Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare form of chondrodysplasia with no extra-skeletal manifestations. MDWH is caused by RMRP mutations but it is differentiated from the allelic condition cartilage-hair hypoplasia (CHH), which in addition to chondrodysplasia is characterized by thin hair, immunodeficiency and increased risk of malignancy. The long-term outcome of MDWH remains unknown. We diagnosed severe agranulocytosis in a subject with RMRP mutations and normal hair. Based on this observation, we hypothesized that MDWH is not a separate nosological entity but may, similar to CHH, associate with late-onset extra-skeletal manifestations.
We collected clinical and laboratory data for a cohort of 80 patients with RMRP mutations followed prospectively for over 30 years and analyzed outcome data for those with features consistent with MDWH.
In our prospective cohort, we identified 10 patients with skeletal but no extra-skeletal features during pre-school age. Eight of these patients developed malignancy or clinically significant immunodeficiency during follow-up. Two of them died during chemotherapy for malignancy. At the time of the first extra-skeletal manifestation, patients were school-aged, 20, 43 and 50 years old. Laboratory signs of immunodeficiency (impaired lymphocyte proliferative responses) were demonstrated in four patients before the onset of symptoms. The patient outside this cohort, who had RMRP mutations, skeletal dysplasia, normal hair and severe agranulocytosis at 18 years of age, underwent hematopoietic stem cell transplantation.
MDWH can present with severe late-onset extra-skeletal manifestations and thus should be re-classified and managed as CHH.