Warburg-Cinotti syndrome
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Synopsis
The syndrome is thought to be caused by activating autophosphorylation mutations in the discoidin domain receptor tyrosine kinase 2 (DDR2), a collagen-responsive receptor tyrosine kinase that regulates connective tissue formation. DDR2 signaling has been shown to regulate the collagen cross-linking involved in remodeling of wound matrices and the fibroblast-mediated contraction of healing wounds. The inheritance pattern is believed to be autosomal dominant.
Affected individuals are often born with clubfoot and have early development of hearing loss, flexion contractures, and skin manifestations. Ocular findings such as corneal neovascularization that eventually result in symblepharon, corneal vascular pannus, and reduced central corneal thickness usually progress throughout life and result in visual impairment in later life. Facial features include narrowing of the nasal bridge, lower / midface retrusion, short palpebral fissures and epicanthal folds, posteriorly rotated ears with thin cartilage, high palate, and mispositioned teeth. Skin findings include generalized thin skin, hair loss, follicular hyperkeratosis, pigmented keloid formation, and sterile abscesses of the hands and feet. Pseudosyndactyly and osteolysis are further acral manifestations.
Cognition is normal and shows no abnormal decline with age, and there is no elevated risk for vascular disease or cancer.
Codes
ICD10CM:M35.9 – Systemic involvement of connective tissue, unspecified
SNOMEDCT:
363045008 – Connective tissue hereditary disorder
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Differential Diagnosis & Pitfalls
- Polyfibromatosis – not associated with conjunctival findings or keloid-like lesions
- Spondylometaepiphyseal dysplasia short limb-hand type (SMED-SL) – loss of function DDR2 variants, premature calcifications
- Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) – not associated with skin disorders, hearing loss, or acroosteolysis
- Mucopolysaccharidoses / Hunter syndrome – cognitive impairment and shortened life span
- Michels syndrome – not associated with skin disorders, hearing loss, or acroosteolysis
- Penttinen progeroid syndrome – associated with premature aging and sparse eyebrows, lashes, and hair
- Keratitis-ichthyosis-deafness (KID) syndrome – associated with palmoplantar keratoderma; causative mutation of connexin-26 (GJB2) and connexin-30 (GJB6) genes
- Progeria – associated with shortened life span
- Hutchinson-Gilford progeria syndrome – associated with shortened life span; causative mutation in laminin A (LMNA) gene
- Nestor-Guillermo progeria syndrome – causative mutation in barrier to autointegration factor 1 (BANF1) gene
- Werner syndrome – causative mutation in RECQ-like DNA helicase type 2 (WRN) gene
- Cockayne syndrome – associated with cognitive decline and shortened life span; causative mutation in excision repair cross-complementing group 8 (ERCC8) gene
- Cutis laxa progeroid type – signs at birth; causative mutation in aldehyde dehydrogenase 18 family member A1 (ALDH18A1) gene
- Fontaine progeroid syndrome – signs at birth; causative mutation in solute carrier family 25-member 24 (SLC25A24) gene
- Corneodermatoosseous syndrome – findings present at birth
- SHORT syndrome – causative mutation in phosphatidylinositol 3-kinase regulatory subunit 1 (PIK3R1) gene
- Wiedemann-Rautenstrauch syndrome – causative mutation in RNA polymerase III subunit A (POLR3A)
- Bloom syndrome – associated with increased cancer risk; causative mutation in RecQ protein-like type 3 (RECQL3)
- Dyskeratosis congenita – associated with bone marrow failure
- Marfan syndrome lipodystrophy type – causative mutation in fibrillin 1 (FBN1) gene
- Lessel syndrome – associated with arteriosclerosis and decreased cognitive abilities; causative mutation in torsin A interacting protein 1 (TOR1AIP1) gene
- Mandibuloacral dysplasia (MAD) – associated with insulin resistance and not associated with corneal vascularization
- Mandibular underdevelopment, deafness, progeroid features, lipodystrophy (MDPL) – causative mutation in DNA polymerase delta 1 (POLD1) gene
- Mucoepithelial dysplasia (Witkop syndrome) – reduced number of desmosomes on electron microscopy
- Juvenile hyaline fibromatosis (JHF) / infantile systemic hyalinosis (ISH) – causative mutation in capillary morphogenesis protein 2 (CMG2) gene
- Torg-Winchester syndrome (osteolysis, nodulosis, and arthropathy) – associated with short stature
- Gorham-Stout syndrome – associated with progressive osteolysis of skull, shoulders, and pelvic girdle
- Neuropathic arthropathy
- Van den Ende Gupta syndrome
- Hajdu-Cheney syndrome
- Mulvihill-Smith syndrome
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Last Reviewed:05/30/2022
Last Updated:07/10/2022
Last Updated:07/10/2022