ESPE Abstracts

Background: Laron syndrome (LS) is a disorder of primary growth hormone (GH) resistance caused by genetic defects in GH and insulin-like growth factor 1 (IGF-1) axis. Here, we present the variable clinical spectrum in two sibling cases of Iraqi Arab origin with GH receptor (GHR) mutation.

CASES: Two siblings referred to our clinic with the chief complaint of short stature. They had been born with a normal weight at term.Their parents were first-degree cousins. The target height for the sister and the brother was 160 cm (-0.53 SDS) and 173 cm (-0.52 SDS), respectively.

Case 1 (11 years 9 months, female): The patient had a height of 127.5 cm (-3.86 SDS), body weight (BW) 31.5 kg (-1.89 SDS), body mass index (BMI) 19.3 kg/m² (0.16 SDS), Tanner Stage II puberty, and Stage I pubic hair growth.Her bone age (BA) was 12 years. She had basal levels of GH 1.28 ng/ml, IGF-1 82 ng/ml (<-2 SDS), and insulin-like growth factor binding protein-3 (IGFBP-3) 2.586 µg/ml (<-2 SDS), and responses of 27.8 ng/ml peak GH to GH stimulation test, and 31% increase to IGF-1 generation test.

Case 2 (14 years 10 months, male): The patient had a height of 139 cm (-4,27 SDS), BW 35.9 kg (-3.2 SDS), BMI 18.58 kg/m² (-0.97 SDS), testicular volume 5/6 mL, and Stage I pubic hair growth.His BA was 13 years.He had basal levels of GH 26.6 ng/ml, IGF-1 97.7 ng/ml (<-2 SDS), and IGFBP-3 2.06 µg/ml (<-2 SDS), and 118% response to IGF-1 generation test. The cases did not have the typical LS phenotype.Their genetic analysis revealed a homozygous c.344A> C (p.Asn115Thr) mutation in the 5th exon of GHR. The siblings did not receive treatment because they did not attend follow-up appointments.They had reached their final heights when they presented three years later (sister: 138.3 cm [-3.92 SDS], brother: 156.3 cm [-3.17 SDS]).

Conclusion: In the literature, three cases are reported with the same mutation as in our cases, all being of Arab origin and having severe LS phenotype and lower final height SDS values and IGF-1 levels than our cases (-4.5 SDS in a female case, and -6.8 and -6.9 SDS in two males).The milder phenotype in our patients despite the same genotype suggests a variable GHR activity potentially due to other modifiers such as downstream variants in the GHR gene in the GH pathway.