This work was supported by grants
This work was supported by grants from the Institute of Cancer Research (ICR) and Biotechnology and Biological Sciences Research Council (BB/I014276/1 and BB/M013782/1).
Main Text In 2006, Warburg et al. described an apparently distinct connective-tissue disorder characterized by blepharophimosis, progressive corneal vascularization, retinal dystrophy, conductive hearing loss, acro-osteolysis, and wasting of subcutaneous tissue in the face, hands, and feet. For updated pictures of the described individual, see Figure 1. Cinotti et al. later reported an individual with similar features. In this report we extend the clinical description by identifying four additional individuals, three of whom are from a single family, and identify the molecular cause of this syndrome. The clinical findings are illustrated in Figures 1 and 2 and are summarized in Tables 1 and S1. Pedigrees are provided in Supplemental Figures S1–S4. Individuals 1 and 2 have been described in detail.1, 2 The proband of the third pedigree (individual 3) is a 31-year-old female with two affected children (Figures 2 and S3). She was born with a clubfoot, which was successfully treated. When she was 5 years old, the first red, linear, and firm keloid-like plaque appeared spontaneously on her left forearm. This was slowly progressive. Over the years, several additional red papules and linear or annular plaques developed on her arms and feet, without preceding trauma or inflammation. In contrast, no keloid formations have occurred after surgical and traumatic wounds, with the exception of one instance after an ear helix piercing. At age 14, finger flexion contractures, preceded by painless, non-erythematous swelling of the involved joints, developed. This progressed to ankylosis of proximal interphalangeal (PIP) joints and cutaneous fusion between the digits and the palm (Figures 2E and 2F). Surgical correction and collagenase injections allowed the fixated digit to extend, but rapid recurrence and progression occurred. Gradual cutaneous fusion of the toes led to little or no 740 Y-P of the toes (Figures 2I and 2J). She has had numerous sterile abscesses of the hands and feet, and these abscesses were often followed by scarring, cutaneous fusions, and contractures. From the age of 25, she developed corneal neovascularization and subsequent pannus and symblepharon formation on the right eye; eventually, there was complete conjunctivalization of the cornea and a reduction of her visual acuity to hand motion only. Her left eye has normal vision, but examination showed limbal stem-cell deficiency (LSCD), a superior corneal vascular pannus, reduction of the central corneal thickness to 419 μm, and endothelial-cell dysfunction with disruption of healthy hexagonal morphology (Figures 2A–2C). Fundoscopy showed normal retinal findings. Her facial features include a mild narrowing of the nasal bridge, mild lower-midface retrusion, and mild epicanthal folds. The lengths of her palpebral fissures are normal. She was diagnosed with hypothyroidism in her 20s. She has generalized thin skin and erythema.The hyperkeratosis of follicular orifices of her arms, neck, and chest resembles keratosis pilaris. Radiographs of the hands showed relatively normal phalanges with contractures. Radiographs of the feet showed small, hypodense distal phalanges and deformed middle phalanges, and in the 3-5th toe severe lateral angulation of the DIP joints could be seen (Figure 2H). She had enlarged frontal sinuses on skull films and no apparent osteolysis. Her eldest daughter (individual 4) had a normal birth and health history in early childhood. She developed contractures of her fourth fingers at 4–5 years of age; these contractures were associated with painless, non-erythematous swelling of the involved joints. Her PIP contractures were ∼90 degrees on the right fourth finger, but less severe on the left third finger. On her palms, she had associated scar-like thickening overlying the flexor tendons of the fourth digits (Figures 2K and 2L). She had a right cholesteatoma removed at age 4; this recurred and was removed again at age 8. On evaluation at age 8.5, she had a faint papular erythematous rash on her arms, face, neck, and chest; a 3 mm bluish papule with a punctate eschar on her right upper arm; and a soft, slightly bluish 1.5–2.5 cm mass on the sole of her left foot. Although her vision was normal, she had a superior corneal vascular pannus and reduced central corneal thickness (right eye 491 μm, left eye 484 μm), but normal endothelial cell morphology on specular microscopy. She has a long face with midface retrusion, a narrow nose, short palpebral fissures, epicanthal folds, and thin ear cartilage. Her skin is thin and somewhat lax, similar to her mother’s, although her feet appear relatively normal.