Rev Esp Endocrinol Pediatr

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Rev Esp Endocrinol Pediatr 2017;8 Suppl(1):8-13 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2017.Apr.388
ALS deficiency in idiopathic short stature
El déficit de ALS en la talla baja idiopática

Enviado a Revisar: 3 Abr. 2017 | Aceptado el: 3 Abr. 2017  | En Publicación: 5 May. 2017
Horacio M. Domené
Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI– División de Endocrinología. Hospital de Niños Ricardo Gutiérrez. Buenos Aires (Argentina)
Correspondencia para Horacio M. Domené, Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI– División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
E-mail: hdomene@cedie.org.ar
Abstract
Resumen

El diagnóstico de talla baja idiopática (TBI) constituye un diagnóstico de exclusión después que un examen físico exhaustivo y una evaluación bioquímica completa hayan podido descartar otras causas de baja estatura. Diferentes defectos moleculares han sido caracterizados en niños con TBI. La deficiencia completa de ALS (ACLSD), caracterizada por deficiencias severas de IGF-I, IGFBP-3 y ALS, resulta de mutaciones en el gen IGFALS.  Casos menos severos de ACLSD, heterocigotos portadores de variantes en el gen IGFALS, podrían estar presentes en un subgrupo de niños con TBI. El estudio de 218 niños normales y 117 niños con TBI, mostró que las variantes no sinónimas fueron más frecuentes en los niños con TBI (15.5% vs. 4.8%; P= 0.0039). De los 16 niños con variantes no sinónimas, uno presentaba ACLSD (heterocigoto compuesto para p.Glu35Glyfs*17/p.Ser490Trp) y otros cinco presentaron ACLSD parcial (heterocigotos portadores para p.Glu35Glyfs*17, p.Arg277His, p.Pro287Leu, and 2 p.Arg548Trp). Una variante resultó en incapacidad completa de la síntesis de ALS (p.Glu35Glyfs*17) y otras dos en síntesis y secreción normales, pero a menores concentraciones (p.Ala330Asp, p.Arg548Trp). La ACLSD completa representa alrededor del 1%, y la ACLSD parcial alrededor del 5% de los niños con TBI, con variantes génicas en el gen IGALS de patogenicidad comprobada o a determinar. La identificación de la ACLSD parcial podría tener implicancias prácticas considerando que estos niños, a diferencia de los pacientes con ACLSD completa, retienen su capacidad de responder al tratamiento con GHrh. La efectividad del tratamiento requiere de un seguimiento prolongado hasta alcanzar la talla adulta.

Key Words: idiopathic short stature, IGF-I, IGFBP-3, ALS, GH resistance Palabras clave: talla baja idiopática, IGF-I, IGFBP-3, ALS, resistencia a la GH

Idiopathic short stature is essentially a diagnosis of exclusion made after physical examination and biochemical assessment ruled out other causes of short stature. Different molecular defects have been characterized in ISS. Complete ALS deficiency (ACLSD), characterized by severe deficiencies of IGF-I, IGFBP-3, and ALS, is caused by mutations in the IGFALS gene. Milder cases of ACLSD, heterozygous carriers of IGFALS gene variants, may be present in a subgroup of ISS children. By studding 218 normal and 117 ISS children, we determined that non-synonymous IGFALS variants were more frequent in ISS (15.5% vs. 4.8%; P=0.0039). From 16 ISS children with non-synonymous variants, one presented ACLSD (compound heterozygous for p.Glu35Glyfs*17/p.Ser490Trp) and other five presented partial ACLSD (heterozygous carriers for p.Glu35Glyfs*17, p.Arg277His, p.Pro287Leu, and 2 p.Arg548Trp). One variant affected ALS synthesis (p.Glu35Glyfs*17) and other two, with normal synthesis and secretion, albeit to lower ALS concentrations (p.Ala330Asp, p.Arg548Trp). Complete ACLSD represented 1%, and partial ACLSD 5% of ISS children, presenting IGALS pathogenic or still no classified variants. Identification of partial ACLSD may have practical implications, considering that these children, different to what was reported in complete ACLSD, retain their ability to respond to rhGH treatment. To prove the efficacy of this treatment requires large follow-up until adult height.

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