Chapter 137. Lipoid Proteinosis and Heritable Disorders of Connective Tissue

Inherited connective tissue disorders are clinically and genetically diverse conditions affecting the skin, joints, and a variety of extracutaneous tissues, including the cardiovascular (CV) system. The nature and severity of the skin phenotype is dependent on the type of mutation as well as the role of the affected protein on dermal structure and function (see Chapter 63). The diagnosis of many inherited connective tissue disorders is clinical, although CLIA-approved genetic testing is increasingly available. A listing of research laboratories that may offer testing can be found at http://www.genetests.org.

A variety of genetically and clinically heterogeneous inherited conditions characterized by varying degrees of skin fragility and hyperextensibility, joint hypermobility, and easy bruising, have been collected under the rubric of the Ehlers–Danlos syndromes (EDS). A new classification system was proposed in 19971 to consolidate and simplify existing subgroups (Table 137-1). Despite these revisions, many patients defy clear-cut classification due to overlapping features. The spectrum of EDS disease severity ranges from nearly imperceptible findings to severe, debilitating disease. As such, it is difficult to estimate EDS prevalence, but if milder forms are included it may be as high as 1:5,000 individuals. The kyphoscoliosis, arthrochalasia, and dermatosparaxis types are considerably less common than the classical, hypermobility, and vascular types. Confusion over the diagnosis of the hypermobility type and its overlap with joint hypermobility syndrome interferes with prevalence estimates. If inclusive definitions are used, it may be the most common subtype. Generalized joint hypermobility is the consistent and unifying finding in all forms of EDS.3 EDS types other than the common classic type and the life-threatening vascular type are discussed in the online edition of the book.

Classical Type

Epidemiology

Classical EDS occurs in 1 in 10,000–20,000 newborns.4

Etiology and Pathogenesis

Approximately half of classical EDS cases are caused by autosomal dominant (AD) defects in the α1 or α2 chain of type V collagen (COL5A1 and COL5A2). Type V collagen is a minor fibrillar collagen that regulates collagen fibril diameter. These mutations may result in dominant negative or haploinsufficient states and approximately one-third of cases are due to haploinsufficiency of the COL5A1 gene.5 Recently, mutations in the signal peptide region of COL5A1, which disrupt type V collagen secretion, have also been identified in patients with classical EDS.6 An additional locus may exist, as several families do not exhibit linkage to COL5A1 or COL5A2.7,8

Patients with features of classic EDS exhibiting defective type I collagen due to AD COL1A1 mutations have also been described.9 These patients have nonglycine substitutions in the type I collagen triple helical domain and, during adulthood, some have developed vascular complications, including spontaneous arterial rupture, similar to the complications of the vascular EDS subtype.10 An autosomal recessive (AR) “cardiac valvular subtype of EDS” exhibits clinical findings of classic EDS as well as the onset of severe cardiac valve problems later in life and results from total loss of the proa2(I) chains of type I collagen due to homozygous or compound heterozygous mutations in COL1A2.11 An AR form of EDS resembling a mild version of classic EDS can result from homozygous tenascin-X (TNX) deficiency. Heterozygotes (especially females) for these mutations may exhibit hypermobility EDS.12

Electron microscopy of the skin in EDS reveals thickened collagen fibrils, highlighting the role of type V collagen in regulating their size. It is proposed that the amino terminus of α1(V) carries a negative charge, conferred by abundant tyrosine residues, and appears to limit fibril growth. Less than 5% of fibrils may exhibit “collagen cauliflowers,” which are rare composite fibrils.13–15

Clinical Findings

Patients with classic EDS typically exhibit some degree of skin and joint hyperextensibility, tissue fragility, and bruising. In the past, patients exhibiting very mild features were termed “mitis.” Typical patients have hyperextensible skin (Fig. 137-1) that recoils easily to its normal position after stretching, in contrast to the skin in cutis laxa (CL). Skin hyperextensibility should be assessed by pulling until resistance is met at a site not subjected to mechanical forces or scarring, such as the volar surface of the forearm. The normal upper limit of extensibility at the volar forearm is 1–1.5 cm. Skin overlying extensor joints tends to be redundant and should not be used to assess extensibility.

The skin is velvety, thin, and bruises easily. Fetuses with classical EDS may exhibit growth retardation, hernias, and joint dislocations. Bruising manifests early in childhood and is often persistent in areas prone to trauma in young children, especially the shins (Fig. 137-2) Tissue fragility can be striking, with seemingly innocuous trauma resulting in disproportionately large skin tears that are relatively painless without excessive bleeding. Wounds often gape.

Even with surgical repair, wounds in EDS often exhibit slow healing and frequent infection. Postoperative wound dehiscence is common if wounds are not adequately secured, often necessitating repeated repairs or secondary intention healing (Fig. 137-3). Even with surgical repair, dehiscence upon suture removal may occur. Healed wounds result in atrophic, often widened cigarette paper-like (or “fish mouth”) scars, especially on pressure points (knees, elbows, forehead, chin) (Figs. 137-2 and 137-3). Hematoma formation, especially at pressure points, often results in persistent hyperpigmentation. Calcification and fibrosis of hematomas produce subcutaneous, nodular molluscoid pseudotumors, most frequently around the elbow and knee. These are often associated with scars. Spheroids are small subcutaneous spherical hard nodules, usually on the forearms and shins that may become calcified and thus detectable radiographically. Additionally, subcutaneous fat herniation on the medial or lateral aspects of the heels or wrists with pressure (piezogenic pedal papules) may be seen. Acrocyanosis and chilblains have also been described in affected individuals.

Joint hypermobility is frequent (Fig. 137-4), and often greatest at the fingers and/or wrists. In suspected patients, including older children and adolescents, it is assessed using the Beighton scale Table 137-2).1,3 Sprains, dislocations or subluxations, scoliosis, and pes planus are common complications and patients frequently describe chronic joint and limb pain, although skeletal radiographs may be normal.16 Patients are typically “double-jointed” and often able to perform various “tricks” with their joints as a result. Such chronic and excessive joint hypermobility frequently leads to early-onset osteoarthritis. Osteoporosis is more common when compared to age-matched controls. Muscle hypotonia and delayed gross motor development are also described. EDS may carry a diagnosis of chronic fatigue syndrome or fibromyalgia due to persistent fatigue and chronic pain.

Most patients with classic or hypermobile EDS are able to extend the tongue to touch the tip of the nose (Gorlin's sign) (Fig. 137-5), although this sign can be displayed by ∼10% of individuals without inherited disorders of connective tissue. Lack of lingual and labial frenulae has recently been noted to be a minor feature of EDS, and is particularly common in patients with the vascular type17 Hypermobility and absence of the frenulae allow some EDS patients to “swallow” their own tongue (eFig. 137-5.1). Hiatal and postoperative hernias as well as anal prolapse have been noted as manifestations of the tissue hyperextensibility and fragility.18 Sexual dysfunction, including dyspareunia is reported, and functional bowel disorders occur in up to half of patients.19

Approximately 40%–50% of affected individuals (in addition to ∼20% of infants born to affected mothers) are born prematurely (32–37 weeks), either due to premature rupture of fetal membranes or chorioamnionitis.20,21 Monitoring during pregnancy and the postpartum period is recommended, because of the risk of premature labor during the third trimester, the increased risk for skin tears, postpartum hemorrhage, and uterine/bladder prolapse.19 The fragility of the already abnormal connective tissue may be worsened by the effect of pregnancy-related hormones that soften connective tissue, such as relaxin.

Patients with classical EDS occasionally exhibit structural heart malformations. Mitral valve prolapse (MVP), and less often tricuspid valve prolapse, may occur and recent reports suggest that aortic root dilatation may occur more frequently than past studies indicated.22 Arterial rupture, intracranial aneurysms, and arteriovenous fistulae have been described in classic EDS, typically in patients exhibiting severe clinical phenotypes, but are much less common than in Marfan syndrome. Baseline echocardiography with measurement of aortic diameter is recommended,19,22 with CT or MRI exams if needed.16 Longitudinal data on progression of aortic dilatation in classic EDS do not exist. The current recommendation is yearly echocardiogram if cardiac abnormalities (aortic dilatation, MVP) are present. If no abnormalities are noted, subsequent studies are only recommended as dictated by symptoms. β-blocker therapy has been successful anecdotally.

Hypermobility Type

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Vascular Type

Epidemiology

This is the most clinically significant EDS subtype due to the risk of arterial or major organ rupture. Inherited in an AD fashion, the incidence is approximately 1 in 100,000–200,000 individuals.4

Etiology and Pathogenesis

Vascular EDS is associated with dominant negative mutations in the type III collagen gene (COL3A1), resulting in reduced amounts of type III collagen in the dermis, vessels, and viscera, as well as decreased production and secretion of type III collagen by cultured fibroblasts.35 More than 320 different mutations have been reported (exon-skipping or missense) and typically lead to disruption of the triple-helical structure of type III collagen. As type III collagen is a homotrimer, mutant proα1(III) chains affect most fibrils, interfering with secretion, and leading to intracellular accumulation. Type III collagen plays an important role in the integrity of both blood vessel walls and the upper dermis. Analysis of type III procollagen and collagen chains and direct genetic testing of COL3A1 have been utilized to test for vascular EDS.

Clinical Findings

The classic quadrad of vascular type of EDS includes a characteristic facial appearance (which may be subtle), thin, translucent skin with a prominent venous pattern (Fig. 137-6), extensive bruising or hematomas, and vascular or visceral rupture (or both).18 Joint hypermobility is usually minimal and limited to the digits. The facial features include a thin nose and upper lip, small earlobes, and sunken, pigmented periocular regions. Subcutaneous fat is decreased, especially of the face and limbs. Widened, thin (papyraceous) scars may be noted on bony prominences. Hematomas, which may be frequent and/or quite large, may develop after minimal to no trauma, such as sphygmomanometer inflation.

Spontaneous rupture of arteries, particularly midsized arteries, may occur during childhood, although its peak age of incidence is the third or fourth decade of life. Mesenchymal abdominal, splenic, and renal arteries are often involved, as is the descending aorta. Aortic rupture/dissection is typically not preceded by detectable aortic dilatation,22 occurs distal to the midaortic arch, and exhibits distal extension. Arterial or intestinal rupture often presents as acute abdominal or flank pain; arterial rupture is the most common cause of death. Stroke is also reported in vascular EDS. Pregnancies may be complicated by pre- and postpartum arterial bleeding, and by intrapartum uterine rupture. Pregnancies carry a 12%–25% fatality rate20,36 Vaginal and perineal tears from delivery heal poorly and caesarean wounds often dehisce.4

Kyphoscoliotic Type

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Arthrochalasia Type

Epidemiology

Clinical Findings

Dermatosparaxis Type

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Other Types of Ehlers–Danlos Syndromes

Laboratory Findings

Routine histopathologic examination of the skin from EDS patients is typically normal. Electron microscopy demonstrates abnormalities in the appearance of collagen fibrils as noted above. Despite the bruising and increased bleeding, tests of platelet function and coagulation are usually normal, further highlighting the underlying defects in skin and blood vessel structural integrity. As noted above for specific subtypes, while genetic diagnosis is possible, especially as a research tool, a variety of biochemical tests are available as well.

Differential Diagnosis

EDS must be distinguished clinically and histologically from CL. In CL, the hyperelastic skin does not return to its normal position after stretching. The kyphoscoliotic and hypermobility forms of EDS must be distinguished from Marfan syndrome, which additionally is characterized by ectopia lentis and characteristic skeletal abnormalities. Molluscoid pseudotumors of the lower legs may mimic subcutaneous granuloma annulare. The easy bruisability and poor wound healing of EDS patients has led to concerns of child abuse.

Vascular EDS exhibits significant clinical similarities to Loeys–Dietz syndrome type 2, an aortic aneurysm syndrome caused by mutations in transforming growth factor (TGF)-β receptor 1 and 2 (TGFBR1 and TGFBR2) genes. These patients also exhibit skin findings including velvety translucent skin, easy bruising, and widened, atrophic scars.60 Prior to detection of arterial anomalies Loeys–Dietz syndrome patients may be misdiagnosed as classic or hypermobility EDS.

Differential Diagnoses

Treatment and Prevention

A multidisciplinary preventative strategy is the most productive approach to the management of EDS patients. Early identification of affected patients with appropriate intervention (pain management, physical therapy, surgery) and education is important.68–70 Nonweight-bearing exercise (swimming) can promote muscle development. Exercise regimens are typically designed to strengthen muscles to stabilize joints and relieve stress. Physical therapy focused on shoulder girdle strengthening, has decreased the frequency of shoulder dislocations in patients with a history of chronic or recurrent dislocation. Some patients use orthopedic devices such as orthotics and braces with benefit.

Avoiding and preventing injuries is of great importance. Assessment of the home environment with modifications to make homes “EDS safe,” such as avoiding hard, sharp edges on furniture and arrangement to prevent or minimize falls, can be helpful. Patients with significant skin fragility or bruising may require protective padding or bandaging and should avoid contact sports and heavy exercise.

When cutaneous wounds do occur, they should be sutured using both subcuticular and cuticular sutures, which are tightly spaced and left in place for a prolonged duration (at least twice as long as standard). Adhesive tapes, bolsters, or pressure bandages are necessary to aid healing, diminish scarring, and lower the risk of hematoma and pseudotumor formation. Close monitoring for postoperative infection is critical and preventative antibiotic therapy is often employed. Pseudotumors of the elbows or knees are typically more easily surgically removed than those on the heels.

Ongoing rheumatologic and orthopedic care may be required to prevent progressive joint disease in certain patients. Low-impact sports are preferable to contact sports and weight training in patients with hypermobility EDS. Ascorbate therapy (∼2 gm/day in adults with proportional decreases in pediatric patients) may improve bruising (but not other findings) in classic EDS. Anti-inflammatory drugs may improve the musculoskeletal pain associated with EDS, but those interfering with platelet function (especially aspirin) should be avoided in patients with significant bruising. Patients with valvular heart disease should be followed by cardiologists, and a baseline echocardiogram with measurement of aortic diameter is recommended before 10 years of age.25

Joint dislocation (with the exception of congenital dislocation of the hip) in EDS typically spontaneously resolves or can be remedied with closed reduction. Patients with hypermobility EDS may benefit from a variety of physical therapy interventions, such as myofascial release therapies and low-resistance exercises for muscle toning. Exercise progression should involve increasing the number of repetitions, frequency, or duration of exercise, rather than increasing resistance and should progress slowly. Pain from writing utensils can be lessened by altering the grip to rest the shaft of writing utensils on the thenar web and holding the tip between the index and ring fingers. Transvaginal pelvic physical therapy has been successfully utilized for abdominal and back pain as well as radicular pain of the lower extremities and dyspareunia. Braces are commonly used to stabilize joints. Intervention is typically multidisciplinary and should involve rheumatology, orthopedic surgery, physical and occupational therapy, and pain management specialists as appropriate. Pain in hypermobility EDS is often undertreated. While reparative or corrective surgeries are often delayed as long as possible, the perioperative complication rate in patients with hypermobility EDS is not increased. Gastrointestinal (GI) symptoms may be quite troublesome and require aggressive therapy with proton pump inhibitors, H2-blockers, and other agents. Calcium and vitamin D supplementation is typically encouraged.31

Patients with vascular EDS should refrain from contact sports or isometric exercise and avoid medications, which impair platelet function. The traditional recommendation has been that invasive vascular procedures should be avoided, unless absolutely necessary (such as with arterial rupture), due to the extremely high risk of vascular rupture. When performed, tissues must be handled with extreme caution due to pronounced intraoperative tissue fragility. A recent series suggested early intervention by skilled surgeons and provided suggestions for management.71 Studies examining the use of β-blockers in vascular EDS are in progress.

Fatigue is a common finding in EDS of most types, present in over three-fourth of patients. It appears most common in hypermobility EDS, but is seen in other forms as well. Contributing factors include disruptions of sleep, impaired self-efficacy, and pain.72 A variety of neuromuscular findings, including reduction in vibration sense and mild-to-moderate muscle weakness, were commonly found in a small group of multiple types of EDS. These symptomatic findings correlated with myopathic features on needle electromyography (EMG) (a mixed neurogenic–myopathic pattern in 60%) as well as muscle ultrasound showing increased echo-intensity and atrophy. The subset of patients with hypermobility EDS resulting from TNX-B haploinsufficiency seem to have fewer neuromuscular issues, although TNX levels correlate inversely with neuromuscular symptoms.73

Pregnancy in the EDS patient should be considered high-risk. The effects of hormonally mediated connective tissue softening on the abnormal connective tissue of EDS have not been studied, but may account for the increased skin fragility, as well as other EDS sequelae, that occur during pregnancy and the immediate postpartum period. Prenatal diagnosis is possible by genetic and biochemical analyses. Unless children are severely affected by their disorder, they generally adjust well to the skin findings and joint hypermobility. The Ehlers–Danlos Foundation is a national support group (www.ednf.org).70

Epidemiology

Marfan syndrome is an AD disorder primarily affecting the skeletal, ocular, and CV systems.74 About 25% of cases occur sporadically, particularly in patients born of older fathers. Parental germline mosaicism has been described.75 The overall prevalence of Marfan syndrome is estimated at approximately 1:5,000–10,000 persons with no racial, gender, or geographic predilection.76 The prognosis for patients with Marfan syndrome has improved over the past three decades due to better medical and surgical treatments.77

Etiology/Pathogenesis

While standard histopathology of affected skin appears normal, with electron microscopy dermal collagen in Marfan syndrome exhibits abnormal thickness, array, and shape, including fibrils of variable thickness, disarray, twisted fibrils, and fibrils with a flower-like appearance and ragged margins, similar to those found in EDS. The content ratio of collagen I to collagen III is also decreased.32 Recently, defects in the architecture of the collagen microfibrils of large vessels, rather than collagen content or cross-linking, have been described.78 The resultant architecture is similar to that seen in abdominal aortic aneurysms and is proposed to explain the weakened aneurysmal vessels in Marfan syndrome.

Marfan syndrome results from heterozygous mutations79 in the profibrillin 1 gene on chromosome 15q21.1.80 The spectrum of clinical phenotypes resulting from FBN1 defects extends beyond classic Marfan syndrome and these disparate conditions have been termed fibrillopathies/fibrillinopathies81 These range from the severe neonatal Marfan phenotype to isolated aortic root dilatation or marfanoid skeletal features without typical CV pathology or ectopia lentis. Fibrillin is a 350-kDa glycoprotein that is a major component of extracellular matrix (ECM) microfibrils, which are structural components of the zonular fibers of the suspensory ligament of the lens and associated with elastic fibers in the aorta and skin. Virtually every family's mutation is different and over 500 mutations have been reported occurring in any of the 65 exons of the gene. No hot spots have been identified, except in cases of neonatal Marfan syndrome. Interestingly, mutations creating premature termination codons appear to lead to milder disease, while those in exons 24–31 are associated with neonatal Marfan syndrome and more severe disease.76,82 Marfan syndrome type II is caused by mutations at the TGFBR2 gene locus.

Fibrillin interacts with latent TGF-β binding protein, sequestering it, and controlling TGF-β availability. Deficiency of fibrillin increases TGF-β availability and fibrillin-1 mutation leads to constitutive activation of latent TGF-β with signaling through both “classic” and noncanonical TGF-β pathways. In vascular tissues, TGF-β is believed to be a critical mediator of both the structure and the function of the vascular ECM, via both matrix deposition and degradation. Increased TGF-β signaling enhances ECM degradation, leading to aneurysm development and progression. Stimulation of either TGF-β pathway can also lead to phosphorylation of Smad, which triggers a profibrotic signaling response. Angiotensin II signals through two receptor types, type 1 (AT1) and type 2 (AT2), which exhibit opposite signaling effects. Angiotensin II signaling through AT1 also increases expression of TGF-β ligands and receptors and stimulates vessel wall fibrosis. In addition to the action of activated TGF-β, macroaggregates of fibrillin monomers form the basic scaffold on which mature elastin fibers are assembled; as a result, abnormal fibrillin creates a disordered microfibril matrix that may further lead to disordered and weak elastic fiber formation and disruption of the microfibril network that connects elastic lamellae to neighboring interstitial cells.83

Research into the impact of these pathways and their potential therapeutic implications for Marfan syndrome is ongoing. Losartan, a blocker of angiotensin II type 1 receptor, has already shown promise in slowing the aortic root dilatation in individuals with Marfan syndrome. Losartan not only blocks TGF-β but appears to decrease phosphorylation of Smad2 independent of its TGF-β effects. Thus, AT1 blockade may interrupt several pathways, which affect vascular remodeling and disease progression.84

Clinical Findings

Marfan syndrome is a generalized connective tissue disorder exhibiting abnormalities of three primary organ systems: ocular (typically lens dislocation); skeletal (excessive extremity length, loose joints, anterior chest deformities, and kyphoscoliosis); and most importantly, CV (classically aortic aneurysm and mitral valve redundancy).81 Many of the typical physical features of Marfan syndrome are age-dependent, making diagnosis in childhood more difficult. No single clinical sign is pathognomonic.85

The “Marfanoid habitus” is characteristically dolichostenomelic (tall and thin), with a lower body segment (pubic symphysis to floor) that is longer than the upper segment (height minus lower segment) (Fig. 137-7). Characteristically, the arm span exceeds the person's height by several centimeters. The distal bones are excessively long (arachnodactyly). Skeletal features of Marfan syndrome are characterized by bone overgrowth and joint laxity. Kyphoscoliosis may be severe and increases with the adolescent growth spurt.86 Thoracic cage abnormalities, such as pectus excavatum (sternal depression) or carinatum (sternal projection), both result from excessive rib overgrowth and are common. The combination of kyphoscoliosis and pectus excavatum rarely compromises cardiopulmonary function. Joint laxity from capsular, ligamentous, and tendinous involvement may cause flat feet, knee or elbow hyperextensibility (genu recurvatum), and occasional joint dislocation. Patellar dislocation is not uncommon; dislocation of the hip, often detected during the newborn period, may be the first sign of Marfan syndrome. Screening tests for joint hypermobility are the thumb (or Steinberg) sign, in which the thumb extends well beyond the ulnar border of the hand when overlapped by the fingers, and the wrist (or Walker–Murdoch) sign, in which the thumb overlaps the fifth finger as they grasp the opposite wrist.86 The underlying joint hyperextensibility and long extremities of Marfan patients often enable them to reach around their back and touch their umbilicus from the opposite side.

Most patients with Marfan syndrome exhibit myopia due to flattening of the corneas and an abnormally long anterior–posterior orbital axis.87 An estimated 50%–70% of patients have ectopia lentis, typically with upward lens displacement. Subluxation and complete dislocation of the lens often lead to secondary ocular abnormalities, including ametropia, myopia, acute glaucoma, and increased risk of retinal detachment.75 As mild displacements may be missed with standard ocular exams, referral to ophthalmology for a dilated slit lamp exam is necessary if a diagnosis of Marfan syndrome is suspected.

CV abnormalities are responsible for the majority of the morbidity and mortality in Marfan patients. CV abnormalities are detected in ∼40% of patients with Marfan syndrome by cardiac examination and almost 100% of patients by autopsy examination. Medial necrosis of the aorta is the most common defect and diffuse dilatation of the proximal segment of the ascending aorta with aortic regurgitation often occurs. Such dilatation is progressive, and may even be detected in utero. The progression of dilatation is not always continuous and this unpredictability mandates frequent monitoring.88 Death in Marfan patients usually occurs in adulthood as a result of CV sequelae, most commonly secondary to dilatation of the aortic root,89,90 leading to aortic dissection or rupture and pericardial tamponade. MVP results from dilation of the mitral valve annulus, with stretching of the chordae and MV leaflet redundancy. It occurs in ∼25% of affected children and adolescents, and in 86% with associated pectus excavatum.91 MVP increases with age, and eventually occurs in ∼75% of patients.92 MVP may lead to abnormal findings on electrocardiogram, mitral valvular regurgitation, and even cardiac arrhythmias leading to sudden death.74

Lack of subcutaneous fat and the presence of striae, most prominent on the upper chest, arms, thighs, and abdomen, are the most common cutaneous manifestations of Marfan syndrome. These cutaneous features are found in up to two-third of patients. Elastosis perforans serpiginosa (see Chapter 69) is more common in individuals with Marfan syndrome, and inguinal or incisional hernias may occur. Skin findings are considered minor diagnostic features in the revised diagnostic criteria.93

Dural ectasia (stretching of the dural sac in the lumbosacral region) often develops in patients with Marfan syndrome. Emphysema has been described, and lung bullae increase the risk of pneumothorax, particularly involving the upper lobes. Oral findings may include a high-arched palate and crowding of anterior teeth.

Neonatal Marfan Syndrome

Infants with the neonatal form of Marfan syndrome have the body disproportion of Marfan syndrome in addition to lax skin, emphysema, ocular abnormalities, joint contractures, kyphoscoliosis, adducted thumbs, crumpled ears, micrognathia, muscle hypoplasia, and deficient subcutaneous fat over joints.94,95 Severe cardiac valve insufficiency and aortic dilatation result in death during the first 2 years of life.

Marfan Syndrome in Pediatric Patients

A recent large retrospective study highlighted clinical features of children in a cohort of more than 1,000 patients with FBN1 mutations. The median age of diagnosis was 6.5 years, and only 30% had a positive family history. Patients with neonatal Marfan syndrome represented 14% of the cohort. Of the affected children, 19% were noted to be severely affected, 32% to have classic Marfan, and 35% of the patients to have probable Marfan syndrome. In the pediatric population, 71% already exhibited dilatation of the ascending aorta. Ectopia lentis was present in approximately half and typical marfanoid skeletal findings in 28%. Aortic arch dilatation was more common in neonatal cases; however, aortic complications were rare in childhood. In uncertain cases the identification of FBN1 mutations often aided diagnosis. While neonatal Marfan syndrome represents a severe de novo early-onset form with associated high mortality, patients diagnosed after adolescence typically resembled adult patients in phenotype. Milder cases were more often had a positive family history, likely because milder cases are more commonly survived to reproductive age. Importantly, pediatric patients often did not meet international criteria for the diagnosis of Marfan syndrome at the time of first examination. As the features of the syndrome increase with age, follow-up examination is critical in suspected pediatric cases to identify affected patients.76

Laboratory Investigation

The diagnosis of Marfan syndrome is based on a constellation of clinical findings. There is no diagnostic laboratory test or histologic abnormality. Increased urinary hydroxyproline and desmosine are not consistent findings. Ophthalmologic examination by an experienced ophthalmologist with interventions as necessary should be performed as early as possible. Orthopedic evaluation as needed and echocardiographic monitoring of aortic root size and valvular function is paramount with cardiology involvement depending on the findings.

Differential Diagnosis

Marfan syndrome is rarely confused with disorders other than homocystinuria (see online edition of this book). However, a variety of conditions exhibit partial phenotypic overlap with Marfan syndrome, including some also caused by fibrillin-1 mutations. These are summarized in Box 137-1.

Treatment

Management of Marfan syndrome has focused on prevention of the disabling and life-threatening potential complications. Early and regular ophthalmologic examinations are required to detect correctable amblyopia and retinal detachment. Ectopia lentis and even complete subluxation may be tolerated for decades. Lens extraction may be required to treat diplopia, glaucoma, cataracts, or retinal detachment. Lasix surgery is contraindicated.

Repair of pectus excavatum is appropriate if cardiopulmonary compromise develops, but is delayed until skeletal maturation is nearly complete to prevent recurrence and should utilize internal stabilization.99 Scoliosis may be lessened in adolescent girls by estrogen therapy, but this may produce an overall decrease in height. Bracing, physical therapy, and vertebral fusion may all be required to prevent severe scoliosis.

A family history of early aortic dissection mandates aggressive monitoring. At a minimum, patients with Marfan syndrome should undergo yearly monitoring. Aortic complications have not been reported in patients with an aortic diameter normal for age or less than 40 mm in diameter (in adults)74 Long-term propranolol therapy has been administered to prevent aortic dilatation by decreasing myocardial contractility,100 but may not affect survival.101 In a small number of children with Marfan syndrome who were recalcitrant to β-blockers, angiotensin II type 1 receptor blockers (losartan and irbesartan) led to a significant decrease in aortic root diameter and dilation of the sinotubular junction. Larger randomized trials examining the effect of these agents are underway.102 Aneurysmal and valvular heart defects may require prosthetic replacement, but this should be delayed for as long as possible to avoid recurrent prosthesis replacement, particularly in growing children. Replacement of the aortic root has led to increased life expectancy and is indicated once the maximal measurement is greater than 5 cm in adults and older children, the rate of size increase is ∼1 cm/year, or progressive aortic regurgitation develops. Patients with known aortic dilatation should avoid caffeine, stressful circumstances, and vigorous exercise. Patients with pulmonary involvement should avoid situations with rapid changes in air pressure, such as scuba diving or flying and, of course, should not smoke.103

Doxycycline inhibits matrix metalloproteinase and has been shown to improve aortic wall architecture and delay aortic dissection in mouse models. Future studies may focus on synergy between doxycycline and losartan, as matrix metalloproteinases can activate TGF-β.77

Children should be excused from participation in physical education in order to avoid potentially harmful exertion, contact sports, and isometric exercises, which might lead to aortic rupture or congenital heart failure. Unfortunately, this can add to the isolation of a child who may already be concerned about an unusual body image or is socially ostracized because of looking “different” or being excessively tall. Importantly, not all patients with Marfan syndrome exhibit striking “classic” phenotypes. When the diagnosis in a patient with an atypical presentation is suspected, one must make certain that appropriate studies are performed, so that potentially lethal internal manifestations are not neglected. The Web site for the National Marfan Foundation is www.marfan.org.

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Differential Diagnosis

Prognosis

Laboratory Investigation

Treatment

Epidemiology

Also known as Grönblad–Strandberg syndrome, this rare entity is a multisystem disorder exhibiting progressive calcification of elastic tissue. It occurs in ∼1:70,000–160,000 individuals but is likely underdiagnosed. Now classified as an AR disorder, occasional pseudodominance is reported and heterozygous carriers may exhibit a phenotype closely resembling pseudoxanthoma elasticum (PXE)123 PXE appears to be more severe in female patients.124 The average age of diagnosis in patients with a positive family history is 8–12 years.125

Etiology and Pathogenesis

The mutated gene in typical PXE is ABCC6, a member of the ATP-binding cassette (ABC) transmembrane transporter family (subfamily C member 6). It encodes multidrug resistance protein 6 (MRP6) and is located on chromosome 16p13.1.126 Most mutations are unique, although two occur more frequently: (1) R1141X, found predominantly in Europe (28.4% of European patients and 18.8% overall) and (2) ABCC6del23–29, which occurs at an overall frequency of 12.9% and is most prevalent in US patients (28.4%).127 MRP6 is expressed primarily in the liver and kidney, two sites not affected by PXE, and little to none is expressed in tissues affected by PXE. Evidence supports the concept that PXE is a “metabolic” disease, with deficiency of hepatic ABCC6 leading to the deficiency of circulating factors necessary to prevent tissue mineralization. This hypothesis is supported by: (1) the progressive nature of the disease; (2) the delayed clinical onset; (3) the inability of serum from PXE patients and Abcc6 null mice to prevent calcium/phosphate precipitation in human smooth muscle cell cultures; and (4) the development of typical calcification in wild-type skin grafted onto a Abcc6 null mouse, but not in Abcc6 null skin grafted onto a wild-type mouse125; and (5) the rescue of PXE mice from developing typical PXE changes by parabiotic pairing with normal mice.128 The great phenotypic heterogeneity exhibited by PXE patients suggests that additional genes or environmental factors contribute to and modify the development of clinical findings. Certain polymorphisms in the promoter of the SPP1 gene (osteopontin) are more frequent in PXE patients than controls, and one is associated with a significantly reduced PXE risk.

Mutations in GGCX, which encodes an enzyme necessary for γ-glutamyl carboxylation of gla proteins, have been described in patients with PXE associated with multiple coagulation factor deficiency.126 In patients with GGCX mutations, PXE, and in ABCC6 null mice, matrix gla protein (MGP), which prevents tissue mineralization when fully carboxylated, is undercarboxylated. It is thought that a factor, such as vitamin K conjugated with glutathione, is potentially transported by ABCC6 from the hepatocyte to the extracellular space, and necessary for MGP carboxylation. ABCC6 deficiency disrupts this transport, leading to defective MGP carboxylation and inability to prevent peripheral tissue mineralization.126 In support of this hypothesis, a recent report described significantly lower levels of vitamin K in the serum of patients with PXE.129

Clinical Findings

Patients with PXE show marked clinical heterogeneity, with some patients displaying lesions of the skin, eye, and systemic vasculature (e.g., GI and coronary vessels),130 while others in the same family (presumably with the same gene mutations) show only involvement of one system. Typically, the skin in PXE demonstrates yellowish, flat-topped, discrete, and confluent papules in the skin creases of the sides and nape of the neck (Fig. 137-8), perineum, axillae, umbilicus, and flexural folds with skin redundancy that increases with advancing age. These changes are often termed “plucked chicken skin.” Calcification of affected skin is common. Multiple comedones have been described in association with the typical skin changes, likely related to elastic fiber degeneration similar to solar elastosis. Perforating periumbilical PXE has also been described.131 Infiltrative oral, anal, and vaginal mucosal lesions may also occur. The dermatologic features generally begin in the second decade but are often subtle and overlooked. Rarely, progression may lead to diffuse skin involvement and/or CL-like laxity in the flexures. Some authors suggest that prominence of the horizontal and oblique mental creases (which separate the lower lip from the chin) prior to 30 years of age is highly specific for PXE. Skin biopsy can be quite helpful, as the typical histologic findings may be found even with minimal or absent skin lesions.132 A differential diagnosis for the characteristic skin lesions of PXE is provided in Box 137-2.

Elastosis perforans serpiginosa is reported in patients with PXE (see Chapter 69).138 Hyperpigmented, reticulated macules, lip telangiectasias, and acneiform and granulomatous lesions have also been described.138,139 While cosmetic concerns over cutaneous lesions may prompt some patients to seek medical input, it is more commonly a visual or vascular complication, such as a GI tract hemorrhage, which prompts patients to seek medical attention.

The most common ophthalmologic finding is angioid streaks (87% of patients). These are radial curvilinear extensions of gray, brown, or reddish coloration from the optic disc, caused by visualization of the choroid through tears in the elastic-rich Bruch's membrane. Calcification of its outer layer, the lamina elastica, leads to fragility and fissuring. Angioid streaks often develop during the third or fourth decade of life, although the youngest patient described was 10 years of age.140,141 Angioid streaks rarely interfere with visual acuity and may progress or remain stationary. Trauma is likely a precipitating factor in the development of neovascularization and hemorrhagic complications. Characteristic irregular retinal epithelial mottling (“peau d'orange”) is commonly seen resulting from degenerated elastic tissue. Peau d'orange retinal changes precede angioid streaks and are the more common ocular finding in children with PXE. Drusen of the optic nerve have also been described, and drusen-like lesions of the posterior pole have been reported in a 12-year-old boy with PXE.140 Additional changes reported in PXE include healing subretinal hemorrhages (“salmon patches”); small scars or white foci that represent residua of past hemorrhage (“pearls”); or pigmented foci from previous hemorrhage (“black dots”).

Loss of vision in PXE tends to occur later in life and is due to scarring and fibrosis from choroidal neovascularization and retinal hemorrhage. It can lead to a disc-shaped degeneration of the central visual area causing central visual loss, although peripheral vision often remains intact.

Calcification of degenerated elastic tissue of the internal lamina of blood vessels with subsequent hemorrhage and/or intimal proliferation is a common and potentially serious complication of PXE. The GI tract and renal vasculature are sites of early manifestations of this degenerative damage, which often presents as acute-onset hemorrhage in the second to fourth decade. It is estimated that 10%–15% of PXE patients will have at least one GI hemorrhagic event. Both hypertension from renal artery stenosis and GI bleeding (especially gastric) may occur as early as adolescence.128 Late vascular sequelae in PXE include cerebrovascular accidents (subarachnoid hemorrhage has been a significant cause of mortality in PXE), intermittent claudication (most common) and myocardial infarction. Severe coronary artery disease has been noted, even in adolescents with PXE; coronary artery bypass surgery may be ameliorative.142 Physical signs may include diminished peripheral pulses, hypertension (three times more common in PXE than the general population), murmurs related to MVP and/or congestive heart failure, and peripheral gangrene. Rectovesical prolapse may also occur.143 Pulmonary and pulmonary vascular involvement is described, but not common. Pregnancy is not contraindicated, but miscarriage rates may be higher in the first trimester, and multiple pregnancies may accelerate the pace of the disease.143

Laboratory Investigation

The histologic changes on biopsy of lesional skin from patients with PXE are diagnostic, showing distinctive broken curls of basophilic elastic fibers with routine hematoxylin and eosin or Verhoeff–van Gieson staining (Fig. 137-9). Calcium deposition on elastic fibers can be easily detected with von Kossa stain. Similar dystrophic fibers have been noted histologically as an incidental finding in inflammatory skin diseases in patients who do not have PXE.144 Electron microscopy shows calcification in a centripetal pattern within elastic fibers.145 Soft tissue radiographs of the upper and lower extremities may reveal vessel wall calcification. Dental radiographs may demonstrate early vascular calcification. Ultrasonography shows a characteristic pattern of dotted increased echogenicity of renal arteries.146 Similar patterns have been described on ultrasound of affected pancreas and spleen. The recommended testing for patients with PXE is summarized in Table 137-3.

Differential Diagnosis

(Box 137-2)

The pebbly pattern and yellow discoloration of flexural skin of classical PXE is quite distinctive. The later development of redundancy may be confused with the sagging skin of CL. Ten percent of patients with β-thalassemia have both angioid streaks and the skin manifestations of PXE, while 16% have only the skin lesions that are clinically and histopathologically typical of PXE.147 d-Penicillamine may induce an acquired form of PXE, but elastic fibers do not become calcified.136,148 PXE-like changes have also been noted both clinically and histologically in long-standing nephrogenic systemic fibrosis.149 (See eFig. 137-9.1.)

Angioid streaks have been described in a variety of disorders, among them EDS, Marfan syndrome, lead poisoning, sickle cell anemia, thalassemia,150 Paget disease of bone, acromegaly and other pituitary disorders, and familial hyperphosphatemia.151

Prevention and Treatment

There is no cure for PXE and a multidisciplinary approach is required to address the myriad manifestations of the disease. Plastic surgery may improve the appearance of sagging skin, although extrusion of calcium particles through the surgical wound may result in delayed healing and unsightly scars.152 Fillers or autologous fat injections have been used to soften the prominent facial creases. GI bleeding can usually be managed conservatively with iced saline lavage and transfusion and rarely requires balloon embolization or surgery for control.153 Anticoagulants [nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin] are typically avoided in PXE patients. All patients should be followed by a retina specialist and instructed in the use of an Amsler grid to detect early symptoms of retinal hemorrhage. There is no ideal treatment for the ophthalmologic complications, although laser photocoagulation (such as verteporfin photodynamic therapy every 3 months)154 may ameliorate the choroidal neovascularization. Recently, intravitreal injections of bevacizumab have been employed for the choroidal neovascularization of PXE with promising results if initiated early.155

Although low calcium (60–1,200 mg/day)156 and low-lipid diets have been advocated, their value has not been clinically tested. A report describing the use of aluminum hydroxide as an oral phosphate binder noted improvement in PXE skin lesions in three of six patients treated.157 Oral ascorbic acid and tocopherol were administered to a single patient with apparent positive response after several years.158 Most recently, a diet with fivefold the standard of magnesium to ABCC6 null mice prevented the development of connective tissue mineralization.159,160 Dietary supplementation with magnesium carbonate, which is used as an antacid and commonly added to table salt to prevent caking, is a simple and attractive therapeutic intervention and studies are ongoing in PXE patients to determine its effectiveness at preventing or ameliorating the progression of the disease.

Regular evaluation and follow-up with a cardiologist should be encouraged. Patients should be advised to protect their eyes from even mild trauma, and about the potential for future visual loss. Because of the potential risk to eyes and calcified vessels when traumatized, contact sports and high-intensity CV exercise should be prohibited for persons with PXE. This can be quite life altering for the child or adolescent, who may not fully understand the consequences of the seemingly minor skin changes. Avoidance of high-cholesterol foods and smoking, control of blood pressure, and safe aerobic exercises may be recommended by the physician. Two support groups are available: (1) the National Association for Pseudoxanthoma Elasticum (www.napxe.org), and (2) PXE International, Inc. (www.pxe.org).

Epidemiology

CL is a heterogeneous group of disorders (Table 137-4) that results from abnormalities in elastic tissue. It is characterized by widespread laxity of skin and, in some cases, involvement of other organs. AD, AR, and X-linked forms exist, with recessive forms the most common. Review of the world literature suggests only ∼200 cases and, importantly, only a striking minority of these patients have a known underlying molecular cause. It is estimated that the success for detecting mutations in patients with AR form of CL (ARCL) type I is only ∼10%.167

Etiology and Pathogenesis

The skin contains a variety of fibers, which contain increasing amounts of elastin as they progress deeper into the skin. Abnormalities in elastic fiber synthesis, stabilization, or degradation may all lead to the clinical phenotype of CL. Elastic fibers are composed of an amorphous elastin component (90% of fibril) surrounded by a microfibrillar sheath based on fibrillin. Elastic fibers do not spontaneously assemble; their construction requires a carefully orchestrated sequence of reactions.161,166 Elastin is synthesized from individual tropoelastin molecules aligned on a network of elastic fibers and the alignment is stabilized via the formation of intermolecular cross-links mediated by copper-dependent lysyl oxidase. Skin elasticity (reversible deformability), as well as that of other tissues such as lung or larger arterial vessels, results from a network composed of elastin fibers. Mutations in the elastin gene (45 kb in length and mapped to 7q11.2.) lead to abnormal elastic fibers (in some due to decreased mRNA stability) and many cases of AD form of CL (ADCL; OMIM #123700).166

Superficial oxytalan fibers extend from the dermoepidermal junction and are composed primarily of microfibril bundles. These extend through elaunin fibers, which run perpendicularly in the papillary dermis and contain a small amount of elastin. Deeper, in the reticular dermis, thick horizontal elastic fibers contain higher amounts of elastin.166 Mutations in genes whose protein products form part of the elastic fiber interface such as fibulin 4 (OMIM #604633) and fibulin 5 (FBLN5, EVEC, or DANCE, OMIM #604580) have been associated with the frequently fatal ARCL type I (OMIM #219100) in humans. Fibulin 5 binds cell surface integrin receptors and key components of elastic fibers, suggesting a role in cell-directed elastic fiber assembly. ARCL type I fibulin 5 mutations lead to abnormal protein folding, decreased secretion, and decreased interaction with elastin and fibrillin-1.169 One patient with ADCL and a duplication in the fibulin 5 gene has been reported.165 Missense mutations in fibulin 4 (EGF-containing fibulin-like ECM protein 2 (OMIM #604633)) have been noted in several patients with unusually severe ARCL type I. Elastic fibers in these patients are severely underdeveloped.170

ARCL type II (Debre type) patients exhibit loss of function mutations in ATP6V0A2, which encodes a subunit of the V-type H+ ATPase. Defects in ATP6V0A2 result in a congenital disorder of glycosylation (CDG-II), due to defective serum protein N- and O-linked glycosylation. Fibroblasts from affected patients demonstrate impaired Golgi trafficking, likely due to abnormal pH regulation in the Golgi compartments. Increased cellular apoptosis also occurs. The exact mechanism by which this leads to the connective tissue defects seen in this syndrome is unclear, although impaired intracellular trafficking may lead to suppressed transport of tropoelastin from the cell.173 Analysis of apolipoprotein C-III isoelectric focusing is diagnostic in all cases.172

Recently, mutations in pyrroline-5-carboxylate synthase (PYCR1), a mitochondrial proline metabolic enzyme, were reported in a group of patients that had previously been diagnosed with a variety of disorders, including wrinkly skin syndrome, De Barsy syndrome, and gerodermia osteodysplastica (GO). This new subgroup has been designated ARCL type II with progeroid features. The resulting abnormal proline metabolism leads to mitochondrial defects and increased cellular apoptosis.171

GO (OMIM #231070) results from mutations in GORAB (SCYL1BP1), a soluble protein highly expressed both in skin and osteoblasts. It interacts with Rab6, which interacts with the conserved oligomeric Golgi complex (COG complex) and is important in Golgi trafficking.174 In contrast to ARCL of the Debre type, no glycosylation defects are present in GO.

The etiology of ARCL type III/De Barsy syndrome remains unknown, however, there is significant clinical overlap with ARCL type II with progeroid features. Molecular analysis of patients carrying the clinical diagnosis of De Barsy syndrome, including mutation screening of PYCR1, should clarify its position as a distinct clinical entity.

Mutations in the ATP7A gene, which encodes a protein member of the P-type adenosine triphosphatase family responsible for copper transport, cause X-linked CL, which is allelic to Menkes syndrome.168 ATP7A mediates copper transport from the GI tract, efflux of excess copper from cells, and delivery of intracellular stores of copper to cuproenzymes.

Acquired forms of CL present after skin inflammation and structural damage of elastic fibers. Increased neutrophil elastase present in affected skin is presumed to disrupt elastic fiber integrity.179 Abnormalities in the genes in which mutations lead to hereditary CL may also play a role in acquired forms of CL. For example, a patient with compound heterozygous elastin mutations showed partial rescue of elastic fiber synthesis by a heterozygous missense mutation in fibulin 5. The resultant elastic fiber system functioned normally, until challenged by Toxocara canis parasite infestation during adolescence, leading to acquired CL.180

Clinical Manifestations

The skin in CL is inelastic and appears pendulous. At birth the infant may appear to have unusually soft and loose skin. The skin is hyperextensible, but does not resume its normal shape after stretching (see eFig. 137-9.2). Persons with CL are often described as having a bloodhound-like facial appearance (Fig. 137-10) and loose skin of the face, neck, shoulders, and thighs often first attracts attention. Young affected children appear aged. Signs of skin fragility are typically absent in contrast to EDS. Both AR and X-linked forms of CL can exhibit congenital onset. Internal organ involvement may be seen with both inherited and acquired CL. The clinical features of described CL subtypes are summarized in Table 137-4.

The ADCL (OMIM #123700) primarily affects the skin. It may present in infancy or adulthood and tends to be relatively benign with a normal life expectancy.163,164

X-linked CL (OMIM #304150) includes patients with the occipital horn syndrome and Menkes disease. Patients with X-linked CL demonstrate distinct congenital findings, including skin laxity, often distal, a thin face with long philtrum and short columella, inverted lower eyelids, a high forehead, and a hooked/beaked nose, as well as large fontanels and brittle hair.

Clinical findings in the ARCL syndromes are quite heterogeneous in both severity and organ involvement. ARCL type I (OMIM #219100) exhibits a severe phenotype with hernias, visceral involvement, and early lethality resulting from profound elastic tissue defects in several organs. The cutaneous findings are pronounced, with loose, hanging, pendulous skin. Children with ARCL type II have distinct clinical findings and can be divided into two groups based on the presence or absence of N- and O-linked glycosylation defects (CDG type II). To date, obvious clinical differences between these groups are not evident. Additional syndromes considered subtypes of CL are summarized in Table 137-4.

Laboratory Investigation

Special stains for elastic tissue (Verhoeff–van Gieson stain) of skin biopsy specimens demonstrate significantly decreased or absent dermal elastic fibers (in both AD and AR forms of CL).166 Remaining fibers are often clumped, short, granular, and fragmented. Increased elastin-associated microfibrils are noted on electron microscopy. Calcification is not typically seen. Electron microscopy is considered diagnostic for most cases of ARCL, revealing moth-eaten elastic fibers, with abnormal elastin fiber branching and reduced elastin synthesis creating loose microfibrils. Increased vascularization of the dermis, reduced collagen bundle size, and underdeveloped elastic fibers reputedly distinguish ARCL type II from wrinkly skin syndrome (WSS).167 Importantly, in both AD and ARCL some patients have exhibited relatively normal electron microscopy and thus the presence or absence of histologic or electron microscopic findings is not necessary for the diagnosis of CL in the clinical setting of loose, hanging skin with decreased elasticity.167 In acquired cases a mononuclear or mixed inflammatory infiltrate containing neutrophils may be present.

An algorithm for evaluation of a new patient with suspected CL has been proposed (Fig. 137-11). Transferrin immunoelectric focusing studies (TIEF) and ApoC-III IEF should be considered in all patients with AR or sporadic CL (especially those with typical facies, late fontanel closure, and developmental delay or central nervous system involvement). It is important to note that CDG may be missed by the TIEF method in young children. However, the ApoC-III IEF pattern is typically abnormal, even in very young patients. Both studies should likely be repeated after 6 months of age.167

Differential Diagnosis

Patients with EDS have skin that regains a normal appearance when released after stretching. Other features of EDS, including joint laxity, increased bruising, and poor wound healing, are not seen with CL. Older patients with PXE may have laxity of skin, especially in flexural areas, but the skin shows a pebbly yellow appearance.181 Histologic examination of lesional skin further distinguishes these entities. A disorder with features of both PXE and CL, as well as deficiency in multiple coagulation factors, results from mutations in the γ-glutamyl carboxylase (GGCX) gene. These patients exhibit mineralized elastic fibers with positive dermal von Kossa staining, and mild retinopathy similar to PXE but with the pronounced skin folds more typical of CL. Patients also exhibit an abnormal bleeding tendency from deficiency of vitamin K-dependent clotting factors (factors II, VII, IX, and X), atherosclerosis, and possibly cerebral aneurysms.182 As in PXE, CL-like changes are also reported in long-standing nephrogenic systemic fibrosis.183

Acquired Cutis Laxa

Acquired forms of generalized and localized CL occasionally occur.137 In type I-acquired CL, ill-defined areas of loose skin appear insidiously but progressively with elastolysis occurring beyond inflammatory areas in many cases. Type I skin lesions involve the head and neck and progress in a cephalocaudal direction. The development of CL is preceded by an inflammatory eruption (urticaria, erythema multiforme, eczematous eruption) in ∼50% of cases. Although type I acquired CL usually begins in adulthood, children have been described with this condition. Pulmonary involvement presents as emphysema and is the most frequent cause of death in acquired cases.137 Severe tracheobronchomegaly is described. Aortic aneurysms with subsequent rupture, and GI and genitourinary diverticulae have also lead to mortality in these patients. Most affected children have not had evidence of systemic elastolysis.

Type II-acquired CL (Marshall syndrome) is a postinflammatory elastolysis characterized by more localized, well-demarcated, nonpruritic erythematous plaques that extend peripherally and have a hypopigmented center. These appear in crops over a period of days to weeks, often in association with fever, malaise, and peripheral eosinophilia. Localized, or less commonly generalized, areas of CL gradually occur at sites of previous inflammation.184 While systemic involvement is rare, fatal aortitis has been reported.185

Acquired CL may develop after drug exposure to penicillin, d-penicillamine,186 or isoniazid. It has been associated with α-1 antitrypsin deficiency, complement deficiency (C3, C4), sarcoidosis, syphilis, systemic lupus erythematosus, systemic amyloidosis, cutaneous mastocytosis,187 and multiple myeloma.

Acquired CL is one of the primary presenting features of hereditary gelsolin amyloidosis (AGel amyloidosis), an AD condition resulting from mutations in gelsolin, an actin modulating protein. Cleavage of the mutant protein creates amyloidogenic protein fragments, which accumulate into amyloid fibrils and are deposited in most tissues. While normal at birth, CL develops with age, initially involving eyelid and scalp skin but eventually becoming more widespread. Patients also note dry skin, pruritus, and fissuring as well as loss of hair. Petechiae and ecchymoses are also common. Noncutaneous findings include corneal lattice dystrophy, as well as cranial and peripheral polyneuropathy. Skin biopsy reveals elastic fiber diminution and fragmentation as well as widespread deposition of AGel amyloid including around elastic fibers. How this leads to destruction of the elastic fibers over time is unknown.188

A transient form of neonatal CL with generalized skin laxity and inguinal hernias has been described in infants born to mothers administered d-penicillamine during pregnancy.189,190 In these cases, the loose skin resolved during the first year of life.

Treatment

While some forms of CL improve with time, others worsen with age. It is important for the clinician to recognize that patients with CL often sustain significant psychological trauma due to their appearance. Intervention as appropriate or desired by the patient, addressing not only the physical aspects of the disease, but the psychological and emotional aspects as well, is critical.

Plastic surgery has been somewhat successful in improving the physical appearance of some patients temporarily and is a reasonable consideration as vasculature and wound healing capability are normal.191 Numerous procedures may be necessary. Herniations are typically repaired when clinically indicated. In cases where cardiopulmonary failure occurs, appropriate drug and ventilatory support is managed by the appropriate specialties. Acquired CL is often recalcitrant to treatment. Dapsone is reported to control acute swelling, which may support a role for neutrophil elastase.192 Botulinum toxin has been used to improve facial cosmesis.193 Recently rescue of elastin insufficiency in mice via introduction of the human elastin gene was described, suggesting a potential avenue for future molecular therapies.194

Epidemiology

Etiology and Pathogenesis

Clinical Findings

Differential Diagnosis

Treatment

Buschke and Ollendorff originally reported the association of connective tissue nevi and osteopoikilosis.207 The disorder is inherited in an AD manner with variable expressivity, but usually complete penetrance. The estimated incidence is 1:20,000.208 It results from loss of function mutations in the LEMD3 gene (also called MAN1).133 LEMD3 appears to antagonize both bone morphogenetic protein (BMP) and TGF-β signaling pathways in human cell lines and, consequently, loss of LEMD3 leads to enhanced TGF-β signaling. Defects in LEMD3 have also been detected in cases of both isolated osteopoikilosis and osteopoikilosis with melorheostosis (“flowing” hyperostosis over the cortex of tubular bones),133 but not in cases of sporadic isolated melorheostosis.209

The connective tissue nevi appear as collections of skin-colored to yellow papules or plaques (dermatofibrosis lenticularis disseminata) that are most commonly located on the buttocks, proximal trunk, and limbs. Many patients begin to develop lesions in early childhood, although later onset and emergence of new lesions while others disappear have also been reported. Histopathologic examination of lesional skin may show increased amounts of elastic tissue (elastoma), although decreased or normal amounts of elastic tissue and abnormalities of collagen have also been described. The bony lesions most frequently appear after 15 years of age. They are discrete spherical areas of increased radiodensity, most frequently noted in the epiphyses and metaphyses of long bone, pelvis, scapulae, carpal, and tarsal bones. The radiographic appearance of the lesions may raise concerns for neoplasia. Although the osteopoikilosis is typically asymptomatic, functional limitation due to decreased mobility of an affected cutaneous area has been reported. Other skeletal abnormalities, including short stature, otosclerosis, and supernumerary vertebrae and ribs have been described. Cataracts and peptic ulcer disease have rarely been reported in patients with Buschke–Ollendorff syndrome. Connective tissue nevi without associated bony changes, morphea, and PXE are the most frequent disorders considered in the differential diagnosis. No therapy is available or necessary.

Epidemiology

Lipoid proteinosis (LP) is also known as hyalinosis cutis et mucosae (OMIM #247100). Only about 300 cases have been reported in the literature. However, it is relatively common in the Namaqualand area of Northern Cape Province in South Africa (frequency of 1 in 300 population). To date, all South African LP patients studied have carried the same mutation (Q276X), likely contributed by a German settler who arrived in 1652 (founder effect).210

Etiology and Pathogenesis

LP is inherited in an AR fashion and is caused by mutations in the gene encoding ECM protein-1 (ECM-1). Although given this name because of its discovery among various connective tissue proteins in a murine stromal cell line, ECM-1 likely has broader functions. ECM-1 is known to inhibit bone mineralization, contribute to epidermal differentiation, and stimulate angiogenesis.211

The ECM1 gene is located next to the epidermal differentiation complex on chromosome band 1q21. ECM-1 is present both in the epidermis and as a secreted protein in the dermis. There are four splice variants: ECM-1a is encoded by the full gene, ECM-1b lacks exon 7, ECM-1c contains an additional exon 5a, and a fourth form shows truncation of 57 amino acids.212 ECM-1a is widely expressed, whereas ECM-1b is expressed only in tonsils, keratinocytes, and the upper respiratory tract. ECM-1c is also expressed in the skin.

ECM-1 appears to have several functions. In the skin, it interacts with several ECM proteins, including perlecan (a heparin sulfate proteoglycan present in basement membranes), fibulin 1C/D, fibulin 3, matrix metalloproteinase 9, fibronectin, the β 3 chain of laminin 332, and collagen type IV. ECM1 may well serve as a “binding core” for cutaneous extracellular and basement membrane proteins.212 The second tandem repeat of ECM1, encoded by exon 7, binds fibulin-1, an extracellular component of most basement membranes. Thus, ECM-1a binds to fibulin, whereas ECM-1b, lacking exon 7, does not.212,213 While ECM-1a is expressed in basal keratinocytes ECM-1b is only expressed in terminally differentiated keratinocytes. Given the differential expression of ECM-1 isoforms in skin, the ability to bind fibulin-1 may be important in keratinocyte differentiation. A report describing ultrastructural evidence of desmosomal detachment in cultured keratinocytes from a pediatric patient with the vesicular lesions of LP suggests a role in normal differentiation as well.214 A recent report in mice found no epidermal alteration in association with over- or underexpression of ECM1, arguing against a role in epidermal differentiation in murine systems, but the relevance for human skin is unclear.215 Both ECM-1a and ECM-1b may stimulate blood vessel endothelial cell proliferation and promote angiogenesis in chicken embryo.216 Abnormalities of the cutaneous vasculature are described in LP.217

Mutations in ECM1 in LP lead to loss of function of ECM-1. The majority of mutations occur in exon 7, with frameshift mutations leading to ablation of the ECM-1a transcript but not that of ECM-1b, which typically lacks exon 7. Mutations outside of exon 7 typically occur in exon 6 and are nonsense or frameshift mutations. Patients with exon 7 mutations may have a slightly milder phenotype than those with nonexon 7 mutations with regard to respiratory and skin (but not neurologic) manifestations.

Antibodies to ECM-1 have been detected in patients with lichen sclerosus (see Chapter 65), which suggests that this disorder represents an acquired form caused by antibody-induced ECM-1 loss.218

Clinical Findings

The most reliable clinical signs for diagnosing LP are a hoarse voice and thickened sublingual frenulum, which prevents patients from protruding the tongue. Secondary features include beaded eyelid papules, infiltration of warty papules of the skin around the elbows and extensor forearms, and mild alopecia. Increased scarring and photoaging of sun-exposed skin may be seen. Scars or scar-like lesions are present in areas of minor trauma but are not increased at sites of surgery or vaccination.210 An algorithm outlining an approach to the patient with suspected LP is shown in Fig. 137-12.

Cutaneous Lesions

The phenotypic features of LP are quite variable, even within families. This is well demonstrated in studies of South African patients, all of whom share the same mutation yet exhibit highly variable phenotypes. The variable expressivity can lead to difficulty in diagnosis of affected patients. The earliest finding in LP is hoarseness from vocal cord infiltration, which occurs at birth or in the first few years of life. Initially, this may be noted as a faint or weak cry and is one of the most striking and consistent features. Hoarseness may progress during the lifetime of a patient. Dysphagia may occur from involvement of the upper aerodigestive tract and esophagus.210,219 Skin lesions usually develop in the first years of life, although the timing of their onset is variable. Importantly, two stages of skin lesions may be noted. A long-neglected and underappreciated clinical feature of LP is the erosions that can develop during childhood.

Blistering can be extensive enough to mimic epidermolysis bullosa. The associated vesicles (and rarely bullae) are typically noninflammatory and heal slowly with hemorrhagic crusting and resultant scarring (Fig. 137-13). Scars may be linear and resemble pseudoporphyria on the face. In some patients, blistering is worse during warmer weather. Skin fragility and easy wounding with minor trauma or friction are noted. Spontaneous development of extrafacial pustular lesions has also been noted. Shedding of sheets of skin, which leaves red oozing areas, has also been described.

The skin lesions of the second stage are better recognized. Although beaded papules along the eyelid margins (moniliform blepharosis) (Fig. 137-14) are considered a classic clinical finding, they are variable and may be subtle. Other cutaneous stigmata include generalized skin thickening with a waxy, yellow appearance as well as areas of distinct papules and nodules. Areas subject to repeated friction or trauma, such as the elbows, halluces, and extensor aspects of the arms and lower legs, may develop overlying hyperkeratosis, which may be quite striking and verrucous (eFig. 137.14.1). The scarring usually begins during childhood and is often worst on the face. It may follow trauma or occur spontaneously, yet no tendency to excessive scarring is noted after surgery or vaccination. Pock-like or acneiform scarring is well described in LP, especially on the face and extremities. Some areas may resemble solar elastosis. Flexural lichenification may also be seen, and patients with LP have been misdiagnosed as having atopic dermatitis. Some patients report increased photosensitivity, and, in some patients, sun-exposed areas exhibit the greatest amount of scarring. Significant pruritus, alterations in the ability to sweat, and abnormal pain sensation have been noted. Alopecia may occur, although it is variable in severity. Nails are normal.219

Related Physical Findings

The mucosae of patients with LP exhibit infiltration and thickening. Early in life, oral erosions may be noted and these may persist.220 Thickening of the lingual frenulum leads to inability to protrude the tongue (Fig. 137-15). The pharynx, tongue, soft palate, tonsils, and lips are typically involved. Laryngeal and pharyngeal involvement may be severe enough to trigger respiratory difficulty, and tracheostomy has been required in rare cases. Shortness of breath or worsening of respiratory difficulties, as well as swelling of the salivary glands (submandibular and parotid), may be triggered by upper respiratory tract infections. Xerostomia and dental caries may be seen.221 Dental abnormalities (absent permanent upper lateral incisors) have also been described. Parotitis from infiltration of Stenson's duct and subsequent blockage can occur.

Central nervous system involvement is a well-recognized, but variable, feature of LP. Amygdala dysfunction has been described, which leads to abnormal perception and appraisal of fear. More recent studies have demonstrated subtle differences between LP patients and normal controls in the judgment of facial expression and emotion, in memory for negative and positive pictures, and in odor-figure association tests. Because of the frequent bilateral amygdala damage, LP has been used as a model disorder for investigation of the function of the amygdala. Neurologic and psychiatric findings include seizures, memory deficits, social and behavioral changes, paranoid symptoms, mental retardation, and aggressiveness. Severe generalized dystonia has also been reported.222

The ocular examination may reveal drusen-like fundal lesions.168 Eyelid infiltration may induce corneal ulcers due to abnormal eyelash positioning, and alopecia of the eyebrows and eyelashes can occur. The abnormal deposition of hyaline material has been detected histopathologically in many internal organs, although this is typically asymptomatic.

Laboratory Tests

Light microscopic evaluation of lesional sections reveals deposition of amorphous eosinophilic material at the dermoepidermal junction, perivascularly, and along adnexal epithelia. There is deposition of hyaline material in the dermis, often perpendicular to the basement membrane (Fig. 137-16). The hyaline material is periodic acid-Schiff positive and diastase resistant, with a composition similar to that of basement membrane. Often arranged in concentric, “onion-skin” layers around vessels, these layers include type III and type IV collagen as well as laminin. Electron microscopy reveals irregular duplication of the lamina densa at the dermal–epidermal junction. Cytoplasmic vacuoles are noted in dermal fibroblasts.223 The presence of lipids varies and is considered a secondary phenomenon due to lipid adherence to glycoproteins present in the hyaline material rather than a primary defect of LP.

The histologic features of the early bullous lesions of LP have only recently been described. Acantholysis of keratinocytes apparently is the cause.224 Electron microscopy suggests an abnormality of desmosomal attachment, with “free-floating” desmosomes noted in bullous lesions. These preliminary findings require confirmation; but are intriguing given the pattern of expression of ECM-1 in the epidermis.214

Three-dimensional analysis of the cutaneous vasculature in LP shows enlarged vessels in the mid- and deep dermis with an orientation parallel to the dermal–epidermal junction. The dermal papillary plexus also lacks capillary loops. As in lichen sclerosus, the subcutaneous plexus and transverse connecting vessels are atretic or poorly formed.217 Such vascular abnormalities may reflect a disturbance of ECM-1 function during angiogenesis.

Special Tests

Computed tomographic scans of the brain reveal bilateral anterior medial temporal lobe calcifications, often bean-shaped, and especially within the amygdala, in 50%–75% of LP patients.222

Histopathologic evaluation of these lesions shows amorphous masses of calcium and bone along with multiple haphazardly arranged small blood vessels with wall calcification and gliotic adjacent tissue. The cortex and white matter show isolated blood vessels occluded by fibrin, parietal calcification, small perivascular infarctions, and demyelination.225 Immunohistochemical staining of skin biopsy specimens may show absence or attenuation of ECM-1. This may prove to be a valid diagnostic test, not only to aid in diagnosis in mild cases but also potentially to direct molecular investigations.226

Differential Diagnosis

(Box 137-3)

Prognosis and Clinical Course

The prognosis of LP is variable. Often, there is progressive worsening of cutaneous features, with clearance during childhood of blistering lesions and progressive development of infiltrative lesions. The hoarseness and mucosal lesions also may progress with time. Although some patients have experienced respiratory complications from upper respiratory tract infiltration that have, in rare cases, led to early mortality, most patients have a normal life span. It is important to recognize the impact of LP on the quality of life of affected patients. The disfiguring nature of the skin lesions, along with the abnormal voice, significantly impacts the interactions of LP patients with others. Patients have increased difficulty in holding jobs.210

Treatment

Many agents, including topical and systemic corticosteroids, oral dimethyl sulfoxide,227 and intralesional heparin, have been investigated and used in the treatment of LP. None of these agents has demonstrated any sustained benefits. A recent report describes the use of acitretin in one patient, with improvement in hoarseness but not skin lesions.228 Given the apparent photoexacerbation of lesions in a subset of LP patients, photoprotection seems reasonable, although there are no data confirming any benefit. Additionally, avoidance of friction or trauma may be helpful given the prominence of lesions on frequently traumatized sites. Early intervention for developmental problems is important, and management of other stigmata by the appropriate specialists is warranted. Various surgical modalities such as dermabrasion and CO2 laser procedures have been used to treat cutaneous lesions. CO2 laser surgery for vocal cord lesions and eyelid papules has been helpful.229,230

Prevention

Prenatal genetic testing in families at risk is theoretically possible using DNA-based analysis.