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

Abstract

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). 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. 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). 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. 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.