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The diagnosis of Laron syndrome should be suspected in infants, older children, or adults who present with a height deficit of −4 to −10 height SDS and with the typical features (shown in Figs 1.1 and 1.2 in Chap. 1) (facial phenotype, dwarfism, obesity, hypogenitalism) identical with those of congenital isolated growth hormone (GH) deficiency (cIGHD), but by laboratory screening, having elevated serum hGH concentration in young age reaching acromegalic levels (see Chap. 2, Fig. 2.3) in the presence of very low or undetectable serum IGF-I. As in neonates and especially premature babies, blood hGH levels are high; determination of serum hGH at this age is useful only for determining the hGH deficiency (Laron et al. 2007).

Evidence for hGH insensitivity (resistance) is obtained by performing an IGF-I generation (stimulation test), i.e., administration of hGH 33 µg/kg s.c. for 4 or preferably 7 days, and determining serum IGF-I before, on day 5 and day 8 (i.e., the morning after the last injection). Lack of rise of the serum IGF-I is diagnostic for Laron syndrome (Fig 4.1) (Daughaday et al. 1969; Laron et al. 1971). The definite diagnosis is the documentation of a molecular defect in the hGH receptor (hGH-R) gene.

Fig 4.1
figure 1

IGF-I stimulation (generation) test in patients with Laron syndrome compared to patients with IGHD (congenital hGH gene deletion). Note: Lack of rise of very low serum IGF-I during exogenous daily hGH administration in patients with Laron syndrome in contradistinction to the marked rise in the IGHD patients. Modified from Laron et al. (1971)

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The location of the molecular genetic defect in the hGH receptor (Shevah et al. 2004a; Shevah et al. 2004b; Shevah and Laron 2006) gene requires preparation of DNA, PCR and sequencing (see Chap. 5 page 33). Lack of serum GHBP (growth hormone-binding protein), a rarely performed determination, discloses that the defect is in the extracellular domain of the GH-R (see pages 31–46). Exception to this seems to be patients with GH receptor mutations in intron 6 and the activation of a pseudo exon resulting in normal GHBP levels (David et al. 2007) in whom GHBP is positive. Mutations in the transmembrane or intracellular domains of the GH-R permitting GH binding to its receptor result in normal or high serum GHBP concentrations (Silbergeld et al. 1997). Low serum levels of IGFBP-3 (Laron et al. 1992a) and/or low IGF-I levels are not diagnostic (Laron et al. 1992b; Laron et al. 2007).

Table 4.1 summarizes the clinical and main laboratory features of untreated Laron Syndrome as compared to congenital isolated GH deficiency (IGHD). It is seen that the only diagnostic distinctions are the high serum hGH levels and lack of rise of IGF-I upon hGH administration. The final proof is obtained by genetic analysis of the hGH receptor gene.

Table 4.1 Comparison between clinical features and diagnostic laboratory characteristics in untreated Laron syndrome (primary GH insensitivity) and isolated GH deficiency (IGHD)
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