Short stature associated with a novel heterozygous mutation in the insulin-like growth factor 1 gene.
BACKGROUND
Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height and head circumference.


OBJECTIVE
The objective of the study was to investigate the clinical features of heterozygous carriers of a novel mutation in the IGF1 gene in comparison with noncarriers in a short family and to establish the effect of human GH treatment.


METHODS
Two children, their mother, and their maternal grandfather carried the mutation and were compared with two relatives who were noncarriers.


RESULTS
The two index cases had severe short stature (height sd score -4.1 and -4.6), microcephaly, and low IGF-I levels. Sequencing of IGF1 revealed a heterozygous duplication of four nucleotides, resulting in a frame shift and a premature termination codon. The mother and maternal grandfather had the same IGF1 mutation. Adult height (corrected for shrinking and secular trend) and head circumference sd score of carriers of the paternally transmitted mutation was -2.5 and -1.8, in comparison with -1.6 and 0.3 in noncarriers, respectively. After 2 yr of GH treatment, both index cases exhibited increased growth.


CONCLUSIONS
Heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation, presumably in combination with other genetic factors for short stature, leads to severe short stature, which can be successfully treated with GH.
van Duyvenvoorde
H A
HA
Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands. h.a.van_duyvenvoorde@lumc.nl
van Setten
P A
PA
Walenkamp
M J E
MJ
van Doorn
J
J
Koenig
J
J
Gauguin
L
L
Oostdijk
W
W
Ruivenkamp
C A L
CA
Losekoot
M
M
Wade
J D
JD
De Meyts
P
P
Karperien
M
M
Noordam
C
C
Wit
J M
JM
D000328:Adult; D001827:Body Height / Q000235:genetics*; D002648:Child; D004392:Dwarfism / Q000235:genetics* / Q000628:therapy; D005260:Female; D016368:Frameshift Mutation; D019382:Human Growth Hormone / Q000627:therapeutic use; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000628:therapy; D010375:Pedigree
D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I