DISEASE CARD

Definition

Classical 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. Mutations in the COL5A1 and the COL5A2 gene, encoding the a1 and the a2-chain of type V collagen respectively, are present in approximately 90% of patients with a clinical diagnosis of classic EDS. Rarely cEDS patients harbor mutations in the COL1A1 gene, with clinical manifestations overlapping with Osteogenesis Imperfecta.

cEDS together with hypermobility EDS constitute approximately 80% of all EDS cases.

Clinical Description

Cutaneous hyperextensibility is one of the cardinal features of classic EDS and becomes manifest within the first years of life. The skin, typically very smooth and velvety, can easily be stretched, usually more than 3cm at the elbows and recoils to its original form upon release. The skin is hyperfragile which means that the dermis splits following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (e.g. shins, chin). Wound healing is delayed and scars often become hyperpigmented and wide, with a "cigarette-paper"-like or papyraceous appearance.^1-3
 

Joint hypermobility is usually generalized, although the degree of severity varies, depending on age, gender, family and ethnic backgrounds. At birth uni- or bilateral dislocation of the hip may happen. 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. Ligamentous laxity of small joints can be such that the affected individuals have difficulty holding a pen. 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.^{1, 3}
 

Easy bruising is another prominent feature of cEDS and in small children it may even be the presenting symptom. There is often a tendency towards prolonged bleeding (e.g. following brushing 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), lower extremity venous varicosities 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.² Arterial rupture has been reporten in COL1A1 associated cEDS.^{4, 5}

Pregnancy in a woman with cEDS can lead to complications in the newborn as well as in the mother. Premature rupture of the membranes and prematurity are common. 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. Pregnant woman are exposed to an increased risk for extension of episiotomy incisions, tearing of the perineal skin and prolapse of the uterus and/or the bladder.²

Clinical Diagnostic Criteria⁶

Major criteria

1. Skin hyperextensibility and atrophic scarring
2. Generalized joint hypermobility (GJH)

Minor criteria

1. Easy bruising
2. Soft, doughy skin
3. Skin fragility (or traumatic splitting)
4. Molluscoid pseudotumors
5. Subcutaneous spheroids
6. Hernia (or history thereof)
7. Epicanthal folds
8. Complications of joint hypermobility (e.g., sprains, luxation/subluxation, pain, flexible flatfoot)
9. Family history of a first degree relative who meets clinical criteria

Minimal criteria suggestive for cEDS:
Major criterion 1. plus either major criterion 2. and/or at least three minor criteria.
Confirmatory molecular testing is obligatory to reach a final diagnosis.

Pathogenesis

Mutations in the genes encoding type V collagen (COL5A1and COL5A2) are the main causes of cEDS. 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. 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.
Rarely, specific mutations in the genes encoding type I collagen (e.g. heterozygous COL1A1 c.934C>T, p.(Arg312Cys) substitution) can cause a cEDS‐phenotype that goes along with an increased risk for vascular rupture. ⁵ 

Diagnosis

The diagnosis of classic EDS is established by family history and clinical examination. (see clinical diagnostic criteria).²
Ultrastructural studies of collagen fibrils by electron microscopy often suggest disturbed collagen fibrillogenesis⁶. 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.⁷
Molecular screening by means of targeted resequencing of a gene panel that includes at least the COL5A1, COL5A2, COL1A1, and COL1A2 genes, or by whole exome or genome sequencing, is indicated. When no mutation can be found, a CNV detection strategy should be additionally added, to screen for large deletions or duplications.
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

See section "Ehlers Danlos Syndrome".

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.⁸
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.⁸

References

<sup>1. Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, et al. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175(1):27-39.
2. Malfait F, Wenstrup RJ, De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med. 2010;12(10):597-605.
3. Ritelli M, Dordoni C, Venturini M, Chiarelli N, Quinzani S, Traversa M, et al. Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis. 2013;8:58.
4. Gaines R, Tinkle BT, Halandras PM, Al-Nouri O, Crisostomo P, Cho JS. Spontaneous ruptured dissection of the right common iliac artery in a patient with classic Ehlers-Danlos syndrome phenotype. Ann Vasc Surg. 2015;29(3):595.e511-594.
5. Malfait F, Symoens S, De Backer J, Hermanns-Lê T, Sakalihasan N, Lapière CM, et al. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007;28(4):387-395.
6. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8-26.
7. Vogel A, Holbrook KA, Steinmann B, Gitzelmann R, Byers PH. Abnormal collagen fibril structure in the gravis form (type I) of Ehlers-Danlos syndrome. Lab Invest. 1979;40(2):201-206.
8. Joseph AW, Joseph SS, Francomano CA, Kontis TC. Characteristics, Diagnosis, and Management of Ehlers-Danlos Syndromes: A Review. JAMA Facial Plast Surg. 2018 Jan 1;20(1):70-75.</sup>