The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4397-4404
Copyright © 1999 by The Endocrine Society
The Essential Role of IGF-I: Lessons from the Long-Term Study and Treatment of Children and Adults with Laron Syndrome
Zvi Laron
Endocrine and Diabetes Research Unit, Schneider Children’s Medical
Center of Israel, Petah Tikva 49202; and Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv 49202, Israel
Address correspondence and requests for reprints to: Prof. Zvi Laron, M.D., Endocrine and Diabetes Research Unit, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tikva 49202, Israel.
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Abstract
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Fifty patients with primary GH resistance (Laron syndrome) due to
molecular defects of the GH receptor or post-receptor pathways were
followed from infancy through adulthood. This condition leading to
long-term insulin-like growth factor-I (IGF-I) deprivation caused
marked growth retardation (-4 to 8 height SD), acromicia,
organomicria, retarded development of the skeletal and muscular
systems, a small cranium, slow motor development, and impairment of
intellectual development in some of the patients. In addition, there
was progressive obesity, insulin resistance, a tendency for
hypoglycemia, followed later in life by hypercholesterolemia and by
glucose intolerance and even diabetes. IGF-I treatment of children with
Laron syndrome, by our and other groups (150–240 µg/day sc),
stimulated growth (8 cm in the first year and 4–5 cm in the following
years) and normalized the biochemical abnormalities. Overdosage led to
adverse effects such as hypoglycemia, edema, swelling of soft tissues,
and hyperandrogenism. It is concluded that primary IGF-I deprivation
induces severe auxological, biochemical, and hormonal changes, the only
treatment being biosynthetic IGF-I administration.
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Introduction
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THE DESCRIPTION of a new syndrome in 1966
that resembled in many clinical and biochemical features isolated GH
deficiency (1), but which in contradistinction was characterized by
very high serum GH levels (2) and very low serum insulin-like growth
factor-I (IGF-I; then called somatomedin) (3, 4), opened new
perspectives to study the physiological role of IGF-I, the interaction
between GH and IGF-I, as well as the differential activities of these
two hormones.
Since our initial description, patients have been diagnosed in various
parts of the world, many being of Mediterranean or Middle Eastern
origin or their descendants (5, 6). Others are spontaneous mutations
(7). There are reports of several hundreds of patients. In addition,
there are many known but not reported patients and probably many so far
undiagnosed patients.
The first attempt to summarize the knowledge accumulated between 1966
and 1992 by various groups of investigation was published in 1993 (8).
The syndrome is also called primary GH resistance or insensitivity and
primary IGF-I deficiency (9).
Further experience gained in the studies of patients with various types
of primary IGF-I deficiency as well as experimental models (Table 1
) enable an update on the
physiopathology of congenital IGF-I deficiency and the pharmacological
effects of IGF-I replacement treatment. Much of the clinical
information reported herein is drawn from my own experience gained
during the long-term follow-up of 50 patients with GH receptor or post
receptor defects, many from birth to late adult age (2, 25), and the
treatment of 10 children (26) and 5 adults (27). Whenever appropriate,
the data is compared with that reported by other investigators.
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Genotype-Phenotype Relation
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Some differential effects of GH and IGF-I can be seen when
evaluating clinical and hormonal characteristics in patients with hGH
gene deletion and patients with Laron syndrome (LS) due to a GH
receptor (GHR) defect (in both there is no GH signal transmission)
compared with a post-GHR defect (partial GH signal transmission) and
with patients having an IGF-I gene deletion or IGF-I receptor (IGF-IR)
defect having intact GH signal transmission (Table 2).
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Table 2. Similarities and differences between patients with
molecular defects in the hGH or IGF-I genes or their receptors
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The effects of GH and IGF-I deficiency or lack of activity on various
growth parameters are identical, pointing to the central role of IGF-I
in anabolic action. Two differences are apparent: patients with
GH-post-receptor defects (16) and IGF-I gene deletion (18) are not as
obese as are patients with hGH gene deletion or GHR defects. This can
be attributed to a normal signal transmission and GH activity on the
adipose tissue and insulin. There is also evidence for other direct
biochemical actions of GH not mediated by IGF-I (28).
There are also some minor phenotypic differences observed in patients
with LS. LS patients with positive GH binding protein (GHBP)
transmembrane and intracellular GHR defects or postreceptor defects are
slightly less short (29, 30) than patients with negative GHBP
(extracellular GHR defects); some also have less typical facial
characteristics of LS (Fig. 1), as also
seen in the patient with IGF-I gene defect (18). Despite the above
differences, all patients with longstanding primary IGF-I deficiency
have many major common features described below in detail (Table 3).
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Figure 1. Typical facial appearance of a 5-yr-old boy
with LS due to a molecular defect of the GHR. Note the sparse hair,
protruding forehead, saddle nose, and small chin.
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Growth
Congenital IGF-I deficiency results in severe growth failure. This
effect is already evident at birth. In patients with a GHR defect
neonatal length 42–48 cm has been reported (2, 5). A neonatal length
of 37 and 38 cm was measured in patients with IGF-I gene deletion (18)
or IGF-IR defect, respectively (19, 21). The intrauterine effect of
IGF-I on growth was also evidenced in the GHR knockout mouse (23). The
different effects on growth between genetic defects in the GHR and
IGF-I gene or its receptor may be due to GH-independent actions of
paracrine IGF-I in the groups of patients with GHR defects.
Postnatally untreated infants with LS slow their growth velocity and
maintain a subnormal growth rate without a pubertal growth spurt,
reaching final heights of between 108 and 136 cm in females and 119 and
142 cm in males (-4 to -10 height SD) (Refs. 5, 25 ;
Table 4; Fig. 2).
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Figure 2. Height of a 16-yr-old girl with LS (left) as
compared with a 15-yr-old healthy girl (right) .
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Body proportions
IGF-I deficiency affects more the growth of the limbs than that of
the trunk, resulting in an abnormally high upper body to lower body
ratio (25). Additionally, the short extremities (chin, hands, feet)
cause the typical appearance of the LS patient.
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Other Sequelae of IGF-I Deficiency
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Long-term IGF-I deficiency in patients with LS is accompanied by a
series of pathological changes other than linear growth retardation (5, 25, 31, 32, 33). The head circumference is subnormal (5), the sphenoid bone
and mandible are underdeveloped (34), subsequently leading to crowding
of the teeth (5, 35), a protruding forehead and a "sunset"
appearance. The teeth are also of bad quality and break easily (7, 35).
The hair is sparse, and nail growth is slow (2, 31). Skeletal
maturation is delayed, and the larynx is narrow, causing a high-pitched
voice (2, 5, 32, 33). There is delayed motor development (2, 5) and
intellectual impairments of various degrees in most of the patients
(36), denoting the essential role IGF-I plays on the nervous tissue.
The genitalia and gonads are small (37), and puberty is delayed (5, 38). Obesity and hyperlipidemia develop gradually to severe degrees
(39) (Fig. 3). Despite a tendency to
hypoglycemia (1, 2, 5, 32, 33, 40) there is relative hyperinsulimenia
and insulin resistance (41). Some of the patients develop glucose
intolerance (42) and even diabetes (41). With age, muscle weakness (43)
and osteoporosis (27) become apparent (Table 4
).
Pharmacological effects of IGF-I
The biosynthesis of IGF-I by recombinant techniques in 1986 (44)
enabled clinical trials with this hormone. Acute experiments in healthy
volunteers revealed a hypoglycemic effect, as well as a fall in serum
triglycerides and total cholesterol (45). Short-term sc administration
was found to decrease also serum insulin and glucagon (46).
These initial trials were soon followed by studies in patients with LS.
We found that bolus injections of IGF-I had a shorter half-life
in LS patients than in healthy subjects (47) and that IGF-I suppressed
not only serum glucose (48) but also serum GHRH, GH, TSH, and insulin
(49) (Table 5). We subsequently
showed this to be due to the stimulation of hypothalamic somatostatin
by IGF-I (50). Long-term administration of IGF-I slightly suppresses
PRL (51) and stimulates gonadotrophins (52, 53).
Determination of metabolically effective doses of IGF-I led to the
initiation of long-term replacement trials; the major studies being the
Kabi Multicenter Study, the Genentech Multicenter Study and our
single-center study using Fujisawa IGF-I.
The major question posed was whether IGF-I treatment is safe and can
reverse the pathological changes induced by long-term IGF-I
deprivation.
Effect of IGF-I replacement treatment on linear growth
IGF-I treatment of infants with LS revealed that their growth
velocity response was less than that of similarly aged infants with
isolated GH deficiency treated with hGH (54). This finding is
interpreted as supportive evidence for the hypothesis put forward by
Green et al. (55) and Isaksson et al. (56) that
hGH action on the epiphyseal cartilage progenitor cells is needed to
enable full expression of the IGF-I effect on the proliferative cell
layer of the epiphyseal plate. If so, this may also be the explanation
why IGF-I treatment of older children with LS results in the 1st year
of treatment in a mean growth velocity of only 8 cm/yr (26, 57, 58, 59)
(Table 6), compared with 10–12 cm/yr in
GH-deficient children treated by hGH (60). Fig. 4 illustrates the growth response of one
of the patients. Excessive IGF-I treatment is associated with adverse
effects (Table 7) that were reversible
with reduction in the IGF-I dose (26, 52, 62).
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Figure 4. Linear growth (A) and growth velocity (B)
response to IGF-I treatment (175 µg/kg once daily sc) of a boy with
LS. Drawn on special growth charts for LS (61 ). The
arrow denotes age at referral.
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Monitoring the total serum IGF-I levels has proven a useful marker of
the IGF-I dose (63). Long-term IGF-I administration raises serum IGF
binding protein-3 levels (64) and, thus, prolonging the biological
half-time of IGF-I (Fig. 5), resulting in
the need to reduce the IGF-I dose with time to prevent or reverse
adverse effects induced by overdosage.
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Figure 5. Overnight fasting serum IGF-I concentration
and 4 h after the IGF-I morning injection during treatment of
children with LS as mean ± SEM. The number of
children is shown in parentheses. IGF-I ng/mL x 0.13 =
nmol/L. Reproduced with permission from Laron et al.
(63 ).
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IGF-I effect on renal function
IGF-I administration to children with LS revealed transitory water
and electrolyte retention (65). Long-term effects in both these
children and adult patients (27) were an increase in glomerular
filtration rate, creatinine clearance, phosphorus reabsorption, and
rises in serum P, alkaline phosphatase, and serum procollagens (66).
There was also a transitory increase in urinary calcium excretion,
without significant changes in serum calcium levels.
IGF-I effect on adipose tissue and fat metabolism
During the 1st year of IGF-I treatment, both children and adults
with LS reduced their excessive adipose tissue mass and lowered the
serum cholesterol, if elevated (26, 27, 39). In subsequent years there
was either a small effect or no effect. The most dramatic effect of
IGF-I on fat metabolism was the significant reduction of serum
lipoprotein (a)[Lp(a)], an independent risk factor of atherosclerosis
(67). This effect is in contrast to that of GH, which raises serum
Lp(a) (68).
IGF-I effects on carbohydrate metabolism
The hypoglycemic effect induced by bolus injection of IGF-I in the
fasting state (45, 48) is abolished during long-term IGF-I
administration, when IGF-I suppresses effect on insulin secretion (26).
This effect leads to an improved glucose tolerance (41), stablization
of serum glucose levels, and a lower tendency for hypoglycemia (26, 69).
IGF-I effect on head circumference
IGF-I replacement treatment of children with LS who have a
subnormal head circum-ference (5, 25) similar to children with
congenital hGH deficiency (70) results in a rapid acceleration of head
growth (7, 71), even after age 10 yr (Fig. 6), denoting that retardation in skeletal
maturation affects also the membranous neurocranium, but also that
IGF-I stimulates brain growth.
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Figure 6. Head circumference growth in five boys with
LS before and during IGF-I treatment drawn on curves for healthy
children.
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Sexual Maturation
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Despite the small gonads and genitalia in children, patients with
LS of both sexes reach, albeit with delay, full sexual development (4, 5, 7) and have no problem of reproduction in early adult age. Of note,
the heterozygote children have a normal phenotype.
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Morbidity
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Despite the longstanding IGF-I deficiency, patients with LS do not
show an increased incidence of infectious diseases. The most striking
pathology is the obesity and progressive development of glucose
intolerance with insulin resistance and osteoporosis. The muscular
weakness puts limitations on mobility, daily activities, and sports.
Despite cardiomicria, the heart adjusts to physical stress (72). No
malignancy due to IGF-I treatment of patients with LS has been
reported.
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Social Impairments
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Due to the marked short stature, the patients with LS have many
difficulties in daily life, starting in early childhood. Among these
are lack of suitable size clothing and shoes, difficulties using
regular furniture in school, the high steps in public transportation,
and, quite often, the intolerant attitudes of the society (73). The
underdevelopment of their muscular strength (43), in addition to their
small body size and lack of high education in the majority of patients,
impairs their employment and income (36). All of the above also raises
difficulties in their relationship to the other sex; among our 40
adults, only four females and three males have married and two females
are divorced.
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Conclusion
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Patients with primary IGF-I deficiency (LS) have many auxological,
biochemical, and hormonal deficiencies, which if untreated, progress
with age and prevent these patients from living a normal life and
become productive citizens. Therefore, IGF-I should be available as an
essential replacement treatment to all patients with LS. In addition,
considering the many physiological roles played by IGF-I learned
from the above syndrome and the pharmacologic use of IGF-I in the
last decade, IGF-I promises to be a much needed drug for clinical use
(74, 75).
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Acknowledgments
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Thanks are due to all the colleagues who have collaborated in
the elucidation of the molecular and physio-pathology of this syndrome.
Special thanks are due to W. H. Daughaday, M.D., R. Keret,
M.Sc., R. Eshet, Ph.D., A. Silbergeld, M.Sc., B. Klinger, M.D., A.
Pertzelan, M.D., and D. Peled, R.N., and last, but not least, to the
patients and their families who showed so much understanding while
undergoing the many investigations.
Received August 30, 1999.
Revised October 7, 1999.
Accepted October 7, 1999.
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Top
Abstract
Introduction
