Виды дисплазий
http://www.ncbi.nlm.nih.gov/books/NBK1279/#eds3.Differential_Diagnosis
All types of Ehlers-Danlos syndrome (EDS) share some degree of joint laxity and skin/soft tissue manifestations.
The other forms of EDS are distinguished by additional connective tissue manifestations [Beighton et al 1998]:
* EDS, classic type includes skin and soft tissue fragility. Mild presentations of the classic type may be mistaken for the hypermobility type. The diagnosis is sometimes revised from hypermobility to classic when the individual or a family member later develops more significant skin and soft tissue manifestations. Approximately 50% of individuals with classic EDS have an identifiable mutation in COL5A1 or COL5A2, the two genes encoding type V collagen. Sequence analysis of these genes is available.
* In EDS, vascular type, the joint laxity is predominantly in small joints, and spontaneous rupture of hollow organs occurs. Dysfunction and/or deficiency of type III collagen, caused by mutations in COL3A1, are responsible for all cases of EDS, vascular type. The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical (protein-based) and/or molecular genetic testing.
* EDS, kyphoscoliotic and dermatosparaxis types are autosomal recessive, rare, and distinguished by more severe skin manifestations and other features. EDS, kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies on demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC, a highly sensitive and specific test. Assay of lysyl hydroxylase enzyme
* EDS, arthrochalasia type is autosomal dominant, rare, and distinguished by congenital hip dislocation and more severe skin manifestations. Pathogenic mutations occur in exon 6 of COL1A1 and COL1A2, causing impaired cleavage of the amino terminal propeptide of the corresponding type 1 procollagen molecules. Clinical testing is available.
Joint laxity is a nonspecific manifestation of dozens of other disorders and syndromes. Some of these are traditionally thought of as heritable disorders of connective tissue or skeletal dysplasias, but many fall outside those general classifications. Most are easily distinguished from EDS by characteristic features and/or involvement of systems other than the joints and skin, but mild presentations can sometimes be misdiagnosed as EDS, hypermobility type. Some examples, in order of likelihood and importance, include the following:
* Marfan syndrome results in additional skeletal, ocular, cardiovascular, pulmonary, and skin/integument manifestations beyond those seen in EDS. Specific clinical criteria are available to establish a diagnosis of Marfan syndrome; it can be confirmed by demonstration of a mutation in FBN1. Joint hypermobility is common in the MASS phenotype (myopia, mitral valve prolapse, mild aortic root dilatation, striae, and minor skeletal manifestations of Marfan syndrome), also caused by mutations in FBN1. Sometimes individuals with hypermobility EDS can have a Marfanoid build and as such resemble individuals with Marfan syndrome or a Marfan-related disorder. However, application of the clinical diagnostic criteria for Marfan syndrome and FBN1 molecular analysis allow differentiation of these conditions.
* Loeys-Dietz syndrome is characterized by multiple arterial aneurysms and tortuosity. Other clinical features are variable, but may include ocular hypertelorism and bifid uvula. The presentation often mimics Marfan syndrome or EDS, vascular type, but prior to detection of the arterial abnormalities, individuals may be misdiagnosed with classic or hypermobility type EDS. The diagnosis is established by detection of a mutation in TGFBR1 or TGFBR2.
* Stickler syndrome. Distinguishing features include sensorineural hearing loss, vitreoretinal abnormalities, and cleft palate. Mutations affecting one of three genes (COL2A1, COL11A1, and COL11A2) have been associated with Stickler syndrome. However, a few families with features of Stickler syndrome are not linked to any of these three loci, so mutations in other genes may also cause the disorder. Stickler syndrome is diagnosed based on clinical features. In many affected individuals and families the diagnosis can be confirmed by molecular genetic testing, but a negative test does not rule out the diagnosis.
* Williams syndrome (WS) is a contiguous gene deletion syndrome characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). The mainstay for diagnosis is detection of the contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (ELN). More than 99% of individuals with the clinical diagnosis of WS have this contiguous gene deletion, which can be detected using fluorescent in situ hybridization (FISH) or targeted mutation analysis. Supravalvular aortic stenosis (SVAS) is caused by mutation (rather than deletion) of ELN. Individuals with either deletion or mutation of ELN have joint laxity, but the classic elastin arteriopathy is not seen in any type of EDS.
* Aarskog-Scott syndrome (faciogenital dysplasia) is an X-linked condition resulting from mutation of FGD1. The most significant distinguishing feature is shawl scrotum, which may become less obvious in adulthood. Widow's peak, short upturned nose, other dysmorphic features, and the inheritance pattern can be additional diagnostic clues. Intellectual disability, which is not associated with any of the types of EDS, is sometimes present.
* Fragile X syndrome is not typically confused with EDS, hypermobility type. When a full mutation of FMR1 is present, fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Males may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), joint laxity and large testes (post-puberty). However, premutation carriers may have joint laxity and EDS-like skin findings without other major manifestations. Family history of intellectual disability, premature ovarian failure and/or fragile X tremor/ataxia syndrome is helpful when present. The frequency of FMR1 premutation among individuals diagnosed clinically with EDS, hypermobility type has not been studied, but fragile X syndrome has not been reported among offspring of women with EDS, hypermobility type.
* Achondroplasia and hypochondroplasia are distinguished by short stature with characteristic skeletal features (marked in achondroplasia, milder in hypochondroplasia). Achondroplasia can be diagnosed by characteristic clinical and radiographic findings in most affected individuals. Molecular genetic testing reveals a mutation in FGFR3 in 99% of individuals with achondroplasia and about 70% of individuals with hypochondroplasia. However, it is clear that locus heterogeneity exists for hypochondroplasia because mutations in other as-yet-unidentified genes can result in similar, if not identical, phenotypes.
* Osteogenesis imperfecta (OI). Distinguished by the presence of fractures and, in some cases, dentinogenesis imperfecta (grey or brown teeth). Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with OI type II, about 90% with OI type I, about 84% with OI type IV, and about 84% with OI type III. About 90% of individuals with OI types I, II, III, and IV (but none with OI types V, VI, and VII) have an identifiable mutation in either COL1A1 or COL1A2.
* Aneuploidies, such as Down, Turner, or Klinefelter syndrome, are usually easily recognized based on dysmorphic features and/or intellectual disability. Small duplications or deletions may be less clinically obvious, but could be suggested by reduced fertility or recurrent pregnancy loss.
Chronic pain and fatigue are major features of fibromyalgia. A subset of individuals with fibromyalgia and/or chronic fatigue syndrome may have EDS as the underlying etiology.
All types of Ehlers-Danlos syndrome (EDS) share some degree of joint laxity and skin/soft tissue manifestations.
The other forms of EDS are distinguished by additional connective tissue manifestations [Beighton et al 1998]:
* EDS, classic type includes skin and soft tissue fragility. Mild presentations of the classic type may be mistaken for the hypermobility type. The diagnosis is sometimes revised from hypermobility to classic when the individual or a family member later develops more significant skin and soft tissue manifestations. Approximately 50% of individuals with classic EDS have an identifiable mutation in COL5A1 or COL5A2, the two genes encoding type V collagen. Sequence analysis of these genes is available.
* In EDS, vascular type, the joint laxity is predominantly in small joints, and spontaneous rupture of hollow organs occurs. Dysfunction and/or deficiency of type III collagen, caused by mutations in COL3A1, are responsible for all cases of EDS, vascular type. The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical (protein-based) and/or molecular genetic testing.
* EDS, kyphoscoliotic and dermatosparaxis types are autosomal recessive, rare, and distinguished by more severe skin manifestations and other features. EDS, kyphoscoliotic form is caused by deficient activity of the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1: lysyl hydroxylase 1). The diagnosis of EDS, kyphoscoliotic form relies on demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC, a highly sensitive and specific test. Assay of lysyl hydroxylase enzyme
* EDS, arthrochalasia type is autosomal dominant, rare, and distinguished by congenital hip dislocation and more severe skin manifestations. Pathogenic mutations occur in exon 6 of COL1A1 and COL1A2, causing impaired cleavage of the amino terminal propeptide of the corresponding type 1 procollagen molecules. Clinical testing is available.
Joint laxity is a nonspecific manifestation of dozens of other disorders and syndromes. Some of these are traditionally thought of as heritable disorders of connective tissue or skeletal dysplasias, but many fall outside those general classifications. Most are easily distinguished from EDS by characteristic features and/or involvement of systems other than the joints and skin, but mild presentations can sometimes be misdiagnosed as EDS, hypermobility type. Some examples, in order of likelihood and importance, include the following:
* Marfan syndrome results in additional skeletal, ocular, cardiovascular, pulmonary, and skin/integument manifestations beyond those seen in EDS. Specific clinical criteria are available to establish a diagnosis of Marfan syndrome; it can be confirmed by demonstration of a mutation in FBN1. Joint hypermobility is common in the MASS phenotype (myopia, mitral valve prolapse, mild aortic root dilatation, striae, and minor skeletal manifestations of Marfan syndrome), also caused by mutations in FBN1. Sometimes individuals with hypermobility EDS can have a Marfanoid build and as such resemble individuals with Marfan syndrome or a Marfan-related disorder. However, application of the clinical diagnostic criteria for Marfan syndrome and FBN1 molecular analysis allow differentiation of these conditions.
* Loeys-Dietz syndrome is characterized by multiple arterial aneurysms and tortuosity. Other clinical features are variable, but may include ocular hypertelorism and bifid uvula. The presentation often mimics Marfan syndrome or EDS, vascular type, but prior to detection of the arterial abnormalities, individuals may be misdiagnosed with classic or hypermobility type EDS. The diagnosis is established by detection of a mutation in TGFBR1 or TGFBR2.
* Stickler syndrome. Distinguishing features include sensorineural hearing loss, vitreoretinal abnormalities, and cleft palate. Mutations affecting one of three genes (COL2A1, COL11A1, and COL11A2) have been associated with Stickler syndrome. However, a few families with features of Stickler syndrome are not linked to any of these three loci, so mutations in other genes may also cause the disorder. Stickler syndrome is diagnosed based on clinical features. In many affected individuals and families the diagnosis can be confirmed by molecular genetic testing, but a negative test does not rule out the diagnosis.
* Williams syndrome (WS) is a contiguous gene deletion syndrome characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). The mainstay for diagnosis is detection of the contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) that encompasses the elastin gene (ELN). More than 99% of individuals with the clinical diagnosis of WS have this contiguous gene deletion, which can be detected using fluorescent in situ hybridization (FISH) or targeted mutation analysis. Supravalvular aortic stenosis (SVAS) is caused by mutation (rather than deletion) of ELN. Individuals with either deletion or mutation of ELN have joint laxity, but the classic elastin arteriopathy is not seen in any type of EDS.
* Aarskog-Scott syndrome (faciogenital dysplasia) is an X-linked condition resulting from mutation of FGD1. The most significant distinguishing feature is shawl scrotum, which may become less obvious in adulthood. Widow's peak, short upturned nose, other dysmorphic features, and the inheritance pattern can be additional diagnostic clues. Intellectual disability, which is not associated with any of the types of EDS, is sometimes present.
* Fragile X syndrome is not typically confused with EDS, hypermobility type. When a full mutation of FMR1 is present, fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Males may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), joint laxity and large testes (post-puberty). However, premutation carriers may have joint laxity and EDS-like skin findings without other major manifestations. Family history of intellectual disability, premature ovarian failure and/or fragile X tremor/ataxia syndrome is helpful when present. The frequency of FMR1 premutation among individuals diagnosed clinically with EDS, hypermobility type has not been studied, but fragile X syndrome has not been reported among offspring of women with EDS, hypermobility type.
* Achondroplasia and hypochondroplasia are distinguished by short stature with characteristic skeletal features (marked in achondroplasia, milder in hypochondroplasia). Achondroplasia can be diagnosed by characteristic clinical and radiographic findings in most affected individuals. Molecular genetic testing reveals a mutation in FGFR3 in 99% of individuals with achondroplasia and about 70% of individuals with hypochondroplasia. However, it is clear that locus heterogeneity exists for hypochondroplasia because mutations in other as-yet-unidentified genes can result in similar, if not identical, phenotypes.
* Osteogenesis imperfecta (OI). Distinguished by the presence of fractures and, in some cases, dentinogenesis imperfecta (grey or brown teeth). Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with OI type II, about 90% with OI type I, about 84% with OI type IV, and about 84% with OI type III. About 90% of individuals with OI types I, II, III, and IV (but none with OI types V, VI, and VII) have an identifiable mutation in either COL1A1 or COL1A2.
* Aneuploidies, such as Down, Turner, or Klinefelter syndrome, are usually easily recognized based on dysmorphic features and/or intellectual disability. Small duplications or deletions may be less clinically obvious, but could be suggested by reduced fertility or recurrent pregnancy loss.
Chronic pain and fatigue are major features of fibromyalgia. A subset of individuals with fibromyalgia and/or chronic fatigue syndrome may have EDS as the underlying etiology.