A form of severe short-limbed dwarfism with hair anomalies, and defective immunity and erythrogenesis.
Metaphyseal Chondrodysplasia McKusick Type; McKusick Syndrome.
First recognized as a distinct entity and described in the Old Order Amish, a religious group in the United States, in 1965 by the American geneticist Victor A. McKusick and colleagues, who is also the founder and one of the editors of the “Online Mendelian Inheritance in Man” (OMIM) database.
Clustering is found in Old Order Amish (1-2 in 1,000 live births) and in certain areas of Finland (1 in 23,000 live births). It is very rare in other populations, where also sporadic cases have been reported. Both genders are equally affected.
Autosomal recessive with reduced penetrance and considerable intra- and interfamilial phenotypic variability. The disorder is caused by mutations in the mitochondrial RNA-processing endoribonuclease (RMRP) gene, which has been mapped to chromosome 9p13.3. This enzyme is responsible for cleavage of RNA in the mitochondrial DNA synthesis and for nucleolar cleaving of pre-rRNA, a ribosomal RNA precursor. Cartilage-Hair Hypoplasia Syndrome is considered a ribosomopathy.
A generalized defect in cellular proliferation has been described, affecting predominately T-cells (resulting in lymphopenia in almost two-thirds of patients), but also involves B-cells (low-serum concentrations of immunoglobulins A and/or G in approximately one-third of patients), neutrophils, and fibroblasts. Increased levels of cyclin B2 mRNA in combination with telomere dysfunction in various types of cells, including T-lymphocytes, are responsible for chromosomal instability leading to alterations of the mitotic spindle checkpoint.
Incomplete extension in the elbows, anterolateral chest deformity, genua vara, and excessive distal length of the fibula relative to the tibia are specific skeletal features. The major radiologic abnormalities are confined to the metaphyseal regions of tubular bones and a biopsy reveals hypoplasia of cartilage to be responsible for the skeletal abnormalities.
Psychomotor development is usually normal in these patients. In about 70% of patients, the birth length is below approximately 2.0 standard deviations below normal and results in progressive dwarfism with a median adult height of 131 cm for males and 122 cm for females. In comparison to the short extremities (all segments are affected with all tubular bones shortened), the disproportionate torso length results in normal or increased relative sitting height. Spine anomalies may include odontoid hypoplasia with C1/C2 instability, lumbar hyperlordosis (in 85%), scoliosis (in 21%), platyspondylia, and narrowed interpeduncular distances. Chest anomalies are detected in approximately two-thirds of patients and may consist of narrowing and/or asymmetry, prominent, anteriorly angulated sternum, and Harrison sulcus with flaring of the lower rib cage at the costochondral ...