Background/Aims: To date, four mutations in the IGFALS gene have been reported. We now describe two children of different ethnic background with total acid-labile subunit (ALS) and severe circulating IGF-I/IGFBP-3 deficiencies resulting from three novel mutations in the IGFALS gene. Patients/Methods: Serum and DNA of patients were analyzed. Results: Case 1 is a 12-year-old boy of Mayan origin. Case 2 is a 5-year-old girl of Jewish/Eastern European (Polish, Russian, Austrian-Hungarian)/Icelandic/European (French, English) ancestry. The reported cases had moderate short stature (–2.91 and –2.14 SDS, respectively), nondetectable serum ALS and extremely low serum concentrations of IGF-I and IGFBP-3. Case 1 harbored a novel homozygous 1308_1316 dup9 mutation in a highly conserved leucine-rich repeat (LRR) 17 motif of exon 2, representing an in-frame insertion of 3 amino acids, LEL. Case 2 harbored a novel heterozygous C60S/L244F mutation in exon 2, located within a highly conserved LRR 1 and LRR 9, respectively. Conclusions: The identification of additional novel IGFALS mutations, resulting in severe IGF-I/IGFBP-3 and ALS deficiencies, supports IGFALS as a candidate gene of the GH/IGF system, implicated in the pathogenesis of primary IGF deficiency, and represents an important part of its differential diagnosis.

Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V: Defects in growth hormone receptor signaling. Trends Endocrinol Metab 2007;18:134–141.
Domene HM, Bengolea SV, Martinez AS, Frystyk J, Ropelato MG, Pennisi P, Scaglia PA, Heinrich JJ, Jasper HG: Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004;350:570–577.
Hwa V, Haeusler G, Pratt K, Little B, Frisch H, Koller D, Rosenfeld R: Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab 2006;91:1826–1831.
Domene HM, Scaglia PA, Lteif A, Mahmud FH, Kirmani S, Frystyk J, Bedecarrás P, Gutiérrez M, Jasper HG: Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations. J Clin Endocrinol Metab 2007;92:4444–4450.
Bogin B, Smith P, Orden AB, Varela Silva MI, Loucky J: Rapid change in height and body proportions of Maya American children. Am J Hum Biol 2002;14:753–761.
Tsubaki J, Hwa V, Twigg SM, Rosenfeld RG: Differential activation of the IGF binding protein-3 promoter by butyrate in prostate cancer cells. Endocrinology 2002;143:1778–1788.
Domene HM, Martinez AS, Frystyk J, Bengolea SV, Ropelato MG, Scaglia PA, Chen J-W, Heuck C, Wolthers OD, Heinrich JJ, Jasper HG: Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency. Horm Res 2007;67:243–249.
Leong SR, Baxter RC, Camerato T, Dai J, Wood WI: Structure and functional expression of the acid-labile subunit of the insulin-like growth factor-binding protein complex. Mol Endocrinol 1992;6:870–876.
Kobe B, Kajava AV: The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 2001;11:725–732.
Janosi JB, Ramsland PA, Mott MR, Firth SM, Baxter RC, Delhanty PJ: The acid-labile subunit of the serum insulin-like growth factor-binding protein complexes. Structural determination by molecular modeling and electron microscopy. J Biol Chem 1999;274:23328–23332.
Pusch CM, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi FK, Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, Meindl A: The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 2000;26:324–327.
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