Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency.

The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis. We describe the clinical and molecular characteristics of two brothers aged 47 and 39 years presenting an uncommon manifestation of congenital hypopituitarism. Sequencing of the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes was performed to confirm the genetic origin of the disorder. A compound heterozygosity in the PROP1 gene has been identified for both probands. The first change represents a mutational hot spot (c.150delA, p.R53fsX164), whereas the second is a novel alteration (p.R112X) that leads to protein disruption. Based on precise genetic diagnosis, an in silico prediction of a p.R112X mutation on protein architecture was performed. The resulting clinical phenotype was surprisingly distinct compared to most patients with genetic alterations in PROP1 reported in the current literature. This may be caused by a residual activity of a newly identified p.R112X protein that preserves over 70 % of the homeodomain structure. This examination may confirm a key role of a DNA-binding homeodomain in maintaining PROP1 functionality and suggests a conceivable explanation of an unusual phenotype.

Bone mass in chronic renal insufficiency patients treated with continuous ambulatory peritoneal dialysis.

Chronic renal failure (CRF) causes deterioration of the fluid, electrolyte, and acid-base balances, azotemia, and impairment of the structure and function of many systems. In the skeletal system, CRF changes both the quality and quantity of the bone through its multifactorial influence on bone metabolism, leading to osteopenia, osteoporosis, and increased risk of fracture. The aim of the present study was to work up the quickest and most sensitive schedule for detecting osteoporosis in chronic renal insufficiency patients treated with CAPD. Thirty-seven uremic patients were included in the study. Bone mineral density was measured by dual-energy x-ray absorptiometry in lumbar spine, femoral neck, forearm (33% distal and ultradistal sites), and total body. Analyzing all five sites, we made the assessment that the prevalence of osteoporosis in our group of patients reached 48.6%. If only one site was evaluated, the ultradistal part of forearm yielded the highest frequency of diagnosis of osteoporosis (37.8%). Next came the femoral neck and total body (21.6% each). When the two sites in the forearm were taken into account together, the incidence of osteoporosis reached 40.5%. We conclude that the quickest and most sensitive method of detecting osteoporosis in CAPD patients is to measure bone mass in both forearm sites (33% distal and ultradistal), then in the femoral neck.

[Markers of bone formation and resorption in primary and secondary hyperparathyroidism]. / Markery tworzenia i resorpcji kosci w pierwotnej i wtórnej nadczynnosci przytarczyc.

Hyperparathyroidism, both primary and secondary in chronic renal failure, leads to pathologic changes in the bones. Newly introduced markers of bone metabolism enable to biochemically detect and evaluate these changes. The aim of our studies was to perform determinations of serum osteocalcin as a marker of bone formation, and C-terminal telopeptide of collagen I (ICTP) as a marker of bone resorption in patients with excessive secretion of parathyroid hormone (PTH). Our studies comprised of 15 patients with primary and 24 patients with secondary hyperparathydroidism. In all patients serum PTH, osteocalcin and ICTP were detected by radioimmunoassay; the correlations between PTH and osteocalcin as well as between PTH and ICTP were also performed. Serum PTH was elevated in both, primary and secondary hyperparathyroidism. In primary hyperparathyroidism serum osteocalcin was moderately or definitely elevated, similarly serum ICTP was high. Following surgical removal of a parathyroid adenoma, concomitantly with a drop in serum PTH there was a rapid normalization of serum osteocalcin and ICTP. Secondary hyperparathyroidism in uraemia was characterised by markedly elevated serum osteocalcin and ICTP which surpassed the concentration of these markers in primary hyperparathyroidism. There was a positive correlation between serum PTH and osteocalcin levels, and a lower correlation between PTH and ICTP. From our studies it is concluded that excessive secretion of PTH in primary and secondary hyperparathyroidism stimulates bone formation and to higher degree--bone resorption.

[Bone mineral density in primary hyperparathyroidism]. / Gestosc mineralna kosci w pierwotnej nadczynnosci przytarczyc.

UNLABELLED: Skeletal complications of advanced hyperparathyroidism include clinically bone pains, muscle weakness, bone deformities and fractures. X-ray studies reveal subperiosteal bone resorption, atrophy of the cortex of long bones, cysts, brown tumours and calcifications of soft tissues; these changes appear in the late period of the disease. In recent onset of hyperparathyroidism bone changes may be detected by X-ray absorptiometry. Thus the aim of our study was to evaluate bone mineral density with the use of dual energy X-ray absorptiometry (DEXA) at two sites: in lumbar vertebral bodies consisting mainly of the trabecular bone and in 1/3 distal part of the radius composed predominantly of the cortical bone. Twenty-three patients with primary hyperparathyroidism were included in our study. Hypercalcemia (ionized calcium above 5.4 mg/100 ml, total calcium above 10.6 mg/100 ml) and increased serum PTH, above 100 pg/ml, were detected in all patients. Isotope scintigraphy using 99mTc-MIBI revealed the presence of a parathyroid adenoma; this was confirmed at surgery and histopathologically. In bone densitometry we found greatly reduced bone mineral density (BMD) in 1/3 distal part of the radius amounting to 66.8 +/- 12.0% of the age-matched range and markedly smaller bone loss in lumbar spine, BMD was 91.7 +/- 14.6%. In 10 patients control densitometry, performed 6-24 months after parathyroid adenomectomy, revealed a marked 10 to 22% increase in bone density of lumbar vertebral bodies in the first year. BMD of the 1/3 distal part of the radius increased to a smaller degree 6.3% per year. CONCLUSIONS: 1. Bone densitometry in primary hyperparathyroidism reveals pronounced decrease in bone mineral density in the 1/3 distal part of the radius and much smaller decrease of the lumbar spine density. 2. Parathyroid adenomectomy leads to a rapid increase in density of the trabecular bone L1-L4 vertebral bodies and much smaller increase in the cortical bone of the radius. 3. Pronounced differences in bone mineral density of cortical bone and trabecular bone surpassing 20% are characteristic of hyperparathyroidism as they do not occur in other types of osteoporosis.