Warburg-Cinotti Syndrome

A number sign (#) is used with this entry because of evidence that Warburg-Cinotti syndrome (WRCN) is caused by heterozygous mutation in the DDR2 gene (191311) on chromosome 1q23.

Description

Warburg-Cinotti syndrome is characterized by progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acroosteolysis (Xu et al., 2018).

Clinical Features

Warburg et al. (2006) described a 42-year-old Danish man with bilateral congenital blepharophimosis, who postoperatively had progressive corneal vascularization, which eventually developed into symblepharon. The patient also had conductive hearing loss, progressive acroosteolysis of the phalanges, arthropathy, loss of subcutaneous fat of the hands, feet, and face, and oligospermia, and he experienced spontaneous pneumothorax 4 times. Electron microscopy of a skin biopsy was consistent with normal epidermis with stimulated differentiation.

Cinotti et al. (2013) reported a 53-year-old Italian man who developed contractures at age 6 years, beginning in the interphalangeal joints and progressing from distal to proximal and from upper to lower limbs. The skin of his hands and feet thickened, and he developed webbing between the toes and progressive osteolysis, resulting in complete disappearance of the toes and distal metatarsals, as well as restrictive multilayered banding of the skin of the palms. At age 25, thickened hyperpigmented keloid plaques appeared at areas of scarring and slowly progressed in size. In the fourth and fifth decades of life, conjunctival pannus with corneal thinning developed in both eyes, and despite repeated surgical removal, the pannus rapidly recurred, eventually leaving only hand-motion vision bilaterally. Examination at age 45 showed severely deformed hands and feet, with multilayered restrictive fibrotic bands on the palms, hyperkeratotic verrucoid hyperpigmented skin on the legs, and bilateral amputation of toes. He also exhibited gum hypertrophy and gynecomastia. X-rays showed bilateral symmetric osteolytic lesions in hands and wrists, severe flexion deformities of the fingers, bony ankylosis of interphalangeal and metacarpophalangeal joints, and complete bilateral osteolysis of the toes with ankylosis of the tibiotarsal joints. The authors noted similarities to the patient previously reported by Warburg et al. (2006), as well as phenotypic overlap with polyfibromatosis (see 126900).

Xu et al. (2018) studied 6 patients with Warburg-Cinotti syndrome, including the 2 men previously reported by Warburg et al. (2006) (patient 1) and Cinotti et al. (2013) (patient 2), a mother and 2 affected children (patients 3, 4, and 5), and an unrelated 35-year-old woman (patient 6). The 31-year-old mother developed keloid-like plaques at age 5 years, without preceding trauma or inflammation. At age 14, finger flexion contractures developed, which progressed to ankylosis of proximal interphalangeal (PIP) joints and cutaneous fusion between the digits and palm. Surgical correction was followed by rapid recurrence. Gradual cutaneous fusion of the toes resulted in little or no separation of the toes. She also experienced numerous sterile abscesses of the hands and feet, followed by scarring, cutaneous fusions, and contractures. At age 25, she developed corneal neovascularization and subsequent pannus and symblepharon formation on the right eye; ultimately there was complete conjunctivalization of the cornea and visual acuity became hand-motion only. Although she had normal vision in her left eye, examination revealed limbal stem cell deficiency, superior corneal vascular pannus, central corneal thinning, and endothelial cell dysfunction with disruption of healthy hexagonal morphology on specular microscopy. Facial dysmorphism, shared with her affected children, included narrow nose, mild midface retrusion, and epicanthal folds. At age 31, she had generalized thin erythematous skin with follicular hyperkeratosis. X-rays showed relatively normal phalanges of the fingers with contractures, and small hypodense distal phalanges and deformed middle phalanges of the toes, with severe lateral angulation of distal interphalangeal (DIP) joints of toes 3 through 5. Her 8-year-old daughter had thin and somewhat lax skin, contractures of her fourth fingers with thickening of the skin over the flexor tendons, and bilateral superior corneal vascular pannus with central corneal thinning. The proband's 5-year-old son had enlargement of several PIP finger joints, mild flexion contractures of several DIP finger joints, and mild follicular hyperkeratosis, as well as prominent superior corneal vascular pannus. The unrelated 35-year-old woman had angiodermatofibromas and exhibited delayed wound healing with keloid-like scarring. She had hypermobile joints, contractures, and generalized enlargement of finger joints. Chronic ulcers on her toes resulted in loss of all toes and a significant portion of forefoot tissue. Facial features included bilateral blepharophimosis and epicanthus, thin nose with small alae nasi, large low-set ears, and high palate.

Clinical Management

Xu et al. (2018) noted that the DDR2 mutations shown to cause WRCN were activating, and suggested that dasatinib, a leukemia drug that also inhibits DDR2, could be used for treatment of affected individuals. In vitro analysis of cultured patient fibroblasts confirmed that dasatnib abolished the observed autophosphorylation of DDR2.

Molecular Genetics

In 6 patients from 4 families with Warburg-Cinotti syndrome, including the Danish man originally reported by Warburg et al. (2006) and the Italian man reported by Cinotti et al. (2013), Xu et al. (2018) identified heterozygosity for missense mutations in the DDR2 gene (L610P, 191311.0006 and Y740C, 191311.0007). The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Functional analysis demonstrated that both mutations were activating.