title: Clinical and biochemical characteristics and bone mineral density of homozygous, compound heterozygous and heterozygous carriers of three novelIGFALSmutations.
abstract: OBJECTIVE
  Acid-labile subunit (ALS) deficiency (ACLSD), caused by homozygous or compound heterozygousIGFALSmutations, 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 ofIGFALSmutations (partial ACLSD).
  
  
  METHODS
  From all available members of five Turkish families, carrying three mutations in exon 2 ofIGFALS(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.
authors.affiliation: Department of Pediatric EndocrinologyGaziantep Children's Hospital, Gaziantep, Turkey.
authors.forename: Emregül
authors.initials: E
authors.lastname: Işık
authors.affiliation: Department of Pediatric EndocrinologyYeditepe University School of Medicine, İstanbul, Turkey.
authors.forename: Belma
authors.initials: B
authors.lastname: Haliloglu
authors.affiliation: Department of GeneticsUniversity Medical Center Utrecht, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: van Doorn
authors.affiliation: Department of Pediatric EndocrinologyHacettepe University Faculty of Medicine, Ankara, Turkey.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Demirbilek
authors.affiliation: Departments of Clinical Genetics.
authors.forename: Sitha A
authors.initials: SA
authors.lastname: Scheltinga
authors.affiliation: Departments of Clinical Genetics.
authors.forename: Monique
authors.initials: M
authors.lastname: Losekoot
authors.affiliation: Departments of PediatricsLeiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D001724:Birth Weight / Q000235:genetics; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002508:Cephalometry; D002648:Child; D005260:Female; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006130:Growth Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010641:Phenotype; D011628:Puberty, Delayed / Q000235:genetics / Q000378:metabolism; D014421:Turkey
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C583557:IGF1 protein, human; C035170:IGF2 protein, human; C515497:IGFBP3 protein, human; 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