Disorders of Collagen Synthesis or Extracellular Matrix The group of disorders of collagen synthesis includes several diseases with cardiac involvement Included in this discussion are Ehlers-Danlos syndrome, cutis laxa, osteogenesis imperfecta, and Marfan syndrome Alcaptonuria also comes into this general group but, as yet, cardiac disease has not become manifest in childhood Direct cardiac involvement does not occur in epidermolysis bullosa, but the heart may be affected when the condition is complicated by amyloidosis Ehlers-Danlos Syndrome Phenotypical features unite the biochemically and genetically heterogeneous group of disorders included in Ehlers-Danlos syndrome The stigmas are hyperextensible skin and joints, easy bruising, and poor healing of wounds A distinctive facial appearance includes epicanthic folds, a flat bridge of the nose, and prominent downward pointing ears Apart from the palms and soles, the skin is smooth and rubbery In later life it may hang in folds from the elbows Premature death is common in the most severe form, and the babies have poor muscular tone In addition to the epicanthic folds, ocular signs include easy eversion of the upper eyelid, known as the Metenier sign, blue scleras, and a dislocated lens A variety of congenital cardiac malformations have been reported,176–178 being found in approximately one-eighth of patients in one study Prolapse of the mitral valve had previously been reported to be common in these patients, but a more recent study shows an incidence similar to that of the general population.148 More than 10 subtypes of Ehlers-Danlos syndrome have been described, but six major subtypes are recognized, comprising nine-tenths of individuals affected Patients typically fall into the hypermobility, classical, or vascular type Classic Ehlers-Danlos syndrome, incorporating types I and II, demonstrates the typical cutaneous findings It most often results from defects in one or more of the collagen or procollagen genes The hypermobility type is similar, with joint hypermobility the predominant clinical feature Both of these types, though not characteristically demonstrating vascular changes, have been shown to be associated with dilation of the aortic root and valvar dysfunction.179 the vascular type, also known as Ehlers-Danlos syndrome type IV, results from mutations in the COL3A1 gene encoding type III collagen and accounts for 5% to 10% of all Ehlers-Danlos cases.180 These patients are at risk for arterial rupture, which typically occurs after the onset of the third decade of life.181 The median survival for patients with Ehlers-Danlos syndrome type IV is up to 48 years of age primarily due to arterial rupture and often without preceding aneurysms Surgery may be needed for life-threatening complications, but a conservative approach is usually preferred owing to tissue characteristics, poor wound healing, and hemorrhage risk.182 A more severe recessive form has been reported, including both the cutaneous findings of the classic form coupled with cardiac valvar involvement.183 Cutis Laxa Cutis laxa is, again, a genetically heterogeneous group of conditions characterized in the phenotype by the skin being so loose that it appears too large for the body Unlike the case in Ehlers-Danlos syndrome, the lax skin is slow to recoil after being stretched Cutis laxa has some features in common with the Ehlers-Danlos syndrome, such as fragility of the skin, hypermobile joints, and easy bruising There are characteristic facies, including a long upper lip, a hooked nose, and a short columella The defect of connective tissue also results in a deep voice, owing to lax vocal cords Hernias and rectal or vaginal prolapse can also be seen The disease can be inherited in both autosomal dominant and autosomal recessive forms From the cardiac standpoint, peripheral pulmonary stenosis184 and aortic dilation have been reported.185 These findings, coupled with reports of supravalvar aortic stenosis,186 have helped lead to the discovery that defects in the elastin gene are one cause of this disorder.187 Defects in other genes, including fibulin-4 and fibulin-5, have also been implicated in some forms.188,189 Another major complication is cor pulmonale, since the associated emphysema is frequently progressive and severe.190 Patients with the neonatal variant of cutis laxa can have severe mitral regurgitation with dysplastic valvar leaflets.191 Osteogenesis Imperfecta Osteogenesis imperfect is caused by mutations in genes for collagen type I Bone fragility is the main clinical feature of this condition Although the fractures are subperiosteal, with little displacement, the multiplicity of fractures leads to bowing of the long bones Additionally, the vertebrae are biconcave, with the disc sometimes perforating the vertebral body to give the appearance known as Schmorl nodes The skull is frequently made up largely of wormian bones and shows frontal and parietal bossing The skeletal deformities lead to short stature The skin is thin but not lax The sclerae are blue in most types In the so-called type III variant of the disease, they may become less blue with age Despite collagen type I being an important cardiac protein clinically, significant cardiac disease is rare in children and young adults with osteogenesis imperfecta.192 The cardiovascular manifestations include aortic and mitral regurgitation owing to dilation of the valvar hinges or, in the latter, to prolapse from ruptured cords It has been suggested that aortic root dilation may be present in a certain subset of patients with osteogenesis imperfecta and that it appears to be nonprogressive.193 In some patients, aortic or mitral valvar disease is severe and may require replacement surgery This carries a higher than normal risk due to bleeding complications related to tissue friability Administration of recombinant factor VIIa may be helpful in controlling bleeding in these patients.194 Aortic stenosis, defects of the oval fossa, and tetralogy of Fallot have also been reported.195 Marfan Syndrome Marfan syndrome is transmitted as an autosomal dominant disease with variable clinical expression The prevalence is estimated at 2 to 3 per 10,000 The disease is due to defects in the FBN1 gene on chromosome 15q21, which encodes fibrillin-1, an important component of connective tissues More than 600 mutations in the gene have been identified, and approximately one-quarter to three-tenths of cases represent new mutations Although expression of the disease is highly variable, even among family members with the same genetic defect, some correlations between genotype and phenotype have been clarified.196 More than seven-tenths of those affected are diagnosed before the age of 10 years Physical features of the syndrome may be present at birth.197 Affected persons are usually very tall, with an increase in the length of the limbs compared with the trunk Their arm span exceeds their height (Fig 59.3A) They have long thin fingers (see Fig 59.3B–C), hypermobile joints, kyphoscoliosis, and chest deformities High arching of the palate, with dental crowding, is