Chapter 210

## Abstract

Abstract

1. Achondroplasia and pseudoachondroplasia are clinically and genetically distinct phenotypes that are among the most common human disorders resulting in short stature. Both are inherited as autosomal dominant conditions. Achondroplasia, the single most common form of human dwarfism, results in most cases from one of two very specific mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Pseudoachondroplasia is caused by a variety of mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Both disorders are characterized by short-limb dwarfism, in which the affected person's arms and legs are relatively short compared to the height of the trunk. Disorders with clinical, radiographic, and molecular features in common with achondroplasia include hypochondroplasia, thanatophoric dysplasia (TD), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Similarly, pseudoachondroplasia and multiple epiphyseal dysplasia (MED) are related.

2. The clinical manifestations of achondroplasia include rhizomelic short stature, frontal bossing with midface hypoplasia, short ribs, trident hand, limited elbow extension, and hyperextensible hips and knees. Infants may have a thoracolumbar kyphosis or gibbus. Spinal stenosis is a common complication in adulthood. Less frequent complications in childhood include cervicomedullary compression secondary to a small foramen magnum, hydrocephalus, and obstructive apnea secondary to small airways. Age-specific mortality is increased in the first 4 years of life and in the fourth to fifth decades.

3. Homozygous achondroplasia is a neonatal lethal condition in which the skeletal manifestations of achondroplasia are exaggerated. Death is usually secondary to respiratory compromise or from cervical cord compression by a very small foramen magnum. In families where both parents have achondroplasia, the children are at 25 percent risk of inheriting the achondroplasia mutation from both parents, resulting in homozygous achondroplasia.

4. The phenotype of hypochondroplasia is similar to that of achondroplasia but milder in degree. The height curves overlap with those of the average population and spinal stenosis is infrequently observed. Learning disabilities may be more common among children with hypochondroplasia than among children with achondroplasia.

5. Thanatophoric dysplasia (TD), a neonatal lethal disorder, is the most severe of the FGFR3 phenotypes. Two types, designated TDI and TDII, are distinguishable on clinical and molecular grounds. The SADDAN phenotype is a recently recognized condition in the achondroplasia family of disorders.

6. Achondroplasia, hypochondroplasia, TDI, TDII, and the SADDAN phenotype are all caused by mutations in the FGFR3 gene. All are dominant phenotypes and most cases occur as a result of new mutation. Most, if not all, new mutations causing achondroplasia occur on the paternal allele.

7. The FGFRs are a family of four tyrosine kinase receptors. They have three immunoglobulin-like regions in the extracellular domain, a transmembrane domain, and a split intracellular tyrosine kinase domain. The different receptors bind fibroblast growth factors (FGFs) with variable affinity. Alternative splicing is a feature of FGFR RNA processing. The receptor monomers dimerize, in a step requiring heparin, before ligand may be bound. The dimerization process is promiscuous; any FGFR monomer may dimerize with any other.

8. FGFR3 has two splice forms depending on which of two alternative exons are used for the C-terminal half of the third immunoglobulin-like domain. FGFR3 with exon IIIb has a high ligand-specificity for acidic FGF/FGF-1 and is expressed in mouse embryo skin and epidermal keratinocytes. The splice form containing exon IIIc is expressed in developing mouse brain and in the spinal cord, as well as in cartilage rudiments of developing bone.

9. The FGFR3 cDNA is 4.4 kb and contains an open reading frame of 2520 nucleotides, encoding an 840-amino-acid protein. The human gene is located at 4p16.3, spans 16.5 kb and has 19 exons. The two most common mutations causing achondroplasia are FGFR3 1138G>A and 1138 G>C, both resulting in a G380R substitution in the transmembrane domain of the receptor. Together, these two mutations account for more than 98 percent of achondroplasia cases. The tight correlation between specific mutations and their consequent phenotypes is a unique feature of the FGFR genes.

10. The two most common FGFR3 mutations causing hypochondroplasia both result in N540K substitutions in the tyrosine kinase domain of the receptor. Genetic heterogeneity is an issue in hypochondroplasia, because in some families the phenotype is not linked to FGFR3. There is allelic heterogeneity among cases of TDI, but to date, all reported cases of TDII are caused by the K650E missense mutations in the tyrosine kinase domain of FGFR3. The SADDAN phenotype is caused by K650M substitutions.

11. The FGFR3 mutations causing achondroplasia, hypochondroplasia, thanatophoric dysplasia, and SADDAN all result in constitutive activation of the receptor. The varying degrees of severity between these phenotypes are due in part to varying degrees of ligand-independent activation of the FGF receptor by their mutations. By contrast, homozygous knockout mice entirely lacking FGFR3 have long bone overgrowth. These observations suggest that the normal function of FGFR3 is necessary for negative regulation of bone growth.

12. Recent molecular studies demonstrate that pseudoachondroplasia and MED are allelic disorders that result from mutations in the COMP gene. MED demonstrates locus heterogeneity as the phenotype results, in a few cases, from mutations in the genes encoding the alpha 2 and alpha 3 chains of type IX collagen (COL9A2 and COL9A3).

13. Clinical features associated with pseudoachondroplasia include normal appearance at birth with deceleration of linear growth between the first and second years of life. The diagnosis is usually made at this time. Shortening of the extremities becomes more obvious over time. The fingers are short and there is excessive laxity of most of the joints. Multiple other skeletal features include genu valgum, genu vara, or “windswept deformities” of the legs, limitations of elbow extension, ulnar deviation of the hand, scoliosis, and odontoid hypoplasia. Osteoarthritis and painful joints are common. Developmental milestones and intelligence are normal. Radiographic features include epiphyseal and metaphyseal changes, vertebral flattening with irregular vertebral endplates, and anterior beaking of the vertebrae.

14. MED is more commonly diagnosed in mid-childhood, presenting with a waddling gate and hip pain. If short stature is present, it is usually mild. Body proportions are normal although the fingers may be short and joint laxity is often excessive. Osteoarthritis is a major complication. The radiographic features are similar to those seen in pseudoachondroplasia, but much milder in degree, with considerably less metaphyseal and vertebral involvement.

15. Both pseudoachondroplasia and MED are autosomal dominant disorders with most cases arising as a result of new mutations. In families previously thought to have a recessive form of pseudoachondroplasia, germ line mosaicism appears to explain the observation of multiple affected children in families with unaffected parents.

16. The COMP gene, located at 19p13.1, is composed of 19 exons and encodes a 2.4-kb mature transcript. The protein is a 540-kDa extracellular matrix glycoprotein. It is a member of the extracellular calcium-binding thrombospondin family. The mature molecule is composed of five identical subunits, each of which contains a pentamer formation domain, four EGF-like domains, seven calcium-binding domains, and a globular domain. It is found in the territorial matrix surrounding chondrocytes.

17. To date, more than 70 COMP mutations are known, less than 10 of which were identified in patients with MED; the remainder were identified in patients with pseudoachondroplasia. Most of the mutations occur in the calcium-binding domains. No relationship between genotype and phenotype is established; similar mutations are found in patients with pseudoachondroplasia and MED.

18. The molecular pathogenesis of pseudoachondroplasia and MED is by a dominant negative effect. Electron microscopy of growth plate cartilage in these conditions demonstrates large lamellar inclusions in the rough endoplasmic reticulum (rER), now known to contain COMP, aggrecan, and type IX collagen. The massive accumulation of these extracellular matrix proteins in the rER causes chondrocyte death in culture, suggesting that the decrease in linear growth is related to the loss of growth plate chondrocytes. Pseudoachondroplasia chondrocytes in vitro make less matrix, with diminished amounts of COMP. The osteoarthritis associated with pseudoachondroplasia and MED may result from a structurally abnormal matrix that is susceptible to early erosion.

19. Although most cases of MED result from COMP mutations, five cases were caused by mutations of COL9A2, located at 1p33-p32.2, or COL9A3, located at 20q13.3. For both genes, the identified mutations alter the acceptor splice site in intron 2 and lead to skipping of exon 3.

20. Genetic heterogeneity in MED and the known occurrence of germ line and somatic mosaicism in pseudoachondroplasia complicate genetic counseling for these conditions.

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