9 pmol/(NR:10.3–28.3); T3 4.28 nmol/l (NR:1.23–3.39) TSH 2.8 mUI/l (NR: 0.5–5) always responsive to TRH. TSH levels remained detectable after supraphysiologic T3 administration while SHBG levels showed a paradoxical decrease in 4/6. Thyroid antibodies, initially present in two subjects, became positive in other two during follow-up. All patients grew normally and presented variable symptoms that were treated according to need. Two patients developed psychiatric disorders. Only one of the four affected parents exhibited clinical signs of RTH (tachycardia and depression). Parent’s thyroid profile showed similar TSH and T3 levels but lower T4 and FT4 than their children. RTH has a distinctive biochemical profile with highly variable clinical manifestations and outcomes. Its recognition and molecular characterization avoid misleading diagnosis. Treatment has to be instituted according to each subject’s own clinical requirements.