Sequential measurements of IGF-I serum concentrations in adolescents with Laron syndrome treated with recombinant human IGF-I (rhIGF-I).

Background Recombinant human insulin-like growth factor 1 (rhIGF-I) has been approved as an orphan drug for the treatment of growth failure in children and adolescents with severe primary IGF-I deficiency (SPIGFD) with little pharmacokinetic data available. Therefore, sequential measurements of serum IGF-I, glucose, potassium, insulin and cortisol were performed in patients treated with rhIGF-I to evaluate their significance in safety and efficacy. Methods Repetitive blood samples were taken after meals before and 30, 60, 120, 180 and 360 min after rhIGF-I injections in two male patients with Laron syndrome at times of dose adjustments. Results Maximal IGF-I concentrations were observed 2 h after injections (495 ng/mL) and concentrations were still higher 6 h after injections than at baseline (303 ng/mL vs. 137 ng/mL). Thirteen percent of all and 33% of maximum IGF-I concentrations were greater than +2 standard deviation score (SDS) calculated for bone age (BA) (IGF-I SDS BA) rather than chronological age (CA) as BA was significantly delayed to CA by 3.2 years (p=0.0007). Height velocities correlated with individual maximum IGF-I SDS BA (ρ=0.735; p<0.0001). Serum insulin, cortisol and glucose did not correlate with IGF-I concentrations, but serum potassium showed a negative correlation (ρ=-0.364; p<0.0001) with IGF-I concentrations. Conclusions Sequential measurements of serum IGF-I, glucose and potassium in patients with Laron syndrome may aid in optimizing and individualizing rhIGF-I treatment. IGF-I concentrations should be referenced according to BA which better reflects the biological age. The inverse correlation of IGF-I and serum potassium concentrations after injections of rhIGF-I has not been reported before and warrants further consideration.

Multiple prevalent fractures in relation to macroscopic bone architecture in patients with cystic fibrosis.

BACKGROUND: The relative risk for bone fractures in patients with cystic fibrosis (CF) and its relationship to macroscopic bone architecture assessed by pQCT and DXA are incompletely defined. METHODS: In a cross-sectional study of 43 CF patients (age, 17.8±6.2years), rate and location of fractures, bone mass, density, geometry, and strength of the radius as well as forearm muscle size were investigated. RESULTS: The fracture rate in CF was 9.2-fold higher compared to an age-matched German control population. The probability of remaining free of any fracture in CF patients at 25years was reduced to 39.8% compared to 84.6% in controls (P<0.001). Assessment of macroscopic bone architecture by DXA and pQCT allowed the differentiation of patients with multiple prevalent fractures with a high sensitivity (up to 100%) and specificity (up to 94.3%). CONCLUSIONS: Bone densitometry is a useful tool for noninvasive assessment of fracture risk in CF patients.

Analysis of the functional muscle-bone unit of the forearm in patients with phenylketonuria by peripheral quantitative computed tomography.

Bone disease in patients with phenylketonuria (PKU) is incompletely characterized. We therefore analyzed, in a cross-sectional study radius macroscopic bone architecture and forearm muscle size by peripheral quantitative computed tomography (pQCT) and muscle strength by hand dynamometry in a large cohort (n = 56) of adolescent and adult patients with PKU aged 26.0 ± 8.9 (range, 11.8-41.5) years. Data were compared with a reference population (n = 700) from the DONALD study using identical methodology. We observed a significant reduction of cortical thickness (z-score -1.01 ± 0.79), Strength-Strain Index (SSI) (z-score -0.81 ± 1.03), and total bone mineral density (BMD) of the distal radius (z-score -1.05 ± 1.00). Mean muscle cross-sectional area (z-score -0.98 ± 1.19) and muscle grip force (z-score -0.64 ± 1.26) were also significantly reduced, indicating an impaired muscular system as part of the clinical phenotype of PKU. SSI positively correlated (r = 0.53, P < 0.001) with the corresponding muscle cross-sectional area in the reference population; however, the regression line slope in PKU patients was less steep (P < 0.001), indicating that bone strength is not adequately adapted to muscle force. In conclusion, the radial bone in PKU patients is characterized by reduced bone strength in relation to muscular force, decreased cortical thickness, and impaired total BMD at the metaphyseal site. These alterations indicate a mixed bone defect in PKU, both of which are due to primary alterations of bone metabolism and to secondary alterations in response to neuromuscular abnormalities.

Levothyroxine Treatment of Euthyroid Children with Autoimmune Hashimoto Thyroiditis: Results of a Multicenter, Randomized, Controlled Trial.

BACKGROUND: Levothyroxine (L-T4) treatment of euthyroid children with Hashimoto thyroiditis (HT) is a controversial issue. PATIENTS AND METHODS: We conducted a prospective, randomized, controlled clinical trial. Out of 79 identified euthyroid patients, 59 started the study; 25 patients (21 female, 4 male; age: 11.8 ± 2.3 years) received L-T4 at a mean dose of 1.6 µg/kg (SD, 0.8) daily, and 34 (27 female, 7 male; age: 12.6 ± 1.2 years) were not treated. Patients developing subclinical hypothyroidism during follow-up (n = 13) were treated with L-T4 and removed from the observation group. As the main outcome measures, thyroid gland volume (determined by ultrasound) as well as serum levels of TSH, free T4, and antibodies against thyroid peroxidase and thyroglobulin were assessed every 6 months for 36 months. RESULTS: At the start, the mean thyroid volume (standard deviation score, SDS) was 2.5 in the treatment group and 1.6 in the observation group. There was a constant decline in mean thyroid volume (SDS) from 2.13 (month 12) to 1.12 (month 30) in the treated group, with a delta thyroid volume of -1.01 SDS. In the observation group, the mean delta thyroid volume increased to +0.27 SDS. The change of the delta thyroid volume was statistically significantly different between both groups during the 12- and 30-month time points (p < 0.05). L-T4 had no effect on thyroid function and serum thyroid antibodies. CONCLUSIONS: L-T4 treatment can decrease the thyroid volume in euthyroid children with HT, but the effect is limited to a definite time period.

Long-Term Neurodevelopmental Outcome of Children Treated with Tri-Iodothyronine after Cardiac Surgery: Follow-Up of a Double-Blind, Randomized, Placebo-Controlled Study.

BACKGROUND: Transient thyroid dysfunction occurs in children after cardiopulmonary bypass (CPB). We demonstrated significant benefits of acute postoperative tri-iodothyronine (T3) treatment for recovery and myocardial function. Now we report the long-term neurodevelopment of these children. METHODS: Twenty-eight children (70% of the original study population) could be recruited for a follow-up examination (median age 10.7 years, range 10-19.6 years) retaining the double-blind, randomized, placebo-controlled protocol. Cognitive function and motor development were tested, as were growth and thyroid and cardiac functions. RESULTS: The median full-scale intelligence quotient of all children was within the reference range and similar in the placebo and T3 groups. Tests for motor and cognitive functions, growth, and thyroid and cardiac functions revealed concurrent results. CONCLUSIONS: Overall intellectual development is preserved in adolescents treated with CPB in infancy irrespectively of low postoperative thyroid hormone concentrations. While acute postoperative T3 treatment in children after CPB improves recovery, no significant long-term effects on neurodevelopment could be detected. We therefore speculate that transient postoperative thyroid dysfunction by means of nonthyroidal illness syndrome is predominantly mediated by extranuclear, nongenomic mechanisms and thus acutely affects the cardiovascular system but not the development of the central nervous system mediated by genomic mechanisms.

Assessment of aortic morphology and compliance in children and adolescents with Ullrich-Turner syndrome (UTS) using magnetic resonance imaging (MRI).

AIM: The aim of this study was to evaluate the morphology and elastic properties of the aorta in children and adolescents with Ullrich-Turner syndrome (UTS) treated with growth hormone, by using magnetic resonance imaging (MRI). METHODS: Thirty-seven conscious UTS patients were examined using a 1.5-T whole-body MRI. Contrast-free three-dimensional (3D)-MR angiographies were performed, including 2D cine MRI, to calculate the aortic compliance (C) and cine of the aortic valve. RESULTS: Changes of aortic morphology were evident in 40% of the patients, whereas six had more than one alteration. A bicuspid aortic valve was identified in three patients that were missed by previous echocardiography. The aortic compliances in UTS patients were similar to those in healthy persons. CONCLUSION: This study shows that aortic morphology and compliance can be assessed by MRI without using contrast agents and without sedation in children and adolescents with UTS.

Guanine nucleotide-binding protein α subunit hypofunction in children with short stature and disproportionate shortening of the 4th and 5th metacarpals.

BACKGROUND: GNAS encodes the α subunit of the stimulatory G protein (Gsα). Maternal inherited Gsα mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals. AIMS: Here we investigated the Gsα pathway in short patients with distinct shortening of the 4th and 5th metacarpals. METHODS: In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsα protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions. RESULTS: In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsα activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified. CONCLUSIONS: Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsα protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsα dysfunction.

Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients.

Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.