Brittle cornea 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 (Brady A et al. 2017).

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 Brittle cornea Syndrome (BCS) is an autosomal recessive, ophthalmologic variant of Ehlers-Danlos Syndrome (Malfait F et al. 2004). BCS occurs in two types. Variant 1 arises from a mutation in the ZNF469 gene, which is located on chromosome 16q24 and codes for zinc finger protein 469.

Variant 2 is caused by mutations (>20 different mutations are known) in the PRDM5 gene, which is located on chromosome 4q27. The gene codes for a protein of the same name. This is a transcription factor that regulates the transcription of matrix proteins.

BCS is characterized by a progressive thinning of the cornea of the eye. Early on, a keratoglobus or keratoconus can occur, as well as myopia, hearing loss and blue sclerae. Classical EDS symptoms, such as hyperactive joints and overstretched skin are frequently observed (Brady et al. 2017).

The clinical symptoms are classified according to major and minor criteria (Brinckmann J 2018)

Major symptoms

• eyes: thin cornea with or without rupture, early progressive keratoconus, early progressive keratoglobus, blue sclerae

Minor symptoms

• Skin: soft velvety translucent
• Eyes: enucleation or corneal scarring after previous rupture, progressive decrease of corneal thickness (stroma), severe myopia, retinal detachment
• skeletal system: scoliosis, arachnodactyly, hypermobility of the small joints, pes planus, hallux valgus, slight finger contractures, hip joint dysplasia

others: numbness, increased stretch of the eardrum, mild muscular hypotension

Detection of genetic mutations

Major symptom: Thin cornea with or without rupture +either

• another major symptom
• or
• 3 other minor symptoms

1. Ayoub S et al (2020) Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome. At J Med Genet A doi: 10,1002/ajmg.a.61523.
2. Bowen et al(2017): Ehlers-Danlos syndrome, classical type. American Journal of Medical Genetics 175C:17-39
3. Brady A et al (2017): Ehlers-Danlos syndrome, rare types. In: Ehlers-Danlos Society. American Journal of Medical Genetics 175C:70-115
4. Brinckmann J (2018) Hereditary connective tissue diseases. In. Plewig et al. (Ed.) Braun-Falco`s Dermatology, Venerology and Allergology, Springer Reference Medizin S 883-890
5. Guarnieri V et al (2019) Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2. On J Med Genet A 179:846-851.
6. Micale L et al (2019) Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome.Genes (Basel) 10: doi: 10.3390/genes10120967.
7. Skalicka P et al (2019) Brittle cornea syndrome: A systemic review of disease-causing mutations in ZNF469 and two novel variants identified in a patient followed for 26 years. Biomed Pap Med Fac Univ Palacky Olomouc Czech Republic. 2019 Apr 17. doi:10.5507/bp.2019.017.
8. Solomons J et al (2013) Dermatosparaxis (Ehlers-Danlos type VIIC): prenatal diagnosis following a previous pregnancy with unexpected skull fractures at delivery. Am J Med Genet A 161A:1122-1125.
9. Van Damme T et al (2016) Expanding the clinical and mutational spectrum of the Ehlers-Danlos syndrome, dermatosparaxis type. Genet Med 18:882-891.
10. Wan Q et al (2018) Brittle cornea syndrome: a case report and review of the literature. BMC Ophthalmol 18:252.