Human acid-labile subunit deficiency: clinical, endocrine and metabolic consequences.
The majority of insulin-like growth factor (IGF)-I and IGF-II circulate in the serum as a complex with the insulin-like growth factor binding protein (IGFBP)-3 or IGFBP-5, and an acid-labile subunit (ALS). The function of ALS is to prolong the half-life of the IGF-I-IGFBP-3/IGFBP-5 binary complexes. Fourteen different mutations of the human IGFALS gene have been identified in 17 patients, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon growth hormone stimulation. Postnatal growth was clearly affected. Commonly, the height standard deviation score before puberty was between -2 and -3, and approximately 1.4 SD shorter than the midparental height SDS. Pubertal delay was found in 50% of the patients. Circulating IGF-II, IGFBP-1, -2 and -3 levels were reduced, with the greatest reduction observed for IGFBP-3. Insulin insensitivity was a common finding, and some patients presented low bone mineral density. Human ALS deficiency represents a unique condition in which the lack of ALS proteins results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. The preserved expression of locally produced IGF-I might be responsible for the preservation of linear growth near normal limits.
Domené
Horacio M
HM
Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires 1425, Argentina. hdomene@cedie.org.ar
Hwa
Vivian
V
Argente
Jesús
J
Wit
Jan M
JM
Wit
Jaan M
JM
Camacho-Hübner
Cecilia
C
Jasper
Héctor G
HG
Pozo
Jesús
J
van Duyvenvoorde
Hermine A
HA
Yakar
Shoshana
S
Fofanova-Gambetti
Olga V
OV
Rosenfeld
Ron G
RG
D000293:Adolescent; D000328:Adult; D000818:Animals; D001724:Birth Weight; D001827:Body Height / Q000235:genetics; D001842:Bone and Bones / Q000378:metabolism; D002113:Calcification, Physiologic; D050260:Carbohydrate Metabolism; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D016368:Frameshift Mutation; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense
D002352:Carrier Proteins; D006023:Glycoproteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II