CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Auxological implications of heterozygous IGFALS mutations
Autor/es:
OLGA V. FOFANOVA-GAMBETTI; VIVIAN HWA; JAN M. WIT; HORACIO M. DOMENÉ; JESÚS ARGENTE; PETER BANG; WOLFGANG HOGLER; SUSAN KIRSH; CATHERINE PIHOKER; HARVEY K. CHIU; LAURIE COHEN; CHRISTINE JACOBSEN; HÉCTOR G. JASPER; RON G. ROSENFELD
Lugar:
New York
Reunión:
Congreso; LWPES/ESPE 8th Joint Meeting; 2009
Institución organizadora:
Lawson Wilkins Pediatric Endocrinology Society
Resumen:
Auxological Implications of Heterozygous IGFALS Mutations Background/Aims. To date, 14 novel mutations of IGFALS in 17 patients (13 families) have been reported. This cohort is highly divergent in ethnicity and countries of residence. The phenotype of homozygous IGFALS mutations is well described, although it may be influenced by ascertainment bias. The effect of heterozygous IGFALS mutations on phenotype is less known. The present study was undertaken to evaluate the impact of heterozygous expression of IGFALS mutations on stature. Patients/Methods. Patient information was derived from an IGFALS Registry (n=55). The Registry includes patients who carry homozygous or compound heterozygous IGFALS mutations (n=17) and family members, who were either heterozygous carriers (HC, n=30), or homozygous wild type (WT, n=8). Height at diagnosis was expressed as SDS (HSDS) for US references. In the whole cohort means were calculated for 3 groups. Within each family in whom height data of one or more WT individuals was available the effect on stature of two mutant alleles versus one; one mutant allele versus WT; and two mutant alleles versus WT was calculated. The differences in HSDS were then pooled and further evaluated. Results. Out of 11 families, 2 (18%) were consanguineous, and 9 (82%) were non-consanguineous; data on 2 families were not available. Two children were adopted. Among 14 IGFALS mutations 8 (57%) were homozygous, and 6 compound heterozygous. According to the type of mutation, 9 (64%) were missense, 2 (14%) in-frame insertions, 2 (14%) frameshifts with premature stop codons, and 1 (7%) a nonsense mutation. In the whole cohort mean ±SD HSDS in patients was -2.36±0.84 (below -2 SDS in 65%); in HC -0.83±1.34 (below -2 SDS in 26%) and in WT -1.02±1.04 (below -2 SDS in 12.5%). The difference in mean HSDS between HC and WT was -0.90±1.51 (n=12, 4 families); between patients and HC: -1.46±0.86 (n=14, 10 families); between patients and WT: -2.13±0.83 (n=3, 3 families). Conclusions. Heterozygosity for IGFALS mutations results in approximately 1.0 SD height loss in comparison with wild type, while homozygosity gives a further loss of 1.5 SD, suggestive for a gene-dose effect. Further studies involving a larger cohort are needed to evaluate the impact of heterozygous IGFALS mutations not only on auxologic characteristics, but also on the GH/IGF system.