3220 PART 12 Endocrinology and Metabolism

The monomers of the three fibrillar collagens are formed from three

polypeptide chains, called α chains, that are wrapped around each other

into a rope-like triple-helical conformation. The triple helix is a unique

structure among proteins, and it provides rigidity to the molecule. It

also orients the side chains of amino acids in an “inside out” manner

relative to most other proteins so that the charged and hydrophobic

residues on the surface can direct self-assembly of the monomers into

fibrils. The triple-helical conformation of the monomer is generated

because each of the α chains has a repetitive amino acid sequence in

which glycine (Gly) appears as every third amino acid. Each α chain

contains ~1000 amino acids. Therefore, the sequence of each α chain

can be designated as (-Gly-X-Y-)n

, where X and Y represent amino

acids other than glycine and n is >338. The presence of glycine, the

smallest amino acid, in every third position in the sequence is critical

because this residue must fit into a sterically restricted space in

the interior of the helix where the three chains come together. The

requirement for a glycine residue at every third position explains

the significant clinical effects of mutations that convert a glycine

residue to an amino acid with a bulkier side chain (see below). Many

of the X- and Y-position amino acids are proline and hydroxyproline,

which, because of their ring structures, provide additional rigidity to

the triple helix. Other X- and Y-positions are occupied by charged or

hydrophobic amino acids that precisely direct lateral and longitudinal

assembly of the monomers into highly ordered fibrils. Mutations that

substitute amino acids in some X- and Y-positions, particularly arginine-to-cysteine substitutions, can also produce genetic diseases.

The fibers formed by the three fibrillar collagens differ in thickness

and length, but they have a similar fine structure. As viewed by electron

microscopy, they all have a characteristic pattern of cross-striations

that are about one-quarter the length of the monomers and reflect

the precise packing into fibrils. The three fibrillar collagens, however,

differ in sequences found in the X- and Y-positions of the α chains

and therefore in some of their physical properties. Type I collagen is a

heterotrimer, composed of two identical α1(I) chains and a third α2(I)

chain that differs slightly in its amino acid sequence. Types II and III

collagen are homotrimers, each composed of three identical α chains

distinct to that type of collagen.

To deliver a monomer of the correct structure to the appropriate

site of fibril assembly, the biosynthesis of fibrillar collagens involves a

large number of unique processing steps (Fig. 413-1). The monomer,

first synthesized as a soluble precursor called procollagen, contains

an additional globular domain at each end. As the pre-proα chains of

procollagen are synthesized on ribosomes, the free N-terminal ends

move into the cisternae of the rough endoplasmic reticulum (ER).

Signal peptides at the N-termini are cleaved, and additional posttranslational reactions begin. Proline and lysine residues in the Y-position

of the Gly-X-Y repeating triplet are hydroxylated along the length

of the helix by the enzymes prolyl 4-hydroxylase (P4H1) and lysyl

hydroxylase (LH1). respectively. Hydroxyproline residues are essential for the three α chains of the monomer to fold into a triple helix at

body temperature. P4H1 requires ascorbic acid as an essential cofactor, an observation that explains why wounds fail to heal in scurvy

(Chap. 333). In scurvy, some of the underhydroxylated and unfolded

protein accumulates in the cisternae of the rough ER and is degraded.

Many hydroxylysine residues are glycosylated with galactose or with

galactose and glucose. Also, a large mannose-rich oligosaccharide is

assembled on the C-terminal propeptide of each chain. The proα chains

are assembled by interactions among these C-terminal propeptides that

control the selection of the appropriate partner chains to form heteroor homotrimers and provide the correct chain registration required for

subsequent formation of the collagen triple helix. After the C-terminal

propeptides assemble the three proα chains, a nucleus of triple helix

is formed near the C-terminus, and the helical conformation is propagated toward the N-terminus in a zipper-like manner that resembles

crystallization. The folding into the triple helix is spontaneous in solution, but as discussed below, identification of rare mutations causing

OI demonstrated that the folding in cellulo is assisted by a number of

ancillary proteins that also prevent collagen fibril formation within

the ER. The fully folded procollagen is then transported to the Golgi

via a specific COPII vesicle process. After further modifications in the

Golgi stack, the procollagen is secreted into the pericellular space where

distinct proteases remove the N- and C-propeptides at specific cleavage

sites. The release of the propeptides decreases the solubility of the resulting collagen ~1000-fold. The entropic energy that is released drives the

O-Gal-Glc

OH

OH OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH OH OH

Glc

Gal

O OH

OH OH OH

OH OH

OH

OH

OH

O

Gal

(Man)n

GlcNAc

S

S S

S

Glc

Gal

O OH

OH OH OH

OH OH

OH

OH

OH

O

Gal

(Man)n

GlcNAc

SH

SH

SH

SH

O-Gal

Assembly of three

procollagen chains

Polypeptide synthesis

Collagen prolyl 4-hydroxylase

Lysyl hydroxylase

Prolyl 3-hydroxylase

Collagen gal-transferase and

glc-transferase

N glycosylated residue

Protein disulfide isomerase

Assembly of triple helix

Secretion of procollagen

in transport vesicles

N and C proteinases

Assembly into collagen

fibrils

Formation of covalent

cross-links

Lysyl oxidase

Cleavage of propeptides

Endoplasmic reticulum Late transport vesicles and

extracellular matrix

FIGURE 413-1 Schematic summary of biosynthesis of fibrillar collagens. (Reproduced with permission from J Myllyharju, KI Kivirikko: Collagens, modifying enzymes and

their mutations in humans, flies and worms. Trends Genet 20:33, 2004.)

3221Heritable Disorders of Connective Tissue CHAPTER 413

self-assembly of the collagen into fibrils. Self-assembled collagen fibers

have considerable tensile strength, but their strength is increased further

by cross-linking reactions that form covalent bonds between α chains in

one molecule and α chains in adjacent molecules. The resulting fibers,

comprised of hundreds or thousands of triple-helical monomers, have

some of the properties of a crystal but have innate imperfections that

make them highly flexible.

Although the assembly of collagen monomers into fibers is largely a

spontaneous reaction, the process in tissues is modulated by the presence of less abundant collagens (type V with type I, and type XI with

type II) and by other components such as a series of small leucine-rich

proteins (SLRPs). Some of the less abundant components alter the rate

of fibril assembly, whereas others change the morphology of the fibers

or their interactions with cells and other molecules. The presence of

these other components is one explanation for why, in some tissues, the

fibers are further assembled into large tendons; in others, into sheets;

and in still others, into complex structures such as the hexagonal array

of fibers that provide both the strength and transparency of the cornea.

Collagen fibers are resistant to most proteases, but during degradation of connective tissues, they are cleaved by specific matrix metalloproteinases (collagenases) that cause partial unfolding of the triple

helices into gelatin-like structures that are further degraded by less

specific proteinases.

■ OTHER COLLAGENS AND RELATED MOLECULES

The unique properties of the triple helix are used to define a family

of at least 28 collagens that contain repetitive -Gly-X-Y- sequences

and form triple helices of varying length and complexity. The proteins

are heterogeneous both in structure and function, and many are the

sites of mutations causing genetic diseases. For example, the type IV

collagen found in basement membranes is composed of three α chains

synthesized from any of six different genes; mutations in the COL4A3,

COL4A4, or COL4A5 genes cause AS.

Fibrillin Aggregates and Elastin In addition to tensile strength,

many tissues such as the lung, large blood vessels, and ligaments

require elasticity. The elasticity was originally ascribed to an amorphous rubber-like protein named elastin. Subsequent analyses, largely

sparked by discoveries of mutations causing the Marfan syndrome

(MFS), demonstrated that the elasticity resided in thin fibrils composed primarily of large glycoproteins named fibrillins. The fibrillins

contain large numbers of epidermal growth factor–like domains interspersed with characteristic cysteine-rich domains that are also found

in latent transforming growth factor β (TGF-β) binding proteins.

The fibrillins assemble into long beadlike strands that also contain

numerous other components including small and variable amounts of

elastin, bone morphogenic proteins (BMPs), and microfibril-associated

glycoproteins (MAGPs). Besides contributing to extracellular matrix

structure, a major role for fibrillins in TGF-β signaling was emphasized

by the discovery of mutations in genes coding for proteins involved in

canonical TGF-β signaling in patients with Marfan-like manifestations,

including thoracic aortic aneurysm.

Proteoglycans The resiliency to compression of connective tissues

such as cartilage or the aorta is largely explained by the presence of

proteoglycans. Proteoglycans are composed of a core protein to which

are attached a large series of negatively charged polymers of disaccharides (largely chondroitin sulfates). At least 30 proteoglycans have been

identified. They vary in their binding to collagens and other components of matrix, but specific functions have not been assigned to most.

The major proteoglycan of cartilage, called aggrecan, has a core protein

of 2000 amino acids that is decorated with ~100 side chains of chondroitin sulfate and keratin sulfate. The core protein, in turn, binds to

long chains of the polymeric disaccharide hyaluronan to form proteoglycan aggregates, one of the largest soluble macromolecular structures

in nature. Because of its highly negative charge and extended structure,

the proteoglycan aggregate binds large amounts of water and small ions

to distend the three-dimensional arcade of collagen fibers found in the

same tissues. It thereby makes the cartilage resilient to pressure.

SPECIFIC DISORDERS

■ OSTEOGENESIS IMPERFECTA

OI is a phenotypically and genetically heterogeneous generalized

connective tissue disorder. The hallmark features of OI are increased

susceptibility to skeletal fractures, bone deformity, and growth deficiency. Bone fragility is based on decreased bone mass and increased

bone brittleness due to defective mineralization. Secondary features

of OI are highly variable even within a type and include blue sclerae,

dentinogenesis imperfecta, hearing loss, basilar invagination, pulmonary function impairment, cardiac valve abnormalities, and ligamentous laxity. Most patients have defects in the structure or quantity of

type I collagen.

Classification OI was originally classified into congenita and tarda

subtypes depending on the age of symptom onset. Sillence proposed

the classification that bears his name for four types based on clinical

and radiologic findings and mode of inheritance. The extension of

the Sillence classification was first based on distinctive bone histology

(types V and VI OI) and subsequently on the discovery of new recessive genes (types VII–XVIII). The debate between classification by

phenotypic severity or gene defects has resulted in clinical and genetic

classifications. The clinical classification can be useful for management

but results in different type assignments in the same family or even

in the same individual over their lifetime. The genetic classification

(Table 413-2) groups patients by the causative gene. Because related

causative genes were discovered close in time to each other, the genetic

classification further groups types by overall mechanism and features

OI as a collagen-related disorder.

Types I–IV OI are due to quantitative or structural defects in type I

collagen itself. Type I is the mildest subtype, with reduced quantity

of structurally normal collagen, and can produce mild or inapparent

skeletal deformities. Most patients have distinctly blue sclerae. Types

II, III, and IV are all caused by structural defects in one of the type I

collagen α chains. Type II produces bone so brittle that infants have in

utero fractures of ribs and long bones and die in the perinatal period.

Type III is progressively deforming with moderate to severe bone

deformity, and type IV has mild to moderate bone fragility and secondary features. Subsequent rare recessive OI types are all collagen-related.

Types V and VI (ITITM5 and SERPINF1) particularly compromise

matrix mineralization. Types VII, VIII, and IX (CRTAP, P3H1, and

PPIB) represent defects in the components of the procollagen prolyl

3-hydroxylation complex that modifies collagen posttranslationally.

Types X–XII (SERPINH1, FKBP10, and BMP1) have compromised

procollagen processing and cross-linking. The final grouping of types

XIII–XVIII (SP7, TMEM38B, WNT1, CREBL1, SPARC, and MBTPS2)

alter osteoblast differentiation and impair collagen matrix quality.

The clinical heterogeneity of affected individuals within a particular OI type and even with the same mutation is not understood, with

unknown modifying factors presumably involved. Among adults with

OI, women are prone to fracture during pregnancy and after menopause. Some variants of mild OI are first detected perimenopausally

and must be distinguished from postmenopausal osteoporosis.

Incidence In North America and Europe, the estimated incidence

of OI is 1 per 10,000–15,000 births, based on a combination of cases

recognized at birth and population surveys for milder cases. In populations with a high level of consanguinity or a founder mutation, the

incidence of the rare recessive forms of OI is a significant addition to

the prevalence of dominant collagen defects.

Effects on Tissue Systems The phenotypic features of OI are

highly variable, even within the types caused by defects in type I

collagen. The following section generally focuses on dominant forms

comprising the majority of cases, except as specified, but the descriptions can be generalized to a large extent.

Musculoskeletal Effects Bone in OI is both weak and brittle. At

the mildest end of the spectrum (type I OI), individuals may have only

several childhood fractures and be limited only from contact sports.

Endocrinology and Metabolism PART 12

3222

TABLE 413-2 Different Types of Osteogenesis Imperfecta (OI)

OI TYPE INHERITANCE

DEFECTIVE

GENE PROTEIN OMIM LOCUS HYPERMINERALIZATION DISTINGUISHING FEATURES

Defects in collagen

structure and processing

I AD COL1A1 Collagen α1 166200 17q21.33 Yes Loss of function of one of the COL1A1 alleles

II–IV AD COL1A1,

COL1A2

Collagen α1 or α2 166210,

259420, 166220

17q21.33, 7q21.3 Yes Structural defects in collagen helix or C-propeptides

Procollagen processing

defects

OI/EDS AD COL1A1,

COL1A2

Procollagen α1

or α2

NA 17q21.33, 7q21.3 Yes Defects in 90 residues at N-terminus of collagen helix that decrease

pN-processing

HBM AD COL1A1,

COL1A2

Collagen α1 or α2 NA 17q21.33 Yes Defects in C-propeptide cleavage site, DXA normal to increased

XIII AR BMP1 BMP1 614856 8p21.3 Yes Deficiency of C-propeptidase

Bone mineralization

defects

V AD IFITM5 BRIL (BRIL5’

MALEP)

610967 11p15.5 Yes Calcification of interosseous membrane, dense metaphyseal band,

hyperplastic callus, mesh-like pattern in lamellar bone

Atypical

VI

AD IFITM5 BRIL (BRIL

Ser40Leu)

610967 11p15.5 Yes Increased osteoid, fish scale pattern in lamellar bone, increased ALP

levels in childhood, symptom onset at birth

VI AR SERPINF1 PEDF 613982 17p13.3 Yes PEDF deficiency, increased osteoid, fish scale pattern in lamellar bone,

increased ALP levels in childhood, onset after age 1 year

Defects in collagen

modification

VII AR CRTAP CRTAP 610682 3q22.3 Yes Absent procollagen prolyl

3-hydroxylation; full OM, rhizomelia, white sclerae

VIII AR LERPE1 P3H1 610915 1p34.2 Yes Absent procollagen prolyl

3-hydroxylation; full OM, rhizomelia, “popcorn” metaphyses; white sclerae

IX AR PPIB CyPB 259440 15q22.31 Yes Absent procollagen prolyl

3-hydroxylation; helix modification varies, without rhizomelia, white sclerae

XIV AR TMEM38B TRIC-B 615066 9q31.2 No Decreased modification of collagen helix

Defects in collagen

folding and cross-linking

X AR SERPINH1 HSP47 613848 11q13.5 ND Severe skeletal deformity, blue sclerae, DI, skin abnormalities, inguinal

hernias

NA AR KDELR2 KDEL ER protein

retention receptor;

interacts with

HSP47

619131 7p22.1 ND Short stature, progressive skeletal deformation requiring recurrent

surgical interventions

XI AR FKBP10 FKBP65 610968 17q21.2 Yes May have congenital contractures

NA AR PLOD2 LH2 609220 3q24 Yes Progressive joint contractures

Osteoblast function and

differentiation

XII AR SP7 OSTERIX 613849 12q13.13 ND Severe skeletal deformity, delayed tooth eruption, facial hypoplasia

XV AD/AR WNT1 WNT1 615220 12q13.12 No May have neurologic defects

XVI AR CREB3L1 OASIS 616215 11p11.2 Yes Defect in RIP pathway

XVII AR SPARC SPARC 616507 5q33.1 Yes Progressive severe bone fragility

XVIII XR MBTPS2 S2P 301014 Xp22.12 Yes X-linked OI, defect in RIP pathway, rhizomelia

Unclassified disorders NA AR FAM46A FAM46A 617952 6q14.1 ND Defect in BMP/TGF-β signaling pathway

NA AR MESD LRP chaperone

MESD

618644 15q25.1 ND Could also be classified with LRP5/6-related disorders

NA AR CCDC134 Coiled-coil domaincontaining protein

134

618788 22q13.2 ND Could also be classified with MAPK/ERK skeletal dysplasias

Abbreviations: AD, autosomal dominant; ALP, alkaline phosphatase; AR, autosomal recessive; BMP, bone morphogenetic protein; DI, dentinogenesis imperfect; DXA, dual-energy x-ray absorptiometry; EDS, Ehlers-Danlos syndrome; HBM,

high bone mass; NA, not applicable; ND, not determined; OM, overmodification; OMIM, Online Mendelian Inheritance in Man; TGF, transforming growth factor.

3223Heritable Disorders of Connective Tissue CHAPTER 413

More severe forms of OI require bone to be partially unloaded with

assistive devices such as walkers or canes; many severe patients use

electric chairs for both the weight bearing and the normal speed of

mobility. In dominant OI, fragility fractures often decrease sharply

after adequate bone mass is gained at puberty. Radiographs generally

show osteopenia in all types, with disordered matrix organization

detected most easily in lower long bones in moderate and severe forms.

In lethal OI, radiographs show continuous beading of ribs from healing

fractures and crumpled and undertubulated long bones. Lateral skull

radiographs may show islands of Wormian bones, even in mild forms.

The appearance of “popcorn” at the metaphyses of long bones occurs

in many type III and IV children and coincides with increased growth

deficiency. Often these bones are so soft that normal muscle pull can

produce severe deformities. Kyphoscoliosis is associated with vertebral

compressions but is not prevented by bisphosphonates, suggesting a

contribution from ligamentous laxity.

OI bone is weak, in that it fractures with a lower load than normal,

and brittle, in that it does not tolerate postyield displacement and

snaps like chalk. The brittleness results from the paradoxical increased

mineralization of OI bone. While dual-energy x-ray absorptiometry

(DXA) bone density measurements uniformly return a reduced value

for OI bone, it is performed with a phantom and detects mineral crystals that are in proper alignment. In contrast quantitative backscattered

electron imaging or three-dimensional (3D) computed tomography

(CT), which detect all mineral in 3D, reveals that both dominant and

recessive (except types XIV and XV) OI bone is hypermineralized. On

histomorphometry, dominant OI bone has proper formation of lamellae but increased turnover, causing decreased bone volume. Type V OI

has mesh-like bone lamellae, as well as a dislocated radial head, and

may have hyperplastic callus formation, while type VI OI has distinctive fish scale lamellae on polarized light microscopy.

Many OI patients across the severity spectrum have increased ligamentous laxity. Patients with defects in processing the N-terminal propeptide of type I procollagen have large and small joint hypermobility

similar to EDS. Muscle weakness of unknown etiology also occurs in

OI, and the weakness and ligamentous laxity contribute to delayed

motor development.

Pulmonary The leading cause of death in OI is pulmonary disease. Young children with severe OI often have repeated pneumonia;

restrictive or obstructive disease often develops in adults. Pulmonary

function is impaired by marked scoliosis and chest wall deformity but

also arises from intrinsic defects of lung parenchyma containing type I

collagen, as shown by declining pulmonary function over time in children without scoliosis. Mice with null CRTAP mutations (type VII OI)

have abnormal alveolar development, and patients with recessive forms

also have pulmonary complications. Evaluation of even asymptomatic

moderate to severe OI patients by spirometry should initiate standard

pulmonary interventions.

Cardiovascular Cardiovascular effects of OI manifest predominantly in adults. With type I collagen as a major component of matrix

in cardiac valves and aortic wall, the most frequent manifestations

are valvular, especially mitral regurgitation and aortic root dilatation.

Impaired mechanical properties occasionally lead to aortic dissection.

Echocardiography is appropriate with heart murmurs or cardiac symptoms and every 3–5 years in asymptomatic patients.

Dentinogenesis Imperfecta Dentinogenesis imperfecta (DI) is

associated with types III and IV OI and recessive types with collagen

processing defects. Tooth agenesis, especially of premolars, is also

found in types III/IV OI. Teeth with disturbed formation of dentin

during development may be translucent gray or have yellowish or

brownish discoloration. Defects are manifest predominantly in primary teeth; detection in secondary teeth may require radiographs to

identify characteristic narrow or obliterated pulp chambers. Crumbling

at the dentin-enamel junction may require capping of teeth. Hypoplastic maxilla and relative mandibular prognathism in moderate to severe

OI can result in type III malocclusion and impair normal chewing,

requiring surgical correction.

Hearing Loss About half of patients with types I, III, and IV OI

develop hearing loss, but its incidence in recessive types is unknown.

Hearing loss usually begins in the second decade and progresses.

The initial conductive loss, based on changes in the inner ear leading

to stapes footplate fixation, can evolve into a mixed conductive and

sensorineural loss. Regular screening allows referral for hearing aids,

stapes surgery, or cochlear implants, as appropriate.

Other Features A variable intensity of blue or grayish sclerae is

a well-known feature of OI. The color is most striking with collagen

defects, especially types I and II OI and defects that affect N-terminal

procollagen processing. Blue sclerae often occur in other connective

tissue disorders such as EDS or MFS and may occur in individuals

without connective tissue defects. Severe neonatal OI with white sclerae

should prompt consideration of recessive forms, especially prolyl

3-hydroxylation defects. Abnormalities of the skull base, such as platybasia and basilar invagination, sometimes progress to clinically devasting basilar impression. Patients with height Z-scores of <–3 should be

CT scanned at 3- to 5-year intervals. Significant growth deficiency is a

cardinal feature of OI, ranging from minimally shorter than siblings in

mild forms to greater extents in some severe cases, with adults shorter

than 5-year-old children. There is both end-organ resistance to growth

hormone (GH) and defective transition to bone at the growth plate.

Types I and IV OI are often responsive to recombinant GH therapy.

Molecular Defects The great majority (80–85%) of cases of

OI are caused by heterozygous mutations in either of the genes

coding for the chains of type I procollagen, COL1A1 or COL1A2

(Table 413-2). Although thousands of unique mutations have been identified in type I collagen, they fall into several structural types. Null

mutations in collagen chains are less detrimental than structural defects.

Null mutations in COL1A1 result in about half the normal level of collagen synthesis, but the collagen in matrix is structurally normal. These

patients have mild type I OI. Null COL1A2 mutations are rare, leading

to an EDS-like condition with progressive cardiac-valvular defects.

Mutations that produce structural changes in type I collagen α

chains cause types II, III, and IV OI. The most common of these are

mutations resulting in substitutions for glycine residues required at

every third residue along the helix. In effect, any of the 338 glycine

residues in the helical domain of either the proα1 or proα2 chain of

type I procollagen is a potential site for a disease-producing mutation.

Other mutations affect the splicing of the exons encoding the α chains.

Because each collagen exon encodes a discrete set of Gly-X-Y triplets,

the abnormal splice products are most often in-frame and cause severe

structural abnormalities. Use of alternative splice sites may lead to

premature termination, mimicking null mutations, and a milder phenotype. Structural abnormalities in the procollagen helical region delay

collagen folding and expose chains to posttranslational hydroxylation/

glycosylation for a longer time. The abnormal procollagen triggers

a cascade of intracellular and extracellular events including delayed

collagen folding, ER stress, abnormal interaction with noncollagenous molecules, impaired osteoblast development and cross-talk with

osteoclasts, and abnormal mineralization. There are some special sets

of procollagen structural mutations with distinct mechanisms within

types II, III, and IV. Mutations in the C-propeptide significantly delay

chain assembly, and resulting procollagen is mislocalized to the ER

lumen. Some of this procollagen is targeted for degradation by the ERassociated proteosomal pathway, while the secreted molecules delay

pericellular processing of the C-propeptide. Mutations in the C-propeptide cleavage site itself prevent processing of the propeptide, leaving

pC-collagen to be incorporated into matrix. This affects matrix mineralization, resulting in an unusual high bone mass form of OI that falls

at the milder end of the type IV OI phenotype. Not surprisingly, null

mutations in the C-propeptidase enzyme, BMP1, cause recessive type

XII OI. Type XII OI is a severe condition because BMP1 is the cleavase

for types I, II, and III procollagens and the glycoprotein decorin, which

is a regulator of fibrillogenesis. Processing defects of the N-propeptide

occur in the cleavage site itself or the 90 helix residues at the amino

end. The persistence of the N-propeptide on a fraction of the molecules

3224 PART 12 Endocrinology and Metabolism

interferes with the self-assembly of normal collagen so that thin and

irregular collagen fibrils are formed. They cause extreme laxity of large

and small joints, intensely blue sclerae, and an OI severity comparable

to type III/IV. Rare substitutions of charged amino acids (Asp, Arg) or

a branched amino acid (Val) in X- or Y-positions produce lethal phenotypes, apparently because they are located at sites for lateral assembly of

the monomers or binding of other components of the matrix.

Starting in 2006, a series of noncollagenous genes have been identified that cause (mostly) recessive OI. Importantly, all the genes have

encoded proteins or cellular processes related to collagen, shifting the

OI paradigm to dominant OI caused by collagen defects or IFITM5

and recessive OI caused by proteins related to collagen modification,

processing, folding, and cross-linking and osteoblast differentiation.

The largest group of patients with OI not caused by collagen gene

mutations have types V and VI OI, affecting bone mineralization. Type V

OI, with dominant inheritance, is unusual in that all patients have the

same recurrent mutation at the 5′-end of IFITM5, which generates

a novel start codon in the transmembrane protein BRIL. The gainof-function mutation causes distinctive radiologic (ossification of

interosseus membrane and dense metaphyseal band) and phenotypic

findings (hypertrophic callus). Osteoblasts with type V OI have

increased mineralization and differentiation in culture. Type VI OI is a

recessive form caused by null mutations in PEDF, a collagen-interacting

molecule with a known antiangiogenic effect. A connection between

types V and VI OI has been revealed by a set of patients with a BRIL

p.S42L substitution who have clinical, histologic, serum marker, and

phenotypic features of type VI OI. Both type VI OI osteoblasts and

BRIL p.S42L osteoblasts have decreased cellular mineralization and

SERPINEF1 expression, while classic type V OI osteoblasts have the

opposite findings. All three types decrease collagen production.

Types VII, VIII, and IX OI are severe recessive forms caused

by deficiency of one of the components of the procollagen prolyl

3-hydroxylation complex, P3H1, CRTAP, or cyclophilin B (PPIB/

CyPB). This complex 3-hydroxylates one proline residue per α chain,

most critically α1(I)P986, in contrast to the proline 4-hydroxylation of

multiple helical residues by P4H1. In murine models, loss of complex

function results in a severe phenotype; while mutation of the P986

residue impairs collagen cross-linking and fine-tuning of collagen

alignment in fibrils. The phenotype of these patients is distinctive for

white sclerae, rhizomelia, and lack of relative macrocephaly; they share

the bone fragility, high bone turnover, and elevated bone mineralization of classical OI.

Some recessive OI types that impair osteoblast function are caused

by mutation in genes not previously understood to affect bone. Regulatory intramembrane proteolysis (RIP) is well known for its role in

cholesterol synthesis, in which cells transport regulatory proteins from

the ER membrane to the Golgi membrane in times of cell stress, where

S1P and S2P Golgi proteases sequentially cleave the transcription

factors, activating them to enter the nucleus. X-linked type XVIII OI

with defective MBTPS2/S2P and type XVI OI with deficiency of an RIP

substrate Oasis, a member of the ATF6 family of stress sensors, indicate

the importance of RIP for bone formation (Table 413-2).

Inheritance and Mosaicism in Germline Cells and Somatic

Cells Types I–V OI are inherited as autosomal dominant traits,

while the rare forms are mostly recessive. Many patients with mild

dominant OI represent familial traits, while sporadic new mutations

are often responsible for dominant severe or lethal cases. Germline

mosaicism in one parent may be the etiology of a severe dominant

mutation in the child; in this circumstance, a second child may be

affected with the same dominant mutation from unaffected parents.

Recessive mutations in genes causing the rare forms of OI lead to more

severe clinical outcomes; many of these offspring do not survive childhood, but moderately to severely affected young adults show us that

these conditions must also be considered.

Diagnosis OI is usually diagnosed on the basis of clinical and

radiographic criteria. The presence of fractures together with blue

sclerae, DI, or family history of the disease is usually sufficient to make

the diagnosis. X-rays reveal a decrease in bone density that can be verified by DXA bone densitometry, as well as characteristic deformities

of long bones, thorax, and cranium. The differential diagnosis varies

with age, including battered child syndrome, nutritional deficiencies,

malignancies, and other inherited disorders such as chondrodysplasias

and hypophosphatasia that can have overlapping presentations. A

molecular diagnosis is now routinely obtained using targeted candidate

gene sequencing, sometimes beginning with the dominant collagen

and IFITM5 panel. Although almost all cases can be diagnosed by

sequencing, some may require bone histology and exome sequencing.

TREATMENT

Osteogenesis Imperfecta

Therapy should be directed toward maximizing the function of

each individual, which includes decreasing fractures and deformity

that interfere with function. Physical and occupational therapy are

critical modalities. They are most commonly utilized after severe

fractures or major surgery and should also be engaged consistently

throughout the life span for maximizing mobility, functions of daily

living, and the extent of physical conditioning possible. Water therapy is particularly useful at all ages. Diet should include adequate

intake of calcium and vitamin D. Many patients are underweight for

height as young children but overweight as adults, and nutritional

management may be useful. Orthopedic procedures are required for

deformities of long bone that interfere with standing or walking or

when a bone has sustained repeated fractures. Intramedullary rods

are often inserted when children are ready to stand and as needed

thereafter to keep bone segments in good alignment and provide

partial unloading of weight from bones. If scoliosis progresses,

stabilization of the spine may be needed to maintain the curve at

<60°. Medical management should also include presymptomatic

screening for hearing loss, cardiac valve dysfunction, pulmonary

function, and, in severe individuals, basilar invagination.

Drugs that have been developed for the therapy of postmenopausal osteoporosis are beneficial for some patients. Bisphosphonates,

antiresorptive drugs that inhibit osteoclasts, increase DXA bone

density and relieve vertebral compressions in most patients. They

are regarded as a mainstay of care in many pediatric centers. However, several Cochran reports have not supported a clear reduction

in fracture rate or bone pain from their use, and the dosing and

duration of use are controversial. Currently, drugs with a boneforming mechanism are in trials for OI, especially monoclonal

antibodies to sclerostin that relieve its inhibition of osteoblast

Wnt/β-catenin signaling, TGF-β inhibitors, and a PTH analogue

that stimulates osteoblasts and is most beneficial for adults with

milder OI. Potential therapies under investigation in animal models

include chemical chaperones and mesenchymal stem cell therapy.

■ EHLERS-DANLOS SYNDROMES

The Ehlers-Danlos syndromes (EDS) comprise a genetically heterogeneous group of heritable conditions that share several characteristics

such as soft and hyperextensible skin, abnormal wound healing, easy

bruising, and joint hypermobility. Additional clinical features that

differ among the EDS subtypes include fragility of soft tissues, blood

vessels, and hollow organs and involvement of the musculoskeletal system. Mutations in genes coding for fibrillar collagens (type I, III, or V)

are found in many patients, but other genes are affected in rare forms.

Classification Several types of EDS have been defined, based on

clinical characteristics, mode of inheritance, and molecular defects

(Table 413-3), and the classification of these types has been a dynamic

process. The current classification defines 13 clinical EDS types that are

caused by alterations in 19 different genes, but a recent study described

another genetically distinct EDS type, bringing the total number of

EDS-associated genes to 20. The EDS classification guides the clinical

diagnosis, molecular confirmation, and genetic counseling of affected

individuals and their family members.

3225Heritable Disorders of Connective Tissue 413 CHAPTER

TABLE 413-3 Different Types of Ehlers-Danlos Syndrome (EDS)

EDS TYPE INHERITANCE OMIM LOCUS GENE PROTEIN KEY MANIFESTATIONS

Defects in collagen

primary structure and

collagen processing

Classical EDS (cEDS) AD 130000

130010

9q34.3

2q32.2

COL5A1

COL5A2

Proα1(V)

Proα2(V)

Skin hyperextensibility with atrophic scarring

Generalized joint hypermobility

Classical EDS (cEDS) AD / 17q21.33 COL1A1 Proα1(I) p.Arg312Cys Skin hyperextensibility with atrophic scarring

Generalized joint hypermobility

Arterial rupture at young age

Vascular EDS (vEDS) AD 130050 2q32.2 COL3A1 Proα1(III) Arterial rupture at young age

Spontaneous sigmoid colon perforation in the absence of known colon

disease

Uterine rupture during third trimester of pregnancy

Carotid-cavernous sinus fistula (in the absence of trauma)

Arthrochalasia EDS (aEDS) AD 130060

130060

17q21.33

7q21.3

COL1A1

COL1A2

Proα1(I)

Proα2(I)

Congenital bilateral hip dislocation

Severe generalized joint hypermobility with multiple dislocations

Skin hyperextensibility

Dermatosparactic EDS (dEDS) AR 225410 5q35.3 ADAMTS2 ADAMTS2 Extreme skin fragility with congenital or postnatal tears

Craniofacial features

Progressively redundant, lax skin with excessive skinfolds

Increased palmar wrinkling

Severe bruisability

Umbilical hernia

Postnatal growth retardation with short limbs

Perinatal complications related to tissue fragility

Cardiac-valvular EDS (cvEDS) AR 225320 7q21.3 COL1A2 proα2(I) Severe progressive cardiac-valvular insufficiency

Skin involvement

Joint hypermobility

Defects in collagen folding

and collagen cross-linking

Kyphoscoliotic EDS

(kEDS-PLOD1)

Kyphoscoliotic EDS

(kEDS-FKBP14)

AR

AR

225400

614557

1p36.22

7p14.3

PLOD1

FKBP14

Lysylhydroxylase 1

FKBP22

Congenital muscle hypotonia

Congenital or early-onset kyphoscoliosis

Generalized joint hypermobility with (sub)luxations

Defects in structure and

function of myomatrix, the

interface between muscle

and ECM

Classical-like EDS type 1 (clEDS1) AR 606408 6p21.33-p21.32 TNXB Tenascin XB Skin hyperextensibility with velvety skin texture and absence of atrophic

scarring

Generalized joint hypermobility

Easily bruisable skin/spontaneous ecchymoses

Myopathic EDS (mEDS) AD/AR 616471 6q13-q14 COL12A1 Proα1(XII) Congenital muscle hypotonia and/or muscle atrophy

Joint contractures

Joint hypermobility

(Continued)

Endocrinology and Metabolism PART 12

3226

TABLE 413-3 Different Types of Ehlers-Danlos Syndrome (EDS)

EDS TYPE INHERITANCE OMIM LOCUS GENE PROTEIN KEY MANIFESTATIONS

Defects in

glycosaminoglycan

biosynthesis

Spondylodysplastic EDS

(spEDS-B4GALT7)

AR 130070 5q35.3 B4GALT7 Galactosyltransferase I

β4GalT7

Short stature (progressive in childhood)

Muscle hypotonia (ranging from severe congenital to mild later-onset)

Bowing of limbs

Skeletal dysplasia

Spondylodysplastic EDS

(spEDS-B3GALT6)

AR 615349 1p36.33 B3GALT6 Galactosyltransferase

II

β3GalT6

Musculocontractural EDS

(mcEDS-CHST14)

AR 601776 15q15.1 CHST14 Dermatan-4

sulfotransferase-1

Congenital multiple contractures (typically adduction/flexion contractures

and talipes equinovarus)

Craniofacial features

Skin hyperextensibility, easy bruising, skin fragility with atrophic scars

Increased palmar wrinkling

Musculocontractural EDS

(mcEDS-DSE)

AR 615539 6q22.1 DSE Dermatan sulfate

epimerase-1

Defects in complement

pathways

Periodontal EDS (pEDS) AD 130080 12p13.31 C1R

C1S

C1r

C1s

Severe and intractable early-onset periodontitis

Lack of attached gingiva

Pretibial plaques

Defects in intracellular

processes

Spondylodysplastic EDS

(spEDS-SLC39A13)

AR 612350 11p11.2 SLC39A13 ZIP13 Short stature (progressive in childhood)

Muscle hypotonia (ranging from severe congenital to mild later-onset)

Bowing of limbs

Skeletal dysplasia

Brittle cornea syndrome (BCS) AR 229200

614170

16q24

4q27

ZNF469

PRDM5

ZNF469

PRDM5

Thin cornea with/without rupture

Early-onset progressive keratoconus and/or keratoglobus

Blue sclerae

Unclassified Classical-like EDS type 2 (clEDS2) AR 618000 7p13 AEBP1 AEBP1 (ACLP) Skin hyperextensibility with atrophic scarring

Generalized joint hypermobility

Foot deformities

Early-onset osteopenia

Unknown Hypermobile EDS (hEDS) ? (AD) 130020 ? ? ? Generalized joint hypermobility

Systemic manifestations of generalized connective tissue fragility

Musculoskeletal complaints

Positive family history

Exclusion of other EDS types and other joint hypermobility-associated

conditions

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ECM, extracellular matrix; OMIM, Online Mendelian Inheritance in Man.

(Continued)

3227Heritable Disorders of Connective Tissue CHAPTER 413

Incidence An incidence of about 1 in 5000 individuals for all

forms of EDS was proposed, with no apparent ethnic predisposition.

The diagnosis of hypermobile EDS is more common in females than

in males, but whether this is due to an increased incidence or more

severe manifestation is unknown. The incidence for other types of

EDS is similar in males and females. With incidences of 1 in 20,000

and 1 in 50,000–200,000 respectively, classical and vascular EDS are

the most common genetically elucidated types of EDS. For the other

types of EDS for which causative variants have been identified, there

are no incidence estimates, but the numbers of people who have been

reported worldwide with these disorders range between ~5 and ~100

individuals per EDS type. Patients with milder forms frequently do not

seek medical attention.

Skin One of the principal features of EDS is skin hyperextensibility,

that is, the skin stretches easily but snaps back after release. The skin

often has a smooth, soft, or velvety feel to it and can be thin and translucent. It is fragile and tears easily, even after minor trauma, and heals

slowly. Widened and thin atrophic scars are frequently observed in different types of EDS. Especially in classical EDS, atrophic scarring may

be widespread, especially over pressure points and exposed areas such

as the forehead, elbows, knees, and shins, with marked widening of

the scars, which are covered by a very thin inelastic skin (papyraceous

scars). Individuals with vascular EDS usually do not have a velvety

hyperextensible skin, but skin can be thin and translucent with visible

superficial veins. Easy bruising is common to most types of EDS and

may manifest itself as spontaneous or recurring hematomas. These may

cause discoloration of the skin due to deposition of hemosiderin, often

referred to as “hemosiderotic” scars, especially in classical, vascular,

and periodontic EDS.

Ligament and Joint Changes Joint hypermobility, another cardinal sign, is variable in severity and usually, but not always, generalized. While often an “asset” in childhood, it can become a serious

burden over time, often complicated by repetitive subluxations,

dislocations, sprains, and chronic joint pain that is difficult to treat.

Other observed musculoskeletal features include congenital bilateral

hip dislocation, spine deformities (scoliosis, kyphosis), pectus deformities (pectus carinatum, pectus excavatum), club feet and other contractures, and in some rare types, a (mild) skeletal dysplasia. Muscle

hypotonia is observed in a number of EDS types and, in combination

with joint laxity, may cause floppy infant syndrome or a delay in

motor development.

Other Features Signs of more generalized connective tissue weakness and fragility can be observed in varying degrees and may help to

distinguish between the different EDS types. Rupture of medium and

large-sized arteries is typical of vascular EDS but has been reported in

a few other types as well, i.e., classical and kyphoscoliotic type. Vascular

EDS patients are also at increased risk for rupture of the gastrointestinal tract, especially the sigmoid colon, and the gravid uterus. Valvular

defects and aortic root dilatation are rare and are also restricted to

some of the rarer types of EDS. Obstetrical and pelvic complications

such as cervical insufficiency, premature rupture of membranes, vaginal lacerations, and organ prolapses (uterus, bladder, rectum) may

occur. Sclerae may be blue, and more severe ophthalmologic complications, including keratoconus, keratoglobus, and scleral or corneal

rupture, may be observed in some rare types.

Molecular Defects Subsets of patients with different types of

EDS have mutations in the structural genes for fibrillar collagen

types I, III, and V (Table 413-3). About 90% of classical EDS

patients harbor a heterozygous mutation in COL5A1 or COL5A2 coding for type V collagen, a minor collagen found in association with type

I collagen. Heterozygous mutations in the COL3A1 gene for type III

collagen, which is abundant in the blood vessel wall, are responsible for

vascular EDS. Arthrochalasia EDS is caused by heterozygous mutations in either COL1A1 or COL1A2 that make type I procollagen resistant to cleavage by procollagen N-proteinase, whereas dermatosparaxis

EDS is caused by biallelic mutations in the gene that codes for the

procollagen N-proteinase itself, thereby reducing its enzyme activity.

The persistence of the N-propeptide causes the formation of collagen

fibrils that are thin and irregular. Other specific mutations in either

COL1A1 or COL1A2 give rise to a few rare subtypes of EDS. These

include the cardiac-valvular type, which is caused by biallelic COL1A2

mutations, leading to a complete absence of α2(I) chains. Patients with

this condition are at risk for severe, progressive cardiac-valvular disease

necessitating valve replacement. A specific arginine-to-cysteine substitution in the type I collagen α chain (p.Arg312Cys) is associated with

an EDS phenotype that resembles that of classical EDS, but patients

appear at increased risk for vascular rupture of medium-sized arteries.

A few patients with a phenotype that couples EDS with signs of moderate to severe myopathy harbor heterozygous or homozygous mutations in COL12A1, coding for type XII collagen, a fibril-associated

collagen with interrupted triple helices. Kyphoscoliotic EDS is caused by

biallelic mutations either in the PLOD1 gene, which encodes procollagen-lysine 5-dioxygenase (lysyl hydroxylase 1), an enzyme required

for formation of stable cross-links in collagen fibers, or in the FKBP14

gene, which encodes FKBP22, an endoplasmic resident molecular chaperone that acts as a quality control on the folded triple helix of type III

collagen. Some patients with clinical characteristics that resemble those

of classical EDS harbor biallelic mutations in either TNXB, encoding

tenascin X, an extracellular matrix glycoprotein that appears to regulate

the assembly of collagen fibers, or in AEBP1, which encodes the extracellular matrix–associated adipocyte enhancer-binding protein

(AEBP1), which assists in collagen polymerization. Spondylodysplastic

EDS is caused by biallelic mutations in B3GALT7, coding for galactosyltransferase I, or in B3GALT6, coding for galactosyltransferase II, both

key enzymes in the biosynthesis of the linker region of glycosaminoglycans. Musculocontractural EDS results from mutations in genes coding

enzymes responsible for dermatan biosynthesis: CHST14, dermatan

4-O-sulfotransferase 1, and DSE, dermatan sulfate epimerase. A rare

spondylodysplastic type of EDS is caused by biallelic mutations in

SLC39A13, encoding the intracellular zinc transporter ZIP13. Brittle

cornea syndrome is caused by biallelic mutations in either ZNF469 or

PRDM5, both (putative) transcriptional regulators. Finally, periodontic

EDS is caused by heterozygous mutations in C1R or C1S, coding for the

complement pathway components C1q and C1s, respectively.

Diagnosis Diagnostic workup comprises clinical examination and

should be followed by genetic testing in individuals who are suspected

to have an EDS subtype. Genetic testing can include targeted mutation

analysis in those with a family history of EDS caused by a known

genetic variant or, more frequently, next-generation sequencing using

multigene panels. Genetic diagnosis should lead to family testing. Of

note, the genetic cause of hypermobile EDS has not been determined,

and therefore, diagnosis of this condition is based on the presence of

clinical manifestations. Correlations between genotype and phenotype

are challenging and only starting to emerge, and as with other heritable diseases of connective tissue, there is a large degree of variability

among members of the same family carrying the same mutation.

TREATMENT

Ehlers-Danlos Syndrome

All patients with EDS should receive multidisciplinary care and,

if available, be part of a patient advocacy community. The precise

treatment depends on the subtype of EDS and the clinical manifestations. Physiotherapy is essential for patients with musculoskeletal

problems. Helmets and/or skin protections or joint protections,

braces, or splints can be used to reduce the risk of injury in patients

with skin fragility or joint hypermobility. Low-resistance exercises

(such as walking or swimming) can improve joint stability, although

exercises that place considerable strain on the joints (such as gymnastics or weightlifting) should be avoided. Monitoring for cardiovascular alterations using noninvasive procedures is recommended

in patients at risk of adverse cardiovascular events only. Given the

rarity of vascular EDS, referral to a center with EDS expertise is of

vital importance. A clear protocol for emergency room evaluation

3228 PART 12 Endocrinology and Metabolism

in the case of major complications should be established, and

patients should carry documentation of their genetic diagnosis,

such as a MedicAlert. The psychosocial impact of a vascular EDS

diagnosis often requires psychological care.

■ CHONDRODYSPLASIAS

(See also Chap. 412) Chondrodysplasias (CDs), also referred to as

skeletal dysplasias or osteochondrodysplasias, encompass a heterogeneous group of disorders characterized by intrinsic abnormalities of

cartilage and bone and are generally characterized by dwarfism and

abnormal body proportions (disproportionate short stature). Many

affected individuals develop degenerative joint changes, and mild CD

in adults may be difficult to differentiate from primary generalized OA.

Classification The Nosology and Classification of Genetic Skeletal

Disorders comprises 461 distinct disorders based on clinical, radiographic, and/or molecular phenotypes. Pathogenic variants affecting

437 different genes have currently been found in 425 of 461 (92%) of

these disorders. The conditions are divided into 42 groups based on

gene/protein families (e.g., the type II collagen group), phenotypic presentation (e.g., spondylometaphyseal dysplasia), and pathophysiology

(i.e., lysosomal storage disorders). One gene may be responsible for

more than one condition (e.g., COL2A1 mutations may cause achondrogenesis type 2, hypochondrogenesis, spondyloepiphyseal dysplasia

congenita, Kniest and Stickler syndromes), or a condition may be due

to mutations in more than one gene (e.g., geleophysic dysplasia can be

caused by mutations in ADAMTSL2, FBN1, and LTBP3).

Incidence The overall incidence of all forms of CD ranges from 1 per

2500 to 1 per 4000 births. Data on the frequency of individual CDs are

incomplete, but the incidence of Stickler syndrome is estimated to range

between 1 in 7500 and 1 in 9000. Therefore, the disease is probably among

the more common heritable disorders of connective tissue. The most common form of inherited disproportionate short stature is achondroplasia,

with an estimated incidence of 1 per 26,000 to 1 per 28,000 live births.

Molecular Defects Mutations in the COL2A1 gene, coding

for the α chain of type II collagen of cartilage, are found in a group

of patients with both mild and severe CDs. For example, a mutation in COL2A1 substituting a cysteine residue for an arginine was

found in a few unrelated families with spondyloepiphyseal dysplasia

(SED) and precocious generalized OA. Mutations in the gene were

also found in some lethal CDs characterized by gross deformities of

bones and cartilage, such as those found in SED congenita, spondyloepimetaphyseal dysplasia congenita, hypochondrogenesis/achondrogenesis type II, and Kniest syndrome. The highest incidence of

COL2A1 mutations, however, occurs in patients with the distinctive

features of the Stickler syndrome, which is characterized by skeletal

changes, orofacial abnormalities, and ophthalmologic and auditory

abnormalities. Most of the mutations in COL2A1 are premature stop

codons that produce haploinsufficiency. In addition, some of the

patients with Stickler syndrome or a closely related syndrome have

mutations in two genes specific for type XI collagen (COL11A1 and

COL11A2), which is an unusual heterotrimer formed from α chains

encoded by COL2A1, COL11A1, and COL11A2. Mutations in the

COL11A1 gene are also found in patients with Marshall syndrome,

which is similar to classic Stickler syndrome, but with more severe

hearing loss and dysmorphic features, such as a flat or retracted midface with a flat nasal bridge, short nose, anteverted nostrils, long

philtrum, and large-appearing eyes.

CDs are also caused by mutations in the less abundant collagens

found in cartilage. For example, patients with Schmid metaphyseal

CD have mutations in the gene for type X collagen, a short, networkforming collagen found in the hypertrophic zone of endochondral

cartilage. The syndrome is characterized by short stature, coxa vara,

flaring metaphyses, and waddling gait. As with other collagen genes,

the most common mutations are of two types: nonsense mutations that

lead to haploinsufficiency and structural mutations that compromise

collagen assembly.

Some patients have mutations in genes for proteins that interact with

collagens. Patients with pseudoachondroplasia or autosomal dominant

multiple epiphyseal dysplasia have mutations in the gene for the cartilage oligomeric matrix protein (COMP), a protein that interacts with

both collagens and proteoglycans in cartilage. However, some families

with multiple epiphyseal dysplasia have a defect in one of the three

genes for type IX collagen (COL9A1, COL9A2, and COL9A3) or in

matrilin-3, another extracellular protein found in cartilage.

Some CDs are caused by mutations in genes that affect early development of cartilage and related structures. Achondroplasia is caused

by mutations in the gene for a receptor for a fibroblastic growth factor

(FGFR3). The mutations in the FGFR3 gene causing achondroplasia

are unusual in several respects. A single-base mutation in the gene

that converts glycine to arginine at position 380 in the FGFR3 gene

is present in >90% of patients. Most patients harbor a sporadic new

mutation, and therefore, this nucleotide change is one of the most

common recurring mutations in the human genome. The mutation

causes unregulated signal transduction through the receptor and

inappropriate development of cartilage. Mutations that alter other

domains of FGFR3 have been found in patients with the more severe

disorders of hypochondroplasia and thanatophoric dysplasia and in a

few families with a variant of craniosynostosis. However, most patients

with craniosynostosis appear to have mutations in the related FGFR2

gene. The similarities between the phenotypes produced by mutations

in genes for fibroblast growth factor (FGF) receptors and mutations in

structural proteins of cartilage are probably explained by the observation that the activity of FGFs is regulated in part by binding of FGFs

to proteins sequestered in the extracellular matrix. Therefore, the situation parallels the interactions between transforming growth factors

(TGFs) and fibrillin in MFS (see below).

Other mutations involve the proteoglycans of cartilage, aggrecan

(AGC1) and perlecan (HSPG2), and in the proteoglycan posttranslational sulphation pathway (DTDST, PAPSS2, and CHST3). Mutations

in >45 other genes have been defined in CDs.

Diagnosis The diagnosis of CDs is made on the basis of the physical appearance, slit-lamp eye examinations, x-ray findings, histologic

changes, and clinical course. Targeted gene and exome sequencing or

more global sequencing strategies are used for molecular diagnosis.

Given the wide spectrum of CD phenotypes, these genetic tests are

becoming critical diagnostic tools. For Stickler syndrome, more precise

diagnostic criteria have made it possible to identify type I variants with

mutations in the COL2A1 gene with a high degree of accuracy. It has

been suggested that the type II variant with mutations in the COL11A1

gene can be identified on the basis of a “beaded” vitreous phenotype

and that the type III variant with mutations in the COL11A2 gene can

be identified on the basis of the characteristic systemic features without

the ocular involvement. Prenatal diagnosis based on analysis of DNA

obtained from chorionic villus or amniotic fluid is possible.

TREATMENT

Chondrodysplasias

The treatment of CDs is symptomatic and is directed to secondary

features such as degenerative arthritis. Many patients require joint

replacement surgery and corrective surgery for cleft palate. The

eyes should be monitored carefully for the development of cataracts

and the need for laser therapy to prevent retinal detachment. In

general, patients should be advised to avoid obesity and contact

sports. Counseling for the psychological problems of short stature

is critical. Several clinical trials therapeutically targeting the FGFR3

pathway in achondroplasia are underway.

■ HERITABLE THORACIC AORTIC

ANEURYSM DISEASE

Heritable thoracic aortic aneurysm disease (HTAD) encompasses

conditions in which aortic disease has a familial occurrence, due to

an underlying genetic defect. HTAD is classified as syndromic or

3229Heritable Disorders of Connective Tissue CHAPTER 413

TABLE 413-4 Heritable Thoracic Aortic Disease and Associated Genes and Proteins

GENE PROTEIN CONDITION OMIM LOCUS

Extracellular matrix proteins COL3A1 α1(III) collagen chain Vascular EDS 130050 2q32

FBN1 Fibrillin 1 Marfan Syndrome 154700 15q21.1

MFAP5 Microfibrillar associated protein 5 Familial thoracic aortic aneurysm 9 616166 12p13.31

LOX Lysyl oxidase Familial thoracic aortic aneurysm 10 617168 5q23.1

TGF-β signaling TGFBR1 Transforming growth factor receptor 1 Loeys-Dietz syndrome 1 609192 9q22.33

TGFBR2 Transforming growth factor receptor 2 Loeys-Dietz syndrome 2 610168 3p24.1

SMAD3 Mothers against decapentaplegic drosophila

homolog 3

Loeys-Dietz syndrome 3 613795 15q22.33

TGFB2 Transforming growth factor β2 Loeys-Dietz syndrome 4 614816 1q41

TGFB3 Transforming growth factor β3 Loeys-Dietz syndrome 5 615582 14q23.3

SMAD2 Mothers against decapentaplegic drosophila

homolog 2

Arterial aneurysms and dissections / 18q21.1

ACTA2 Smooth muscle actin α2 Familial thoracic aortic aneurysm 6 611788 10q23.31

Smooth muscle contraction MYH11 Smooth muscle myosin heavy chain 11 Familial thoracic aortic aneurysm 4 132900 16p13.11

MYLK Myosin light chain kinase Familial thoracic aortic aneurysm 7 613780 3q21.1

PRKG1 Protein kinase cGMP-dependent type 1 Familial thoracic aortic aneurysm 8 615436 10q11.2-q21.1

Abbreviations: EDS, Ehlers-Danlos syndrome; OMIM, Online Mendelian Inheritance in Man; TGF, transforming growth factor.

nonsyndromic. Syndromic HTAD may associate with ocular, craniofacial, musculoskeletal, and skin features, with a recognizable, yet sometime subtle, phenotype. They are caused by mutations in genes that code

for extracellular matrix proteins. Besides syndromic HTAD, there are

several nonsyndromic forms of HTAD; patients with these conditions

do not display an outward recognizable phenotype and are classified

as having familial thoracic aortic aneurysm (FTAA). More extensive

genetic screening in cohorts of patients with thoracic aortic aneurysm is,

however, slowly revealing that there is no strict boundary between syndromic and nonsyndromic HTAD entities (Table 413-4) (Chap. 280).

Classification The most common form of syndromic HTAD is

MFS, caused by mutations in the gene for fibrillin-1 (FBN1). MFS was

initially characterized by a triad of features: (1) skeletal changes that

include long, thin extremities, frequently associated with loose joints;

(2) reduced vision as the result of dislocations of the lenses (ectopia

lentis); and (3) aortic aneurysms. An international panel has developed

a series of revised Ghent criteria that are useful in classifying patients.

Other major syndromic HTADs include different genetic variants of

Loeys-Dietz syndrome (LDS) (TGFBR1, TGFBR2, TGFB2, TGFB3,

SMAD2, and SMAD3) and vascular EDS (COL3A1). Rare forms of

syndromic HTAD include Shprintzen-Goldberg syndrome (SKI),

Meester-Loeys syndrome (BGN), and arterial tortuosity syndrome

(ATS) (SLC2A10).

Incidence and Inheritance The incidence of MFS is among the

highest of any heritable disorder: ~1 in 3000–5000 births in most racial

and ethnic groups. The related syndromes are less common. Mutations

are generally inherited as autosomal dominant traits, but about onefourth of patients have sporadic new mutations. The LDSs are less

common, but their exact incidence is currently unknown.

Skeletal Effects Patients with MFS typically display a marfanoid

habitus with tall stature and long limbs. The ratio of the upper segment

(top of the head to the top of the pubic ramus) to the lower segment

(top of the pubic ramus to the floor) is usually 2 standard deviations

below mean for age, race, and sex. The fingers and hands are long and

slender and have a spider-like appearance (arachnodactyly). Overlapping features in MFS and LDS include scoliosis or kyphoscoliosis;

anterior chest deformities, including pectus excavatum, pectus carinatum, or asymmetry; pes planus; pneumothorax; and dural ectasia. A

few patients have severe joint hypermobility similar to EDS. Clubfeet,

joint contractures, and cervical spine instability are more frequently

observed in LDS. Patients with SMAD3 mutations are particularly

prone to premature OA.

Cardiovascular Features Cardiovascular abnormalities are the

major source of morbidity and mortality both in MFS and LDS

(Chap. 280). Patients with MFS often have mitral valve prolapse that

develops early in life and that progresses to mitral valve regurgitation

of increasing severity in about one-quarter of patients. Dilation of the

root of the aorta and the sinuses of Valsalva are characteristic and ominous features of MFS that can develop at any age. The rate of dilation

is unpredictable, but it can lead to aortic regurgitation, dissection of

the aorta, and rupture. Dilation is probably accelerated by physical and

emotional stress as well as by pregnancy. Cardiovascular features of LDS

also include dilatation of the aortic root at the level of the sinus of Valsalva, which can progress to dissection or rupture when left untreated.

LDS is also known for its involvement of aneurysms affecting arterial

branches of head, neck, thoracic and abdominal aorta, lung, and lower

extremities and for the presence or tortuosity of these vessels. In contrast to MFS, congenital heart malformations are often noted.

Ocular Features Myopia is the most common ocular feature of

MFS and often presents in early childhood. Displacement of the lens

from the center of the pupil (ectopia lentis) occurs in ~60% of MFS

patients. The ocular globe is frequently elongated. Retinal detachment,

early cataract formation, and glaucoma can occur. Ectopia lentis does

not usually occur in LDS, but other ocular features may be present,

such as blue sclerae, strabismus, amblyopia, and myopia.

Other Features MFS patients typically have a high arched palate.

Patients with LDS characteristically display hypertelorism (widely

spaced eyes) and cleft palate or bifid (split) uvula. They may also

have craniosynostosis. Shared mucocutaneous features include striae,

typically over the shoulders and buttocks, and inguinal and incisional

hernias. Patients with LDS may display more EDS-like skin features,

such as thin translucent skin and widened scars.

Molecular Defects More than 90% of patients clinically classified as having MFS by the Ghent criteria have a mutation in the

gene for fibrillin-1 (FBN1). Mutations in the same gene are found

in a few patients who do not meet the Ghent criteria. Most FBN1 gene

mutations are unique and are scattered throughout its 65 coding exons.

Approximately 10% are recurrent new mutations that are largely

located in CpG sequences known to be “hot spots.” About one-third of

the mutations introduce premature termination codons, and about

two-thirds are missense mutations that alter calcium-binding domains

in the repetitive epidermal growth factor–like domains of the protein.

Rarer mutations alter the processing of the protein. As in many genetic

diseases, the severity of the phenotype cannot be predicted from the