Adult patients with Laron syndrome tend to develop the metabolic syndrome.

BACKGROUND: The metabolic Syndrome is the name of a cluster of abnormal clinical and metabolic states, which constitute a risk factor for diabetes and cardiovascular disease. AIM: To determine whether adult patients with Laron Syndrome with excessive obesity develop the characteristics of the Metabolic Syndrome. SUBJECTS: Out of a cohort of adult patients with Laron Syndrome followed in our clinic, records of 23 patients (12 females, 11 males) were found to have sufficient data for analysis. METHODS: The degree of obesity was determined by the measurement of subscapular skinfold thickness (SSFT), BMI and total body DEXA. NAFLD was determined by liver ultrasonography, serum lipids including adiponectin leptin, insulin and glucose were assessed by radioimmunoassay. RESULTS: Both female and male patients were markedly obese with 59% and 39% fat of the total body mass respectively, as were total and LDL cholesterol, triglycerides and adiponectin. Some had developed NAFLD. They also suffered from insulin resistance and glucose intolerance. Eleven patients (3 females, 8 males) developed diabetes. All had varying degrees of hypertension. Eight subjects (3 females, 5 males) suffered from cardiovascular disease. One female died at aged 53 years, and two males died at ages 75 and 78 years. CONCLUSION: With advancing age and increasing obesity, adult patients with Laron Syndrome developed the characteristics of Metabolic Syndrome including diabetes and cardiovascular disease.

The second to fourth digit ratio in patients with congenital IGF-1 Deficiency.

The relationship between the length of the second and fourth ring finger (2D:4D ratio) is a sexually dimorphic trait, higher in females than in males. It is established during early prenatal development under the influence of sex hormones, as demonstrated in numerous studies both in humans and in mice. The current study involves patients with congenital GH/IGF-1 deficiency, a population not yet investigated. The 2D:4D ratio was measured from hand x-rays and compared with normal hand x-rays taken from the Greulich & Pyle Atlas. The analyses of our results revealed that patients with congenital GH/IGF-1 deficiency show an identical 2D:4D ratio for both sexes, but a higher (more feminine) ratio than the normal population. These findings may be explained by a higher estrogen effect resulting from the absence of a functional GH-IGF-1 axis prenatally.

Health and Lifestyle of Adult Patients with Congenital Isolated Growth Hormone Deficiency Treated in Childhood.

BACKGROUND: Treatment of patients with childhood growth hormone deficiency is usually terminated at the end of puberty. Follow-up into adult age is rare, even more so in patients with congenital isolated growth hormone deficiency (cIGHD). OBJECTIVES: To assess the clinical and social characteristics of adults with cIGHD who received growth hormone (hGH) treatment in childhood. METHODS: Thirty-nine patients (23 men, 16 women) diagnosed in our clinic with cIGHD at 7 ± 4.2 years, and treated with hGH during childhood for 2-18 years, were followed into adulthood (mean age 30.7 ± 13.3 years). Ascertained detailed data were found for 32 patients. RESULTS: Mean ± SD height for males was 160.2 ± 10.6 cm and for females 146.4 ± 5.4 cm. All patients achieved full sexual development and 14 were married. After cessation of GH treatment and with advanced age all exhibited a progressive increase in adiposity to the degree of obesity. Twelve patients suffered from hyperlipidemia, 4 developed diabetes mellitus, and 5 have cardiovascular diseases. One patient died in an accident. None developed cancer. Of the 39 patients, 22 have an education level of high school or higher, and 2 are in special institutions. Most are employed in manual labor. CONCLUSIONS: Patients with congenital IGHD who do not receive early and regular replacement treatment are prone to lag in achieving normal height and suffer from educational and vocational handicaps.

A Novel Variant c.97C>T of the Growth Hormone Releasing Hormone Receptor Gene Causes Isolated Growth Hormone Deficiency Type Ib

Congenital isolated growth hormone deficiency (IGHD) type 1b is an autosomal recessive genetic condition caused by mutations of growth hormone (GH)-1 or the growth hormone releasing hormone receptor (GHRH-R) genes. Affected subjects present with symptoms of growth hormone deficiency (GHD) with low but detectable levels of growth hormone (GH), short stature and responsiveness to GH therapy. We describe a 13-month old girl with severe growth failure who showed a low GH response to two GH provocation tests and a modest increase of insulin-like growth factor-1 (IGF-1) to an IGF-1 generation test. Whole exome sequencing revealed a novel homozygous variant of the GHRH-R gene (c.97C>T), leading to a premature stop codon. Administration of recombinant human GH improved linear growth. This is the first report of a c.97C>T mutation of the GHRH-R gene.

IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome.

Laron syndrome (LS) is a unique model of congenital IGF-I deficiency. It is characterized by dwarfism and obesity, and is caused by deletion or mutations of the growth hormone receptor (GH-R) gene. It is hypothesized that LS is an old disease originating in Indonesia and that the mutated gene spread to South Asia, the Middle East, the Mediterranean region and South America.

Growth, development, puberty and adult height of patients with congenital multiple pituitary hormone deficiencies.

OBJECTIVE: Congenital MPHD is a rare condition caused by mutations in pituitary transcription factors genes: PROP1, POU1F1 (PIT1), HESX1, LHX3, LHX4. DESIGN: We evaluated in a retrospective study the effects on growth and development in 29 patients with congenital MPHD (cMPHD), during hGH replacement therapy alone and combined with sex hormones. Twenty nine patients with cMPHD were included and diagnosed, treated and followed in our clinic from diagnosis to adult age. Measurements on growth and development were taken by the same medical team. RESULTS: Mean birth weight of 21/29 neonates was 3126 ± 536 g. Mean birth length of 7/29 neonates was 48.7 ± 2 cm. Neuromotor development was normal or slightly delayed. Mean age at referral was 9.5 ± 7 years (m), 6.7 ± 3.5 years (f) (p=0.17). Height (SDS) before treatment was -2.8 ± 1.0 (m), -2.8 ± 1.0 (f) (p=0.99). Mean age at initiation of hGH treatment was 9.9 ± 6.7 years (m), 10.3 ± 4.2 years (f) (p=0.85). Mean age at initiation of sex hormone treatment was 17.0 ± 3.5 years (m), 17.1 ± 2.3 years (f) (p=0.88). Penile and testicular sizes were below normal before and after treatment. Head circumference (SD) was -1.9 ± 0.9 before and -0.6 ± 1.8 at end of treatment (p<0.001). Adult height (SDS) reached -1.1 ± 0.6 (p<0.001) for both males and females. CONCLUSION: Despite the multiple pituitary hormone deficiencies including hGH, children with congenital MPHD present with a better auxological development than children with congenital IGHD or congenital IGF-1 deficiency. These findings may be due to irregular and incomplete hormone deficiencies increasing with progressive age and late initiation of puberty.

Genetic Mutations, Birth Lengths, Weights and Head Circumferences of Children with IGF-I Receptor Defects. Comparison with other Congenital Defects in the GH/IGF-I axis.

BACKGROUND: In recent years more and more genetic defects along the GHRH-GH-IGF-I axis have been reported. Mutations of the IGF-I receptor (R) are a rare abnormality of whom only the heterozygote progenies survive. OBJECTIVES: To summarize, from the literature, data on birth length, weight and head circumference of neonates with IGF-I-R mutations, and to correlate the data with that of other types of mutations in the GH/IGF-I axis. SUBJECTS: Sixty seven neonates from 24 published articles were included and forty seven different mutations of the IGF-I (R) located on chromosome 15 have been identified. RESULTS: Mean (±SD) birth length (BL), available for 26, (10 M, 16F) neonates with a gestational age of 34-41weeks, was 44.2±4cm; one was premature (30cm at 31 weeks). There was a significant correlation between birth length and gestational age (GA) r=0.71 (p>.001). Mean birth weight (BW) of 41 neonates (18M, 23F) was 2388±743gr. Two premature neonates weighed 650gr and 950gr respectively. The BW correlated significantly with gestational age, (males: r=0.68; p=0.007, females: r=0.49; p=0.024). The BMI of 25 neonates ranged from 6 to 13. In 22 records marked microcephaly was ascertained or stated. Nine of 16 mothers were short (133 -148cm), m±SD = 150.5±7.3cm.

Fifty seven years of follow-up of the Israeli cohort of Laron Syndrome patients-From discovery to treatment.

Clinical and laboratory investigations of dwarfed children newly Jewish immigrants from Yemen and Middle East and who resembled patients with isolated growth hormone deficiency were started by our group in 1958. In 1963 when we found that they have high serum levels of hGH, we knew that we had discovered a new disease of primary GH insensitivity. It was subsequently coined Laron Syndrome (LS, OMIM #262500). The etiopathogenesis was disclosed by 2 liver biopsies demonstrating a defect in the GH receptor. Subsequent investigations demonstrated deletions or mutations in the GHR gene. The defect lead to an inability of IGF-I generation, resulting in severe dwarfism, obesity, and other morphologic and biochemical pathologies due to IGF-I deficiency. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Following closely our cohort of 69 patients with LS enabled us to study its features in untreated and IGF-I treated patients. This syndrome proved to be a unique model to investigate the effects of IGF-I dissociated from GH stimulation. In recent studies we found that homozygous patients for the GHR mutations are protected lifelong from developing malignancies, opening new directions of research.

Growth, development, puberty and adult height before and during treatment in children with congenital isolated growth hormone deficiency.

OBJECTIVE: To describe the growth, development and puberty in children with congenital IGHD before and during hGH treatment. SUBJECTS: Patients with cIGHD treated by hGH between the years 1958-1992. SETTING: All patients were diagnosed, treated and followed in our clinic. PARTICIPANTS: Data were found in 37/41 patients (21 m, 16 f). 34 had hGH-1A deletions, 7 GHRH-R mutations. Patients, referred after age 25, were excluded. RESULTS: The birth length of 10/37 neonates was 48.29±2.26 (44-50) cm. Birth weight of 28/37 neonates was 3380±370 g (m), 3230±409 g (f). Neuromotor milestones were variable. Age at referral was 5.7±4.2 y (m) and 5.6±3.8 y (f). Initiation of hGH treatment (35µg/kg/d) was 7.5±4.8, (0.8-15.08) y (m) and 6.8±4.36 (0.8-16.5) y (f). Height SDS increased from -4.3 to -1.8 (m) and from -4.5 to -2.6 (f). Head circumference increased from -2.6 to -1.3 (m) and from -2.7 to -2.3 (f). BMI increased from 15.8 to 20.6 (m) and from 15.5 to 20.4 (f). There was a negative correlation between age of hGH initiation and change in height SDS (r=-0.66; ρ<0.01), same for bone age (r=-0.69; ρ<0.01). Upper/lower body ratio decreased from 2.5±2.1 (m±SD) to 1.08±0.1 (ρ<0.0005). Puberty was delayed in boys, less so in girls. Mean age of 1st ejaculation (14 m) was 17.6±2.2 y and of menarche (14 f. was 13.7±1.2 y. In both genders there was a positive correlation between age at start of hGH and age at onset of puberty (r=0.57; ρ<0.01). All reached full sexual development but the penile and testicular sizes were below normal. There was a positive correlation between length of hGH treatment and final testicular volume (r=0.597, ρ=0.05) and a negative correlation between the age at initiation of hGH treatment and final testicular volume(r=-0.523, ρ=0.018). All were obese and hGH treatment increased the adiposity progressively (r=0.418, ρ=0.013). CONCLUSION: Early diagnosis and treatment of cIGHD enables normal or near normal growth, development and puberty.

Biphasic response of subscapular skinfold thickness to hGH or IGF-1 administration to patients with congenital IGHD, congenital MPHD and Laron syndrome.

OBJECTIVE: To evaluate changes in adiposity in congenital GH/IGF-1 deficient children during hGH or IGF-1 treatment. SUBJECTS AND METHODS: 27 children with congenital isolated growth hormone deficiency (cIGHD) treated with hGH for 2.5-€“15.2 years (mean 10.0 ± 3.4), 18 children with congenital multiple pituitary hormone deficiency (cMPHD), treated with hGH for 2.3-€“17.9 years (mean 6.1 ± 4.3), and 14 children with Laron syndrome (LS) treated with IGF-1 for 1.2-12 years (mean 5.5 ± 3.7) were studied. Changes in the degree of adiposity were evaluated by subscapular skinfold thickness (SSFT), before, during and up to 2 years after treatment. All the children had various degrees of obesity. RESULTS: During the pretreatment period, cIGHD patients showed little changes in SSFT (P = 0.45), cMPHD and LS patients showed an increase in SSFT (P = 0.01, P = 0.06 respectively). During the initial 0.6-1.1 years of hGH/IGF-1 treatment, the SSFT decreased in all 3 groups (P < 0.001), while during subsequent years a significant increase in SSFT (P < 0.001) was observed, in all types of patients, notably in females. Only the cIGHD patients demonstrated a significant correlation between the degree of SSFT decrease and height SDS gain (R = -ˆ’0.56, P = 0.002) in the first period of treatment. CONCLUSIONS: Short term replacement therapy of 0.6-€“1.1 years with either hGH or IGF-1, induced a reduction in subscapular subcutaneous fat whereas prolongation of therapy led to an increase in the subcutaneous fat.

Differential effects of hGH and IGF-I on body proportions.

UNLABELLED: The differential growth effects of hGH and IGF-I on the upper/lower (U/L) body segment in relation to height (Ht) were analyzed in 15 patients with isolated Growth hormone deficiency (IGHD,:7M, 8F) mean age 5.0 +/- 3.2 (SD) years treated with hGH; 21 patients with multiple pituitary hormone deficiency including growth hormone (MPHD: 14M, 7F) aged 10.0 +/- 3.8, treated with hGH; 9 patients with Laron Syndrome (LS) (4M,5F) aged 6.9 +/- 5.6 years treated with IGF-I; 9 boys with intrauterine growth retardation (IUGR) aged 6.3 +/- 1.25 years treated by hGH; and 22 boys with idiopathic short stature (ISS) aged 8.0 +/- 1.55 years treated by hGH. The dose of hGH was 33 microg/kg/day, that of IGF-I 180-200 microg/kg/day. RESULTS: the U/L body segment ratio in IGHD patients decreased from 2.3 +/- 0.7 to 1.1 +/- 0.7 (p <0.001), and the Ht SDS increased from -4.9 +/- 1.3 to 2.3 +/- 1 (p < 0.001) following treatment. In MPHD patients the U/L body segment decreased from 1.1 +/- 1.1 to -0.6 +/- 1.0 (p < 0.001), and the Ht SDS increased from -3.3 +/- 1.4 to -2.5 +/- 1.0 (p < 0.009). In the LS group the U/L body segment ratio did not change with IGF-I treatment but Ht improved from -6.1 +/- 1.3 to -4.6 +/- 1.2 (p < 0.001), The differential growth response of the children with IUGR and with ISS resembled that of the children with LS. CONCLUSIONS: hGH and IGF-I act differentially on the spine and limbs.

Head circumference in untreated and IGF-I treated patients with Laron syndrome: comparison with untreated and hGH-treated children with isolated growth hormone deficiency.

BACKGROUND: Head circumference (HC) is a simple and practical measure of brain size, development and longitudinal measurements of the HC in childhood are an index of brain growth. OBJECTIVE: To determine the effects of long IGF-I deficiency and treatment on HC in patients with Laron syndrome (LS). PATIENTS: 20 untreated adult LS patients, aged 48.4±11.2 years and 13 LS patients treated between ages of 5.6±4 to 11.3±3 years were studied. 15 patients with congenital IGHD treated between age 6.1±4 and 13±4 by hGH served as controls. METHODS: HC was expressed as standard deviation (SD) and Ht as SDS. HC was measured and plotted on Nellhaus charts. Linear height (Ht) was measured by a Harpenden Stadiometer. CONCLUSIONS: The mean HC deficit of the adult untreated LS males was -2.9±0.6 SD compared to a Ht deficit of -7.0±1.7 SDS. The HC of the LS adult females was -3.6±1 SD compared to a Ht SDS of -6.9±1.5 (p<0.001). IGF-I treatment (150-200 µg/kg once daily) increased the HC from -3.3±0.9 (m±SD) to normal values (0.87±1.8 SD) (p<0.001) in 11/13 children. The Ht SDS deficit decreased only by 1.5 SDS. hGH treatment of cIGHD children increased the HC from -2.0±1.8 to 0.3±1.2 SD and the Ht SDS from -4.8±1.6 to 1.6±1.0.