Periodontal ehlers-danlos syndrome Q79.6

Ehlers-Danlos Syndrome (EDS) is a heterogeneous group of hereditary connective tissue diseases whose main clinical features are overstretchability of the skin and hyperreflexia of the joints. Depending on the type of disease and the underlying gene mutations, vessels, muscles, ligaments, tendons and internal organs are also affected (Brinckmann J 2018).

So far, 19 gene mutations are known to trigger EDS. The various mutations lead to changes in the structure, production or processing of collagen or of proteins that interact with collagen. The frequency of occurrence in the population is assumed to be 1:5,000 to 1:10,000, making EDS a rare disease (orphan disease).

The very rare periodontal Ehlers-Danlos syndrome (pEDS) is caused by autosomal-dominantly inherited mutations in the genes C1R or C1S (pEDS type I; pEDS type II), which are both located on chromosome 12p31. C1R codes for the complement C1r, the C1S gene for the complement C1s. Mutations in these genes lead to severe, persistent periodontitis, which occurs in childhood or adolescence. The gums often do not lie sufficiently close to the tooth (missing attachment of the gum tissue) (Brady et al. 2017; Kapferer-Seebacher I et al. 2016).

An important gene associated with Ehlers-Danlos syndrome, periodontal type, 2, is the C1S gene (complement C1s).

Major symptoms:

• Skin: Pretibial hyperpigmentation
• Gums: severe periodontal disease that cannot be controlled therapeutically (occurring in childhood and adolescence)
• Other: positive family history

Minor symptoms:

• Skin: haematoma formation, increased fragility, atrophic scars, acrogeria, increased vein marking
• Skeletal system: hypermobility especially of the distal joints, marfanoid face

others: hernias, increased infections

• Detection of the genetic defect
• Major criterion: severe periodontal disease that can hardly be influenced therapeutically

or

• Major criterion: missing gum attachment + two other major criteria + 1 minor criterion

Kapferer-Seebacher et al (2016) studied 2 families with Ehlers-Danlos syndrome and periodontitis. In the first family, the 45-year-old female proband had easily overstretched skin, easy hematomas, easily injured skin with pretibial hemosiderotic pigmentation, and early-onset periodontitis that led to tooth loss in her teens. The father, 1 sister, and 1 brother and 2 of the sons had a similar phenotype. Other characteristics of the proband and her affected sister included marked spinal osteoarthritis, vulnerable skin on the fingers and legs, irritable bowel symptoms, and flu-like symptoms without fever. Three of the affected individuals were diagnosed with malignancies, including a Wilms tumor.

In the second family, the proband was a 75-year-old man with features of periodontal EDS, including hyperelastic easily injured skin, easy bruising, atrophic scars, pretibial discoloration, and scoliosis. By age 60, he had lost 20 teeth. Eight of 9 affected relatives also had early-onset periodontitis, gingival recession, early tooth loss, and pretibial discoloration. Furthermore, 4 affected relatives developed malignancies, including uterine, breast, and colon cancers, and lymphocytic lymphoma of the lung.

1. Brady A et al (2017): Ehlers-Danlos syndromes, rarer types. In: Ehlers-Danlos Society. American Journal of Medical Genetics 175C:70-115.
2. Bowen et al (2017): Ehlers-Danlos syndrome, classical type. American Journal of Medical Genetics 175C:17-39
3. Brinckmann J (2018) Hereditary connective tissue disorders. In. Plewig et al (eds) Braun-Falco`s Dermatology, Venereology and Allergology, Springer Reference Medicine pp 883-890.
4. Byers PH et al (2019): Diagnosis, natural history and management in vascular Ehlers-Danlos syndrome. American Journal of Medical Genetics 175C:40-47.
5. Kapferer-Seebacher I et al (2016) Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement.Am J Hum Genet 99: 1005-1014.
6. Reinstein, E., Wang, R. Y., Zhan, L., Rimoin, D. L., Wilcox, W. R. Ehlers-Danlos type VIII, periodontitis-type: further delineation of the syndrome in a four-generation pedigree. Am. J. Med. Genet. 155A: 742-747, 2011Reinstein E et al. (2011) Ehlers-Danlos type VIII, periodontitis-type: further delineation of the syndrome in a four-generation pedigree. Am J Med Genet 155A: 742-747