Definition

Laron syndrome, or Laron-type dwarfism, is an autosomal recessive disorder characterized by an insensitivity to growth hormone (GH), caused by a variant of the growth hormone receptor. It causes short stature.

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Wikigenes

Classification of growth hormone insensitivity

1) Primary GH insensitivity (eg, Laron syndrome, hereditary and/or congenital defects)

•Growth hormone receptor (GHR) defects (quantitative and qualitative)

•Abnormalities of GH signal transduction (postreceptor defects)

•Primary defects of insulinlike growth factor-1 (IGF-I) synthesis or secretion

2) Secondary GH insensitivity (acquired conditions; may be partial or transient)

•Circulating antibodies to GH that inhibit GH action

•Antibodies to the GHR

•Primary defects of IGF-I synthesis

•GHI caused by malnutrition

•GHI caused by liver disease

•Other conditions that cause GHI

Pathophysiology

LS is a familial disorder with an autosomal recessive form of inheritance. The underlying metabolic defect concerns a lack of responsiveness to GH. Patients with LS typically have low serum levels of IGF-I, despite serum levels of GH that are within the reference range or elevated. Exogenous GH does not accelerate their growth or stimulate serum levels of IGF-I or insulinlike growth factor binding protein-3 (IGFBP-3). Cellular unresponsiveness to GH was demonstrated in vitro by the failure of GH to stimulate erythroid progenitor cells from the peripheral blood of patients.
Direct evidence of a defect in the GHR came in 1984 when Laron and colleagues demonstrated that hepatic microsomes obtained by liver biopsy of 2 patients did not bind radiolabeled GH. With the advent of modern molecular biology, the human GHR has been cloned and characterized. This led to the observation that serum GH binding protein (GHBP) was structurally identical to the extracellular domain of the GHR. Subsequently, absence of circulating GHBP was demonstrated in patients with LS. The initial studies of the GHR gene in Israeli patients with LS showed that some, but not most, contained gene deletions.

To date, 33 mutations of the GHR have been discovered in approximately half of the 250 patients with LS that have been reported. Most of these comprise a wide variety of point mutations, of which the vast majority have been in the extracellular domain. Mutations resulting in defective GHR dimerization or abnormal GH-GHR signal transduction have also been reported. Other forms of GHI with similarly severe insulinlike growth factor (IGF) deficiency (eg, from defects in IGF synthesis or secretion) have clinical features essentially identical to those of GHI secondary to GHR deficiency.

Epidemiology

Race: Ethnic background is known for approximately 90% of the patients reported to have LS. A significant majority (65%) are of known Semitic origin. This group includes Arabs, Asian Jews, and a large genetic isolate of Ecuadorian conversos (Jewish individuals who converted to Christianity during the Spanish Inquisition). The Ecuadorian group and the Israeli Moroccan/Sephardic Jewish patients are believed to be derived from a common ancestor, likely in medieval Spain prior to the expulsion of Jews in 1492 during the inquisition. Many conversos escaped to the New World, settling in remote mountains in efforts to avoid the inquisitors who pursued them. Consanguinity and propagation of the mutation was in large part a product of such geographic isolation.

The largest genetic isolates have been those reported in Israel and Ecuador, whereas smaller ones have been reported in Turkey and in the Bahamas. Numerous patients of Indian, Pakistani, and Italian ethnicity have been reported. Roughly 90% of patients with LS can trace their origins to the Mediterranean area, the Middle East, or to the Indian Peninsula. While no obvious explanation exists for this geographic localization, consanguinity was or still is common in most of the above noted populations.

Sex: Sex predilection varies significantly in the reported populations. The male-to-female (M:F) ratio for the original 26 Israeli patients was 0.73:1. In Ecuador, the initial impression was that of a marked predominance among females, with an M:F ratio of 0.5:1, but this was not observed upon reanalysis. Outside of Israel and Ecuador, the M:F ratio is 1.5:1. No clear explanation for these differences currently exists, and most experts believe that no sex difference exists in the incidence of LS.

Age: LS is a congenital disorder.

Insulin-like growth factor (IGF-1): a growth hormone

IGF-1 and IGF-2 were identified in 1957 by Salmon and Daughaday. and designated “sulphation factor” by their ability to stimulate sulphate incorporation into rat cartilage. Froesch et al described the non-suppressible insulin-like activity (NSILA) of two soluble serum components (NSILA I and II). In 1972, the labels sulphation factor and NSILA were replaced by the term somatomedin. denoting a substance under control and mediating the effects of GH. In 1976, Rinderknecht and Humbel isolated two active substances from human serum, which owing to their structural resemblance to proinsulin were renamed “insulin-like growth factor 1 and 2” (IGF-1 and 2). IGF-1 is the mediator of the anabolic and mitogenic activity of GH.

THE IGF-1 GENE

The IGF-1 gene is on the long arm of chromosome 12q23–23. The human IGF-1 gene consists of six exons, including two leader exons, and has two promoters.

In recent years, new technologies have enabled many advances in the so called growth hormone (GH) axis. Thus, it has been found that GH secretion from the anterior pituitary is regulated not only by GH releasing hormone (GHRH) and somatostatin (GH secretion inhibiting hormone), but also by other hypothalamic peptides called GH secretagogues, which seem to act in synergism with GHRH by inhibiting somatostatin. One of these has been cloned and named Ghrelin. The interplay between GHRH and somatostatin induces a pulsatile GH secretion, which is highest during puberty. GH induces the generation of insulin-like growth factor 1 (IGF-1, also called somatomedin 1) in the liver and regulates the paracrine production of IGF-1 in many other tissues.

THE IGF BINDING PROTEINS (IGFBPs)

In the plasma, 99% of IGFs are complexed to a family of binding proteins, which modulate the availability of free IGF-1 to the tissues. There are six binding proteins. In humans, almost 80% of circulating IGF-1 is carried by IGFBP-3, a ternary complex consisting of one molecule of IGF-1, one molecule of IGFBP-3, and one molecule of an 88 kDa protein named acid labile subunit. IGFBP-1 is regulated by insulin and IGF-1; IGFBP-3 is regulated mainly by GH but also to some degree by IGF-1.

THE IGF-1 RECEPTOR

The human IGF-1 receptor (type 1 receptor) is the product of a single copy gene spanning over 100 kb of genomic DNA at the end of the long arm of chromosome 15q25–26. The gene contains 21 exons and its organisation resembles that of the structurally related insulin receptor. The type 1 IGF receptor gene is expressed by almost all tissues and cell types during embryogenesis. In the liver, the organ with the highest IGF-1 ligand expression, IGF-1 receptor mRNA is almost undetectable, possibly because of the “downregulation” of the receptor by the local production of IGF-1. The type 1 IGF receptor is a heterotetramer composed of two extracellular spanning α subunits and transmembrane β subunits. The α subunits have binding sites for IGF-1 and are linked by disulphide bonds. The β subunit has a short extracellular domain, a transmembrane domain, and an intracellular domain. The intracellular part contains a tyrosine kinase domain, which constitutes the signal transduction mechanism. Similar to the insulin receptor, the IGF-1 receptor undergoes ligand induced autophosphorylation. The activated IGF-1 receptor is capable of phosphorylating other tyrosine containing substrates, such as insulin receptor substrate 1 (IRS-1), and continues a cascade of enzyme activations via phosphatidylinositol-3 kinase (PI3-kinase), Grb2 (growth factor receptor bound protein 2), Syp (a phophotyrosine phosphatase), Nck (an oncogenic protein), and Shc (src homology domain protein), which associated to Grb2, activates Raf, leading to a cascade of protein kinases including Raf, mitogen activated protein (MAP) kinase, 5 G kinase, and others.

Homozygous microdeletion of the POU1F1, CHMP2B, and VGLL3 genes in chromosome 3-A novel syndrome

Microdeletion syndromes include numerous syndromic phenotypes associated with intellectual disability and dysmorphic features. A patient with a novel microdeletion of chromosomal region 3p11.2-p12.1 containing POU1F1, chromatin-modifying protein 2B (CHMP2B), and vestigial-like 3 (VGLL3) genes. This patient was diagnosed as having a neonatal multiple pituitary hormone [growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin] deficiency. In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability. She also displayed an unusual growth pattern characterized by unresponsiveness to high doses of GH replacement therapy during infancy and early childhood and an accelerated growth rate beginning at the age of 4.5 years. Insulin-like growth factor (IGF)-1 levels were consistently extremely low or undetectable. Extensive medical and genetic analysis ruled out primary and secondary GH insensitivity. The distinct phenotype and the peculiar growth pattern observed in this affected patient, not reported to have been observed in other cases with POU1F1 gene inactivity, suggest that the other two deleted genes play a possible role in the development of this syndrome. This hypothesis may be supported by the fact that both the CHMP2B and VGLL3 genes are expressed in the liver and the growth plate, the two main target organs of the GH/IGF-1 axis. The homozygous deletion of the CHMP2B gene, previously associated with frontotemporal dementia, may contribute to the intellectual disability observed in this patient.

Medical Care

•The only effective treatment currently available for patients with classic GHI is recombinant human IGF-I (rhIGF-I).
•For those with secondary forms of GHI, the underlying cause (eg, malnutrition, liver disease) should be identified and treated appropriately.

•Infants with LS may require more frequent feedings to avoid hypoglycemia.

•Periodic blood sugar monitoring is necessary for some patients with LS and for all patients with LS who are receiving rhIGF-I therapy.

Consultations: A pediatric orthopedic surgeon may be consulted, as indicated.

Diet: The dietary recommendations for LS are mainly to ensure adequate caloric intake to facilitate growth and avoid hypoglycemia.

Activity: Participation in contact sports may be contraindicated in some cases depending on the degree of osteopenia and fracture risk.