ESPE Abstracts (2015) 84 P-2-403

Homozygous Carriers of a Novel IGFALS Mutation are 1.5 SD Shorter than Heterozygous Relatives and Tend to have Lower Bone Mineral Density

Emregül Isıka, Jaap van Doornb, Hüseyin Demirbilekc, Monique Losekootd & Jan-Maarten Wite

aPediatric Endocrinology, Gaziantep Children’s Hospital, Gaziantep, Turkey; bSection Metabolic Diseases, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; cFaculty of Medicine, Pediatric Endocrinology, Hacettepe University, Ankara, Turkey; dDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; eDepartment of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

Background: There are limited data on differences in height, bone mineral density (BMD) and pubertal delay between homozygous and heterozygous carriers of IGFALS defects.

Objective and hypotheses: To describe clinical and laboratory features and BMD of homozygous and heterozygous carriers of a novel IGFALS mutation in a large Kurdish family.

Method: Index cases were two first degree cousins presenting with short stature, low IGF1, very low IGFBP-3 and normal baseline GH, caused by a homozygous (c.1462G>A, p.Asp488Asn) mutation in IGFALS. This novel IGFALS mutation introduces a new N-glycosylation site, which may lead to misfolding of the protein leading to its relatively rapid intracellular degradation. All family members consented to genetic, clinical and laboratory assessment. Age at menarche (females) and age at accelerating growth, testicular growth and shaving (males) were recorded. Height and biochemical findings were expressed as SDS, and BMD (Horizon DXA, Hologic) as z-score (NHANES). Ternary complex formation was investigated by size-exclusion chromatography.

Results: Eight homozygous carriers (6<18.0 years), 11 heterozygotes (7<18 years) and one non-affected (height −0.9 SDS) were studied. Homozygotes were 1.5 SD shorter than heterozygous carriers, who were 1.7 SD shorter than the population’s mean. Delayed puberty could be evaluated in two homozygotes (both delayed) and six heterozygotes (4/6 delayed). Serum IGF1, IGFBP-3 and ALS showed the expected pattern for complete and partial ALS deficiency, respectively. BMD tended to be lower in homozygous carriers (NS), possibly partially caused by height differences. Ternary complex formation was markedly diminished in sera from homozygous patients, and heterozygotes showed an intermediate pattern.

Table 1
Mean (SD)Homozygotes (n=8)Heterozygotes (n=11)P-value
Age (years)11.7±5.221.5±16.10.283
Height SDS−3.3 (0.6)−1.7 (1.0)0.003
Height SDS range−4.2 to −2.7−3.2 to −0.1
IGF1 SDS (age<18)−2.2 (0.3) (n=6)−0.7 (0.7) (n=5)0.006
IGFBP-3 SDS (age<18)−4.0 (0.7) (n=6)0.1 (0.7) (n=5)0.006
IGFBP-2 SDS−1.04 (0.9)−0.5 (1.4)0.237
ALS SDS−4.6 (1.5)−1.5 (0.8)<0.001
BMD z-score−1.3 (1.2)−0.6 (0.4)0.110

Conclusion: Homozygous carriers of the IGFALS mutation were 1.5 SD shorter than heterozygous carriers, BMD z-score tended to be lower and pubertal delay appeared frequent in both groups.

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