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Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with nonsyndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with nonsyndromic OFCs. Screening for IRF6 mutations in apparently nonsyndromic cases has been performed in several modestly sized cohorts with mixed results. In the current study we screened 1521 trios with presumed nonsyndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and nonsyndromic OFCs. We combined our results with other similar studies (totaling 2,472 families) and conclude that causal IRF6 mutations are found in 0.24%-0.44% of apparently nonsyndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.

Cartilage oligomeric matrix protein, also known as thrombospondin-5 (TSP-5), is an extracellular matrix protein found primarily in cartilage and musculoskeletal tissues. TSP-5 is of interest because mutations in the gene cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED/EDM1). Both PSACH and EDM1 have a characteristic chondrocyte phenotype distinguished by giant rough endoplasmic reticulum (rER) cisternae containing TSP-5 and other extracellular matrix proteins such as type IX collagen and matrilin-3. The accumulation of proteinaceous material in the rER compromises cellular function and leads to premature chondrocyte death. Both in vitro and in vivo models have been generated with varying degrees of success to study the cellular mechanisms of the disease process. Here we review and discuss in vitro and in vivo PSACH and MED model systems and describe two transgenic mouse lines expressing human mutant TSP-5 protein. These model systems have revealed several important features of the PSACH cellular pathology: unfolded protein response activation, upregulation of apoptosis and inappropriate assembly of matrix network in the rER. Some of these models are valuable reagents that may be of use in testing therapeutic interventions. (Part of a Multiauthor Review).

Pseudoachondroplasia (PSACH) is a skeletal dysplasia caused by a mutation in cartilage oligomeric matrix protein (COMP), a glycoprotein of normal cartilage matrix. PSACH chondrocytes have a distinctive phenotype with enlarged rER cisternae containing COMP, aggrecan, type IX collagen, and chaperone proteins. Ultrastructural studies suggested that this accumulation compromises cell function, hastening cell death, and consequently reducing the number of cells in the growth plate contributing to linear bone growth. Using the alginate bead system, we cultured control and PSACH chondrocytes for twenty weeks and one year to determine the effect of the mutation on size and number of cartilage nodules; and the presence of apoptotic cell death (TUNEL assay). At 20 weeks, beads containing PSACH or control chondrocytes did not differ in size and number of cartilage nodules or number of TUNEL-positive cells. After one year, nodule number, size and percent cartilage per bead were significantly less in PSACH nodules, and the number of cells staining positive for apoptosis was significantly greater than in controls (71.8% vs. 44.6%). The increase in apoptosis in PSACH nodules correlates with a decrease in growth of cartilage, supporting our hypothesis that death of damaged cells contributes to the growth plate defects in PSACH.

Multiple exostosis, biparietal foramina, minor craniofacial abnormalities, and mental retardation are characteristic of the syndrome associated with a proximal deletion of 11p (MIM # 601224), which has been shown to be a true contiguous gene deletion syndrome. The presence of multiple exostosis is associated with deletion of the EXT2 gene. Similarly, the presence of biparietal foramina has been shown to be associated with the deletion of ALX4 located proximally to EXT2. Specific genes related to mental retardation and craniofacial abnormalities, however, have yet to be identified. We report on a family with a microdeletion of 11(pll.2p11.2) with multiple exostosis and biparietal foramina without mental retardation or craniofacial abnormalities. Our results suggest that genes related to mental retardation and craniofacial development must be located outside of the D11S1785-D11S1385 region.

Pseudoachondroplasia (PSACH) (OMIM#177170) and multiple epiphyseal dysplasia (MED) are separate but overlapping osteochondrodysplasias. PSACH is a dominantly inherited disorder characterized by short-limb short stature, loose joints, and early-onset osteoarthropathy. The diagnosis is based on characteristic clinical and radiographic findings. Only mutations in the cartilage oligomeric matrix protein (COMP) gene have been reported in PSACH, and all family studies have been consistent with linkage to the COMP locus on chromosome 19. Multiple epiphyseal dysplasia (MED) is a relatively mild chondrodysplasia but like PSACH, MED causes early-onset joint degeneration, particularly of the large weight-bearing joints. Given the clinical similarity between PSACH and MED, it was not surprising that the first MED locus identified was the COMP gene (EDM1). Mutations causing MED have now been identified in five other genes (COL9A1, COL9A2, COL9A3, DTDST, and MATN3), making MED one of the most genetically heterogeneous disorders. This article reviews the clinical features of PSACH and MED, the known mutations, and the pathogenetic effect of COMP mutations on the cartilage extracellular matrix.

The EXT family of putative tumor suppressor genes affect endochondral bone growth, and mutations in EXT1 and EXT2 genes cause the autosomal dominant disorder Hereditary Multiple Exostoses (HME). Loss of heterozygosity (LOH) of these genes plays a role in the development of exostoses and chondrosarcomas. In this study, we characterized EXT genes in 11 exostosis chondrocyte strains using LOH and mutational analyses. We also determined subcellular localization and quantitation of EXT1 and EXT2 proteins by immunocytochemistry using antibodies raised against unique peptide epitopes. In an isolated non-HME exostosis, we detected three genetic hits: deletion of one EXT1 gene, a net 21-bp deletion within the other EXT1 gene and a deletion in intron 1 causing loss of gene product. Diminished levels of EXT1 and EXT2 protein were found in 9 (82%) and 5 (45%) exostosis chondrocyte strains, respectively, and 4 (36%) were deficient in levels of both proteins. Although we found mutations in exostosis chondrocytes, mutational analysis alone did not predict all the observed decreases in EXT gene products in exostosis chondrocytes, suggesting additional genetic mutations. Moreover, exostosis chondrocytes exhibit an unusual cellular phenotype characterized by abnormal actin bundles in the cytoplasm. These results suggest that multiple mutational steps are involved in exostosis development and that EXT genes play a role in cell signaling related to chondrocyte cytoskeleton regulation.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most common human malformations with an average prevalence of 1 in 1,000 live births. The cause(s) of NSCLP remain unclear as the relative roles of genes, of the environment, and/or of chance alone are unknown. The purpose of this study was to evaluate the potential role of environmental factors in the cause of NSCLP, to determine if other birth defects aggregate in families with at least one individual affected with NSCLP, and to investigate the frequency of cancer in the first- and second-degree relatives of NSCLP index-cases. Included in this study were 196 index-cases and their families. Information pertaining to environmental factors and pedigree information was obtained on each family. Analysis showed that no single environmental factor could explain the occurrence of NSCLP in this population. The frequency of other birth defects in these families was 1.2%, which is not increased over that in the general population. One hundred seven cancers were reported in 72 of the 196 families included in the study. The frequency of cancer was not significantly increased in the first- or second-degree relatives of the NSCLP index cases or in those families with a positive family history of NSCLP. No childhood or adult cancers were reported in any of the 196 NSCLP index cases.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1) are allelic disorders caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). PSACH is a dominant condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthritis. EDM1 is a less severe skeletal dysplasia associated with average to mild short stature, joint pain, and early-onset osteoarthritis. COMP is an extracellular matrix protein present in cartilage, ligament, and tendon tissues. Here, we report on nine novel mutations in COMP causing PSACH and EDM1. Four of these mutations are in exons 13C and 14 where no previous mutations had been reported. One of those mutations was identified in two separate EDM1 families. In addition, we have identified the first case of PSACH resulting from an expansion of the five aspartates in exon 17B. We are also reporting a mutation in a third PSACH family with somatic/germline mosaicism. Therefore, this report increases the range of mutations that cause PSACH and EDM1 and provides additional regions to target for mutational analysis.

DSPG3, the human homolog to chick PG-Lb, is a member of the small leucine-rich repeat proteoglycan (SLRP) family, including decorin, biglycan, fibromodulin, and lumican. In contrast to the tissue distribution of the other SLRPs, DSPG3 is predominantly expressed in cartilage. In this study, we have determined that the human DSPG3 gene is composed of seven exons: Exon 2 of DSPG3 includes the start codon, exons 4–7 code for the leucine-rich repeats, exons 3 and 7 contain the potential glycosaminoglycan attachment sites, and exon 7 contains the potential N-glycosylation sites and the stop codon. We have identified two polymorphic variations, an insertion/deletion composed of 19 nucleotides in intron 1 and a tetranucleotide (TATT)n repeat in intron 5. Analysis of 1.6 kb of upstream promoter sequence of DSPG3 reveals three TATA boxes, one of which is 20 nucleotides before the transcription start site. The transcription start site precedes the translation start site by 98 nucleotides. There are 14 potential binding sites for SOX9, a transcription factor present in cartilage, in the promoter, and in the first intron of DSPG3. We have examined the evolution of the SLRP gene family and found that gene products clustered together in the evolutionary tree are encoded by genes with similarities in genomic structure. Hence, it appears that the majority of the introns in the SLRP genes were inserted after the differentiation of the SLRP genes from an ancestral gene that was most likely composed of 2–3 exons.

We previously reported on cognitive and respiratory factors in a series of infants with achondroplasia (ACH). We now present the results of neuropsychological evaluation and magnetic resonance imaging in 16 school-age children with ACH, 7 of whom had been included as infants in our previous report. We examined the neuroanatomic and cognitive status of this sample, as well as the predictive stability of the prior infant assessment. Seventeen normally developing children of average stature and 21 preterm children with arrested (compensated, unshunted) hydrocephalus constituted the comparison groups. Brain volumes of children with ACH were significantly larger than those of the comparison groups. In addition, children with ACH exhibited kinking of the medulla and neuroanatomic abnormalities consistent with arrested hydrocephalus, including enlarged ventricles and hypoplasia of the corpus callosum. Cognitive abilities at school age were average, although mild deficits were seen on visual-spatial tasks, similar to those obtained by the hydrocephalic comparison group. Only gross motor coordination deficits distinguished the ACH group from the hydrocephalic controls. Infant assessment overestimated later school-age IQ scores in those infants with ACH who scored above average. These findings point to generally preserved cognitive skills in selected children with ACH at early school age, although children with ACH should be evaluated individually as they are at risk for cognitive, academic, and motor deficits.

Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthrosis. PSACH is caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). We are reporting on mutations in COMP in 12 patients with PSACH, including ten novel mutations. Eleven of the mutations are in exons 17A, 17B, and 18A, which encode the calcium-binding domains, and one mutation is in exon 19, which encodes part of the carboxy-terminal globular domain. Two of the mutations identified are the common delGAC(1430-1444) in exon 17B, which accounts for 36% of identified PSACH mutations. This report increases the range of mutations in COMP that cause PSACH and provides additional evidence for the importance of the calcium-binding domains and the globular domain to the function of COMP.

"Idiopathic" talipes equinovarus (ITEV) is a nonsyndromal congenital anomaly of one or both feet. Casting and surgery are often necessary to obtain correct foot alignment. In spite of treatment, residual deformities of the feet occur and calf muscles may be hypoplastic. The cause of ITEV is unknown but genetic factors have been postulated. Complex segregation analysis was performed on 173 ITEV families including 93 Caucasian and 48 Hispanic families. The recessive mixed model was the best fitting model and no differences were found based on ethnicity. These results confirm previous studies suggesting that there is a genetic component to the development of ITEV.

Previous genetic studies of idiopathic talipes equinovarus (ITEV) suggest an environmental and genetic component to the etiology of ITEV. The present study was undertaken to assess the role of causal factors in the development of ITEV. A total of 285 propositi were ascertained, with detailed family history information available in 173 cases and medical records on the remaining 112 propositi. Information was collected on specific prenatal, parental, and demographic factors. No racial heterogeneity was noted among any of the factors. The overall ratio of affected males to females was 2.5:1. The incidence of twinning among all propositi was significantly increased (P=0.006) above the expected population frequency. A family history of ITEV was noted in 24.4% of all propositi studied. These findings, in addition to the detailed analysis of 53 pedigrees with ITEV history, suggest the potential role of a gene or genes operating in high-risk families to produce this foot deformity.

Infantile cortical hyperostosis (ICH), Caffey disease, is a multifocal, inflammatory skeletal process with classic onset before the fifth month of life and resolution by the age of 3 years. A severe phenotype with early prenatal onset has also been described. Inheritance is generally accepted a autosomal dominant with variable expression and penetrance. However, occurrence in siblings with no family history has been reported, raising the possibility of heterogeneity and the existence of a severe autosomal recessive form. We describe a third family with prenatally diagnosed ICH in two siblings, providing further evidence for this form of inheritance.

Pseudoachondroplasia (PSACH) is a spondylo-epi-metaphyseal dysplasia characterized by disproportionate short stature, generalized ligamentous laxity, and precocious osteoarthritis. PSACH is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene, which codes for a noncollagenous protein expressed in the territorial matrix of chondrocytes. Autosomal dominant inheritance has been demonstrated in many families; however, autosomal recessive inheritance has been suggested in some severe familial cases. Alternatively, germline/somatic mosaicism has been proposed and is credible, since it has been shown that dominantly inherited and sporadic cases of PSACH are caused by the same genetic defect. Here, we present evidence demonstrating somatic mosaicism in two PSACH families that were originally considered to represent autosomal recessive inheritance. The results of this study suggest that autosomal recessive inheritance is unlikely and all cases of PSACH should be studied for mutations in COMP.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, located on chromosome 8q24.1, has been cloned and is encoded by a 3.4-kb cDNA. Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma. Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth mutation resulted in a substitution of leucine for arginine. Loss of heterozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revealed multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. One sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarcoma underwent LOH for EXT1 and chromosome 3q. These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma.

Pseudoachondroplasia (PSACH) is a well-characterized autosomal dominant dwarfing condition. A great deal of information is available about orthopedic complications, but little is known about extraskeletal complications in adulthood. This study was undertaken to delineate the natural history of PSACH at all ages. Seventy-nine individuals responded to an extensive questionnaire that included information about deformities, operations, general health, chronic diseases, and reproduction. PSACH individuals were ascertained through the University of Texas Medical Genetics patient population, a genetic linkage study, and the social organization, Little People of America. The results show that PSACH individuals with a family history do not have a distinct or more severe phenotype than new mutation cases. There were not differences in the number of orthopedic complications, operations, or number of offspring between these two groups. Less than half of affected adults reported having total hip replacement surgery, which was less common than previously reported. Extraskeletal complications were generally uncommon. There were four cases of cancers in 41 individuals queried. Premature osteoarthritis was the major health problem for PSACH individuals. PSACH individuals are generally healthy but have problems associated with debilitating osteoarthritis.

Standard curves developed for the general population cannot be used to assess the growth of an individual who has a condition that results in disproportionate short stature. For this reason, efforts have been made to develop growth curves specific for several of the chondrodysplasias. However, data concerning weight for height have been largely lacking, although they may be of particular importance for conditions such as achondroplasia, where there is some consensus that an increased prevalence of obesity is a particular problem. In this paper we provide standard weight for height curves for males and females with achondroplasia, and discuss the use of several indices which have been applied to the assessment of body fat in the general population.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage capped prominences that develop from the epiphyses of the long bones. EXT is heterogeneous with three different locations currently identified on chromosomes 8, 11, and 19. Recently, we identified and studied 12 large multigenerational EXT families. Linkage analyses demonstrates that 6 of these families map to 8q24 and 6 to 11p. None of the families map to the chromosome 19 locus. The results suggest that there are two major loci, on chromosomes 8 and 11, involved in the cause of EXT. The locus on chromosome 19 remains to be confirmed.

Multiple epiphyseal dysplasia (MED) comprises a group of hereditary chondrodysplasias in which there are major anatomic abnormalities of the long tubular bones. The Fairbank and Ribbing types are the most frequently cited types of MED. They are primarily defined radiographically and are autosomal dominant conditions. Recently, MED in one family was shown to map to the pericentromeric region of chromosome 19 and is probably allelic to pseudoachondroplasia. We have tested linkage with six short tandem repeat markers from chromosome 19 to autosomal dominant MED in one four-generation family and to MED in a unique family with three of seven siblings affected and with unaffected parents. Autosomal dominant MED in family 1 was linked with a maximum LOD score, at D19S212, of 3.22 at a recombination fraction (theta) of .00. Linkage to chromosome 19 was excluded with MED in the other family, under both autosomal recessive and autosomal dominant, with either reduced-penetrance or germ line-mosaicism models. Linkage to candidate genes COL9A1, COL9A2, and COL11A2 was tested and excluded for both genetic models in this family. COL11A1 was excluded under a recessive model. We have confirmed linkage of autosomal dominant Fairbank MED to chromosome 19 and have demonstrated that MED is genetically heterogeneous.

Nonsyndromic cleft lip with or without cleft palate (CLP) is a common craniofacial anomaly, the etiology of which is not known. Population studies have shown that a large proportion of cases occur sporadically. Recently, segregation analyses applied to CLP families have demonstrated that an autosomal dominant/codominant gene(s) may cause clefting in cases. Associations of autosomal dominant CLP and nonsyndromic cleft palate (CP) with HLA and F13A genes on chromosome 6p have been suggested previously. Linkage to these two areas on chromosome 6p were tested in 12 autosomal dominant families with CLP. With a LOD score of -2 or less for exclusion, no evidence of linkage was found to four chromosome 6p markers. Multipoint analysis showed no evidence of a clefting locus in this region spanning 54 cM on chromosome 6p in these CLP families.

Achondroplasia and pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG), a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probes encoding CSPGCP were used to identify restriction fragment length polymorphisms (RFLPs) in DNA from a panel of control individuals. No gross alterations at the CSPGCP locus were noted in DNA from 37 individuals with achondroplasia and 5 individuals with pseudoachondroplasia. In addition, allelic frequencies of the RFLPs were not significantly different among controls and patients with either condition. In one three-generation family with achondroplasia, close linkage of the CSPGCP locus and the skeletal dysplasia was excluded using a Bgl II polymorphism. Similarly, in a three-generation family with pseudoachondroplasia, the CSPGCP gene was not tightly linked to the disease phenotype. These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or pseudoachondroplasia in these families.

Two families with non-syndromic cleft lip and cleft palate are described. The linear pattern of inheritance through several generations is difficult to explain by conventional multifactorial models. The pedigrees strengthen the suggestion that a dominantly inherited mutation exists with a major influence on clefting of the lip and palate alone.

There is a substantial genetic component in the orthopedic population studied. Twenty-five percent of the new patients and 46% of the specialty clinic populations had a genetic disorder. The single-gene component was 7.2% and 13% in these two patient populations studied. In comparison to the previously studied pediatric populations, the single-gene component was almost double that found in the inpatient pediatric population, and seven times greater than that in the outpatient pediatric population. Our results suggest that genetic counseling should play an important part in orthopedic care and management, especially at the orthopedic and tertiary referral centers.