Skeletal dysplasias are distinguished by what part of the skeleton and/or bone is involved in various types of short stature.  Metaphyseal dysplasia (MCD) refers to a group of skeletal disorders in which the diagnostic findings primarily involve the metaphyses of the tubular bones.  Other bones are usually normal or only slightly affected. The metaphyseal involvement may be mild (as in Schmid’s MCD) or more severe (as in Jansen’s MCD).  Some MCD syndromes have associated extra-skeletal features (e.g. MCD – McKusick type which is also known as Cartilage Hair Hypoplasia). There appears to be a new type of chondrodysplasia with a distinctive pattern of involvement, as described by Lee et al.  An eight-year-old boy with a distinctive form of metaphyseal chondrodysplasia and a previously described family with 4 generations affected are the focus of Lee’s report. The child had short stature and the birth weight was 3 kg.  Bilateral genu varus and wrist swelling were first noted at 4 years of age. The mother had mild wrist flaring.  She was not disproportionate by U/L ratio.  At 8 7/12 years the boy’s height was -2.9 SD below the mean and his U/L ratio was 1.21 (normal 1.0).  No significant differences were noted in the length of the upper versus the lower part of each extremity, the spine, the facial configuration or the hair.  Skeletal survey revealed metaphyseal abnormalities affecting proximally and distally the tibias, fibulas, femurs, humeri, radii and ulnar bones and the hands, but the spine was unaffected.  The physical and radiological findings did not fit the Schmid, McKusick, or Jansen types of MCD.  A very rare autosomal dominant 4 generation affected condition described by Rosenberg and Lohr (Eur J Pediatr 1986;145:40-45) has features similar to those of this patient, except the patients in this family reportedly had a wedge deformity and platyspondyly of the spine which Lee et al believed to be within the range of normal variance.  No molecular studies were reported in the four patients reported by Rosenberg et al or in this 8-year-old boy.

 

Lee YS, et al.  A distinctive type of metaphyseal chondrodysplasia with characteristic thickening of the distal ulna and radius: Possible MCD–Rosenberg.  Am J Med Genet 2003;119A:50-56.

 

Another example of describing a chondrodystrophy by the sites where skeletal abnormalities occur is rhizomelic chondrodysplasia punctata (RCP).  This rare autosomal recessive disorder has severe shortening of the proximal long bones (rhizomelia), bilateral cataracts and severe growth and psychosocial delay.  White et al report the natural history of rhizomelic chondrodysplasia punctata.  Radiographic evidence of stippled epiphyses is present and MRI examination of the cervical spine is often abnormal (kinking without compression of the cord and/or compression of the cord).  All children with RCP are born with severe joint contractures that improve with time although not before many of the patients (40-85%) die by one year of age.  Less than 10% of the 48 cases described in respect to death were alive by 12 years of age.

Biochemical analysis and complementation studies allowed separation of the 97 patients whose data were tabulated to be differentiated on the basis of peroxisomal enzymes into three types:  (Type 1) a spectrum of PEX7 gene mutations, (Type 2) mutations in the acyl-CoA:diOHacetonePO4 acyltransferase (DHAPAT) gene, and (Type 3) mutations in the ADAPS (alkyl-diOHacetonePO4 synthesis) gene. 

The value of this article by White et al is that there has been a sincere attempt to delineate the natural history of RCP.  The authors systematically address health concerns that arise in infants and children with RCP.  The intent of White et al is to present evidence-based guidance to care providers so they can better help families understand and cope with this diagnosis.  For example, 90% of infants survive for the first year and 50% survive until 6 years.  Previously, death was believed to almost always occur early in infancy or childhood.  Medical personnel or parents concerned and/or involved with patients with suspect or proven diagnosis of RCP are strongly encouraged to read the complete article.

 

White A, et al.  Natural history of rhizomelic chondrodysplasia punctata.  Am J Med Genet 2003;118A:332-342.

 

Other examples of chondrodystrophies are those in the subgroup known as spondylo-epi-metaphyseal dysplasia (SEMDs) which includes a number of disorders each defined by the combination of vertebral, epiphyseal, and metaphyseal anomalies present.

One such entity is the Dyggve-Melchior-Clausen Syndrome (DMCS) which is characterized by short trunk dwarfism (<-4SD) with specific radiological appearances most likely reflecting abnormalities of the growth plates including platyspondyly (flattened peripheral bodies) with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests.  Mental retardation is an inherent part of the syndrome.  DMCS is progressive and clinical features are reminiscent of a storage disorder, specifically Morquio’s disease, but the two conditions can be differentiated by the absence of corneal clouding, deafness, valvular disease and/or mucopolysacchariduria, all of which are characteristic of Morquio’s disease.

Ghouzzi et al have used a positional cloning strategy to identify the DMC gene.  They detected 7 deleterious mutations within a gene predicted from a human transcript (FLJ20071) in 10 DMC families.  The DMC gene transcript is widely distributed but appears abundant in chondrocytes and fetal brain.  The authors cannot explain the function of the gene product at this time, but conclude that the DMC syndrome results from loss of function of a gene that they propose to name Dymeclin, which may have a role in the process of intracellular digestion of protein.

 

Ghouzzi VE, et al.  Mutations in a novel gene dymeclin (FLJ20071) are responsible for Dyggve-Melchoir-Clausen syndrome.  Hum Mol Genet 2003;12:357-364.

 

A fourth example of types of chondrodysplasia and how they are designated is the entity called acrocapitofemoral dysplasia which is characterized by short stature of variable degrees with short limbs and brachydactyly. It is included in the differential diagnosis of hypochondroplasia.  These patients also have large heads and often have pectus deformities.  Epiphyseal changes are present at the shoulders, knees, ankles, hands, hips and proximal femurs.  The latter are egg shaped with very short femoral necks.  Shortened tubular bones characterize the brachydactyly.  Congenital anomalies are limited to the skeletal system and intelligence is characteristically unaffected.

Homozygosity mapping by descent was performed in two consanguineous families. The Indian hedgehog gene (IGG) was found to be mutated in affected individuals. The nucleotide changes are seen in the amino terminal signaling domain, which is responsible for short and long range signaling. Thus, it appears to affect the regulation and proliferation of the hypertrophic chondrocytes in the growth plate. The authors postulate that the mutations cause an increased rate of chondrocyte differentiation by diminished Indian Hedgehog signaling in the growth plate.

 

Hellemans J, et al.  Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomoal recessive disorder with cone-shaed epiphyses in hands and hips.  Am J Med Genet 2003;72:1040-1046.

 

First Editor’s Comment: The genome project has made identification of mutated genes relatively easy to identify. The effects of different mutations of the same gene has been particularly evident among the chondrodystrophies, both in relating two different entities to different mutations of the same gene and differentiating and identifying different gene abnormalities for what used to be thought the same disease entity.  Unfortunately descriptive names are often misleading because there is tremendous overlap among these entities. The most recently updated classification of skeletal dysplasias can be found at www.csmc.edu/genetics/skeldys.

 

Judith Hall, OC, MD

 

Second Editor’s Comments: One is struck by the clinical resemblance of acrocapitofemoral dysplasia (ACFD) to achondroplasia.  The phenotype is not identical, but the rhizomelic shortening of limbs, large head with prominent forehead, narrow thorax, bowing of the knees and even overgrowth of the proximal fibula on X-ray are similar.  The reason for this resemblance may lie in the relationship of Ihh to FGFR3, which is mutated in achondroplasia, in the growth plate.  Both regulate chondrocyte proliferation: Ihh positively and FGFR3 negatively.  In ACFD the positive effect on proliferation is lost; however in achondroplasia the mutations are activating in nature so that they enhance the anti-mitotic effects of FGFR3. In other, both lead to reduced chondrocyte proliferation.  A consequence of the anti-mitotic effects of FGFR3 mutations in achondroplasia is a reduction in the number of terminally differentiating chondrocytes.  Since these cells are the source of Ihh, the achondroplasia mutations secondarily reduce the production and local effects of Ihh.  Thus, these two disorders look alike to clinicians because they involve disturbances of the same regulatory pathways in the growth plate. 

 

William Horton, MD