5 Connective Tissue, Skin, and Bone Disorders Elias I. Traboulsi CONNECTIVE TISSUE DISORDERS Pseudoxanthoma Elasticum Pseudoxanthoma elasticum (Grönbald–Strandberg syndrome) (PXE) affects about 1 in 70,000 to 1 in 100,000 individuals. It is characterized by skin abnormalities in the neck, axilla, and other flexural areas, breaks in Bruch’s membrane with formation of angioid streaks, and disruption of arterial walls producing gas- trointestinal and other hemorrhages, calcification, and occlusive vascular changes. The vasculopathy is characterized by frag- mentation and calcification of the elastic component of the media, leading to vascular fragility and atherosclerosis. The vas- culopathy results in gastrointestinal hemorrhages, neurological abnormalities,122 coronary atherosclerotic heart disease, renal failure and hypertension, and peripheral vascular disease.36 The disease becomes manifest in the third decade, but gastrointesti- nal hemorrhage has been reported as early as 6 or 7 years of age. Mitral valve prolapse occurs in 70% of patients.155 Cutaneous findings are characteristic and consist of yellowish, xanthoma- tous lesions that coalesce to form peau d’orange plaques in areas of skin folds such as the neck, axilla, and genital, popliteal, and periumbilical regions. Mucosal lesions can also be present on the lower lip, rectum, and vagina. Skin biopsy reveals fragmen- tation and clumping of elastic fibers in the dermis with scat- tered calcifications. The gene causing both recessive and dominant varieties of PXE has been mapped to chromosome 16p13.1272 and identified as the ABCC6 (MRP6) gene, a member of the ATP transporter 227 228 handbook of pediatric eye and systemic disease family. Molecules presumably transported by ABCC6 may be essential for extracellular matrix deposition or turnover of con- nective tissue at specific sites in the body.15 Given the high expression of ABCC6 in liver and kidney, ABCC6 substrates may be transported into the blood. A deficiency of specific ABCC6 substrates may affect a range of connective tissue sites throughout the body and specifically the elastic fiber assembly. A number of mutations that support autosomal recessive inheritance have been found, and an R114X mutation was found in families segregating autosomal dominant and autosomal recessive PXE. Initial debates as to number of varieties and modes of inheritance were caused by the variability of disease expression within families and among patient groups; some have predominant ocular disease with mild cutaneous findings and vice versa. Based on a study of 180 cases, Pope213–215 postulated the existence of two dominant and two recessive varieties with 47% of cases having recessive disease. Neldner193 found that 97% of patients probably had recessive disease. An additional recessive variant with severe ocular findings and relatively mild cutaneous and vascular changes may exist in Afrikaners and Belgian patients.61,293 The classic variety involving skin, blood vessels, and the eye corresponds to type I recessive in Pope’s classification. Histopathological findings may allow preclinical diagnosis in familial instances.108 Angioid (blood vessel-like) streaks occur in 85% of patients with PXE, and 70% of these patients experience subsequent visual loss.46,96 The streaks represent linear discontinuities in Bruch’s membrane starting at the optic nerve head and radiat- ing toward the equator of the globe. The elastic layer of Bruch’s membrane is abnormal and calcific; this leads to cracks involv- ing the full thickness of the membrane.37 Fibrovascular prolifer- ation from the choroid and through the crack may lead to serous or hemorrhagic detachment of the retinal pigment epithelium. Angioid streaks may remain stationary or may progress inter- mittently in number, length, or width. Visual symptoms result from retinal hemorrhages, extension of angioid streaks into the macula, choroidal atrophy or sclerosis, and retinal pigment epithelial atrophy. Angioid streaks are best visualized using flu- orescein angiography.119,236 Other ocular findings in PXE include a peau d’orange appearance to the fundus and scattered punched- out chorioretinal lesions in the fundus periphery (Fig. 5-1).37,255 Secretan et al.245 analyzed the retinal and choroidal vascular abnormalities in eyes with angioid streaks (AS) associated with chapter 5: connective tissue, skin, and bone disorders 229 FIGURE 5-1. Fundus of patient with pseudoxanthoma elasticum. Note peau d’orange appearance and optic nerve head drusen. PXE. Color photographs and fluorescein angiograms of 54 eyes of 27 consecutive patients with AS and PXE were examined retrospectively. Four (7%) of the 54 eyes had a major vascular abnormality at the level of the disc; this took the form of a large vascular loop corresponding to an arteriovenous communication between retina and choroid in 3 eyes (6%) and an anastomosis between two retinal arteries in 1 eye (2%). The management of patients with PXE consists of treatment of vascular complications and cardiac valvular and myopathic lesions, and, when possible, photocoagulation of choroidal neo- vascularization that may complicate the AS. Because testing for the genetic mutation(s) responsible for PXE is not routine, genetic counseling must be done with caution. Sherer et al.254 described four families in which one or more children were diag- nosed with PXE. Detailed examination of the parents was carried out, including skin biopsy and ophthalmologic exami- nation. In three of the four families, one parent had limited phe- notypic expression, such as ocular findings without skin lesions or very mild skin lesions with no ocular findings. In the other family, one parent had very mild skin and ocular disease. All four affected parents had diagnostic skin biopsy findings. In none of the four families was the inheritance pattern clear cut. Although the inheritance pattern of PXE has been debated, clin- ically significant stigmata of PXE, which are not always readily 230 handbook of pediatric eye and systemic disease apparent, can occur in successive generations. Therefore, all first-degree relatives of affected patients should undergo a full dermatological examination as well as a funduscopic examina- tion. If even mild typical skin or eye findings are present, then skin biopsy should be performed. Ehlers–Danlos Syndrome There are several types of Ehlers–Danlos syndrome (Table 5-1). Characteristic joint hyperextensibility and skin laxity are demonstrated in Figure 5-2. Ehlers–Danlos syndrome type VI (lysyl hydroxylase deficiency) is the form of most interest to ophthalmologists because of the potential for rupture of the globe or retinal detachment following minor trauma. Judisch et al.131 observed spontaneous rupture of the globe in the absence of lysyl hydroxylase deficiency. Their patient probably had the syndrome of macrocephaly–Ehlers–Danlos VI phenotype reported later by Cadle et al. in 1985.29 Other similar patients have been reported since and have had normal levels of lysyl hydroxylase.238,313 Zlotogora et al.313 divided patients with the so- called brittle cornea syndrome into two groups. The first group comprises Tunisian Jewish patients with red hair and ocular fragility, and the second larger group is composed of patients of TABLE 5-1. Clinical Features of Ehlers–Danlos Syndrome. Type, inheritance, gene, and locus Clinical features Ocular features I (gravis) Most common; hyperextensible Stretchable lids; OMIM #130000 skin; easy bruisability; retinal Autosomal dominant cigarette-paper scarring; detachment COL5A1 gene defects difficult healing; six different has been 2q31, 17q21.31–q22, errors of metabolism reported 9q34.2–q34.3 II (mitis) Like type I but milder; may be None OMIM #130010 most common form of EDS Autosomal dominant COL5A1 and COL5A2 gene defects 9q34.2–q34.3 III (benign hypermobility) Severe hypermobility of all joints None OMIM #130020 without musculoskeletal Autosomal dominant abnormalities; minimal skin COL3A1 gene defect changes; autosomal dominant 2q31 chapter 5: connective tissue, skin, and bone disorders 231 TABLE 5-1. (continued) Type, inheritance, gene, and locus Clinical features Ocular features IV (ecchymotic or Sack) Abnormalities of medium and large None OMIM #130050 arteries with spontaneous Autosomal dominant arterial rupture at a young age; COL3A1 gene defect bowel perforation; thin and 2q31 transparent skin; minimal hyperextensibility of joints and skin laxity V Minimal joint hypermobility; None OMIM #305200 marked skin hyperextensibility; X-linked recessive mitral valve prolapse VI (ocular) Blue sclerae; OMIM #225400 Hypotonia in infancy followed by spontaneous Autosomal recessive severe scoliosis, recurrent joint rupture of Lysyl hydroxylase dislocations and stretchable skin; globe; deficiency high risk for catastrophic arterial glaucoma; 1p36.3–p36.2 rupture keratoconus VII (dermatosparaxis) Short stature; extreme generalized Hypertelorism; OMIM #225410 joint hypermobility; moderate epicanthus Autosomal recessive skin stretchability and ADAMTS2 gene defect bruisability 5q23 VIII Accompanying periodontosis None OMIM #130080 Autosomal dominant IX Occipital bony horns; loose stools; None OMIM #304150 obstructive uropathy; bladder X-linked diverticulae; joint laxity; hooked Cu(2ϩ)-transporting nose; short broad clavicles; fused ATPase, alpha carpal bones; mild mental polypeptide defect retardation Xq12–q13 X Mild clinical findings None OMIM #225310 Autosomal dominant Possible fibronectin defect 2q34 XI Familial joint instability None OMIM #147900