Primary growth hormone insensitivity (Laron syndrome) and acquired hypothyroidism: a case report

<p>Abstract</p> <p>Introduction</p> <p>Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance of severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor 1 values.</p> <p>Case presentation</p> <p>We report the case of a 15-year-old Caucasian girl who was diagnosed with Silver-Russell syndrome at the age of four and a half years. Recombinant growth hormone was administered for 18 months without an appropriate increase in growth velocity. At the age of seven years, her serum growth hormone levels were high, and an insulin-like growth factor 1 generation test did not increase insulin-like growth factor 1 levels (baseline insulin-like growth factor 1 levels, 52 μg/L; reference range, 75 μg/L to 365 μg/L; and peak, 76 μg/L and 50 μg/L after 12 and 84 hours, respectively, from baseline). The genetic analysis showed that the patient was homozygous for the R217X mutation in the growth hormone receptor gene, which is characteristic of Laron syndrome. On the basis of these results, the diagnosis of primary growth hormone insensitivity syndrome was made, and recombinant insulin-like growth factor 1 therapy was initiated. The patient's treatment was well tolerated, but unexplained central hypothyroidism occurred at the age of 12.9 years. At the age of 15 years, when the patient's sexual development was almost completed and her menstrual cycle occurred irregularly, her height was 129.8 cm, which is 4.71 standard deviations below the median for normal girls her age.</p> <p>Conclusion</p> <p>The most important functional tests for the diagnosis of growth hormone insensitivity are the insulin-like growth factor 1 generation test and genetic analysis. Currently, the only effective treatment is daily administration of recombinant insulin-like growth factor 1 starting from early childhood. However, these patients show a dramatically impaired final height. In our case, unexplained central hypothyroidism occurred during treatment.</p

A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment.

Objective: Here we report on a new case of human aromatase de!ciency in a man of 26 years of age andpresent the results of !ve year follow-up during trandermal estradiol (tE2) substitution, focusing on bonegrowth and mineralization. The lack of patient's compliance to tE2 treatment, resulting in low but detectableserum estradiol levels, provides helpful information about the physiological estradiol needed in serum toguarantee a complete bone maturation and mineralization.Design: Clinical case report study.Methods: Genetic, biochemical and hormonal evaluations and the study of bone health were performedbefore and during estrogen treatment.Results: Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin,mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightlyabove the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compoundheterozygosity due to 23 bp deletion in exon IV and a point mutation in the !rst nucleotide of intron IX of theCYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and boneturnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiolraised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy.Conclusions: This new case of aromatase de!ciency underlines the role of estrogen on skeletal maturation,BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuousestrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a completebone maturation and mineralization and to prevent the worsening of body skeletal proportions. Thecomprehension of this physiological aspect has relevant clinical signi!cance especially for the developmentof new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men

The Growth Hormone (GH) Response to the Arginine Plus GH-Releasing Hormone Test Is Correlated to the Severity of Lipid Profile Abnormalities in Adult Patients with GH Deficiency

The aim of the present study was to correlate the degree of the GH response to the combined arginine and GHRH (ARG1GHRH) test with clinical status in 157 adult hypopituitary patients and 35 healthy controls. On the basis of the GH response to ARG1GHRH, the 192 subjects were subdivided into 5 groups: group 1, very severe GH deficiency (GHD; 65 patients with GH peak ,3 mg/L); group 2, severeGHD (37 patients withGHpeak between 3.1–9 mg/L); group 3, partial GHD (25 patients with GH peak between 9.1–16.5 mg/L); group 4, non-GHD (30 patients with GH peak .16.5 mg/L); and group 5 (35 controls with GH peak .16.5 mg/L). Plasma insulin-like growth factor I (IGF-I) concentrations were lower (P , 0.001) in patients of group 1 (74.4 6 6.7 mg/L) and group 2 (81.4 6 6.8 mg/L) than in those of group 3, 4, and 5 (163.6 6 40.6,185.9621, and 188.8611.1 mg/L, respectively). Plasma IGF-binding protein-3 concentrations were lower (P , 0.01) in group 1 (2.1 6 0.2mg/L) and group 2 (2.0 6 0.2 mg/L) than in group 3 (3.4 6 0.7 mg/L)and group 5 (3.8 6 0.2 mg/L). In patients of group 1, total cholesterol (228.365.7 mg/dL) and triglycerides levels (187.4615.3 mg/dL) were higher than those in group 3 (196.6 6 9.6 and 115.8 6 10.1 mg/dL, respectively), group 4 (176.8 6 11.3 and 101.4 6 12.5 mg/dL, respectively), and group 5 (160 6 6.9 and 99.3 6 5.4 mg/dL, respectively). High density lipoprotein cholesterol levels were lower in patients of group 1 (45.2 6 2.4 mg/dL) than in those of group 4 (54.7 6 3.5 mg/dL; P , 0.05) and group 5 (53.6 6 2 mg/dL; P , 0.001), whereas low density lipoprotein cholesterol levels were higher in patients of group 1 (127.3 6 7.9 mg/dL), group 2 (129.2 6 9.5 mg/dL), and 3 (133 6 9 mg/dL) than in those of group 5 (102.467.4 mg/dL; P,0.05). Patients of group 2 had total cholesterol, high density lipoprotein cholesterol, and triglycerides levels at an intermediate level with respect to those in groups 1, 3, and 4. Among the five groups, no difference was found in fasting glucose concentrations, heart rate, or systolic and diastolic blood pressures.Asignificant increase in fat body mass and a decrease in lean body mass and total body water were found in all patients compared to controls. Disease duration was significantly shorter in patients of group 4 than in those of the remaining three groups (P , 0.001). A significant correlation was found between the GH peak after ARG1GHRH and disease duration (r 5 20.401; P , 0.001), plasma IGF-I (r 5 0.434; P , 0.001), total cholesterol (r520.324; P , 0.001), and triglycerides levels (r520.219; P , 0.05). A significant multiple linear regression coefficient was found between the GH peak after ARG1GHRH and plasma IGF-I levels (t 5 2.947; P , 0.005), total cholesterol levels (t 5 22.746; P , 0.01), and disease duration (t 5 22.397; P , 0.05). In conclusion, the results of the present study indicate that the degree of the GH response to ARG1GHRH is correlated with the severity of lipid profile abnormalities and substantiate the reliability of the ARG1GHRH test for the diagnosis of GHD in adults. Because at present GH treatment is recommended only in adult patients with severe GHD, patients with a GH response below 9 mg/L to the ARG1GHRH test should be treated with GH, as should patients with a peak GH response to an insulin tolerance test below 3 mg/L. (J Clin Endocrinol Metab 84: 1277–1282, 1999

Traumatic brain injury (TBI) and lipid profile abnormalities: study 12 months after the brain injury

Aim of this study was to evaluate lipid profile and the severity of GHD, in a large group of TBI patients with or without GH deficiency. We assayed lipid profile (Total-, HDL- Cholesterol, Triglycerides) in 62 TBI subjects 12 months after TBI (41 M, 21 F, 13–81 yrs, BMI: 24.6±0.6 kg/m2), and in 62 sex-, age- and BMI-matched controls. Based on the GH peak after GHRH+ARG test, patients were stratified as: 1) severe GHD (GH peak ≤ 9 μg/l; n=13; 20.9%); 2) partial GHD (GH peak in between 9.1–16.5 μg/l; n=6; 9.7%); 3) non-GHD (GH peak >16.5 μg/l; n=43; 69.3%). IGF-I levels were lower (P<0.001) in patients with severe GHD (88.7±11.1 μg/L) than in those with partial GHD, non-GHD and in controls (148.1±33.9, 219.2±10.7, and 251.8±10.8 μg/L, respectively). HDL-cholesterol were lower (P<0.01) in patients with severe GHD (44.1±2.7 mg/dL) than in those non-GHD and in controls (54.4±1.3 and 59.3±1.1, respectively), while, no significant differences was found in partial GHD. In patients with severe GHD, total- and HDL-cholesterol ratio (4.9±0.4, P<0.01) were higher than in those with partial GHD (4.4±0.2,), non-GHD (3.9±0.2), and controls (2.9±0.1). In addition, partial GHD patients had total- and HDL-cholesterol ratio (4.4±0.2, P<0.01) higher than those non-GHD (3.9±0.2), and controls (2.9±0.1). Triglycerides levels were not different among severe GHD, partial GHD and non GHD TBI patients and controls. In all subjects, a significant correlation was found between the GH peak and age (r=−0.41; P<0.01), BMI (r=−0.33; P<0.05), IGF-I (r=0.36; P<0.01), total cholesterol (r=−0.37; P<0.05), HDL cholesterol (r=0.36; P<0.05), total- and HDL- cholesterol ratio (r=−0.47; P<0.01). IGF-I was correlated with age (r=−0.54, P<0.001), total cholesterol (r=−0.46; P<0.01), HDL cholesterol (r=0.39; P<0.05), total- and HDL- cholesterol ratio (r=−0.51; P<0.01). In conclusion, impairment of lipid profile was evident in TBI patients with severe GH