The first homozygous mutation (S226I) in the highly-conserved WSXWS-like motif of the GH receptor causing Laron syndrome: supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration.
OBJECTIVE
The study describes for the first time, a homozygous mutation in the WSXWS-like motif of the human GH receptor (GHR) in a patient with Laron syndrome and describe laboratory data during treatment with GnRHa to suppress puberty and dihydrotestosterone (DHT).


METHODS
A 16-year-old boy at Tanner puberty stage 2 with Laron syndrome was born SGA to consanguineous parents, presented severe growth retardation, obesity and micropenis.


METHODS
GHR coding region was sequenced. GH, GHBP, IGF-I and IGFBP-3 were determined before, during and after GnRHa and DHT treatment.


RESULTS
A homozygous mutation in exon 7, replacing serine by isoleucine in codon 226 was identified. S226 is the last serine belonging to the WSXWS-like motif in GHR. No specific effect of S226I mutation in heterozygous state was observed. Laboratory data at the prepubertal age showed markedly high GH, low GHBP, IGF-I and IGFBP-3 levels. Re-evaluation at pubertal age showed normal basal serum IGFBP-3 levels and low but near normal IGF-I levels. We also noticed a sustained decrease in GH, IGF-I and IGFBP-3 levels after blocking puberty, which was not affected by short- and long-term DHT treatment. Pubertal hormonal profile was re-established after the GnRHa therapy was discontinued to allow the reactivation of the gonadal axis.


CONCLUSIONS
The homozygous mutation S226I in WSXWS-like motif of GHR causes GH insensitivity. The decrease in IGF-I and IGFBP-3 levels after GnRHa therapy, which was not reversed with DHT administration, suggests that sex steroids have, through oestradiol, a GH-independent action on IGF-I and IGFBP-3 levels. A direct effect of GnRHa on GH secretion cannot be excluded.
Jorge
Alexander A L
AA
Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas, Sao Paulo, Brazil. alexj@usp.br
Souza
Silvia C A L
SC
Arnhold
Ivo J P
IJ
Mendonca
Berenice B
BB
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D016384:Consensus Sequence; D013196:Dihydrotestosterone; D006130:Growth Disorders / Q000188:drug therapy / Q000235:genetics*; D013006:Growth Hormone / Q000097:blood; D006720:Homozygote; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010446:Peptide Fragments / Q000627:therapeutic use; D011627:Puberty / Q000097:blood; D011986:Receptors, Somatotropin / Q000235:genetics*
C470407:(N-acetyl-tyr1,D-arg2)fragment 1-29 amide; D018972:Insulin-Like Growth Factor Binding Protein 3; D010446:Peptide Fragments; D011986:Receptors, Somatotropin; D013196:Dihydrotestosterone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone