Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040C→T) in exon 41 of the gene encoding the α1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric α1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040C→T) in exon 41 of the gene encoding the α1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric α1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.

No abstract

Background: Alendronate has been widely used in the treatment of patient with osteoporosis; several studies have demonstrated the long-term efficacy and safety of alendronate (Fosamax) in patient with osteoporosis. Secondary hyperparathyroidism has been described in patient with chronic renal failure due to stimulation of parathyroid cells by stimuli such as hyperphosphatemia, hypocalcemia and calcitriol deficiency, leading to parathyroid gland hyperplasia. Case Report: We describe a patient who developed secondary hyperparathyroidism despite elevated levels of vitamin D, and normal renal function, while on alendronate, vitamin D and calcium for severe osteoporosis. In August 1998 a 43 year old female was referred to our endocrine clinic for severe osteoporosis. She was found to have normal PTH, serum calcium, phosphorus, urinary calcium excretion, and creatinine clearance. Her 25-hydroxyvitamin D [25-(OH)vitD] level was 16.4 ng/mL. She was started on alendronate 70 mg/w, vitamin D 50,000 IU/w, and calcium 2 g/d. She responded well to this treatment with improvement in her bone mineral density and vitamin D level. In June 2002 she developed secondary hyperparathyroidism, (PTH = 176 pg/mL, calcium of 8.8 mg/dL, normal ionized calcium, 25(OH)vitD = 45.1 ng/mL, 24 h urinary calcium = 240 mg/d). The patient eventually underwent neck exploration in 2004, during which 3 1/5 hyperplastic parathyroid glands were excised. Subsequently the PTH level returned to normal. Discussion: Secondary hyperparathyroidism has classically been described in patients with renal failure or severe vitamin D deficiency due to constant stimulation of parathyroid cells by hyperphosphatemia, hypocalcemia and calcitriol deficiency, leading to parathyroid gland hyperplasia. Skeletal resistance to the calcemic action of PTH is another factor that appears to contribute to the genesis of secondary hyperparathyroidism in chronic renal failure. Recently several studies have demonstrated that alendronate impairs the ability of PTH to increase bone mineral density in osteoporotic patients, possibly by reducing the impact of PTH on bone formation. The present case demonstrates the occurrence of parathyroid hyperplasia and secondary hyperparathyroidism, despite absence of conventional etiologic factors. We propose the possibility of long-term alendronate therapy and skeletal resistance to the effect of PTH as a mechanism of hyperparathyroidism in this patient.