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

• Published in: European journal of endocrinology Vol. 176; no. 6; pp. 657 - 667
• Main Authors: Işık, Emregül, Haliloglu, Belma, van Doorn, Jaap, Demirbilek, Hüseyin, Scheltinga, Sitha A, Losekoot, Monique, Wit, Jan M
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.06.2017; Oxford University Press
• Subjects: Absorptiometry, Photon; Adolescent; Biochemical characteristics; Birth weight; Birth Weight - genetics; Body Mass Index; Bone density; Bone Density - genetics; Bone mineral density; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cephalometry; Child; Clinical Study; Densitometry; Dual energy X-ray absorptiometry; Female; Glycoproteins - genetics; Glycoproteins - metabolism; Growth Disorders - diagnostic imaging; Growth Disorders - genetics; Growth Disorders - metabolism; Heterozygote; Homozygote; Humans; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor II; Insulin-Like Growth Factor II - metabolism; Insulin-like growth factor-binding protein 2; Insulin-like growth factor-binding protein 3; Male; Mutation; Phenotype; Phenotypes; Physical growth; Puberty; Puberty, Delayed - genetics; Puberty, Delayed - metabolism; Serum levels; Turkey
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/EJE-16-0999

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.