Laron syndrome: typical and atypical forms

4 Laron syndrome: typical and atypical forms K A T I E A. W O O D S M A R T I N O. S A V A G E

Laron syndrome (LS), also known as growth hormone receptor deficiency (GHRD) or GH insensitivity syndrome (GHIS), is a rare form of inherited growth hormone resistance. The first description of this syndrome was by Laron et al in 1966 in a consanguineous Yemenite Jewish family. The three affected siblings had the classical features of severe GH-deficiency yet markedly elevated levels of immunoreactive serum GH. The parents were of normal stature but were consanguineous, suggesting an autosomal recessive pattern of inheritance. Subsequently, there have been over 200 LS cases reported in the world literature, with clustering of patients in areas where consanguinity is common, such as the Middle Eastern regions and the Mediterranean (Rosenfeld et al, 1994). The largest concentration of patients with LS has been reported from Ecuador, where so far 63 patients have been identified from an inbred population believed to originate from Jews who converted to Christianity during the Spanish Inquisition (Rosenbloom et al, 1990; Guevara-Aguirre et al, 1993). It was originally hypothesized that LS was due to the endogenous secretion of an abnormal GH molecule that was detectable on radioimmunoassay yet was not biologically active (Laron et al, 1966). However, a number of subsequent studies indicated that the GH molecule in LS patients was normal (Bala and Beck, 1973; Eshet et al, 1973; Jacobs et al, 1976). Clinical studies on affected patients indicated that the disorder was in fact due to GH resistance with failure of somatomedin (IGF-I) generation and other metabolic responses after administration of exogenous GH (Laron et al, 1971; New et al, 1972; Van den Brande et al, 1974). In 1980, Golde et al found that GH failed to stimulate erythroid progenitor cells from the peripheral blood of two patients, and 4 years later it was demonstrated that hepatocytes from two LS patients failed to bind GH, the first direct evidence of a GH receptor (GHR) defect (Eshet et al, 1984). Following the characterization of the GHR gene in 1987 two distinct molecular defects in the GHR gene of LS subjects were identified: a complex gene deletion in two patients of Oriental Jewish descent (Godowski et al, 1989) and a point mutation in a Mediterranean family (Amselem et al, 1989). There have now been over 20 different point Bailli~re's Clinical Endocrinology and Metabolism-371 Vol. 10, No. 3, July 1996 Copyright © 1996, by Bailli6re Tindall 1SBN 0--7020-2093-1 AI! rights of reproduction in any form reserved 0950-351X/96/020371 + 17 $12.00/00

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K . A . WOODS AND M . O .

SAVAGE

mutations identified, indicating the genetic heterogeneity of the condition (Rosenfeld et al, 1994; see also Chapter 3). The cloning of the IGF-I gene (Jansen et al, 1983) led to the possibility of therapy with recombinant IGF-I, which has now been used in the short-term in several groups of LS patients with considerable success in stimulating linear growth (Laron et al, 1992a,b; Walker et al, 1992; Wilton, 1992; Guevara-Aguirre et al, 1995; Ranke et al, 1995; see Chapter 6). As a result of this development, a large European collaborative survey to identify children with LS was set up that now comprises over 70 cases (Savage et al, 1995). This large group of patients is unique as they come from such a diverse genetic and geographical background and, interestingly, there appears to be considerable clinical and biochemical heterogeneity. This finding has led to the suggestion that 'partial' GHR defects may exist and account for a proportion of the much larger group of patients with 'idiopathic' and 'familial' short stature (see Chapter 5). Furthermore, a number of atypical forms of LS have emerged, which will be discussed later in this chapter, raising the possibility that defects in genes other than the GHR gene that mediate GH action may produce some cases of inherited GH resistance. In this chapter, we will start by describing the 'classical' LS patient, and then move on to discuss atypical LS and the implications this may have both for our greater understanding of the aetiology of short stature and the cellular basis of GH action. CLASSICAL LARON SYNDROME Clinical features As originally reported by Laron and co-workers, there is a striking similarity in the appearance of the LS patient and that of severe inherited GH deficiency, which is usually the result of a complete GH gene deletion. Much of the information about the clinical features of patients with LS has been obtained from the two major population concentrations in Israel and Ecuador (Laron et al, 1980, 1993; Laron, 1984; Rosenbloom et al, 1990, 1992; Guevara-Aguirre and Rosenbloom, 1993; Rosenfeld et al, 1994). Some of the Israeli patients have been found to have a complex gene deletion of their GHR gene, and all but one of the Ecuadorian patients are homozygous for a splice site defect of the GHR gene (Berg et al, 1992; Meacham et al, 1993). The recent cohort of European patients is the only large heterogeneous group to be studied (Savage et al, 1993, 1995).

Growth and puberty There is a variable effect on birth weight and length amongst the various populations studied, the difficulty being compounded by the lack of ethnicspecific reference data. However, there appears to be mild intrauterine growth retardation. Laron found in his cohort of Israeli patients that birth length was less than - 2 S.D. in 12 out of 20 patients (Laron et al, 1993) and

LARON SYNDROME: TYPICAL AND ATYPICAL FORMS

373

in the European LS population the median birth length was -1.59 S.D. (Savage et al, 1993). In both the Israeli and Ecuadorian cohorts birth weight was normal but in the European cohort median birth weight was reduced at -0.72 s.D. (Laron, 1984; Rosenbloom et al, 1990; Savage et al, 1993). The most comprehensive data on the postnatal growth of untreated LS patients has been collated by Laron et al (1993) who followed 24 patients from infancy through to final heights and constructed male and female growth curves. Longitudinal data is also available over several years for 27 Ecuadorian children (Guevara-Aguirre et al, 1993; Rosenfeld et al, 1994). In both of these groups it is evident that growth failure occurs from very early infancy. The prepubertal heights of Laron's group varied between - 4 and - 8 S.D. and in the Ecuadorian patients between -6.8 and -9.6 S.D. In Laron's group the growth velocity after age 3 was maintained at 4-5 cm/year in girls and in boys at 3-4 cm/year. In both sexes there was no pubertal growth spurt. Girls stopped growing after 16-19 years after entering puberty at the normal time, whereas boys had a delayed onset of puberty at 16 years on average that resulted in their growth continuing until around age 20. Final heights in this group were a mean of 119.5 (+8.5 S.D.) cm for girls and 124.1 (_+8.5 s.D.) cm for boys. In the Ecuadorian group, there was no difference between the timing of puberty between males and females, with 50% entering puberty at the normal time and the other 50% being delayed by up to 7 years. A pubertal growth spurt was noted in three Ecuadorian patients (Guevara-Aguirre et al, 1993).

Development The intellectual development of these patients varies between above average in the Ecuadorian population (Guevara-Aguirre et al, 1993), normal in the European group (Savage et al, 1993) and impaired in the Israeli group (Frankell and Laron, 1968). Delayed motor development is common and has been suggested to be secondary to hypomuscularity (Rosenfeld et al, 1994). Bone age is universally delayed for chronological age but advanced for height age. There is prolonged retention of the primary teeth resulting in problems with dental decay and crowding of teeth in the older children. In the permanent teeth, the third molar was found to be missing in more than 90% of patients, with frequent hypodontia (Sarnat et al, 1988). Micropenis has been a frequent finding in all groups studied. At puberty there is normal secondary sexual development in both sexes and fertility has been documented in males and females from both Israel and Ecuador (Laron et al, 1980; Menashe et al, 1991).

Physicalfeatures The abnormal physical appearance of the LS child has been recognized even at birth by some Ecuadorian parents with other affected relatives by their facial features, sparse hair, small hands and feet and hypoplastic fingernails (Rosenfeld et al, 1994). The facies become more obviously

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K. A. WOODS AND M. O. SAVAGE

abnormal by early childhood, with typical features being a rather large head, prominent forehead, depressed nasal bridge and a small midface. Some children demonstrate the 'setting sun' sign, which combined with delayed closure of the anterior fontanelle can give the impression of hydrocephalus. Detailed facial morphometry has shown the most striking abnormality to be shortening of the vertical dimension of the face (or facial height: Figure 1), which closely correlates with the degree of short stature (Leonard et al, 1994, 1995). Head width, in contrast, is relatively preserved (Leonard et al, 1994). Blue scleras and a high-pitched voice are other commonly observed features (Laron, 1984). Head length +4

Head width

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Facial height

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-12 Figure 1. Cranio-facial measurements in children with LS plotted against scale of standard deviation scores. O, Male; O, female, n = 14. Reproduced from Savage et al (1995, Acta Paediatrica 411 (supplement): 87-90) with permission. Auxology standards are from Hall et al.

LARON SYNDROME: TYPICAL AND ATYPICAL FORMS

375

Laron found an increased upper to lower segment ratio in his patients at all ages (Laron, 1984), but this abnormality has not been found in either the Ecuadorian or European children using the ratio appropriate for bone age (Savage et al, 1993; Guevara-Aguirre et al, 1993). The Ecuadorian adults do have an increased upper to lower segment ratio, however, indicating persistence of child-like body proportions (Guevara-Aguirre et al, 1993). The LS child generally appears chubby and has increased skinfold thickness from early infancy, with a particular excess of truncal fat (Laron, 1984). The weight for height ratio may be normal or even low in childhood however, because of reduced muscle and bone mass (Laron, 1984; Guevara-Aguirre et al, 1991). Obesity becomes more pronounced at puberty and into adulthood, resulting in the weight for height ratio becoming increased at this stage.

Other abnormalities Congenital dislocation of the hips occurs with an increased frequency in both the Ecuadorian and the Israeli group and hip dysplasia has been found in 25% of the Ecuadorian group as well as several sporadic cases in the other populations (Laron, 1984; Rosenbloom et al, 1990). Two abnormalities that seem specific to the Ecuadorian patients are ptosis with facial asymmetry; which occurs in 16%, suggested to be secondary to intrauterine hypomuscularity and limited elbow extension (Rosenfeld et al, 1994). Laron has described a high incidence of congenital malformations in his patients that include cleft lip, strabismus, nystagmus, cataract, clinodactyly undescended testes and aortic stenosis (Laron, 1984). These have not been reported in other LS patients: it is unclear whether they are associated with LS or simply a reflection of the high degree of consanguinity in the population studied.

Mortality and morbidity Comparing affected and unaffected siblings under the age of 7 years in the Ecuadorian group there appears to be a statistically significant increased mortality in the affected individuals (18% versus 11%, p < 0.05; Rosenfeld et al, 1994). The deaths were caused by the usual childhood infectious diseases of the area such as pneumonia, diarrhoea and meningitis in both groups. Above this age group no increased mortality could be detected.

Biochemical features

Serum GH The finding of an elevated basal GH, as in the original cases of LS reported by Laron, is frequent but not invariable. For example in the European survey of 27 LS patients, although the median GH concentration was 15.9 t-tg/1, the individual values ranged from 0.5-79 gg/1 (Savage et al, 1993). Detailed 24 hour GH profiles have been performed by several

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K. A. WOODS AND M. O. SAVAGE

groups and have demonstrated that GH continues to be secreted in its normal pulsatile fashion, explaining this variability in basal values (Elders et al, 1973; Keret et al, 1988; Cotterill et al, 1991, 1992). In general, the number of GH peaks remain the same but the magnitude of these peaks is greater than normal, with failure of the normal suppression to undetectable GH levels during the nocturnal troughs. Keret et al (1988) calculated the human GH (hGH) production rate in three young adults with LS and found it to be three times that of an age matched control. Most commonly, GH provocation tests reveal an exaggerated GH rise, however there is again wide variability: in the European survey, of the 23 patients who had provocation tests the median peak GH was elevated at 74 p.g/1, but the range was from 12-230 ~tg/1 (Savage et al, 1993). If the basal GH is extremely elevated there may be a paradoxical fall, for example from 130-60 ~tg/1 following insulin induced hypoglycaemia in one 7 year old boy (Elders et al, 1973). There is no consistent response to oral or intravenous glucose tolerance tests: in some patients the GH level suppresses fully, in others there is partial suppression and in some a paradoxical increase in GH levels (Laron et al, 1971; Najjar et al, 1971; Elders et al, 1973; Alcaniz et al, 1978). Cotterill and co-workers studied the GH responses to GH releasing hormone (GHRH) and somatostatin in two prepubertal LS subjects and found increased GH secretion following GHRH and suppression following somatostatin, suggesting that the hypothalamo-pituitary axis remains intact in LS (Cotterill et al, 1991). GH secretion was also completely suppressed following IGF-I administration (Cotterill et al, 1993).

Insulin-like growth factors IGF-I. IGF-I is thought to be the major effector hormone for growth and is predominantly under the control of GH (Clemmons and Van Wyk, 1984). Extremely low serum IGF-I levels are found in both LS and GHD (Laron et al, 1971; Blum et al, 1990; Savage et al, 1993). In GHD however, administration of exogenous GH usually results in a brisk rise in IGF-I levels whereas the lack of response of this hormone to GH is one of the most classical features of LS (Laron et al, 1971; Rosenfeld et al, 1981; Savage et al, 1993). Using a sensitive IGF binding protein (IGFBP)-blocked radio-immunoassay for IGF-I, all IGF-I values in the European cohort were below the 0.1st percentile for age and the 0.1st percentile has been proposed as a diagnostic cut-off (Blum et al, 1992). Interestingly, in the Ecuadorian group children up to 16 years had a significantly lower level of IGF-I than those above 16 years (mean 3.4 ~tg/1 versus 25.1 ~tg/1, P < 0.00001). It has been suggested that this finding may suggest a stimulatory role for sex steroids in IGF-I production that is independent of their effect upon GH secretion (Guevara-Aguirre et al, 1993). In the European survey the IGF-I response to GH stimulation (the IGF-I generation test) was studied in each patient and formed part of the criteria for inclusion in the study (Table 1). This involved the administration of

377

LARON SYNDROME: TYPICAL AND ATYPICAL FORMS

hGH 0.1 U/kg of body weight daily for 4 days, with IGF-I and IGFBP-3 measurements on day 1 prior to the first GH injection and on day 5 after the last injection. Using a cut-off value of an increase in IGF-I from basal of 15 gg/1, a clear separation between the accepted and excluded groups was obtained (Blum et al, 1994). Table 1. Scoring system for Laron syndrome used in the European survey. Test

Parameter

Criterion

Score

Auxology GH profile Basal IGFs

Height Minimum GH IGF-I IGFBP-3 IGF-I increase IGFBP-3 increase % GH bound

< - 3 SDS > 4 mU/l < 0.1 percentile < 5th percentile < 15 ttg/1 < 0.4 mg/1 < 10%

1 1 1 1 1 1 1

IGF generation GH binding

A total score of 5 points or more was taken to indicate LS. Reproduced from Blum et al (1994, Acre Paediatrica 399 (supplement): 117-124) with permission.

IGF-H. IGF-II has also been found to be significantly decreased in LS, in both the Ecuadorian patients (prepubertal mean 70.4~tg/1) and the European group in which it was below the 5th percentile of the normal range in all patients (median 135gg/1) (Guevara-Aguirre et al, 1993; Savage et al, 1993). This low value is not thought to be a direct effect of GHR dysfunction but secondary to the low IGFBP-3 (see below): on a molar basis the sum of the concentrations of IGF-I and IGF-II is almost identical to the concentration of IGFBP-3 (Ranke et al, 1991).

Insulin-like growth factor binding proteins (IGFBPs) Most of the circulating IGF-I and IGF-II is bound to specific binding proteins of which six classes are currently known (IGFBP-1-6). IGFBP-3 is the predominant IGFBP in the blood, and once bound to either IGF-I or IGF-II associates with the so-called acid-labile subunit (ALS), thereby producing a large 150 kDa ternary complex that is retained within the intravascular space and is considered to act as a reservoir and buffer for IGFs (Baxter, 1990). It has been suggested that IGFBP-3 levels may be a more reliable measure of tissue exposure from circulating IGF-I than IGF-I itself as they show less variability throughout the day (Blum et al, 1990). Like IGF-I, GH appears to be the major regulator of IGFBP-3 and ALS (Hardouin et al, 1989; Baxter, 1990; Blum et al, 1990; Cohen et al, 1991).

IGFBP-3. As might be expected, IGFBP-3 levels are extremely low in LS. In the Ecuadorian population mean serum IGFBP-3 levels were 226 ng/ml prepubertally and 433 ng/ml in adults (mean values in the control adult population were 2665ng/ml for males and 2347ng/ml for females: Guevara-Aguirre et al, 1993). In the European group the median basal IGFBP-3 concentration was 530 ng/ml and all values were far below the

378

K.A.

W O O D S A N D M. O. SAVAGE

5th percentile for age (Savage et al, 1993). The IGFBP-3 levels were also measured during the IGF-I generation test and remained well below the 5th percentile, the median value increasing to 760 ng/ml. Blum has suggested that a basal IGFBP-3 of less than the 5th percentile for age and an IGFBP-3 increment of 400 ng/ml or less could be used as further diagnostic criteria for LS (Table 1). Comparison of the IGF-I generation test accuracy for distinguishing GHD from LS showed that the IGFBP-3 increment was more discriminatory than the IGF-I increment although neither value could completely distinguish the two groups (Blum et al, 1992). Although IGFBP-3 is known to be GH-dependent, studies in hypophysectomized rats had indicated that exogenous IGF-I was capable of independently stimulating an increase in serum IGFBP-3 levels (Zapf et al, 1989). However, no significant increase in IGFBP-3 has been observed in LS individuals treated with recombinant IGF-I, suggesting that in humans IGFBP-3 may be directly regulated by the GH/GHR interaction (Gourmelen et al, 1991; Laron et al, 1992b; Wilson et al, 1993).

Acid-labile subunit. ALS, the third component of the ternary complex, is also low in LS, and similarly to IGFBP-3 shows no increase in LS patients treated with IGF-I suggesting a similar GH-dependent mechanism of control (Gargosky et al, 1993). IGFBP-1 and IGFBP-2. Unlike IGFBP-3, IGFBP-1 and -2 are not thought to be GH-dependent. Savage et al (1993) have studied the levels of IGFBP-1 and IGFBP-2 by radio-immunoassay in their European cohort. IGFBP-2 levels were normal, but in the majority of patients, IGFBP-1 levels were elevated above the 95th percentile for age although they still showed the normal physiological fall during childhood. They suggested that this modest increase in IGFBP-1 may be secondary to suppression of insulin secretion (Savage et al, 1993). Growth hormone binding protein (GHBP) GHBP is a specific, high affinity, low capacity binding protein for GH present in human serum (Baumann et al, 1986; Herington et al, 1986a,b). It has been shown to be identical to the N-terminal domain of the GHR including most, if not all, of the extracellular hormone binding region of the receptor (Leung et al, 1987). Hence GHBP represents a circulating form of the extracellular domain of the GHR. In man and rabbit it is thought to be produced by proteolytic cleavage of the GHR protein (Trivedi and Daughaday, 1988), and in rodent species by alternative splicing of the GHR gene (Baumbach et al, 1989; Smith et al, 1989). The two main methods used for analysis of GHBP are a GH binding assay and more recently a ligand-mediated immunofunctional assay (LIFA: Daughaday and Trivedi, 1987; Baumann et al, 1987; Mercado et al, 1993). Both of these assay methods are based on the ability of GHBP to bind GH and hence a reduced GHBP level may indicate reduced amounts of normal GHBP, normal amounts of GHBP with reduced or absent ability to bind GH

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LARON SYNDROME: TYPICAL AND ATYPICAL FORMS

or a combination of the two. The first measurements of GHBP in LS were by column chromatography and indicated that GHBP was undetectable (Daughaday and Trivedi, 1987; Baumann et al, 1987). When measured in the Ecuadorian cohort, first by column chromatography (Rosenbloom et al, 1990) and subsequently by LIFA (Guevara-Aguirre et al, 1993), although most of the GHBP levels were low or undetectable, there were a few patients who had levels in the low normal range. All these patients are homozygous for the same GHR splice site mutation and hence the variability cannot be explained by genetic heterogeneity. It is postulated that inter-individual variability in the proportion of gene products that are abnormally spliced leads to this phenomenon (Berg et al, 1992). Subsequently, several LS patients from areas other than Ecuador have been reported with normal GHBP. The contribution of this biochemical variant of LS was not appreciated, however, until it was found that over 20% of the European cohort were in this category (Figure 2: Savage et al, 1993). This finding in such a heterogeneous population has interesting implications in terms of the genetic basis of LS.

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380

K. A. WOODS AND M. O. SAVAGE

Carbohydrate metabolism Hypoglycaemia is a common feature in LS. In both the Israeli and Ecuadorian populations 45% have had symptoms of hypoglycaemia in childhood (Rosenfeld et al, 1994), and frequent episodes of asymptomatic hypoglycaemia have been documented (Guevara-Aguirre et al, 1995). Serum insulin levels have generally been found to be low and relative insulinopenia is maintained following an oral glucose load (Laron, 1984). The hypoglycaemia usually improves with age, although it may reappear during fasting, and Laron (1984) has documented insulin resistance with some patients developing hyperinsulinism in adulthood. It is suggested that the mechanism of hypoglycaemia is similar to that of severe GHD: namely the lack of the anti-insulin effect of GH, and the low insulin levels may be a compensatory event.

A T Y P I C A L P H E N O T Y P E S IN LS The large multi-centre study of European LS patients that is currently in progress has provided unique information regarding the range of LS phenotypes, allowing comparison of a large number of LS patients within this genetically and geographically heterogeneous population, which includes individuals from eight European countries (Savage et al, 1995). The other unique feature of this study is that patients were recruited using a scoring system that combined height standard deviation score (SDS) and biochemical indices that were analyzed in central laboratories (Table 1). The maximum score using this system is 7, but patients with scores of 5 or above were accepted into the study, so that the individuals could have up to two variables that were not consistent with classical LS. Out of a total of 164 patients put forward, 81 were diagnosed as LS and started on IGF-I therapy. Of these, data is presented on 65 in this chapter. One of the most striking findings of the study has been the range of phenotypes exhibited by the patients, with considerable variability in facial appearance, severity of short stature and biochemical indices. Height SDS varied between -3.2 to -10.4 (Figure 3) and IGFBP-3 SDS (which corrects for the variability of IGFBP-3 with age), ranged from -3 to -14.7. Interestingly, amongst the group as a whole there was a significant correlation between IGFBP-3 SDS and height SDS (Figure 4), suggesting that hereditary GH resistance may be a continuum from the severe classic LS case to milder forms that may present with less severe growth failure and biochemical disturbance (Blum et al, 1992). The contribution of this potential group of GH-resistant patients to the larger number of children currently diagnosed as having 'idiopathic' or 'familial' short stature remains to be established (see Chapter 5). Atypical facial appearance Some of the patients recruited into the study do not exhibit the typical facial

381

LARON SYNDROME: TYPICAL AND ATYPICAL FORMS

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382

K. A. WOODS AND M. O. SAVAGE

appearance previously found to be associated with LS. These patients were found amongst those who had less severe growth retardation. Detailed facial auxology has been performed on a subgroup of patients and has demonstrated a close correlation with the facial height SDS and the height SDS (Leonard et al, 1995), and therefore the most likely explanation for this finding may be that the relative facial disproportion in these patients is so mild as to result in the facies appearing normal.

GHBP positive LS One of the most striking findings to emerge from the European survey has been the number of GHBP 'positive' patients with normal or even elevated levels of GHBP. As GHBP is a circulating form of the extracellular domain of the GHR this finding implies that the GH resistance of these patients is not a result of failure of the GH to bind to the GHR, but due to a defect that affects other critical aspects of GHR function such as dimerization, intracellular signalling or intracellular processing. Indeed the first GHR mutation to be discovered in this group produces a mutant receptor that is unable to dimefize, yet retains GH binding ability (Duquesnoy et al, 1994). The other possibility in these patients is that they have defects in genes other than the GHR gene, that are important in downstream signalling from the GHR. In support of this hypothesis, a segregation study in the families of four of the GHBP positive patients from the European cohort does not support a causative role for the GHR gene (Woods et al, 1995). Hence the molecular study of these individuals is of great interest and is discussed further in Chapter 3.

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LARON SYNDROME: TYPICAL AND ATYPICAL FORMS

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Direct clinical and biochemical comparison of the GHBP positive and negative patients from the European study has revealed a number of interesting differences between the groups. Firstly, the GHBP positive group, although still heterogeneous, appears generally to have milder GH resistance with less severe growth failure (mean height S.D. score -5.1 versus -6.7 for the GHBP negative group, P=<0.001). Despite this milder phenotype the correlation of height SDS with IGFBP-3 SDS still exists in the GHBP positive group (Figure 5). Facial auxology has not yet been formally studied in the GHBP positive individuals, but clinically, over one third of the patients have atypical facies for LS (Figure 6). Whether this finding is simply a representation of the milder GHinsensitivity or whether it reflects a different aetiological basis for the LS in these patients remains to be seen. Hence the clinical data in this group supports the suggestion that GHBP positive LS may have a heterogeneous molecular aetiology.

SUMMARY Since the original description of LS by Laron in 1966, this rare condition has continued to assume an importance far beyond the number of affected cases as a unique model of GHR dysfunction. Recently, the potential of therapy with recombinant IGF-I has led to the recruitment and detailed study of patients from a heterogeneous genetic and geographical background and the realization that hereditary GH resistance is itself a heterogeneous condition, with considerable variation in clinical, biochemical and molecular features between patients. For the scientist, further study of the 'atypical' LS patient may lead to important insights into the signalling pathway between GH and IGF-I. For the clinician, the challenge lies in establishing the contribution of inherited forms of GH resistance to the group of children with idiopathic short stature, with the potential of offering therapy to these patients based on an understanding of the aetiological basis of their disorder.

REFERENCES Alcaniz JJ, Salto L & Barcelo B (1978) GH secretion in two siblings with Laron's dwarfism: The effects of glucose, arginine, somatostatin and bromocriptine. Journal of Clinical Endocrinology and Metabolism 47: 453-456. Amselem S, Duquesnoy P, Attree O et al (1989) Laron dwarfism and mutations of the growth hormone receptor gene. New England Journal of Medicine 321: 989-995. Bala RM & Beck JC (1973) Fractionation studies on plasma of normals and patients with Laron dwarfism and hypopituitary gigantism. Canadian Journal of Physiology and Pharmacology 91: 845-852. Baumann G, Stolar MW, Amburn K et al (1986) A specific growth hormone-binding protein in human plasma: Initial characterisation. Journal of Clinical Endocrinology and Metabolism 62: 134-141. Baumann G, Shaw MA & Winter RJ (1987) Absence of plasma growth hormone-binding protein in Laron-type dwarfism. Journal of Clinical Endocrinology and Metabolism 65: 814-816.

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