Katie A. Woods

Clinical and Endocrine Characteristics in Atypical and Classical Growth Hormone Insensitivity Syndrome

Objective: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder ‘atypical’ GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. Methods: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. ‘classical’ required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), ‘atypical’ required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. Results: Fifty patients [24 males, 26 females, aged 8.6 ± 4.6 years (mean ± SD)] had ‘classical GHIS’, 9 patients (7 males, 2 females, aged 7.8 ± 4.1 years) had ‘atypical GHIS’, 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS –4.0 ± 1.4) compared to classical GHIS (–6.7 ± 1.4), less reduction in IGFBP-3 SDS (atypical –5.5 ± 3.3; classical –8.6 ± 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). Conclusions: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.

Growth Hormone Insensitivity: Pathophysiology, Diagnosis, Clinical Variation and Future Perspectives

The study of genetic growth hormone (GH) insensitivity is an evolving field. GH insensitivity syndrome (GHIS), otherwise known as Laron syndrome, is a heterogeneous disorder. Biochemical features consist of severe insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) deficiency and elevated GH secretion. In a heterogeneous ‘European’ cohort of GHIS patients, features varied from classical to moderate abnormalities of phenotype and endocrine disturbance. A study of facial features within this series showed that a mild subgroup existed with normal facies, mild short stature and moderate biochemical abnormalities. Overlap with idiopathic short stature (ISS) exists, with heterozygous mutations of the GH receptor demonstrated to cause impaired growth. This ‘partial’ GHIS has not yet been defined endocrinologically. GH sensitivity, measured by IGF-I and IGFBP-3 responses in the IGF-I generation test, may reveal abnormalities in ISS, although it is likely that the dose of recombinant human GH and frequency of sampling in the test need to be modified.

Insulin-like growth factor (IGF)-I gene deletion.

Insulin-like growth factor-I (IGF-I) deficiency is a clinical condition usually associated with severe post-natal growth failure and characterized by a combination of auxological, clinical, and metabolic abnormalities caused by decreased IGF-I biologic action [1–3]. IGF-I deficiency can result from a defect in the IGF-I gene or in its promoter or can be secondary to disorders in growth hormone (GH) synthesis and action, in the type 1 IGF receptor or in the IGF-binding proteins (IGFBPs) (Table 1). IGF-I, in common with many other growth factors, exerts physiological effects in virtually every organ and tissue during fetal and postnatal life [4]. A great deal has been learned about the genetic causes of IGF-I deficiency over the past few decades. By 1996, many patients with GH receptor (GHR) mutations had been identified [5–7]. These patients presented with either the clinical phenotype of classical Laron syndrome [8] or with atypical clinical features, the latter associated sometimes with a milder biochemical abnormality [7]. The development of IGF knockout models has provided clear evidence of the important role of circulating and locally produced IGF-I in both fetal and postnatal growth and development [9–13]. The cloning of the IGFI gene [14] and peptide characterization [15] also led to the development of recombinant human IGF-I (rhIGF-I) that has been used therapeutically since the late 1980’s [16]. Since then, rhIGF-I has been safely used in the treatment of patients with classical and atypical Laron syndrome [8,16–20]. This treatment was also used in the patient with an IGF-I gene deletion described by our group [21–23].

The Broad Spectrum of Inherited Growth Hormone Insensitivity Syndrome

Growth hormone (GH) insensitivity syndrome (GHIS) results in severe short stature and metabolic disturbances, but when this disorder is studied in more detail it is clear that there is marked clinical and biochemical heterogeneity. Many genetic defects of the GH receptor have been reported in inherited GHIS, but it now seems likely that some cases might be the result of defects of other genes or of links in the post-receptor cascade.

Insulin-like growth factor-I deficiency caused by a partial deletion of the IGF-I gene: Effects of rhIGFmi therapy

Summary Insulin-like growth factor-I (IGF-I) is one of the most important regulator of growth. IGF-I deficiency is associated with prenatal and post-natal growth failure and may arise primarily as a result of GH receptor/post-receptor abnormalities or defects in the synthesis and transport of IGF-I. We have previously reported a 17.2-year-old boy with severe growth retardation and undetectable serum levels of IGF-I caused by a partial deletion of the IGF-I gene. This short review will concentrate on results of a recent study which examined the effects of rhIGF-I therapy on the GH-IGF system of this patient. Similar to healthy individuals, this patient had normal IGFBP-3 but elevated ALS levels. IGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBPs and insulin levels.

Relations phenotype-genotype dans l'insensibilite a l'hormone de croissance

Growth hormone (GH) insensitivity is associated with several different mutations of the GH receptor gene and a recently described new genetic disorder of the IFGI gene. The phenotype and biochemical characteristics were studied in 82 patients with growth hormone insensitivity, from 23 different countries, with a mean age of 8.25 years. Mean height SDS was -6.09. SDS of the IGF binding protein -3 (IGF BP3) was 7.99. Twenty three per cent of the patients were GH binding protein (GHBP) positive (> 10%). Mean height SDS score was -6.5 in the GHBP negative patients and -4.9 in the GHBP positive patients (p < 0.001). Fifteen different mutations of the GH receptor gene were identified in 27 patients. There were no relationships between the type of mutation or the involved GH receptor gene exon and height or IGFBP-3 SDS. The new phenotype due to a partial deletion of the IGFI gene was described in a 15-year-old boy who presented with a severe intrauterine growth retardation, a very poor postnatal statural growth, a neurosensorial deafness and a mild mental retardation. He had elevated GH levels, normal levels of IGFBP3, undetectable levels of IGFI, and showed no response to GH treatment. A partial deletion concerning the exons 4 and 5 of the IGFI gene was found. Thus, GH insensitivity is associated with large variations in the clinical and biochemical phenotypes.

Growth hormone insensitivity.

Growth hormone insensitivity (GHI) describes a group of disorders characterized by deficient biological action of GH. GH insensitivity may be of primary origin, that is, related to defects in genes coding for functional proteins essential for GH action or secondary to acquired pathology such as inflammatory or nutritional disorders. This article will describe GH insensitivity of primary origin, which in children presents as growth failure leading to adult short stature. Metabolic symptoms, such as hypoglycaemia, may also occur. Cardinal biochemical features are normal or elevated GH secretion and IGF-1 deficiency. Therapy for GH insensitivity consists of recombinant human IGF-1, which can lead to height gain resulting in catch-up growth and adult height within the normal range.