History

Patients with features of Ehlers–Danlos syndrome (EDS) were described as early as the mid-1600s. The first comprehensive report of this condition was published in 1892 by Tschernogobow . Drs Ehlers and Danlos, Danish and French dermatologists, respectively, contributed to a comprehensive clinical description in the early 1900s, and this constellation of findings became known as the Ehlers–Danlos syndrome in 1936. The genetic nature of EDS was noted in 1949, and soon thereafter it was suggested that the phenotype resulted from abnormal collagen. The genetic heterogeneity of EDS became evident in the 1960s, and molecular defects in collagen synthesis were first described in 1972.

In the past, EDS was divided into 11 subtypes (numbered I–XI) based primarily upon clinical features. In 1997, a consensus conference was held and a revised nosology was proposed . Currently, the molecular basis of most major forms of EDS is known and a new international classification was proposed in 2017, recognizing 13 subtypes ( Table 97.2 ).

Epidemiology

Features suggestive of EDS (e.g. loose-jointedness) are present in a relatively large number of individuals in the general population, especially in certain African groups. However, more stringent diagnostic criteria that include findings in the skin and joints, at a minimum, estimate the incidence of EDS to be ~1 in 5000.

Pathogenesis

EDS is a genetically as well as clinically heterogeneous group of connective tissue disorders that most often result from disruption of collagen fibrils ( Fig. 97.1 ). The collagen family includes 28 distinct proteins that differ in their tissue distributions and functions (see Ch. 95 ). Each collagen consists of three α-chain polypeptides, many of which are synthesized as precursor pro-α-chains; a trimeric collagen molecule may be either a homotrimer or heterotrimer consisting of the same versus two or three genetically different kinds of polypeptides, respectively. There are 45 distinct α-chains, each encoded by a different gene .

Collagen biosynthesis, secretion and fibril assembly – relationship of pathology to the major subtype of Ehlers–Danlos syndrome.

AD, autosomal dominant; AR, autosomal recessive; Glc-Gal, glucosyl-galactosyl residue attached to the hydroxyl group (OH) of lysine residues; S-S bonds, disulfide bonds.

The pathogenesis of EDS can involve mutations in genes for collagen-processing enzymes as well as those encoding collagen α-chains. The latter result in either dominant-negative effects, e.g. disruption of trimers and fibrils due to incorporation of mutant collagen α-chains, or haploinsufficiency. The precise phenotype depends upon the nature of the mutation(s) and the type of collagen or other protein that is affected.

Several forms of EDS are caused by dominant-negative mutations in the genes encoding α-chains of type I ( COL1A1, COL1A2 ), type III ( COL3A1 ), and type V ( COL5A1, COL5A2 ) collagens. Characteristic examples include splice site mutations that can result in an in-frame deletion of a single exon and missense mutations that lead to a glycine substitution in the collagenous domain. The resultant “mutant” polypeptides are incorporated into the polymeric collagen molecules and disrupt the formation, secretion, and/or thermal stability of triple helices. As a consequence, the collagen fibrils are often reduced in amount as well as structurally abnormal.

Haploinsufficiency is caused by a heterozygous loss-of-function mutation, usually associated with a premature termination codon. These types of mutations often result in unstable mRNA that undergoes accelerated decay, leading to an absence of the corresponding polypeptide. Haploinsufficiency can also be caused by a missense mutation encoding a polypeptide that cannot be incorporated into collagen triple helices. Haploinsufficiency occurs when the synthesis of only 50% of the normal amount of the collagen is not enough to form fully functional fibrils, thus resulting in a disease phenotype.

Vascular EDS can result from either dominant-negative mutations in COL3A1 or haploinsufficiency of type III collagen, with the latter associated with a delayed onset of arterial complications and prolonged survival . Collagen III is an important component of arterial and intestinal walls and a less abundant component of dermal connective tissue. However, a reduced amount of type III collagen leads to small or variably sized dermal collagen fibrils and thinning of the dermis, emphasizing the role of type III collagen in fibrillogenesis. A decreased amount of collagen III in the dermis has also been detected in some patients with the periodontal and kyphoscoliotic types of EDS which, unlike vascular EDS, are not caused by COL3A1 mutations.

Classic EDS can be caused by dominant-negative mutations in COL5A1 and COL5A2 or (in 30–50% of cases) haploinsufficiency of type V collagen ( COL5A1 ). The role of type V collagen in collagen fibrillogenesis is to limit fibril diameter, explaining the ~25% increase in fibril diameter that is observed by electron microscopy in affected individuals.

Arthrochalasia EDS results from heterozygous COL1A1 and COL1A2 mutations that specifically affect the amino-terminal cleavage site of procollagen I N-peptidase and thereby disrupt processing of type I collagen pro-α-chains. Biallelic loss-of-function mutations in ADAMTS2 which encodes this procollagen I N-peptidase are responsible for dermatosparaxis EDS. The latter disorder is characterized by irregular and thin collagen fibrils containing type I collagen with an intact N-propeptide, termed pN-collagen. Kyphoscoliotic EDS is caused by biallelic mutations in PLOD1 , which encodes another collagen-processing enzyme, lysyl hydroxylase; this leads to reduced hydroxylysine content in collagen polypeptides and altered cross-linking of collagen fibrils.

Complete tenascin-X deficiency via biallelic null mutations underlies an autosomal recessive form of EDS with features similar to those of classic EDS . Tenascin-X is an ECM protein that is thought to reinforce associations among collagen fibrils and may also regulate the structure and stability of elastic fibers. EDS can also result from defective glycosaminoglycan processing due to mutations in genes encoding galacto­syltransferases ( B4GALT6, B3GALT7 ), dermatan-4-sulfotransferase 1 ( CHST14 ), and dermatan sulfate epimerase ( DSE ) (see Ch. 95 ). Other EDS types occur through diverse mechanisms including disruption of intracellular zinc homeostasis (solute carrier family 39, member 13 [ SLC39A13 ]), protein folding in the endoplasmic reticulum (FK506-binding protein 14 [ FKBP14 ]), and the classical complement pathway ( C1R , C1S ).

Clinical Features

The general features of EDS include hyperextensible fragile skin and joint hypermobility ( Fig. 97.2A, B ). The Beighton scale can be utilized to assess the latter , and different subtypes of EDS have additional manifestations that allow their classification into the six major categories defined by the 1997 consensus conference ( Fig. 97.3 ). Table 97.2 outlines the other recognized variants of EDS.

Clinical features of Ehlers–Danlos syndrome (EDS).

Patients with classic EDS demonstrating hyperextensible skin ( A ), joint hypermobility at the wrist ( B ), atrophic horseshoe-shaped scars on the shin ( C ), piezogenic papules on the heel ( D ), and the Gorlin sign ( E ).

A–C, Courtesy, Addenbrooke’s Hospital, Cambridge, UK.

Approach to the patient with presumed Ehlers–Danlos syndrome.

AD, autosomal dominant; AR, autosomal recessive.

Typical skin findings are present, to a varying degree, in all subtypes of EDS . Skin hyperextensibility can be assessed on the volar surface of the distal forearm or wrist, where the upper limit of normal extensibility is 1–1.5 cm. The skin also tends to be fragile, splitting readily due to trauma, particularly on the knees, elbows, shins, and forehead. These wounds present with a gaping, “fish-mouth” appearance; healing may be delayed and dehiscence is common. The resulting scars are typically atrophic and widen over time ( Fig. 97.2C ), although some affected individuals develop hypertrophic scars. Sites of repeated trauma develop a variety of secondary lesions such as molluscoid pseudo­tumors, which are fleshy nodules of redundant skin and fibrous tissue that favor the knees and elbows. Multiple small, hard, mobile nodules over bony prominences such as the ulnar and tibial borders are also a frequent finding. These subcutaneous spheroids are thought to represent calcified fat globules. Easy bruising is commonly observed, reflecting the fragility of small blood vessels. Dermatologic disorders that are associated with, but not specific to, EDS include elastosis perforans serpiginosa and piezogenic papules ( Fig. 97.2D ).

Classic EDS is inherited in an autosomal dominant fashion and presents with hypermobile joints as well as hyperextensible fragile skin that is prone to bruising. Scars are typically widened and atrophic, often with a “cigarette paper” appearance. The skin also tends to be soft, with a slightly doughy or velvety texture. At least half of affected individuals can touch the tip of their nose with their tongue (Gorlin sign), compared to 10% of the general population ( Fig. 97.2E ). Although classic EDS may be associated with mild aortic root dilation and mitral valve prolapse, each in ~5% of patients, these findings are rarely of clinical significance . Other frequent musculoskeletal manifestations include pes planus, hypotonia, and temporomandibular joint dysfunction.

Patients with tenascin-X deficiency , which has autosomal recessive inheritance, have a phenotype similar to that of classic EDS but with relatively normal scarring. This variant is occasionally associated with congenital adrenal hyperplasia due to deletion of the contiguous gene encoding 21-hydroxylase.

Hypermobile EDS is the most common variant and has autosomal dominant inheritance. The most prominent clinical feature is generalized joint hypermobility, typically leading to recurrent joint dislocations that can cause chronic pain and eventual osteoarthritic changes. Easy bruising is common, and the skin tends to be soft but only mildly hyperextensible. Patients may have autonomic dysfunction presenting with orthostatic intolerance and gastrointestinal symptoms .

Vascular EDS is an autosomal dominant disorder characterized by thin translucent skin with extensive bruising and a high risk of arterial, intestinal, and uterine ruptures . Spontaneous arterial rupture has the highest incidence in the third and fourth decades of life but may occur earlier, and median survival is ~50 years . Affected individuals often have a characteristic facial appearance, with a “pinched” nose, thin lips, micrognathia, hollow cheeks, and prominent “staring” eyes due to decreased periorbital adipose tissue. Small earlobes and fine scalp hair are additional features.

Kyphoscoliotic EDS is an autosomal recessive disorder that features skin hyperextensibility, generalized joint hypermobility, severe hypotonia at birth, delayed gross motor development, progressive congenital scoliosis, and scleral fragility that can lead to rupture of the ocular globe. Additional findings may include atrophic scars, easy bruising, fragility of other tissues (rarely arterial rupture), a marfanoid habitus, microcornea, and osteopenia.

Arthrochalasia EDS is inherited in an autosomal dominant fashion. The major clinical features include severe generalized joint hypermobility with recurrent subluxations and congenital bilateral hip dislocation. Patients may also present with hyperextensible skin, atrophic scars, easy bruising, hypotonia, scoliosis, and mild osteopenia.

Dermatosparaxis EDS is a very rare autosomal recessive disorder that, unlike other forms of EDS, presents with skin that is sagging and redundant as well as extremely fragile. The skin has a highly characteristic soft, doughy consistency, and it tears and bruises easily ( Fig. 97.4 ). Additional findings include premature rupture of fetal membranes, large umbilical or inguinal hernias, delayed closure of the fontanelles, distinctive facies with puffy eyelids and micrognathia, blue sclerae, gingival hyperplasia, abnormal dentition, and short limbs.

Extensive bruising on the shins in a patient with the dermatosparaxis type of Ehlers–Danlos syndrome (EDS).

Similar changes can be seen in vascular EDS.

Courtesy, Julie V Schaffer, MD.

Pathology and Laboratory Findings

Histopathologic examination of the skin is usually noncontributory. Nonspecific increases in elastic fibers have been reported, particularly in areas of repeated trauma or molluscoid pseudotumors. However, in vascular EDS the dermis is often reduced to ~25% of its normal thickness, and immunohistochemical staining may show intracellular accumulation of type III collagen.

Electron microscopy in classic EDS often shows collagen fibrils with variable diameters and occasional large “cauliflower” fibrils with an irregular contour. Ultrastructurally, arthrochalasia and dermatosparaxis types of EDS are characterized by angular and “hieroglyphic” appearances of collagen fibrils in cross-section, respectively.

Traditionally the diagnosis of EDS has been based upon clinical findings, but nowadays genetic testing is available for all the major forms of EDS except for the hypermobile type. Protein electrophoresis of collagens extracted from cultured dermal fibroblasts can be helpful in demonstrating specific collagen defects, particularly in the vascular, arthrochalasia, and dermatosparaxis types of EDS . Analysis of the urine for an increased deoxypyridinoline : pyridinoline ratio may be used as a screening test for kyphoscoliotic-type EDS, and tenascin-X deficiency can be demonstrated by an ELISA of a serum sample .

Differential Diagnosis

In addition to the major forms of EDS discussed above, other uncommon variants should also be considered (see Table 97.2 ). Several previously described rare subtypes of EDS, including type V (X-linked variant) and type X (fibronectin type), are currently excluded from the EDS nosology due to a lack of clear descriptions of their clinical features and unknown molecular bases. The previous EDS type IX, an X-linked recessive condition known as occipital horn syndrome, is now considered to represent a form of cutis laxa (see Table 97.6 ) rather than EDS. In contrast to cutis laxa, which is characterized by loose and sagging skin with decreased resilience, the skin of patients with EDS (except the dermatosparaxis type) retains its elasticity and recoil. Although some patients with EDS, in particular the kyphoscoliotic type, have a marfanoid body habitus, they do not typically exhibit other findings of Marfan syndrome ( Table 97.3 ), a distinct heritable connective tissue disorder due to mutations in the fibrillin 1 gene ( FBN1 ) (see Table 97.1 ).

The phenotype of Loeys–Dietz syndrome (LDS; formerly known as LDS type II) can mimic that of vascular EDS, with overlapping features including translucent skin, easy bruising, atrophic scarring, joint hypermobility, and arterial rupture (see Table 95.5 ). However, some patients with LDS have additional features such as a bifid uvula, hypertelorism, and facial milia. Patients with vascular EDS and other types that result in extensive bruising are often suspected to have a bleeding disorder, and they may present to a dermatologist after a hematologic evaluation fails to reveal any abnormalities.

The brittle cornea syndrome is a rare autosomal recessive condition that has phenotypic overlap with kyphoscoliotic-type EDS, with ocular fragility, blue sclerae, and keratoconus in association with scoliosis, joint hypermobility, and variable skin findings that may include acral wrinkling as well as hyperextensibility and fragility (see Table 95.5 ).

Treatment

The most important intervention is prevention of trauma to the skin, such as the use of shin guards and avoidance of contact sports. Delaying suture removal for up to twice as long as usual plus use of sutures with prolonged tensile strength may improve healing and the appearance of surgical scars.

In vascular EDS, affected individuals are at high risk of arterial and bowel ruptures. Use of celiprolol, a long-acting β ₁ -antagonist with partial β ₂ -agonist properties, may reduce the incidence of arterial dissection . Approximately 5% of pregnancies in women with vascular EDS are complicated by fatal uterine or arterial rupture ; it is unclear whether elective caesarean section reduces these risks, and patients should be managed in a high-risk obstetric unit with multidisciplinary input.

History

The French dermatologist Balzer first described the skin manifestations of PXE and associated elastic degeneration in the skin and heart in 1884 , which was followed 5 years later by a similar case report by Chauffard . Based on these two cases, Darier coined the name “pseudo-xanthome élastique” in 1896 to differentiate this condition from xanthomas . In the late 1920s, Grönblad and Strandberg recognized the association of the characteristic skin manifestations with angioid streaks, and the cardiovascular manifestations were better defined two decades later. More recently, the molecular defects that underlie PXE were identified, clarifying the mode of inheritance, which had previously been debated .

Epidemiology

PXE is an autosomal recessive disease, with a prevalence estimated to be from 1 in 25 000 to 1 in 100 000. There is no racial predilection but a slight female preponderance . Skin changes of PXE usually appear during childhood, but the diagnosis is frequently not made until serious systemic or ocular complications develop in the third or fourth decade of life. Mild cutaneous and ocular findings have also been observed in heterozygous carriers .

Pathogenesis

Loss-of-function mutations in both copies of ABCC6 can be identified in most patients with PXE. ABCC6 encodes an ATP-binding cassette (ABC) transporter with a high degree of homology to the multidrug resistance-associated proteins. ABCC6 is predominantly expressed in the basolateral membrane of hepatocytes, where it serves as an efflux pump. The absence of functional ABCC6 in PXE patients results in reduced ATP secretion from hepatocytes, which leads to reduced plasma concentrations of a mineralization inhibitor – inorganic pyrophosphate (PPi) . Serum levels of fetuin A, a major anti-mineralization protein secreted from the liver, are also significantly reduced in PXE patients . Expression of other systemic inhibitors of mineralization such as nucleotidase-5′ ecto (NT5E; converts AMP to adenosine) and osteopontin may also be down-regulated, while expression of mineralization-promoting alkaline phosphatase is upregulated .

Biallelic mutations in ENPP1 , which encodes the ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme that regulates production of PPi, can cause generalized arterial calcification of infancy (GACI), a rare autosomal recessive disorder that is usually lethal during the first six months of life. However, biallelic ENPP1 mutations occasionally cause PXE, and mutations in ABCC6 underlie a subset of GACI, thus demonstrating pathogenic and phenotypic overlap between the two conditions .

Biallelic mutations in the γ-glutamyl carboxylase gene ( GGCX ) cause PXE-like skin changes plus deficiency in vitamin K-dependent coagulation factors . A combination of heterozygous mutations in GGCX and ABCC6 has also been identified in patients with cutaneous findings of PXE . The GGCX enzyme catalyzes the vitamin K-dependent γ-glutamyl carboxylation that is necessary for activation of both coagulation factors in the liver and the matrix gla protein in peripheral connective tissues. When carboxylated (activated), matrix gla protein prevents ectopic mineralization.

The pathogenesis of PXE and related conditions is therefore related to decreased anti-mineralization activity. Calcification of elastic fibers in the mid and deep dermis, the media and intima of mid-sized arteries, and Bruch’s membrane of the eye produces the characteristic clinical and histopathologic changes of PXE ( Fig. 97.5 ).

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