A number sign (#) is used with this entry because of evidence that anauxetic dysplasia-1 (ANXD1) is caused by homozygous or compound heterozygous mutation in the RMRP gene (157660) on chromosome 9p13.

Anauxetic dysplasia (ANXD1) is a form of spondylometaepiphyseal dysplasia characterized by the prenatal onset of extreme short stature, an adult height of less than 85 cm, hypodontia, and mild mental retardation. Major radiographic characteristics are late-maturing ovoid vertebral bodies with concave dorsal surfaces in the lumbar region; small capital femoral epiphyses; hypoplastic femoral necks; hypoplastic iliac bodies and shallow acetabulae; irregular metaphyseal mineralization and demarcation of the long tubular bones; short first and fifth metacarpals with widened shafts; very short and broad phalanges with small, late-ossifying epiphyses and bullet-shaped middle phalanges; and midface hypoplasia. The number of chondrocytes is severely reduced in the resting and proliferating cartilage, with diminished columnization of the hypertrophic zone (summary by Thiel et al., 2005).

Mutations in RMRP also cause 2 milder types of short stature with susceptibility to cancer, cartilage-hair hypoplasia (CHH; 250250) and metaphyseal dysplasia without hypotrichosis (250460).

Genetic Heterogeneity of Anauxetic Dysplasia

Anauxetic dysplasia-2 (ANXD2; 617396) is caused by mutation in the POP1 gene (602486) on chromosome 8q22. ANXD3 (618853) is caused by mutation in the NEPRO gene (617089) on chromosome 3q13.

Menger et al. (1996) described 3 sibs born to first-cousin Jordanian parents. These children had extreme disproportionate short stature with final adult height in 1 individual being 85 cm. The children had a distinct facial appearance with hypotelorism, prognathism, and hypodontia. Three children had a short trunk with lumbar hyperlordosis, and the oldest affected individual had kyphoscoliosis. There was rhizomelic shortening of the limbs with brachydactyly of the hands and feet. The large joints were prominent and the oldest affected individual had limited extension at the elbows. Rocker-bottom feet with prominent heels were present. Pubertal development was normal. All were said to be slightly mentally retarded. Radiographs showed midface hypoplasia with a steep skull base and enlarged J-shaped sella. The vertebrae were oval-shaped in the youngest sib and foreshortened in the oldest. The lateral aspects of the iliac bodies were hypoplastic with slanting acetabular roofs; the pubic bones were gracile. The femoral heads were very small with no femoral necks present. All the tubular bones were severely short with irregular metaphyses and small, deformed epiphyses. Carpal bone age was delayed. The phalanges were short and broad and the terminal phalanges hypoplastic. Iliac crest biopsy in one of the affected children showed a severely distorted growth plate with only a few chondrocytes present. There was almost absent columnization of the hypertrophic zone and marked irregularity of the osteochondral junction. Electron microscopy showed dilation of the rough endoplasmic reticulum in the remaining hypertrophic chondrocytes with granular material present. The collagen fibrils in the surrounding matrix seemed small. One of the affected children had Fanconi anemia (see 227650); the authors believed that this was an unrelated finding.

Horn et al. (2001) reported 2 brothers, born to nonconsanguineous German parents, who they believed had the same condition as that described by Menger et al. (1996). These children also had extreme disproportionate short stature with shortening of the long bones and the bones of the hands and feet, with flexion contractures of the elbows. Both boys had marked lumbar hyperlordosis, and one of them had thoracic kyphosis. Radiographic examination showed irregular and widened metaphyses with very small epiphyses and severely delayed carpal bone ossification. There was platyspondyly of the thoracic spine. The tubular bones of the hands were short and broad. Skull x-ray showed a J-shaped sella. Light microscopy of the specimens from the iliac crest, vertebral bodies, and femoral and tibial growth plates showed marked hypocellularity of the resting cartilage with rounded chondrocytes, and a reduced number of proliferating chondrocytes with diminished columnization of the hypertrophic zone. Both children had delayed development. At the age of 4 years, 1 child had developed respiratory insufficiency and quadriplegia that was attributed to cervical cord compression. After 4 months of ventilation, the child died. The second child was reported to be well at 11 years of age but at that age was found to have aortic stenosis. He was also found to have atlantoaxial subluxation and underwent cervical fusion.

By genomewide homozygosity mapping in a large consanguineous family segregating anauxetic dysplasia, Thiel et al. (2005) identified linkage to a 18.7-cM region on chromosome 9p21-p13 (maximum multipoint lod of 3.0). Fine-mapping with additional members of this and another affected family refined the linkage to a 17.1-cM region between markers D9S1114 and D9S1874, resulting in an 11.15-Mb candidate region (maximum lod of 3.1).

The transmission pattern of ANXD1 in the families reported by Thiel et al. (2005) was consistent with autosomal recessive inheritance.

In affected individuals from 3 unrelated families with anauxetic dysplasia, including the Jordanian family originally reported by Menger et al. (1996) and the German family reported by Horn et al. (2001), Thiel et al. (2005) sequenced the candidate gene RMRP and identified homozygous or compound heterozygous mutations (157660.0018-157660.0021) that segregated with the disorder. Mutations in this gene also cause 2 milder types of short stature with susceptibility to cancer, cartilage-hair hypoplasia (CHH; 250250) and metaphyseal dysplasia without hypotrichosis (250460). Thiel et al. (2005) showed that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the CHH founder mutation (157660.0001) affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin (123836) mRNA levels but severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA by allowing normal mRNA processing, and, therefore, genetically separate the different functions of RNase MRP.

Horn et al. (2001) concluded that this condition is distinct from other forms of spondylometaepiphyseal dysplasia and the same as the condition described by Menger et al. (1996). Horn et al. (2001) proposed the name 'anauxetic dysplasia' (from the Greek term for 'not growing' or 'not permitting growth') on the basis of extreme dwarfism resulting from a severe pre- and postnatal disturbance of skeletal growth and differentiation.