A number sign (#) is used with this entry because of evidence that metaphyseal dysplasia without hypotrichosis (MDWH) is caused by homozygous or compound heterozygous mutation in the RMRP gene (157660) on chromosome 9p13.

Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare autosomal recessive skeletal dysplasia. Patients present in childhood with isolated chondrodysplasia. Hair is normal in most patients. Some patients develop later-onset extraskeletal manifestations including immunodeficiency and malignancy (summary by Vakkilainen et al., 2020).

Mutations in RMRP also cause 2 other skeletal dysplasias, anauxetic dysplasia-1 (ANXD1; 607095) and cartilage-hair hypoplasia (CHH; 250250), which, although more severe, share some features with MDWH.

Verloes et al. (1990) presented a series of 6 patients with skeletal changes precisely like those of cartilage-hair hypoplasia (CHH; 250250), but without hypotrichosis or immunodeficiency. Two of the patients were sibs. Microscopic examination of the hair showed a reduction in the diameter of the hair shaft. Verloes et al. (1990) suggested that this may be a form of metaphyseal dysplasia allelic to CHH.

Vakkilainen et al. (2020) reported a patient with a phenotype consistent with metaphyseal dysplasia without hypotrichosis (MDWH) in childhood who developed severe bone marrow failure in early adulthood. Birth length was short (-2.4 SD) and she developed progressive short stature that did not respond to growth hormone therapy. At age 7 years radiographs showed skeletal changes consistent with epiphyseal dysplasia, particularly in the hands and hips; mild metaphyseal involvement was also seen but became less apparent with age. She had several surgeries for leg deformities and developed scoliosis. Hair was normal. She had mild lymphopenia, but no other immunologic evaluations were pursued. Evaluation for fatigue at age 18 years showed pancytopenia with no detectable neutrophils. Bone marrow exam showed normal cellularity, but absence of granulopoiesis and overrepresentation of lymphocytes. Because of persistence of agranulocytosis despite medical treatment, she received a hematopoietic stem cell transplant from an HLA-identical donor. Despite normal bone marrow cellularity and full chimerism, peripheral blood cell counts remained low 11 months after the transplant.

Vakkilainen et al. (2020) collected clinical and laboratory data on 80 Finnish patients with mutations in the RMRP gene followed for over 30 years, 10 with only skeletal features during preschool age meeting the criteria for MDWH, and 70 with a clinical presentation typical of CHH. When clinical symptoms, radiographic features, and laboratory results between these 2 groups were compared, the only difference seen was that the mean birth length was larger among those with MDWH (-2.03 SD vs -3.06 SD, p = 0.03). Among the 10 MDWH patients, 8 developed extraskeletal manifestations later in life. Two developed malignancy (Hodgkin lymphoma and neuroendocrine carcinoma); both patients died during cancer treatment. Six patients developed signs of immunodeficiency including recurrent episodes of otitis media, rhinosinusitis, pneumonia, and bronchiectasis. Abnormal lymphocyte proliferation was detected in 4 patients before the development of clinical immunodeficiency and malignancy. Two of the 10 patients with MDWH had not yet developed extraskeletal manifestations at ages 28 and 34 years, other than pollen allergy. However, one of these had an asymptomatic specific antibody deficiency and the other had low levels of peripheral B cells. The authors proposed that patients with MDWH can develop serious late-onset extraskeletal manifestations and should be reclassified and managed as CHH.

The transmission pattern of MDWH in the families reported by Bonafe et al. (2002) was consistent with autosomal recessive inheritance.

In 2 unrelated boys with the cartilage-hair hypoplasia variant with only skeletal manifestations, Bonafe et al. (2002) identified compound heterozygous mutations (157660.0001; 157660.0009-157660.0011) in the RMRP gene that segregated with the disorder in both families. Bonafe et al. (2002) suggested that short stature and metaphyseal changes associated with cone-shaped epiphyses of the hands should raise the diagnostic possibility of a CHH-related disorder that can then be confirmed by mutation analysis.

In a patient with MDWH, Vakkilainen et al. (2020) identified compound heterozygosity for variants in the RMRP gene (157660.0023 and 157660.0024).

In 10 Finnish patients with MDWH, Vakkilainen et al. (2020) found that 7 were homozygous for the common 71A-G founder mutation (157660.0001) and 3 were compound heterozygous for the founder mutation with 263G-T (157660.0002). No evidence of genotype-phenotype correlation was seen.