DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, CLASSIC TYPE
Synonymous Ehlers-Danlos syndrome I (Gravis type), Ehlers-Danlos syndrome II (Mitis type)
Estimated prevalence 1 - 9 / 100.000
OMIM 130000, 130010
Inheritance Autosomal dominant
Gene (s) COL5A1 (120215), COL5A2 (120190), COL1A1 (120150)

Definition

The term Ehlers-Danlos syndrome (EDS) does not describe a specific disease but a group of connective tissue disorders that share the clinically manifestations of skin hyperextensibility, articular hypermobility and tissue fragility [1]. In the “Villefranche” classification, the formerly used Roman numerals were replaced by six descriptive main types (Table 1). Besides the six main types, EDS also includes a series of “other” types, that are either not clearly classified or poorly characterized [2, 3].

Classic Ehlers-Danlos syndrome (cEDS) is an autosomal dominant connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising and generalized joint hypermobility. The two subtypes of classic EDS, cEDS-type 1 (Gravis type) and cEDS-type 2 (Mitis type), form a continuum of clinical findings and differ only in their phenotypic severity. Mutations in the COL5A1 and the COL5A2 gene, encoding the a1 and the a2-chain of type V collagen respectively, are identified in approximately 50% of patients with a clinical diagnosis of classic EDS [4]. Besides mutations in collagen-V, cEDS patients have been reported to harbor mutations in the COL1A1 gene, with clinical manifestations overlapping with Osteogenesis Imperfecta [5].

Table 1: Villefranche classification of the six main types of EDS.

Descriptive type Numerical type Genes
Classic type EDS I (Gravis)
EDS II (Mitis)
COL5A1
COL5A2
COL1A1
Hypermobility type EDS III TNXB
COL3A1*
Vascular type EDS IV COL3A1
Kyphoscoliosis type EDS VI PLOD1
Arthrochalasia type EDS VIIA
EDS VIIB
COL1A1
COL1A2
Dermatosparaxis type EDS VIIC ADAMTS2

*Only one patient has been reported to carry a mutation in the COL3A1 gene.

Clinical Description

Cutaneous hyperextensibility is one of the cardinal features of classic EDS. The skin is typically very smooth and velvety. It is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is delayed and scars become wide, with a "cigarette-paper"-like or papyraceous appearance [4].

Joint hypermobility is usually generalized and can range in severity. It depends on age, gender, family and ethnic backgrounds and should be assessed using the Beighton scale (Table 2) [2, 4]. At birth uni- or bilateral dislocation of the hip may be present. Complications of joint hypermobility include habitual joint subluxation and dislocation, foot deformities such as congenital clubfoot or pes planus, temporomandibular joint dysfunction, joint effusions, and osteoarthritis. Primary muscular hypotonia may occur and cause delayed motor development, problems with ambulation, and mild motor disturbance. Some adult individuals may suffer from chronic musculoskeletal pain, despite normal radiographs.

Table 2: Beighton scale of hypermobility.

Joint/Finding Negative Unilateral Bilateral
Passive dorsiflexion of the 5th finger >90° 0 1 2
Passive flexion of thumbs to the forearm 0 1 2
Hyperextension of the elbows beyond 10° 0 1 2
Hyperextension of the knees beyond 10° 0 1 2
Forward flexion of the trunk with knees fully extended and palms resting on the floor 0 1
A total score of at least 5 defines hypermobility

Easy bruising is another prominent feature of classic EDS and in small children it may even be the presenting symptom to the pediatrician. There often is a tendency towards prolonged bleeding, e.g. following brushing of the teeth, in spite of a normal coagulation status. Other clinical signs of classic EDS include molluscoid pseudotumors (fleshy lesions associated with scars), subcutaneous spheroids (small, hard cyst-like nodules), piezogenic papules (painful herniations of adipose tissue globules through the fascia into the dermis) and manifestations of generalized tissue extensibility, such as cervical insufficiency, inguinal and umbilical hernia and recurrent rectal prolapse in early childhood. Structural cardiac malformations are uncommon in the classic type of EDS. Mitral valve prolapse and, less frequently, tricuspid valve prolapse may occur [4].

Pregnancy in a woman with classic EDS can lead to complications in the newborn as well as in the affected woman. Premature rupture of the membranes (if the fetus is affected) and prematurity are common. In the severe (gravis) form of classic EDS, prematurity occurs in approximately 50% of cases; in the mild (mitis) form, prematurity does not occur more frequently than normal. Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn. For an affected woman, there is also an increased risk for extension of episiotomy incisions, tearing of the perineal skin, and prolapse of the uterus and/or the bladder [4].

Pathogenesis

Ultrastructural studies by electron microscopy of skin biopsies from patients with classic EDS show that the collagen fibrils have an increased diameter and are highly variable in width and shape, with occasional flower-like deformities of the fibrils (cauliflowers), suggesting a disturbed fibrillogenesis of the collagen fibrils [6]. In at least half of the patients with classic EDS, mutations in one of the genes encoding type V collagen (COL5A1and COL5A2) are detected and mutations in COL1A1 were shown in patients with classic EDS with clinical manifestations overlapping with osteogenesis imperfecta.

Collagen type V is a quantitatively minor fibrillar collagen, which is widely distributed in a variety of tissues such as skin, tendon, bone and cornea. In most vertebrate tissues it is present mainly as [a1(V)]2a2(V) heterotrimers. Type V collagen co-assembles with type I collagen to form heterotypic fibrils and it has a regulatory function on the diameter of those fibrils. The most common types of molecular defects lead to haplo-insufficiency of COL5A1 mRNA [7]. In approximately one-third of classic EDS patients, nonsense, frameshift or splice site mutations that introduce a premature termination codon are responsible for a non-functional COL5A1 allele. These mutations lead to mRNA instability, presumably through nonsense-mediated decay of mRNA (NMD). The predicted outcome of these mutations is synthesis of about half the amount of normal type V collagen. A limited number of structural mutations in the COL5A1 and the COL5A2 gene have been demonstrated in patients with classic EDS. These mutations affect the structural integrity of type V collagen, resulting in the production of a functionally defective type V collagen protein. The majority are splice site mutations that result in exon deletion and very few point mutations that result in the substitution of glycine by a bulkier amino acid in the triple helical region of the collagen molecule.

Diagnosis

The diagnosis of classic EDS is established by family history and clinical examination. The combination of the three major diagnostic criteria (skin hyperextensibility, tissue fragility, joint hypermobility) is highly specific for presence of classic EDS [4].

Ultrastructural studies of collagen fibrils by electron microscopy often suggest disturbed collagen fibrillogenesis [6]. Cauliflower deformities of collagen fibrils are characteristic. However, these findings are not specific for EDS and therefore not diagnostic. Furthermore, ultrastructural changes, usually most pronounced in the central parts of the reticular dermis, may be missed if the skin biopsy is not full thickness.

Biochemical protein-based analysis of radioactively labeled type V collagen, extracted from cultured dermal fibroblasts, is an ineffective method for routine diagnostic evaluation. The chains of type V collagen are synthesized by fibroblasts at low levels, so that quantization and evaluation of alterations in electrophoretic mobilities are poorly reproducible.

Polymorphic markers in the expressed region of the genomic DNA may be used to determine if both COL5A1 alleles have stable transcripts. Initially, testing determines if the individual is heterozygous for one of several COL5A1 polymorphic exonic markers in genomic DNA. Then, COL5A1 cDNA is tested to determine if both alleles are present. If only one of the two COL5A1 alleles is present in cDNA, it is assumed that the absent allele is "null." COL5A1 "null" allele testing requires cultured fibroblasts, as it examines both genomic DNA and cDNA. It does not identify mutations within the COL5A1 gene. COL5A1 null allele testing detects a "null" COL5A1 allele in approximately 30% of individuals with classic EDS.

Sequence analysis of the COL5A1 and the COL5A2 gene can identify a disease-causing mutation in approximately 50% of classic EDS patients.

Prenatal testing may be available for families in which linkage has been established or the disease-causing mutation has been identified in an affected family member.

Treatment

Children with pronounced skin fragility and easy bruising should wear protection in the form of pads or bandages over the forehead, knees and shins, in order to avoid skin tears and bruises. Later in life patients often choose to avoid contact sports. Dermal wounds should be closed without tension, preferably in two layers. Deep stitches should be applied generously. Cutaneous stitches should be left in place twice as long as usual and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scars.

In children with hypotonia and delayed motor development, a physiotherapeutic program is important. Non-weight-bearing muscular exercise, such as swimming, is useful to promote muscular development and coordination. Sports with heavy joint strain such as contact sports are discouraged. Anti-inflammatory drugs may help in patients with joint pain. Patients with muscle hypotonia and joint instability with chronic pain may have to adapt their lifestyle and their professional choices accordingly. Emotional support and behavioural and psychological therapy may be indicated in order to accept and cope with the handicap. Long-term chronic pain may result in the need for mental health services. A baseline echocardiogram with aortic diameter measurement is recommended prior to the age of 10 years with follow-up studies timed according to whether an abnormality has been diagnosed.

References

1
Beighton P. The Ehlers-Danlos syndromes. In: Beighton P. (ed.) : McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis: Mosby 1993. Pp. 189-251.

2
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. (1998) Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997. Am J Med Genet 77:31-37.

3
Byers PH, Murray ML. (2012) Heritable Collagen Disorders: The Paradigm of the Ehlers-Danlos Syndrome. J Invest Dermatol 132(E1):E6-E11.

4
Malfait F, Wenstrup RJ, De Paepe A. (2010) Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med 12:597-605.

5
Malfait F, Symoens S, Goemans N, Gyftodimou Y, Holmberg E, López-González V, Mortier G, Nampoothiri S, Petersen MB, De Paepe A. (2013) Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome. Orphanet J Rare Dis 8:78. doi: 10.1186/1750-1172-8-78.

6
Vogel A, Holbrook KA, Steinmann B, Gitzelmann R, Byers PH. (1979) Abnormal collagen fibril structure in the gravis form (type I) of Ehlers-Danlos syndrome. Lab Invest 40:201-206.

7
Wenstrup RJ, Langland GT, Willing MC, D'Souza VN, Cole WG. (1996) A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro-alpha-1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I). Hum Molec Genet 5:1733-1736.