Laron syndrome primary GH resistance

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The following describes adult patients with primary IGF1 deficiency due to primary GH resistance or insensitivity (i.e. Laron syndrome). In 1966 and in 1968 our group described a new hereditary syndrome resembling IGHD, but

FIG. 1. Appearance of a 58 year old patient with GH deficiency due to a PROP/ gene mutation. Note wrinkled and loose skin.

FIG. 2. Appearance of a 70 year old patient with GH deficiency due to a PROP / mutation. Note absence of grey hair and loose skin. For details see text. Reproduced with permission from Krzisnik et al (1999).
FIG. 3. Early ageing appearance of a 39 year old female with Laron syndrome.

with very high serum hGH levels (Laron et al 1968). Since then we have been following in Israel a cohort of 51 patients from infancy to adulthood (Laron 1999a, Laron & Parks 1993). Since the first description several hundred patients, or their descendants, have been described with Laron syndrome, mainly in Mediterranean and Mid-Eastern populations (Rosenfeld et al 1994, Laron 1999a). This syndrome is caused by deletions or mutations in the GH receptor or postreceptor pathways (Godowski et al 1989, Amselem et al 1996, Laron 1999a, 1999b), leading to an inability by the liver and possible other tissues to generate IGF1 (Laron et al 1971), the anabolic effector hormone of GH (Laron 1999c). Studying adult patients with Laron syndrome (Laron & Klinger 1993, 1994, Laron 1999b) we observed that these patients remain very short (females, 108— 136 cm; males, 119—142 cm; adult height), have an early ageing appearance (such as a wrinkled face at an early adult age; Fig. 3), and relatively thin skin on their hands. Abramovici et al (1983) performed skin biopsies in six children and late adolescents and found that patients with Laron syndrome had bundles of thickened elastic fibres in the upper dermis.

Even young adult patients presenting with Laron syndrome develop marked general and visceral obesity (Fig. 4), high cholesterol levels (Laron & Klinger 1993), reduced muscular strength (Brat et al 1997), insulin resistance (Laron et al

FIG. 4. Marked obesity in a 41 year old female with Laron syndrome.

1997), osteoporosis (Laron & Klinger 1994), and/or suffer from psychological deficiencies (Galatzer et al 1993), all features characteristic for normal ageing and usually apparent at a later age. The oldest patient followed by us is a 73 year old male; one lady examined by us only once and suspected (but not proven) to have Laron syndrome died at age 53. She had suffered from asthma and coronary heart disease (Laron 1999b). Also, adult patients in the large Ecuadorian cohort of Laron syndrome patients have been reported to have reached ages of 70 years or more (Rosenbloom et al 1999). It is of note that with one exception none of our adult patients has grey hair. However, they have a tendency for baldness (in males) and thin hair (in females) (Laron et al 2001).

In conclusion, the relatively small number of adult patients with IGHD or MPHD never previously treated with GH, as well as patients with primary IGF1 deficiency (Laron syndrome) not treated by IGF1, show a series of early developing characteristics compatible with ageing such as thinning and wrinkling of skin, obesity, muscle weakness, osteoporosis and hyperlipidermia.

In contradistinction to the postulation of Rosen & Bengtsson (1990) that hypopituitary patients have premature mortality due to cardiovascular disease (Rosen et al 1993), the patients with GH and IGF1 deficiency live a long life, despite the signs of early ageing. One big difference between our patients and those reported by Rosen et al (Rosen & Bengtsson 1990, Rosen et al 1993) is that almost all of those reported by Rosen and colleagues had tumours, mostly pituitary adenomas, and were treated either by surgery or irradiation; all were MPHD and received a combination of hormone replacement treatments with the exception of GH. Therefore, those patients cannot be compared to the patients with IGHD and/ or IGF1 deficiency, and the statement that GH or IGF1 deficiency shortens the lifespan seems incorrect.

A review of animal studies using models of GH or IGF1 deficiency also revealed that the lifespan in these animals is prolonged compared to intact animals.

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