Importance of dietary calcium and vitamin D in the treatment of hypercalcaemia in Williams-Beuren syndrome.

Abstract Background: Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by the deletion of 26-28 genes on chromosome 7. Fifteen percent of WBS patients present with hypercalcaemia during infancy, which is generally mild and resolves spontaneously before the age of 4 years. The mechanisms underlying the transient hypercalcaemia in WBS are poorly understood. Case: We report a case of severe symptomatic hypercalcaemia in a patient with WBS, in which treatment with mild calcium restriction, hyperhydration and repeated bisphosphonate administration only resulted in short-lasting effects. Long-term lowering of serum calcium was only achieved after reducing calcium and vitamin D intake to the bare minimum. Conclusions: This case illustrates the potential severity of hypercalcaemia in WBS, and demonstrates that both the cause as well as the solution of this problem may be found in the intestinal absorption of calcium. We hypothesise that the phenotypical resemblance between WBS and transient idiopathic infantile hypercalcaemia can be explained by similarities in the underlying genetic defect. Patients suffering from transient infantile hypercalcaemia were recently described to have mutations in CYP24A1, the key enzyme in 1,25-dihydroxyvitamin D3 degradation. In the light of this new development we discuss the role of one of the deleted genes in WBS, Williams syndrome transcription factor (WSTF), in the etiology of hypercalcaemia in WBS

Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections.

Contains fulltext : 51083.pdf (publisher's version ) (Closed access)The complement system is an essential element in our innate defense against infections with Neisseria meningitidis. We describe 2 cases of meningococcal septic shock, 1 of them fatal, in 2 children of a Turkish family. In the surviving patient, alternative pathway activation was absent and factor D plasma concentrations were undetectable. Concentrations of mannose-binding lectin (MBL), C1q, C4 and C3, factor B, properdin, factor H, and factor I were normal. Mutation analysis of the factor D gene revealed a T638 > G (Val213 > Gly) and a T640 > C (Cys214 > Arg) mutation in the genomic DNA from the patient, both in homozygous form. The consanguineous parents and an unaffected sister had these mutations in heterozygous form. In vitro incubation of factor-D-deficient plasma of the boy with serogroup B N meningitidis showed normal MBL-mediated complement activation but no formation of the alternative pathway C3-convertase C3bBbP, and severely decreased C3bc formation and terminal complement activation. The defect was restored after supplementation with factor D. In conclusion, this is the second report of a factor D gene mutation leading to factor D deficiency in a family with meningococcal disease. This deficiency abolishes alternative-pathway dependent complement activation by N meningitidis, and leads to an increased susceptibility to invasive meningococcal disease