Growth Hormone Insensitivity with Immunodeficiency

Alternative Names

  • Laron Syndrome due to Postreceptor Defect
  • Laron Type Dwarfism II
  • LTD2
  • Growth Hormone Insensitivity due to Postreceptor Defect
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Disorders of other endocrine glands

OMIM Number

245590

Mode of Inheritance

Autosomal recessive

Gene Map Locus

17q11.2

Description

Growth hormone insensitivity is a condition characterized by severe growth failure, in the presence of normal-to-elevated concentrations of circulating growth hormone and resistance to exogenous growth hormone therapy. Typical clinical features of the condition include a congenital growth failure, delayed bone age, frontotemporal hairline recession, bossing, hypoplastic nasal bridge, shallow orbits, hypomuscularity, walking delay, limited elbow extensibility, hypercholesterolemia, and delayed puberty with normal reproduction. In addition, children affected with Larson syndrome also show a form of primary immunodeficiency. This insensitivity to the growth hormone can arise from different etiologies including postreceptor defects.

Diagnosis of the condition requires a careful work-up, keeping in mind the various etiologies of the broader growth hormone resistance disease/growth hormone insensitivity. Unlike GHRD, hypoglycemia is usually not seen in the case of GHI. The only specific treatment available for affected patients is the administration of recombinant human insulin growth factor-I. It is important that patients who receive this form of therapy be monitored regularly for blood sugar variations. Additionally, a small proportion of such patients may also require a tonsillectomy/adenoidectomy as a result of the adverse effect of lymphoid hyperplasia. Long term prognosis is very good, with the exception of an increased risk for cardiovascular disease.

Molecular Genetics

Mutations in the signal transducer and activator of transcription 5B (STAT5B) gene have been shown to cause Laron syndrome. The human growth hormone, mediates its effects through its binding to the growth hormone receptor (GHR), thereby, activating it. This activation further switches on down-stream pathways, including the STAT pathway, that culminate in the regulation of several genes involved in the growth, such as IGF-I, IGFBP-3, and ALS. In this light, it is clear to see how pathological mutations in the STAT5B gene could result in clinical features of postreceptor growth hormone insensitivity. In addition, the primary immunodeficiency observed in this condition can also be explained by the vital role played by the downstream effecter molecules, such as insulin growth factor in the immune system.

Epidemiology in the Arab World

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Other Reports

Kuwait

Hwa et al. (2007) described two siblings from Kuwait, born to healthy consanguineous parents who showed features typical of Laron syndrome due to postreceptor defect. Both children showed poor postnatal growth and had severe growth retardation. The younger child was also found to suffer from juvenile idiopathic arthritis, suggesting autoimmune irregularities. The older sibling was diagnosed with bronchiectasis and intestinal pneumonitis. The children had normal basal serum growth hormone and growth hormone binding protein levels. However, levels of IGF-I, IGFBP-3 and ALS levels were way below normal. Sequencing of the GHR gene revealed no mutations, whereas when the STAT5B gene was sequenced, a homozygous deletion of a single G at the exon13-intron13 junction was revealed. The parents were heterozygous. Interestingly, although both the parents had heights within the normal range, they were consistently below the mean.

Palestine

Laron et al. (1993) reported the cases of three sibs, born of first-cousin parents, with Laron syndrome and normal serum GHBP who underwent long-term treatment with biosynthetic IGF1 with results indicating a post-GH receptor defect. Basal serum levels of growth hormone were high and IGF1 low, but, in contradistinction to the classic form of Laron syndrome, serum GHBP and insulin-like growth factor-binding protein-3 (IGFBP3) were normal in these patients. Laron et al. (1993) concluded from the results of short-term treatment with human growth hormone and short- and long-term IGF1 administration that the GH receptor and the signal transmission for IGFBP-3 synthesis were normal but that a defect existed in the post-GH receptor mechanism for the generation of IGF1. Treatment with IGF1 for 1 year increased the growth velocity by 47 to 96% in the 2 older children. The sibs showed the typical clinical features of Laron syndrome: they were very short and obese, had acromicria, small genitalia (in the boys), and a high-pitched voice. A prominent forehead was demonstrated in 1 patient. It is perhaps significant that females on both sides of the family, aunts of the 3 sibs, and the paternal grandmother were very short, being less than 2 standard deviations below the mean. This may represent heterozygous manifestation.

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