Identification of nine novel mutations in cartilage oligomeric matrix protein in patients with pseudoachondroplasia and multiple epiphyseal dysplasia

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. Am. J. Med. Genet. 85:486–490, 1999. © 1999 Wiley-Liss, Inc.     

Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED.     

Lung hypoplasia and severe pulmonary hypertension in an infant with double heterozygosity for spondyloepiphyseal dysplasia congenita and achondroplasia

A rare instance of double heterozygosity for spondyloepiphyseal dysplasia congenita and achondroplasia is presented. Despite midface hypoplasia, thorax deformity and lung hypoplasia, the child survived the neonatal period. Severe pulmonary hypertension, already present at birth, led to right heart failure and death at the age of 1 year.     

A large family with multiple epiphyseal dysplasia linked to COL9A2 gene

We describe a large family, including 54 affected individuals, with multiple epiphyseal dysplasia (MED) with involvement of the peripheral joints only. In this family, a mutation in the COL9A2 gene was detected. Every affected person has involvement of the knee joints. Other involved joints are the elbow, ankle, wrist, hand, and feet joints. Involvement of the shoulder or hip joints is never seen after adolescence. The height of the affected individuals is short to normal; spinal involvement is never seen. The penetrance of the gene is complete. However, the expression of the gene is highly variable. Am. J. Med. Genet. 77:234–240, 1998. © 1998 Wiley-Liss, Inc.     

Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia

Mutations in the cartilage oligomeric matrix protein (COMP) gene are responsible for two dominantly inherited skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Mutation analysis of the COMP gene in Korean patients with PSACH and MED was performed. All nine patients with PSACH had mutations in the COMP gene, while three of the five patients with MED had detectable COMP mutations. Eight mutations, including three novel mutations, were identified in the COMP gene in the patients with PSACH and MED. Six mutations were found within the calmodulin-like repeats (CLRs) domain, especially in the seventh CLR and the other two mutations were in exon 16 outside of CLRs, which encode the C-terminal globular domain. Among the three novel mutations, two were missense mutations (Asp473Tyr, Asp482His) and one was a consecutive two-codon deletion, delAspAsp(469–473) in the five consecutive aspartic acid residues. All three novel mutations produced the PSACH phenotype. Electronic Publication     

Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation

We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.     

Dominant inheritance of multiple epiphyseal dysplasia, myopia and deafness

An Afrikaner kindred in South Africa had a dominantly inherited skeletal dysplasiablindness-deafness syndrome. The affected individuals had reduced stature and a round, flattened facies. The bone changes resembled multiple epiphyseal dysplasia with additional minor abnormalities in the phalanges, femoral heads and spine. Progressive myopia, retinal thinning and crenated cataracts led to visual disturbance, while conductive deafness represented the third component of the triad. The syndromic significance of associated asteroid hyalosis is uncertain.     

Perceptions of the outcome of orthopedic surgery in patients with chondrodysplasias

As part of a larger survey of patients with chondrodysplasias, 197 patients or their parents were asked whether they had undergone orthopedic surgery related to their chondrodysplasia and, if so, to rate their impression of the outcome. Seventy-four patients (37.6%) had undergone a total of 152 procedures (221 if concurrent bilateral operations are counted separately). The percentage of patients treated surgically ranged from a low of 8.3% for hypochondroplasia to a high of 87.5% for diastrophic dysplasia. Of the patients who had surgery, the mean number of procedures per patient ranged from 1.0 for hypochondroplasia to 2.69 for pseudoachondroplasia. Of 180 individual procedures related to the limbs, the outcome in 88.8% was judged 'a bit better' or higher and in 68.8% 'much better' or higher. The responses ranged from a low of 70.4 and 66.7%, respectively for proximal femoral osteotomies to a high of 100 and 85.9% for hip replacement. The comparable figures for spine related surgery were 81.8 and 48.5% with a low of 58.3 and 50.0% for foramen magnum-cervical surgery and a high of 93.8 and 43.8% for thoracolumbar procedures. The expressed perception of lack of satisfaction varied not only by procedure but by diagnosis. Overall, patients perceived a high level of post-surgical improvement, although a number experienced subsequent deterioration and the need for further intervention.     

Revisit of multiple epiphyseal dysplasia: ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes

Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous group of diseases characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. The purpose of this study was to investigate the frequency of mutations in individuals with a clinical and radiographic diagnosis of MED and to test the hypothesis that characteristic radiological findings may be helpful in predicting the gene responsible. The radiographs of 74 Korean patients were evaluated by a panel of skeletal dysplasia experts. Six genes known to be associated with MED (COMP, MATN3, COL9A1, COL9A2, COL9A3, and DTDST) were screened by sequencing. Mutations were found in 55 of the 63 patients (87%). MATN3 mutations were found in 30 patients (55%), followed by COMP mutations in 23 (41%), and COL9A2 and DTDST mutations in one patient (2%) each. Comparisons of radiographic findings in patients with COMP and MATN3 mutations showed that albeit marked abnormalities in hip and knee joints were observed in both groups, the degree of involvement and the morphology of dysplastic epiphyses differed markedly. The contour of the pelvic acetabulum, the presence of metaphyseal vertical striations, and/or the brachydactyly of the hand were also found to be highly correlated with the genotypes. The study confirms that MATN3 and COMP are the genes most frequently responsible for MED and that subtle radiographic signs may give precious indications on which gene(s) should be prioritized for mutational screening in a given individual.     

A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia

Diastrophic dysplasia sulfate transporter (DTDST) is required for synthesis of sulfated proteoglycans in cartilage, and its loss-of-function mutations result in recessively inherited chondrodysplasias. The 40 or so DTDST mutations reported to date cause a group of disorders termed the diastrophic dysplasia (DTD) group. The group ranges from the mildest recessive form of multiple epiphyseal dysplasia (r-MED) through the most common DTD to perinatally lethal atelosteogenesis type II and achondrogenesis 1B. Furthermore, the relationship between DTDST mutations, their sulfate transport function, and disease phenotypes has been described. Here we report a girl with DTDST mutations: a compound heterozygote of a novel p.T266I mutation and a recurrent p.DeltaV340 mutation commonly found in severe phenotypes of the DTD group. In infancy, the girl presented with skeletal manifestations reminiscent of Desbuquois dysplasia, another recessively inherited chondrodysplasia, the mutations of which have never been identified. Her phenotype evolved with age into an intermediate phenotype between r-MED and DTD. Considering her clinical phenotypes and known phenotypes of p.DeltaV340, p.T266I was predicted to be responsible for mild phenotypes of the DTD group. Our results further extend the phenotypic spectrum of DTDST mutations, adding Desbuquois dysplasia to the list of differential diagnosis of the DTD group.     

Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype

We report two patients with clinical and radiological findings of achondroplasia, who had the most common FGFR3 mutation occurring in thanatophoric dysplasia type I and hypochondroplasia, respectively. Thanatophoric dysplasia is usually a lethal condition, but the patient carrying this mutation is alive and presents a medical history similar to that of patients with achondroplasia. The events leading to such a discrepancy between genotype and phenotype are unclear. These rare cases may influence an appropriate medical and genetic counseling. © 2001 Wiley‐Liss, Inc.     

Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.     

Syndrome of multiple epiphyseal dysplasia (ribbing type) with rhizomelic shortness,cleft palate,and micrognathia in two unrelated patients

We report on two unrelated patients with an apparently new syndrome. In each family they are the only affected members, their parents are not consanguineous, and paternal and maternal ages are not advanced. At birth each patient was noted to have a marked Robin phenotype (cleft of the secondary palate and micrognathia) plus rhizomelic shortness. Delay in the appearance of long bone epiphyses was noted and followed by small fragmented and later very flat epiphyses of all long bones. The fibulae are short and radial heads dislocated. Scoliosis and marked genu valgum developed in both. Both patients have normal intelligence, vision, and hearing. Both have mildly upward slanting palpebral fissures, broad nasal tip, and apparent hypertelorism. © 1996 Wiley-Liss, Inc.     

Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early-onset osteoarthritis. Six genes responsible for MED have been identified, including COMP, COL9A1, COL9A2, COL9A3, DSTDT and MATN3. MATN3 encodes matrilin-3, a cartilage-specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the beta-sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation (p.F105S) is located outside the beta-sheet region, within an alpha-helix region.     

Multiple epiphyseal dysplasia,ribbing type: A novel point mutation in the COMP gene in a South African family

Multiple epiphyseal dysplasia is broadly categorised into the more severe Fairbank and the milder Ribbing types. In this paper we document mild MED in a South African kindred, and demonstrate that heterozygosity for a mutation in the cartilage oligomeric matrix protein (COMP) gene causes the condition. The mutation, C1594G, implies a N523K substitution, altering a residue at the carboxyl-terminal end of the calmodulin-like region of COMP. The identification of this mutation demonstrates that the spectrum of manifestations from mild MED through pseudoachondroplasia can all be produced by structural mutations in COMP. Am. J. Med. Genet. 68:396–400, 1997. © 1997 Wiley-Liss, Inc.     

A de novo frameshift FGFR1 mutation extending the protein in an individual with multiple epiphyseal dysplasia and hypogonadotropic hypogonadism without anosmia

Multiple epiphyseal dysplasia (MED) is a genetically and clinically heterogeneous disease with both dominant and recessive inheritance. Eight different genes are known to cause the disease but in 15% of cases of MED, no mutation is found. Fibroblast growth factor receptor 1 (FGFR1) is a crucial regulator of bone formation and when mutated, can cause diseases with skeletal manifestations; nevertheless, MED has not been described in individuals with FGFR1 mutations. In this report, we describe a proband with MED and congenital normosmic hypogonadotropic hypogonadism (HH). DNA analysis showed a de novo frameshift variant in FGFR1 likely explaining the HH (p.Arg852Thrfs*165). No other mutation was found after a large gene sequencing panel, exome sequencing and an array CGH, except for a variant of unknown significance in FBN1 (rs755375255), but there were no features of a disease associated with FBN1 mutations and this variant is found a few times in population databases. We thus discuss the possibility that MED might be a new skeletal feature associated with FGFR1 mutations.     

Syndrome of short stature,microcephaly, mental retardation,and multiple epiphyseal dysplasia—Lowry-Wood syndrome

We describe a brother and a sister with a syndrome of short stature, microcephaly, mental retardation, and multiple epiphyseal dysplasia. The parents were normal. This appears to be the second example of the syndrome first described by Lowry and Wood [1975] in two boys who had epiphyseal dysplasia, short stature, microcephaly, and nystagmus; one of these patients was mildly mentally retarded. The Lowry-Wood syndrome probably is an autosomal recessive trait.