Young Thai sisters with growth hormone insensitivity or Laron syndrome

The clinical manifestations and hormonal investigations in our patients were consistent with the diagnosis of GHI syndrome, i.e., extremely short stature phenotypes associated with high concentrations of circulating GH with low IGF-1 and IGFBP-3 levels. Additionally, the IGF-1 generation test failed to induce a significant increase in serum IGF-1 and IGFBP-3 confirming GH resistance. The diagnosis was also strongly suggested by a previously described scoring system [7]. Molecular genotype analysis of DNA from both sisters revealed a homozygous mutation in exon 7 of the GHR. This mutation at position hg19 chr5 g.[42711311C>T] (= c.723C>T, p.G223G old nomenclature; p.G241G new nomenclature) does not change the genetic code, but is predicted to create a new donor splice site and therefore interfere with mRNA splicing (HGMD number CS971752) [13].

Laron et al. first described 3 children with phenotypic features of GH deficiency associated with high serum GH levels and no response to exogenous GH treatment [1]. Laron syndrome is an autosomal recessive condition, which usually presents with severe postnatal growth failure. The clinical features of patients with GHI are similar to those with severe GH deficiency including severe growth retardation, typical craniofacial appearance, and hypoglycemic episodes because of insensitivity to GH [4, 5, 7]. Biochemical investigations showed GH resistance, with high concentrations of circulating GH associated with low levels of IGF-1 and IGFBP-3. GH-binding protein levels are low when the mutation is identified in the extracellular domain of the GH receptor. As such, exogenous GH administration does not increase serum IGF-1 and IGFBP-3 levels significantly.

These 2 Thai sisters had clinical features and hormonal profiles consistent with a GHI disorder. A clinical scoring system has been devised to identify patients with suspected GHI, which includes height standard deviation score (SDS), basal GH level, basal IGF-1 level, IGF-1 response to an IGF-1 generation test, and GH-binding protein (GHBP) level [7]. In a series of 27 cases of GHI from 8 European countries and Australia [7], median height of the patients was – 6.1 SDS and weight was –3.2 SDS. Additionally, 33% of these patients had evidence of hypoglycemia. Birth weight and birth length were normal or slightly below average (median birth weight –0.72 SDS, range 1.75 to –3.92), suggestive of a possible prenatal effect of GH resistance. The parents of the young sisters reported here, had heights below average for Thai growth standards [6]. This has previously been reported in the parents of patients with GHI secondary to GHR mutations [5]. Blue sclera are a clinical feature of Laron syndrome, initially described in the original report of the Ecuadorean cohort in 1990 [8]. GHR spans 87 kilobases and consists of 9 coding exons [9]. The GHR protein consists of a large extracellular domain involved in GH binding and GHR dimerization, a single transmembrane domain that anchors the receptor to the cell surface, and an intracellular domain involved in GH signaling. The circulating GH-binding protein corresponds to the extracellular domain of GHR. Numerous GHR defects have been reported worldwide and are associated with a range of phenotypes [10]. A milder phenotype, which may not have the cardinal features of Laron syndrome, is reported in patients with dominant negative GHR mutations and the intronic pseudoexon GHR mutations compared with those with missense and nonsense GHR mutations who have more severe growth failure [5].

Additionally, a group of patients with GHI have a positive correlation between height SDS and IGF-1 SDS and IGFBP-3 SDS [10]. Guevera-Aguirre et al. originally described the correlation of height SDS with serum IGF-1 in adults with Laron syndrome and with IGFBP-3 in adults and children [4]. Some GHR defects are more common in certain ethnic groups such as the homozygous GHR splice site mutation known as E180 in the Ecuadorian GHI population [11] and exon 3, 5, and 6 deletion in Oriental Jewish families [9, 12]. The same exon 7 (723 C>T) GHR mutation carried by these 2 Thai sisters was previously identified in a Spanish patient with Laron syndrome [13]. Although this mutation does not change the genetic code, the mutated sequence creates a putative cryptic donor splice site [ggtgagt], resulting in the deletion of 63 nucleotides from the mRNA, and 21 amino acids in the carboxy-terminal end of the extracellular domain of the GHR. This defect can be compared to the mutation identified in Ecuadorean patients with Laron syndrome [11] and another exon 7 splice site mutation that results in the elimination of 21 amino acids from the extracellular domain of the GHR reported in a Bahamian genetic isolate of Anglo-Saxon origin [14]. Consistent with our patients, the Bahamian patients also had severe short stature (height SDS range –3.7 to –6.3) and clinical features suggestive of LS including the typical craniofacial appearance and truncal obesity.

In conclusion, we report 2 Thai sisters who have a homozygous mutation of the GHR gene. To our knowledge, this is a first report of Laron syndrome in Thais confirmed by genotyping.