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.     

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     

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.     

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.     

COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia

The skeletal dysplasias are a clinically and genetically heterogeneous group of conditions affecting the development of the osseous skeleton and fall into the category of rare genetic diseases in which the diagnosis can be difficult for the nonexpert. Two such diseases are pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), which result in varying degrees of short stature, joint pain and stiffness and often resulting in early onset osteoarthritis. PSACH and some forms of MED result from mutations in the cartilage oligomeric matrix protein (COMP) gene and to aid the clinical diagnosis and counselling of patients with a suspected diagnosis of PSACH or MED, we developed an efficient and accurate molecular diagnostic service for the COMP gene. In a 36-month period, 100 families were screened for a mutation in COMP and we identified disease-causing mutations in 78% of PSACH families and 36% of MED families. Furthermore, in several of these families, the identification of a disease-causing mutation provided information that was immediately used to direct reproductive decision-making.     

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.     

Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up

In this study, we followed-up the family with bilateral hereditary micro-epiphyseal dysplasia (BHMED) originally described by Elsbach [1959: J Bone Joint Surg [Br] 41-B:514-523]. Clinical re-examination of all available family members resulted in further delineation of the clinical and radiological phenotype, which is distinct from common multiple epiphyseal dysplasia (MED). Linkage analysis excluded EDM1, EDM2, and EDM3 as candidate genes. Linkage and mutation analysis of matrilin-3 (MATN-3) revealed a new pathogenic mutation confirming that BHMED is indeed a distinct disease entity among MED and MED-like disorders.     

Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: description of 12 patients

Multiple epiphyseal dysplasia (MED) is characterized by pain and stiffness in joints and delayed and irregular ossification of epiphyses. Causative mutations have been recognized in six different genes. We have identified disease-causing mutations in the gene encoding matrilin-3, an extracellular matrix protein, in seven families with autosomal dominant MED. Review of the clinical and radiographic features in 12 of the affected family members shows a uniform pattern of skeletal anomalies in all patients with considerable degree of variability in severity, both between and within families. The characteristic clinical findings are onset of symptoms in early childhood with predominance of knee and hip related complaints, normal stature, and early-onset osteoarthritis. Radiographs show small and irregular epiphyses and mild metaphyseal irregularities and striations, especially at the knees and hips and mild spinal changes. Despite overlap, both clinically and radiographically, with other forms of MED, the described features may help to differentiate this particular form from other entities within the MED spectrum.     

Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes

Multiple epiphyseal dysplasia (MED) is a mild chondrodysplasia affecting the structural integrity of cartilage and causing early-onset osteoarthrosis in adulthood. The condition is genetically heterogeneous. Mutations in the COMP gene and in two genes (COL9A2; COL9A3), coding respectively for the alpha2(IX) and alpha3(IX) chains of type IX collagen, can cause the autosomal dominant forms of MED. Mutations in the DTDST gene have recently been identified in a recessive form of MED. However, for the majority of MED cases, the genetic defect still remains undetermined. We report a three-generation family with an autosomal dominant form of MED, characterised by normal stature, joint pain in childhood and early-onset osteoarthrosis, affecting mainly the hips and knees. Based on discordant inheritance among affected individuals linkage of the phenotype to the COMP, COL9A1, COL9A2, COL9A3 genes was excluded. Our study provides evidence that at least another locus, distinct from COL9A1, is involved in autosomal dominant MED.     

Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia

We report on a form of multiple epiphyseal dysplasia with striking acromelic shortness in a woman and five of her ten children. The somatometric and metacarpo-phalangeal pattern profile of the affected individual showed short limb dwarfism and shortness of all the tubular bones of the hand. Epiphyseal irregularities and shortness of the 4th metatarsal bones were outstanding. The disorder showed a dominant and probably autosomal pattern of inheritance with variability of expression. The measurement of metacarpo-phalangeal profiles allowed an objective and quantitative assessment of brachydactyly. In the family reported here, there was a clear discrepancy between the severity of shortness of hands and feet and the severity of shortness of stature. This family also illustrates the effects of a single gene in a large kindred, therefore describing the range and variability of a phenotype not otherwise available.     

Expanded phenotype of cranioectodermal dysplasia (Sensenbrenner syndrome)

Cranioectodermal dysplasia (CED) is an autosomal recessive condition characterized by defects of ectoderm-derived structures and characteristic bone anomalies. We report on a 27-month-old Caucasian girl with CED, pre- and postnatal growth retardation, microcephaly, hypoplasia of the posterior corpus callosum, photophobia, and aberrant calcium homeostasis. Since new traits were encountered, we reviewed all reported patients and one unpublished case and compared the frequency rates of the individual manifestations. The findings present in all patients are dolichocephaly and rhizomelia. Ectodermal dysplasia manifestations are variable. Short thorax and heart defect are inconsistent. Previously unreported anomalies include growth deficiency, delayed psychomotor development, microcephaly, photophobia, and abnormal calcium homeostasis. These clinical manifestations may facilitate the diagnosis of this condition. Am. J. Med. Genet. 70:349–352, 1997. © 1997 Wiley-Liss, Inc.     

SLC26A2 disease spectrum in Sweden – high frequency of recessive multiple epiphyseal dysplasia (rMED)

Diastrophic dysplasia (DTD) is an autosomal recessive skeletal dysplasia caused by SLC26A2 mutations. Clinical features include short stature, joint contractures, spinal deformities, and cleft palate. SLC26A2 mutations also result in other skeletal dysplasias, including the milder recessive multiple epiphyseal dysplasia (rMED). DTD is overrepresented in Finland and we speculated that this may have influenced the prevalence and spectrum of SLC26A2‐related skeletal conditions also in Sweden. We reviewed the patient registry at Department of Clinical Genetics, Karolinska University Hospital, Stockholm to identify subjects with SLC26A2 mutations. Seven patients from six families were identified; clinical data were available for six patients. All but one patient had one or two copies of the Finnish SLC26A2 founder mutation IVS1+2T>C. Arg279Trp mutation was present in compound heterozygous form in five patients with phenotypes consistent with rMED. Their heights ranged from ?2.6 to ?1.4 standard deviation units below normal mean and radiographic features included generalised epiphyseal dysplasia and double‐layered patellae. Two rMED patients had hypoplastic C2 and cervical kyphosis, a severe manifestation previously described only in DTD. Our study confirms a high prevalence of rMED in Sweden and expands the phenotypic manifestations of rMED.     

Anthropometric studies in five children and their mother with a severe form multiple epiphyseal dysplasia.

We report on a form of multiple epiphyseal dysplasia with striking acromelic shortness in a woman and five of her ten children. The somatometric and metacarpo-phalangeal pattern profile of the affected individual showed short limb dwarfism and shortness of all the tubular bones of the hand. Epiphyseal irregularities and shortness of the 4th metatarsal bones were outstanding. The disorder showed a dominant and probably autosomal pattern of inheritance with variability of expression. The measurement of metacarpo-phalangeal profiles allowed an objective and quantitative assessment of brachydactyly. In the family reported here, there was a clear discrepancy between the severity of shortness of hands and feet and the severity of shortness of stature. This family also illustrates the effects of a single gene in a large kindred, therefore describing the range and variability of a phenotype not otherwise available.     

儿童发育性髋关节发育不良解剖学改变与影像学表现

背景:发育性髋关节发育不良是常见的儿童髋关节发育畸形,该病不同时期的治疗效果不同,早期治疗疗效较好,并发症较少,远期的预后更好,可以减少复发率,减轻经济压力,提高生活质量,所以,临床上对发育性髋关节发育不良的早期诊断越来越重要。目的:对发育性髋关节发育不良的解剖学改变及影像学表现的研究进展进行综述。方法:以"DDH,Anatomy,X-ray Radiography,CT,MRI,Ultrasound"为英文检索词,"发育性髋关节发育不良,解剖,X线摄影,CT,MRI,超声"为中文检索词,对PubMed、Springerlink等英文数据库及万方、CNKI等中文数据库进行检索,检索时限为1990年1月至2019年12月,排除与文章研究目的无关及重复性研究,纳入符合标准的55篇文献进行综述。结果与结论:影像学诊断作为一种无创性的检查手段,已经成为诊断发育性髋关节发育不良首选的检查方法,而明确其解剖学改变更有助于临床影像学诊断,常规X射线片能够进行发育性髋关节发育不良的快速筛查;MRI有助于分辨软组织结构以及骨性结构早期信号改变;三维CT能够多角度评价髋臼骨性结构改变,排除了体位因素造成的遮挡;超声同样能够进行发育性髋关节发育不良筛查,并对关节积液更加敏感。所以,不同的影像学检查各有优势,相辅相成,提高发育性髋关节发育不良的早期诊断率。     

Exclusion of type II and type VI procollagen gene mutations in a five-generation family with multiple epiphyseal dysplasia

We have studied a family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) inherited through at least 5 generations. Bilateral deformity of the hips with subsequent degenerative arthritis was the most common and most severe change observed in the affected relatives. Abnormalities of the knees, ankles, and shoulders were also noted in some affected individuals. Radiological examination showed changes in affected joints consistent with epiphyseal dysplasia. In early stages, the articular surfaces appeared flattened or irregular in shape. In advanced stages, epiphyseal fragmentation, joint surface erosion, and extensive remodeling were observed. The abnormalities of the epiphyses suggested that the primary defect might be in a structural component of the epiphyseal cartilage matrix. The gene encoding type II collagen (COL2A1) was tested for genetic linkage to MED in this family by restriction fragment length polymorphism (RFLP) analysis. Recombination between COL2A1 and MED was observed, ruling out COL2A1 as the site of the mutation. The genes encoding the 3 chains of type VI collagen were also excluded on the basis of discordant inheritance. The disease in this family is therefore not the result of mutations in the genes encoding type II or type VI collagen. © 1993 Wiley-Liss, Inc.