Genetic and Clinical Spectrum of Osteopetrosis.

Osteopetrosis (OP) is a multi-systemic inborn disorder characterized by heterogeneous clinical presentations on the basis of a variety of mutated genes. We performed a retrospective analysis in patients with OP from 28 European centers on behalf of the ESID and the EBMT. Main objectives of this analysis were survival and quality of life with respect to genetic background, initial clinical presentation, and treatment modality.

A set of clinical parameters, genetic findings, transplant information and follow up data were collected using specific questionnaires. Questionnaires were sent at several time points to European centers treating patients with OP and the collected data were stored in a central OP database. DNA sequencing of candidate genes involved in human OP was done predominantly at laboratories in Milan, Paris and Ulm.

Data of 173 patients and of 134 hematopoietic stem cell transplantations (HSCT) were obtained during a time frame between 1983 and 2008. In the whole cohort, mutations in the following genes were detected: 47% biallelic TCIRG1, 9% biallelic CLCN7, 6% monoallelic CLCN7, 5% OSTM1, 2% RANK, 1% RANKL; 30% of patients have no mutations in these genes or could not be tested completely. In 23% of patients HSCT was not considered because of severe neurological problems or other complications mostly in the context of OSTM1 or CLCN7 mutations, or because of less severe phenotypes mainly due to monoallelic CLCN7 mutations (autosomal dominant OP, ADO).

Follow up data of 103 transplanted patients were available. With respect to donor type, the probability of survival at 2 years was 88% for matched family donors, 80% for matched unrelated donors, 68% for HLA-haploidentical donors and 54% for mismatched unrelated donors. There was no significant difference in survival of patients with different gene mutations but a trend to a worse long term outcome in CLCN7 patients. Most notably, several major sequelae were present in the majority of surviving patients. Visual impairment or dwarfism were found in about 2/3 of children showing no significant influence of the affected genes. About 10% of patients are suffering from significant persistent neurological problems after HSCT, which were found in patients with TCIRG and CLCN7 mutations. The quality of life were judged as normal by the parents in about 2/3 of surviving patients.

HSCT in infantile OP results in acceptable survival rates even after HLA-nonidentical transplants. However, outcome is influenced by a set of specific disease related problems and long term sequelae. The heterogeneity of OP necessitates an individualised therapeutic strategy respecting the genetic background, the clinical presentation and the type of the available donor.

No relevant conflicts of interest to declare.