Autosomal Recessive Osteopetrosis (ARO) presents early in life with extreme sclerosis of the skeleton, reduction of bone marrow spaces, hepatosplenomegaly, cranial nerves compression and severe growth failure. ARO is often lethal and at present the only therapy is HSCT, which should be performed as soon as possible in order to obtain a major benefit. ARO is genetically heterogeneous and delays in clinical diagnosis sometimes occur, due to its rareness and to the presence of complex phenotypes which may be misinterpreted. Therefore, the molecular classification of the disease is essential to promptly establishing the appropriate treatment.
We report the use of exome sequencing in the molecular diagnosis of two siblings initially thought to be affected by intermediate osteopetrosis, which identified a homozygous mutation in the CTSK gene. Prompted by this finding, we investigated additional patients addressed to us for recessive osteopetrosis and found CTSK mutations in four of them, whose clinical and radiographic features were retrospectively found to be compatible with, but not typical for, Pycnodysostosis. So, we recommend that CTSK gene be included in the molecular diagnosis of intermediate forms of human ARO and, in general, of high-density bone conditions.
We also describe the first patient with mild osteopetrosis due to recessive TCIRG1 mutations causing an incomplete splicing defect, allowing for the production of the small amount of protein sufficient for dampening the clinical outcome. This finding widens the clinical spectrum that may arise from recessive mutations in TCIRG1, demonstrating that extremely rare, mild forms of TCIRG1-dependent ARO exist, so this gene should also be included in the molecular work-up of intermediate cases.
Overall, we underline the difficulties of differential diagnosis in patients whose clinical appearance does not fit the classical malignant or benign picture, and confirm the role of exome sequencing in the molecular classification of genetically heterogeneous diseases.
17 May 2014 - 20 May 2014