Clinical and biochemical characteristics and bone mineral density of homozygous, compound heterozygous and heterozygous carriers of three novel IGFALS mutations

Objective: Acid-labile subunit (ALS) deficiency (ACLSD), caused by homozygous or compound heterozygous IGFALS mutations, is associated with moderate short stature, delayed puberty, low serum IGF-I and ALS and extremely low serum IGFBP-3. Its effect on birth weight, head circumference, bone mineral density (BMD), serum IGF-II and IGFBP-2 is uncertain, as well as the phenotype of heterozygous carriers of IGFALS mutations (partial ACLSD). Design: From all available members of five Turkish families, carrying three mutations in exon 2 of IGFALS (c. 1462G > A, p. Asp488Asn (families A, B, E); c. 251A > G, p. Asn84Ser (families C and E) and c. 1477del, p. Arg493fs (family D)), clinical, laboratory and BMD data were collected. Methods: Auxological and biochemical findings were expressed as SDS for age and gender. Ternary complex formation in serum was investigated by size-exclusion chromatography. BMD using DXA bone densitometry was adjusted for height and age (Ha-BMD z-score). Results: In ACLSD (n = 24), mean +/- s.d. height SDS (-2.7 +/- 1.2), head circumference SDS (-2.3 +/- 0.5) and body mass index (BMI) (-0.6 +/- 1.0 SDS) were lower than those in partial ACLSD (n = 26, P <= 0.01) and birth weight SDS (n = 7) tended to be lower (-2.2 +/- 1.1 vs -0.6 +/- 0.3 in partial ACLSD (P = 0.07)). Serum IGF-I was -3.7 +/- 1.4 vs -1.0 +/- 1.0, IGF-II: -5.6 +/- 0.7 vs -1.3 +/- 0.7, ALS: <-4.4 +/- 1.2 vs -2.1 +/- 0.9 and IGFBP-3: -9.0 +/- 1.9 vs -1.6 +/- 0.8 SDS respectively (P < 0.001). Ha-BMD z-score was similar and normal in both groups. Conclusions: To the known phenotype of ACLSD (i. e. short stature, reduced serum levels of IGF-I and ALS, extremely low serum IGFBP-3 and disturbed ternary complex formation), we add reduced birth weight, head circumference and serum IGF-II.