• Discovery of the Condition In 1966, Laron, Pertzelan, and Mann- heimer described the surprising find- ing of abnormally high concentrations of immunoreactive serum growth hor- mone in three Yemenite Jewish sib- lings who had hypoglycemia and other clinical and laboratory signs of growth hormone deficiency (GHD). Two years later the Israeli investigators reported 19 more patients (total 22), all oriental Jews, with an apparent autosomal re- cessive mode of transmission in con- sanguineous families (Laron et al. 1968). Subsequent studies in Israel and elsewhere demonstrated that the circu- lating growth hormone (GH) in these patients was normal, that exogenous GH administration did not stimulate sulfation factor activation [later identi- fied as insulin-like growth factor I (IGF-I)], and that their liver microsomes failed to bind radioiodine-labeled GH [reviewed in Rosenfeld et al. (1994)]. • Genetic Definition The recognition that circulating GH- binding protein (GHBP) in rabbit serum corresponded to liver cytosolic GHBP (Ymer and Herrington 1985) was followed by reports of absence of circulating GHBP in patients with Laron syndrome (Baumann et al. 1987, Daughaday and Trivedi 1987). At the same time, human GHBP was purified, cloned, and sequenced, and found to be structurally identical to the extra- cellular hormone-binding domain of the membrane bound GH receptor (GHR) (Leung et al. 1987). The entire human GHR gene was characterized by Godowsky et al. (1989), who demon- strated that both the coding and 3′- untranslated regions of the receptor are encoded by nine exons, numbered 2–10. Exon 2 encodes a secretion sig- nal peptide, exons 3–7 the extracellular domain, exon 8 the transmembrane do- main, and exons 9 and 10 the cytoplas- mic domain and 3′-untranslated region. The report of the characterization of the gene included the first description of a genetic defect of the GHR, a non- contiguous deletion of exons 3, 5, and 6, in two Israeli patients with Laron Münsterberg A, Lovell-Badge R: 1991. Expres- sion of the mouse anti-Müllerian hormone gene suggests a role in both male and female sex differentiation. Development 113:613–624. Oréal E, Pieau C, Mattei MG, et al.: 1998. Early expression of AMH in chicken embry- onic gonads precedes testicular SOX9 ex- pression. Dev Dynamics 212: 522–532. Orth JM: 1984. The role of follicle-stimulating hormone in controlling Sertoli cell prolifer- ation in testes of fetal rats. Endocrinology 115:1248–1255. Pasqualini T, Chemes H, Rivarola MA: 1981. Testicular testosterone levels during pu- berty in cryptorchidism. Clin Endocrinol 15:545–554. Racine C, Rey R, Forest MG, et al.: 1998. Re- ceptors for anti-Müllerian hormone on Ley- dig cells are responsible for its effects on steroidogenesis and cell differentiation. Proc Natl Acad Sci USA 95:594–599. Rey R, Lordereau-Richard I, Carel JC, et al.: 1993. Anti-Müllerian hormone and testos- terone serum levels are inversely related dur- ing normal and precocious pubertal develop- ment. J Clin Endocrinol Metab 77:1220–1226. Rey R, Mebarki F, Forest MG, et al.: 1994. Anti-Müllerian hormone in children with androgen insensitivity. J Clin Endocrinol Metab 79:960–964. Rey R, Al-Attar L, Louis F, et al.: 1996. Testic- ular dysgenesis does not affect expression of anti-Müllerian hormone by Sertoli cells in pre-meiotic seminiferous tubules. Am J Pathol 148:1689–1698. Shen WH, Moore CCD, Ikeda Y, Parker KL, Ingraham HA: 1994. Nuclear receptor steroidogenic factor 1 regulates the muller- ian inhibiting substance gene: a link to the sex determination cascade. Cell 77:651–661. Tran D, Josso N: 1982. Localization of anti- Müllerian hormone in the rough endoplas- mic reticulum of the developing bovine Sertoli cell using immunocytochemistry with a monoclonal antibody. Endocrinology 111:1562–1567. Tran D, Meusy-Dessolle N, Josso N: 1981. Waning of anti-Müllerian activity: an early sign of Sertoli cell maturation in the devel- oping pig. Biol Reprod 24:923–931. Voutilainen R, Miller WL: 1987. Human Mül- lerian inhibitory factor messenger ribonu- cleic acid is hormonally regulated in the fetal testis and in adult granulosa cells. Mol Endocrinol 1:604–608. 276 © 1998, Elsevier Science Ltd, 1043-2760/98/$19.00. PII: S1043-2760(98)00070-8 TEM Vol. 9, No. 7, 1998 Lessons from the Genetics of Laron Syndrome Arlan L. Rosenbloom and Jaime Guevara-Aguirre In the decade since the cloning and sequencing of the growth hormone receptor (GHR) and the recognition that the circulating GH-binding protein (GHBP) is structurally identical to the extracellular domain of the GHR, 34 mutations have been described. These include one deletion, eight nonsense mutations, eleven missense mutations, four frameshift mutations and ten splice mutations. More than half of the 131 patients with Laron syndrome whose molecular defects have been identified comprise the Ecuadorian cohort who share a single splice mutation. Variable expression of different homozygous or compound heterozygous defects of the GHR is no greater than the variation within a genetically homogeneous population. Some features, such as birth size and intelli- gence, are unlikely to be affected by GHRD. Greater understanding of the genetics, physiology, and clinical expression of abnormalities in the GH–GHR–IGF-I (insulin-like growth factor I) axis necessitates a recon- sideration of the classification of GH insensitivity (GHI). A.L. Rosenbloom is at the Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32608, USA; and J. Guevara-Aguirre is at the Instituto En- docrinologia Metabolismo y Reproduccion, Casilla 6337-CCI, Quito, Ecuador.