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.

Abstract

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).

PATIENTS:

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 AND MEASUREMENTS:

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.

CONCLUSION:

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.

• Authors: Alexander A L Jorge, Silvia C A L Souza, Ivo J P Arnhold, Berenice B Mendonca
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 60 Issue 1 Pg. 36-40 (Jan 2004) ISSN: 0300-0664 [Print] England
• PMID: 14678285 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (N-acetyl-tyr1,D-arg2)fragment 1-29 amide
• Insulin-Like Growth Factor Binding Protein 3
• Peptide Fragments
• Receptors, Somatotropin
• Dihydrotestosterone
• Insulin-Like Growth Factor I
• Growth Hormone

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Base Sequence
• Child
• Consensus Sequence
• Dihydrotestosterone
• Growth Disorders (drug therapy, genetics)
• Growth Hormone (blood)
• Homozygote
• Humans
• Insulin-Like Growth Factor Binding Protein 3 (blood)
• Insulin-Like Growth Factor I (analysis)
• Male
• Molecular Sequence Data
• Mutation
• Pedigree
• Peptide Fragments (therapeutic use)
• Puberty (blood)
• Receptors, Somatotropin (genetics)