Different phenotype of Laron syndrome in two siblings with poor response to recombinant IFR-1 therapy

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 632-648-Pediatric Growth Case Reports
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-642
Bryan Ghanny*1, Yevgeniy Apostolov2, Amrit Pal S Bhangoo3, Steven Nigel Ghanny4 and Svetlana B Ten5
1SUNY DOWNSATE, Brooklyn, NY, 2University of Arkansas for Medical Sciences., 3Miller Children's Hospital, Long Beach, CA, 4Hackensack UMC, Hackensack, NJ, 5Maimonides Med Ctr, Brooklyn, NY
Background: Insensitivity to GH resulted from conformational changes or mutation of GHR frequently results to Laron syndrome leaving treatment with recombinant IGF1 (rIGF1) as treatment of choice. However in some cases therapy with rIGF1 has poor efficacy or no effect at all on the growth. The mechanism rIGF1 insensitivity in Laron syndrome is poorly understood.

 

Aim: To assess expression of the key signaling molecules relevant to GHR- and IGF1-regulated growth in case of severe resistance to rGH and rIGF1 treatment.

 

Patients and Methods: Two consanguineous Pakistani male siblings with homozygous GHR mutation (108bp inframe pseudoexon 6Ψ) were recruited for this study. In addition, their heterozygous mother with normal height and 5 control individuals with normal height were recruited. After consent, blood samples were collected from all participants and RNA has been extracted from cellular fraction. Expression of the following genes has been studied by real-time RT-PCR: GHR, STAT5b, IGFR1, IRS1, AKT1, osteoblast differentiation factor RUBx2, β-Catenin, GCR, FKBP4 and FKBP5. 18s ribosomal RNA served as housekeeping gene control.

 

Results: Sibling 1 and sibling 2 had severe short stature with height SDS -4.0 and -5.7 respectively. Both had a poor response to both rGH (0.3-0.7mg/kg/week) and rIGF1 (0.24 mg/kg/day). The final adult height was -3.0 and -5.7 SDS respectively.

The real-time RT-PCR studies in sibling 1 revealed the expression of several genes at significantly lower than controls levels: GHR (-56.1%), STAT5b (-11.3%), IGF1R (-5.3%), RUNx2 (-23.1%), IRS1 (-41.8%). In sibling 2 the expression of STAT5b, RUNx2 was significantly lower than controls (-7.6% and -31.8% respectively). The expression of GHR and IGF1R in sibling #2 was no different from healthy controls. Heterozygous mother had normal expression of GHR and significantly lower of STAT5b, RUNx2 (-18.8% amd -17.7% respectively). Expression of AKT, the major signaling molecule of IGF-1 pathway, was slightly lower in sibling #2 and mother (-20%). b-catenin (WNT pathway) was not affected in either one of the siblings. Finally, expression of GCR was relatively decreased in both patients and their mother compared to controls (-26.0%, -28.5% and -32.6% respectively) while expression of FKBP4 was significantly lower both siblings (-48.8% and -27.4%) and FKBP5 was significantly lower in sibling #1 only (-32.7%).

Conclusions: Our data revealed that poor response to rIGF1 in Laron syndrome is associated with decreased expression of IGF1R, STAT5B, RUNx2 and IRS1 molecules. Finally, decrease in GCR expression and disbalance in FKBP4 and FKBP 5 molecules expression may be contributive to relative glucocorticoid resistance of these patients leading to overall poor response to treatment and exacerbation of their medical condition.

Nothing to Disclose: BG, YA, APSB, SNG, SBT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm