3216 PART 12 Endocrinology and Metabolism

of the hands and feet produces a paw-like appearance, which may be

mistaken for acromegaly. Arthralgias, pseudogout, and limited mobility may also occur. The disorder must be differentiated from secondary

hypertrophic osteopathy that develops during the course of serious

pulmonary disorders. The two conditions can be differentiated by

standard radiography of the digits in which secondary pachydermoperiostosis has exuberant periosteal new bone formation and a smooth

and undulating surface. In contrast, primary hypertrophic osteopathy

has an irregular periosteal surface.

There are no diagnostic blood or urine tests. Synovial fluid does not

have an inflammatory profile. There is no specific therapy, although a

limited experience with colchicine suggests some benefit in controlling

the arthralgias.

■ OSTEOCHONDRODYSPLASIAS

These include several hundred heritable disorders of connective tissue.

These primary abnormalities of cartilage manifest as disturbances in

cartilage and bone growth. Selected growth-plate chondrodysplasias are

described here. For discussion of chondrodysplasias, see Chap. 413.

Achondrodysplasia This is a relatively common form of shortlimb dwarfism that occurs in 1 in 15,000 to 1 in 40,000 live births. The

disease is caused by a mutation of the fibroblast growth factor receptor

3 (FGFR3) gene that results in a gain-of-function state. Most cases are

sporadic mutations. However, when the disorder appears in families,

the inheritance pattern is consistent with an autosomal dominant

disorder. The primary defect is abnormal chondrocyte proliferation at

the growth plate that causes development of short, but proportionately

thick, long bones. Other regions of the long bones may be relatively

unaffected. The disorder is manifest by the presence of short limbs

(particularly the proximal portions), normal trunk, large head, saddle

nose, and an exaggerated lumbar lordosis. Severe spinal deformity may

lead to cord compression. The homozygous disorder is more serious

than the sporadic form and may cause neonatal death. Vosoritide, an

analog of C-type natriuretic peptide, increased growth among children

in phase 3 clinical trials. Treatment is controversial among patient

support communities. Infigratinib, a selective FGFR1-3 tyrosine kinase

inhibitor, is in phase 2 clinical trials. Pseudoachondroplasia clinically

resembles achondrodysplasia but has no skull abnormalities.

Enchondromatosis This is also called dyschondroplasia or Ollier’s

disease; it is also a disorder of the growth plate in which the primary

cartilage is not resorbed. Cartilage ossification proceeds normally, but

it is not resorbed normally, leading to cartilage accumulation. The

changes are most marked at the ends of long bones, where the highest

growth rates occur. Chondrosarcoma develops infrequently. The association of enchondromatosis and cavernous hemangiomas of the skin

and soft tissues is known as Maffucci’s syndrome. Both Ollier’s disease

and Maffucci’s syndrome are associated with various malignancies,

including granulosa cell tumor of the ovary and cerebral glioma.

Multiple Osteochondromas This is also called multiple exostoses

or diaphyseal aclasis; it is a genetic disorder that follows an autosomal

dominant pattern of inheritance. In this condition, areas of growth

plates become displaced, presumably by growing through a defect in

the perichondrium. The lesion begins with vascular invasion of the

growth-plate cartilage, resulting in a characteristic radiographic finding of a mass that is in direct communication with the marrow cavity

of the parent bone. The underlying cortex is resorbed. The disease is

caused by inactivating mutations of the EXT1 and EXT2 genes, whose

products normally synthesize heparan sulfate chains. The resulting

heparan sulfate deficiency impacts signaling pathways and leads to

ectopic chondrogenesis. Solitary or multiple lesions are located in the

metaphyses of long bones. Although usually asymptomatic, the lesions

may interfere with joint or tendon function or compress peripheral

nerves. The lesions stop growing when growth ceases but may recur

during pregnancy. There is a small risk for malignant transformation

into chondrosarcoma. Palovarotene, a retinoic acid receptor agonist, is

in clinical trials.

EXTRASKELETAL (ECTOPIC)

CALCIFICATION AND OSSIFICATION

Deposition of calcium phosphate crystals (calcification) or formation

of true bone (ossification) in nonosseous soft tissue may occur by one

of three mechanisms: (1) metastatic calcification due to a supranormal

calcium × phosphate concentration product in extracellular fluid; (2)

dystrophic calcification due to mineral deposition into metabolically

impaired or dead tissue despite normal serum levels of calcium and

phosphate; and (3) ectopic ossification, or true bone formation. Disorders that may cause extraskeletal calcification or ossification are listed

in Table 412-2.

■ METASTATIC CALCIFICATION

Soft tissue calcification may complicate diseases associated with significant hypercalcemia, hyperphosphatemia, or both. In addition,

vitamin D and phosphate treatments or calcium administration in the

presence of mild hyperphosphatemia, such as during hemodialysis,

may induce ectopic calcification. Calcium phosphate precipitation

may complicate any disorder when the serum calcium × phosphate

concentration product is >75. The initial calcium phosphate deposition

is in the form of small, poorly organized crystals, which subsequently

organize into hydroxyapatite crystals. Calcifications that occur in

hypercalcemic states with normal or low phosphate have a predilection

for kidney, lungs, and gastric mucosa. Hyperphosphatemia with normal or low serum calcium may promote soft tissue calcification with

predilection for the kidney and arteries. The disturbances of calcium

and phosphate in renal failure and hemodialysis are common causes of

soft tissue (metastatic) calcification.

■ TUMORAL CALCINOSIS

This is a rare genetic disorder characterized by masses of metastatic

calcifications in soft tissues around major joints, most often shoulders,

hips, and ankles. Tumoral calcinosis differs from other disorders in that

the periarticular masses contain hydroxyapatite crystals or amorphous

calcium phosphate complexes, whereas in fibrodysplasia ossificans progressiva (below), true bone is formed in soft tissues. About one-third of

tumoral calcinosis cases are familial, with both autosomal recessive and

autosomal dominant m

14 PART 12 Endocrinology and Metabolism

manifestations are due to narrowed cranial foramens with neural

compressions that may result in optic atrophy, facial paralysis, and

deafness. Adults may have an enlarged mandible. Serum ALP levels

may be elevated, which reflect the uncoupled bone remodeling with

high osteoblastic formation rates and low osteoclastic resorption. As

a result, there is increased accumulation of normal bone. Endosteal

hyperostosis with syndactyly, known as sclerosteosis, is a more severe

form. The genetic defects for both sclerosteosis and van Buchem’s disease have been associated with mutations in the SOST gene.

■ MELORHEOSTOSIS

Melorheostosis (Greek, “flowing hyperostosis”) may occur sporadically

or follow a pattern consistent with an autosomal recessive disorder. The

major manifestation is progressive linear hyperostosis in one or more

bones of one limb, usually a lower extremity. The name comes from the

radiographic appearance of the involved bone, which resembles melted

wax that has dripped down a candle. Symptoms appear during childhood as pain or stiffness in the area of sclerotic bone. There may be

associated ectopic soft tissue masses, composed of cartilage or osseous

tissue, and skin changes overlying the involved bone, consisting of

scleroderma-like areas and hypertrichosis. The disease does not progress in adults, but pain and stiffness may persist. Laboratory tests are

unremarkable. Somatic mutations in MAP2K1, which increases MEK1

activity downstream of the RAS pathway, and SMAD3, which upregulates the TGF-β/SMAD pathway, have been identified in affected bone

in patients with melorheostosis. There is no specific treatment. Surgical

interventions to correct contractures are often unsuccessful.

■ OSTEOPOIKILOSIS

The literal translation of osteopoikilosis is “spotted bones”; it is a

benign autosomal dominant condition in which numerous small,

variably shaped (usually round or oval) foci of bony sclerosis are seen

in the epiphyses and adjacent metaphyses. The lesions may involve any

bone except the skull, ribs, and vertebrae. They may be misidentified

as metastatic lesions. The main differentiating points are that bony

lesions of osteopoikilosis are stable over time and do not accumulate

radionucleotide on bone scanning. In some kindred, osteopoikilosis is

associated with connective tissue nevi known as dermatofibrosis lenticularis disseminata, also known as Buschke-Ollendorff syndrome. Most

cases are caused by mutations in LEMD3, which is involved with bone

morphogenetic protein (BMP) signaling. Histologic inspection reveals

thickened but otherwise normal trabeculae and islands of normal cortical bone. No treatment is indicated.

■ HEPATITIS C–ASSOCIATED OSTEOSCLEROSIS

Hepatitis C–associated osteosclerosis (HCAO) is a rare acquired diffuse osteosclerosis in adults with prior hepatitis C infection. After a

latent period of several years, patients develop diffuse appendicular

bone pain and a generalized increase in bone mass with elevated serum

ALP. Bone biopsy and histomorphometry reveal increased rates of

bone formation, decreased bone resorption with a marked decrease in

osteoclasts, and dense lamellar bone. One patient had increased serum

OPG levels, and bone biopsy showed large numbers of osteoblasts

positive for OPG and reduced osteoclast number. Empirical therapy

includes pain control, and there may be beneficial response to bisphosphonate. Long-term antiviral therapy may reverse the bone disease.

DISORDERS ASSOCIATED WITH

DEFECTIVE MINERALIZATION

■ HYPOPHOSPHATASIA

This is a rare inherited disorder that presents as rickets in infants and

children or osteomalacia in adults with paradoxically low serum levels

of ALP. The frequency of the severe neonatal and infantile forms is

about 1 in 100,000 live births in Canada, where the disease is most

common because of its high prevalence among Mennonites and Hutterites. It is rare in African Americans. The severity of the disease is

remarkably variable, ranging from intrauterine death associated with

profound skeletal hypomineralization at one extreme to premature

tooth loss as the only manifestation in some adults. Severe cases are

inherited in an autosomal recessive manner, but the genetic patterns

are less clear for the milder forms. The disease is caused by a deficiency

of tissue nonspecific (bone/liver/kidney) ALP (TNSALP), which,

although ubiquitous, results only in bone abnormalities. Protein levels

and functions of the other ALP isozymes (germ cell, intestinal, placental) are normal. Defective ALP permits accumulation of its major

naturally occurring substrates including phosphoethanolamine (PEA),

inorganic pyrophosphate (PPi), and pyridoxal 5′-phosphate (PLP). The

accumulation of PPi interferes with mineralization through its action

as a potent inhibitor of hydroxyapatite crystal growth.

Perinatal hypophosphatasia becomes manifest during pregnancy

and is often complicated by polyhydramnios and intrauterine death.

The infantile form becomes clinically apparent before the age of

6 months with failure to thrive, rachitic deformities, functional craniosynostosis despite widely open fontanels (which are actually hypomineralized areas of the calvarium), raised intracranial pressure, and flail

chest with predisposition to pneumonia. Hypercalcemia and hypercalciuria are common. This form has a mortality rate of ~50%. Prognosis

seems to improve for the children who survive infancy. Childhood

hypophosphatasia has variable clinical presentation. Premature loss of

deciduous teeth (before age 5) is the hallmark of the disease. Rickets

causes delayed walking with waddling gait, short stature, and dolichocephalic skull with frontal bossing. The disease often improves during

puberty but may recur in adult life. Adult hypophosphatasia presents

during middle age with painful, poorly healing metatarsal stress fractures or thigh pain due to femoral pseudofractures. Presentation may

be subtle with muscle pain or recurring headaches as the predominant

symptoms. It is important to recognize hypophosphatasia in adults

because treatment with bisphosphonates can result in increased rather

than decreased bone fragility.

Laboratory investigation reveals low ALP levels and normal or

elevated levels of serum calcium and phosphorus despite clinical and

radiologic evidence of rickets or osteomalacia. Serum parathyroid

hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels

are normal. The elevation of PLP is specific for the disease and may

even be present in asymptomatic parents of severely affected children.

Because vitamin B6

 increases PLP levels, vitamin B6

 supplements

should be discontinued 1 week before testing. Clinical testing is available to detect loss-of-function mutation(s) within the ALPL gene that

encodes TNSALP.

In contrast to other forms of rickets and osteomalacia, calcium and

vitamin D supplementation should be avoided because they may aggravate hypercalcemia and hypercalciuria. A low-calcium diet, glucocorticoids, and calcitonin have been used in a small number of patients

with variable responses. Because fracture healing is poor, placement of

intramedullary rods is best for acute fracture repair and for prophylactic prevention of fractures. In 2015, asfotase alfa, a tissue-nonspecific

ALP was approved as enzyme replacement therapy for the perinatal/

infantile- and juvenile-onset forms. With 7 years of therapy, children

with perinatal/infantile forms showed sustained improvements in

mineralization, along with improvements in other features, such as

respiratory function and growth.

■ AXIAL OSTEOMALACIA

This is a rare disorder characterized by defective skeletal mineralization

despite normal serum calcium and phosphate levels. Clinically, the disorder presents in middle-aged or elderly men with chronic axial skeletal

discomfort. Cervical spine pain may also be present. Radiographic findings are mainly osteosclerosis due to coarsened trabecular patterns typical of osteomalacia. Spine, pelvis, and ribs are most commonly affected.

Histologic changes show defective mineralization and flat, inactive

osteoblasts. The primary defect appears to be an acquired defect in

osteoblast function. The course is benign, and there is no established

treatment. Calcium and vitamin D therapies are not effective.

■ FIBROGENESIS IMPERFECTA OSSIUM

This is a rare condition of unknown etiology. It presents in both sexes;

in middle age or later; and with progressive, intractable skeletal pain

3215Paget’s Disease and Other Dysplasias of Bone CHAPTER 412

and fractures; worsening immobilization; and a debilitating course.

The only biochemical abnormality is elevated ALP. Radiographic

evaluation reveals generalized osteomalacia, osteopenia, and occasional pseudofractures. Histologic features include a tangled pattern

of collagen fibrils with abundant osteoblasts and osteoclasts. Use of

growth hormone led to substantial short-term clinical improvement

in two adult patients, but long-term outcomes are unknown. No other

effective treatment is known. Spontaneous remission has been reported

in a small number of patients.

FIBROUS DYSPLASIA AND MCCUNEALBRIGHT SYNDROME

Fibrous dysplasia is a sporadic disorder characterized by the presence

of one (monostotic) or more (polyostotic) expanding fibrous skeletal

lesions composed of bone-forming mesenchyme. The association of

the polyostotic form with café au lait spots and hyperfunction of an

endocrine system such as pseudoprecocious puberty of ovarian origin

is known as McCune-Albright syndrome (MAS). A spectrum of the

phenotypes is caused by activating mutations in the GNAS1 gene,

which encodes the α subunit of the stimulatory G protein (Gs

α). As the

postzygotic mutations occur at different stages of early development,

the extent and type of tissue affected are variable and explain the mosaic

pattern of skin and bone changes. GTP binding activates the Gs

α regulatory protein and mutations in regions of Gs

α that selectively inhibit

GTPase activity, which results in constitutive stimulation of the cyclic

AMP–protein kinase A signal transduction pathway. Such mutations

of the Gs

α protein–coupled receptor may cause autonomous function

in bone (parathyroid hormone receptor); skin (melanocyte-stimulating

hormone receptor); and various endocrine glands including ovary

(follicle-stimulating hormone receptor), thyroid (thyroid-stimulating

hormone receptor), adrenal (adrenocorticotropic hormone receptor),

and pituitary (growth hormone–releasing hormone receptor). The skeletal lesions are composed largely of mesenchymal cells that do not differentiate into osteoblasts, resulting in the formation of imperfect bone.

In some areas of bone, fibroblast-like cells develop features of osteoblasts

in that they produce extracellular matrix that organizes into woven bone.

Calcification may occur in some areas. In other areas, cells have features

of chondrocytes and produce cartilage-like extracellular matrix.

Clinical Presentation Fibrous dysplasia occurs with equal frequency in both sexes, whereas MAS with precocious puberty is more

common (10:1) in girls. The monostotic form is the most common and

is usually diagnosed in patients between 20 and 30 years of age without

associated skin lesions. The polyostotic form typically manifests in

children <10 years old and may progress with age. Early-onset disease

is generally more severe. Lesions may become quiescent in puberty

and progress during pregnancy or with estrogen therapy. In polyostotic

fibrous dysplasia, the lesions most commonly involve the maxilla and

other craniofacial bones, ribs, and metaphyseal or diaphyseal portions

of the proximal femur or tibia. Expanding bone lesions may cause pain,

deformity, fractures, and nerve entrapment. Sarcomatous degeneration

involving the facial bones or femur is infrequent (<1%). The risk of

malignant transformation is increased by radiation, which has proven

to be ineffective treatment. In rare patients with widespread lesions,

renal phosphate wasting and hypophosphatemia may cause rickets or

osteomalacia. Hypophosphatemia may be due to production of a phosphaturic factor by the abnormal fibrous tissue.

MAS patients may have café au lait spots, which are flat, hyperpigmented skin lesions that have rough borders (“coast of Maine”) in contrast to the café au lait lesions of neurofibromatosis that have smooth

borders (“coast of California”). The most common endocrinopathy is

isosexual pseudoprecocious puberty in girls. Other less common endocrine disorders include thyrotoxicosis, Cushing’s syndrome, acromegaly, hyperparathyroidism, hyperprolactinemia, and pseudoprecocious

puberty in boys.

Radiographic Findings In long bones, the fibrous dysplastic

lesions are typically well-defined, radiolucent areas with thin cortices and a ground-glass appearance. Lesions may be lobulated with

trabeculated areas of radiolucency (Fig. 412-4). Involvement of facial

bones usually presents as radiodense lesions, which may create a leonine appearance (leontiasis osea). Expansile cranial lesions may narrow

foramens and cause optic lesions, reduce hearing, and create other

manifestations of cranial nerve compression.

Laboratory Results Serum ALP is occasionally elevated, but calcium,

parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels are normal. Patients with extensive polyostotic lesions

may have hypophosphatemia, hyperphosphaturia, and osteomalacia.

The hypophosphatemia and phosphaturia are directly related to the

levels of fibroblast growth factor 23 (FGF23). Biochemical markers of

bone turnover may be elevated.

TREATMENT

Fibrous Dysplasia and MAS

Spontaneous healing of the lesions does not occur, and there is

no established effective treatment. Improvement in bone pain and

partial or complete resolution of radiographic lesions have been

reported after IV bisphosphonate therapy. Denosumab given every

3 months is effective in reducing bone turnover markers and could

be a therapeutic option in difficult cases. Surgical stabilization is

used to prevent pathologic fracture or destruction of a major joint

space and to relieve nerve root or cranial nerve compression or

sinus obstruction.

OTHER DYSPLASIAS OF BONE

AND CARTILAGE

■ PACHYDERMOPERIOSTOSIS

Pachydermoperiostosis, or hypertrophic osteoarthropathy (primary

or idiopathic), is an autosomal dominant disorder characterized by

periosteal new bone formation that involves the distal extremities. The

lesions present as clubbing of the digits and hyperhidrosis and thickening of the skin, primarily of the face and forehead. The changes usually

appear during adolescence, progress over the next decade, and then

become quiescent. During the active phase, progressive enlargement

FIGURE 412-4 Radiograph of a 16-year-old male with fibrous dysplasia of the right

proximal femur. Note the multiple cystic lesions, including the large lucent lesion

in the proximal midshaft with scalloping of the interior surface. The femoral neck

contains two lucent cystic lesions.

3216 PART 12 Endocrinology and Metabolism

of the hands and feet produces a paw-like appearance, which may be

mistaken for acromegaly. Arthralgias, pseudogout, and limited mobility may also occur. The disorder must be differentiated from secondary

hypertrophic osteopathy that develops during the course of serious

pulmonary disorders. The two conditions can be differentiated by

standard radiography of the digits in which secondary pachydermoperiostosis has exuberant periosteal new bone formation and a smooth

and undulating surface. In contrast, primary hypertrophic osteopathy

has an irregular periosteal surface.

There are no diagnostic blood or urine tests. Synovial fluid does not

have an inflammatory profile. There is no specific therapy, although a

limited experience with colchicine suggests some benefit in controlling

the arthralgias.

■ OSTEOCHONDRODYSPLASIAS

These include several hundred heritable disorders of connective tissue.

These primary abnormalities of cartilage manifest as disturbances in

cartilage and bone growth. Selected growth-plate chondrodysplasias are

described here. For discussion of chondrodysplasias, see Chap. 413.

Achondrodysplasia This is a relatively common form of shortlimb dwarfism that occurs in 1 in 15,000 to 1 in 40,000 live births. The

disease is caused by a mutation of the fibroblast growth factor receptor

3 (FGFR3) gene that results in a gain-of-function state. Most cases are

sporadic mutations. However, when the disorder appears in families,

the inheritance pattern is consistent with an autosomal dominant

disorder. The primary defect is abnormal chondrocyte proliferation at

the growth plate that causes development of short, but proportionately

thick, long bones. Other regions of the long bones may be relatively

unaffected. The disorder is manifest by the presence of short limbs

(particularly the proximal portions), normal trunk, large head, saddle

nose, and an exaggerated lumbar lordosis. Severe spinal deformity may

lead to cord compression. The homozygous disorder is more serious

than the sporadic form and may cause neonatal death. Vosoritide, an

analog of C-type natriuretic peptide, increased growth among children

in phase 3 clinical trials. Treatment is controversial among patient

support communities. Infigratinib, a selective FGFR1-3 tyrosine kinase

inhibitor, is in phase 2 clinical trials. Pseudoachondroplasia clinically

resembles achondrodysplasia but has no skull abnormalities.

Enchondromatosis This is also called dyschondroplasia or Ollier’s

disease; it is also a disorder of the growth plate in which the primary

cartilage is not resorbed. Cartilage ossification proceeds normally, but

it is not resorbed normally, leading to cartilage accumulation. The

changes are most marked at the ends of long bones, where the highest

growth rates occur. Chondrosarcoma develops infrequently. The association of enchondromatosis and cavernous hemangiomas of the skin

and soft tissues is known as Maffucci’s syndrome. Both Ollier’s disease

and Maffucci’s syndrome are associated with various malignancies,

including granulosa cell tumor of the ovary and cerebral glioma.

Multiple Osteochondromas This is also called multiple exostoses

or diaphyseal aclasis; it is a genetic disorder that follows an autosomal

dominant pattern of inheritance. In this condition, areas of growth

plates become displaced, presumably by growing through a defect in

the perichondrium. The lesion begins with vascular invasion of the

growth-plate cartilage, resulting in a characteristic radiographic finding of a mass that is in direct communication with the marrow cavity

of the parent bone. The underlying cortex is resorbed. The disease is

caused by inactivating mutations of the EXT1 and EXT2 genes, whose

products normally synthesize heparan sulfate chains. The resulting

heparan sulfate deficiency impacts signaling pathways and leads to

ectopic chondrogenesis. Solitary or multiple lesions are located in the

metaphyses of long bones. Although usually asymptomatic, the lesions

may interfere with joint or tendon function or compress peripheral

nerves. The lesions stop growing when growth ceases but may recur

during pregnancy. There is a small risk for malignant transformation

into chondrosarcoma. Palovarotene, a retinoic acid receptor agonist, is

in clinical trials.

EXTRASKELETAL (ECTOPIC)

CALCIFICATION AND OSSIFICATION

Deposition of calcium phosphate crystals (calcification) or formation

of true bone (ossification) in nonosseous soft tissue may occur by one

of three mechanisms: (1) metastatic calcification due to a supranormal

calcium × phosphate concentration product in extracellular fluid; (2)

dystrophic calcification due to mineral deposition into metabolically

impaired or dead tissue despite normal serum levels of calcium and

phosphate; and (3) ectopic ossification, or true bone formation. Disorders that may cause extraskeletal calcification or ossification are listed

in Table 412-2.

■ METASTATIC CALCIFICATION

Soft tissue calcification may complicate diseases associated with significant hypercalcemia, hyperphosphatemia, or both. In addition,

vitamin D and phosphate treatments or calcium administration in the

presence of mild hyperphosphatemia, such as during hemodialysis,

may induce ectopic calcification. Calcium phosphate precipitation

may complicate any disorder when the serum calcium × phosphate

concentration product is >75. The initial calcium phosphate deposition

is in the form of small, poorly organized crystals, which subsequently

organize into hydroxyapatite crystals. Calcifications that occur in

hypercalcemic states with normal or low phosphate have a predilection

for kidney, lungs, and gastric mucosa. Hyperphosphatemia with normal or low serum calcium may promote soft tissue calcification with

predilection for the kidney and arteries. The disturbances of calcium

and phosphate in renal failure and hemodialysis are common causes of

soft tissue (metastatic) calcification.

■ TUMORAL CALCINOSIS

This is a rare genetic disorder characterized by masses of metastatic

calcifications in soft tissues around major joints, most often shoulders,

hips, and ankles. Tumoral calcinosis differs from other disorders in that

the periarticular masses contain hydroxyapatite crystals or amorphous

calcium phosphate complexes, whereas in fibrodysplasia ossificans progressiva (below), true bone is formed in soft tissues. About one-third of

tumoral calcinosis cases are familial, with both autosomal recessive and

autosomal dominant modes of inheritance reported. The disease is also

associated with a variably expressed abnormality of dentition marked

by short bulbous roots, pulp calcification, and radicular dentin deposited in swirls. The disorder is caused by gene mutations in GALNT3,

FGF23, or α-Klotho, leading to FGF23 deficiency or resistance. The

reduced activity of FGF23 leads to increased renal tubular reabsorption

of phosphate, elevated serum phosphate, and spontaneous soft tissue

calcification from elevated calcium-phosphate concentration product.

The disease usually presents in childhood and continues throughout

the patient’s life. The calcific masses are typically painless and grow at

variable rates, sometimes becoming large and bulky. The masses are often

TABLE 412-2 Diseases and Conditions Associated with Ectopic

Calcification and Ossification

Metastatic calcification

Hypercalcemic states

 Primary hyperparathyroidism

 Sarcoidosis

 Vitamin D intoxication

 Milk-alkali syndrome

 Renal failure

Hyperphosphatemia

 Tumoral calcinosis

 Secondary hyperparathyroidism

 Pseudohypoparathyroidism

 Renal failure

 Hemodialysis

 Cell lysis following chemotherapy

 Therapy with vitamin D and

phosphate

Dystrophic calcification

Inflammatory disorders

 Scleroderma

 Dermatomyositis

 Systemic lupus erythematosus

Trauma-induced

Ectopic ossification

Myositis ossificans

 Postsurgery

 Burns

 Neurologic injury

 Other trauma

 Fibrodysplasia ossificans

progressiva

3217Heritable Disorders of Connective Tissue CHAPTER 413

located near major joints but remain extracapsular. Joint range of motion

is not usually restricted unless the tumors are very large. Complications

include compression of neural structures and ulceration of the overlying

skin with drainage of chalky fluid and risk of secondary infection. Small

deposits not detected by standard radiographs may be detected by 99mTc

bone scanning. The most common laboratory findings are hyperphosphatemia and elevated serum 1,25-dihydroxyvitamin D levels. Serum

calcium, parathyroid hormone, and ALP levels are usually normal. Renal

function is also usually normal. Urine calcium and phosphate excretions

are low, and calcium and phosphate balances are positive.

An acquired form of the disease may occur with other causes of

hyperphosphatemia, such as secondary hyperparathyroidism associated with hemodialysis, hypoparathyroidism, pseudohypoparathyroidism, and massive cell lysis following chemotherapy for leukemia.

Tissue trauma from joint movement may contribute to the periarticular calcifications. Metastatic calcifications are also seen in conditions

associated with hypercalcemia, such as in sarcoidosis, vitamin D intoxication, milk-alkali syndrome, and primary hyperparathyroidism. In

these conditions, however, mineral deposits are more likely to occur in

proton-transporting organs such as kidney, lungs, and gastric mucosa

in which an alkaline milieu is generated by the proton pumps.

TREATMENT

Tumoral Calcinosis

Therapeutic successes have been achieved with surgical removal of

subcutaneous calcified masses, which tend not to recur if all calcification is removed from the site. Reduction of serum phosphate

by chronic phosphorus restriction may be accomplished using

low dietary phosphorus intake alone or in combination with oral

phosphate binders. The addition of the phosphaturic agent acetazolamide may be useful. Limited experience using the phosphaturic

action of calcitonin deserves further testing.

■ DYSTROPHIC CALCIFICATION

Posttraumatic calcification may occur with normal serum calcium

and phosphate levels and normal ion-solubility product. The deposited mineral is either in the form of amorphous calcium phosphate

or hydroxyapatite crystals. Soft tissue calcification complicating connective tissue disorders such as scleroderma, dermatomyositis, and

systemic lupus erythematosus may involve localized areas of the skin

or deeper subcutaneous tissue and is referred to as calcinosis circumscripta. Mineral deposition at sites of deeper tissue injury including

periarticular sites is called calcinosis universalis.

■ ECTOPIC OSSIFICATION

True extraskeletal bone formation that begins in areas of fasciitis

following surgery, trauma, burns, or neurologic injury is referred to

as myositis ossificans. The bone formed is organized as lamellar or

trabecular, with normal osteoblasts and osteoclasts conducting active

remodeling. Well-developed haversian systems and marrow elements

may be present. A second cause of ectopic bone formation occurs in an

inherited disorder, fibrodysplasia ossificans progressiva.

■ FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

This is also called myositis ossificans progressiva; it is a rare autosomal

dominant disorder characterized by congenital deformities of the hands

and feet and episodic soft tissue swellings that ossify. The disorder is

caused by an activating mutation in activin receptor A type 1. Ectopic

bone formation occurs in fascia, tendons, ligaments, and connective

tissue within voluntary muscles. Tender, rubbery induration, sometimes precipitated by trauma, develops in the soft tissue and gradually

calcifies. Eventually, heterotopic bone forms at these sites of soft tissue

trauma. Morbidity results from heterotopic bone interfering with normal movement and function of muscle and other soft tissues. Mortality

is usually related to restrictive lung disease caused by an inability of the

chest to expand. Laboratory tests are unremarkable.

There is no effective medical therapy. Bisphosphonates, glucocorticoids, and a low-calcium diet have largely been ineffective in halting

progression of the ossification. Palovarotene and REGN2477 (also

known as garetosmab), an anti–activin A antibody, are currently in

clinical trials. Surgical removal of ectopic bone is not recommended,

because the trauma of surgery may precipitate formation of new areas

of heterotopic bone. Dental complications, including frozen jaw, may

occur following injection of local anesthetics.

Acknowledgment

The authors acknowledge the contribution of Dr. Murray J. Favus to this

chapter in previous editions of Harrison’s.

■ FURTHER READING

Boyce AM, Collins MT: Fibrous dysplasia/McCune-Albright syndrome: A rare, mosaic disease of Gαs

 activation. Endocr Rev 41:345,

2020.

Majoor BC et al: Outcome of long-term bisphosphonate therapy

in McCune-Albright syndrome and polyostotic fibrous dysplasia.

J Bone Miner Res 32:264, 2017.

Ralston SH et al: Diagnosis and management of Paget’s disease of

bone in adults: A clinical guideline. J Bone Miner Res 34:579, 2019.

Reid IR et al: Treatment of Paget’s disease of bone with denosumab:

Case report and literature review. Calcif Tissue Int 99:322, 2016.

Shapiro JR, Lewiecki EM: Hypophosphatasia in adults: Clinical

assessment and treatment considerations. J Bone Miner Res 32:1977,

2017.

Singer FR et al: Paget’s disease of bone: An endocrine society clinical

practice guideline. J Clin Endocrinol Metab 99:4408, 2014.

Tan A et al: Long-term randomized trial of intensive versus symptomatic management in Paget’s disease of the bone: The PRISM-EZ Study.

J Bone Miner Res 32:1165, 2017.

Wu CC et al: Diagnosis and management of osteopetrosis: Consensus

guidelines from the osteopetrosis working group. J Clin Endocrinol

Metab 102:3111, 2017.

Section 5 Disorders of Intermediary

Metabolism

413 Heritable Disorders of

Connective Tissue

Joan C. Marini, Fransiska Malfait

CLASSIFICATION OF CONNECTIVE

TISSUE DISORDERS

Some of the most common conditions that are transmitted genetically

in families are disorders that produce clinically obvious changes in

the bone, cartilage, skin, or relatively acellular tissues such as tendons

that have been loosely defined as connective tissues. Because of their

heritability, some of the disorders were recognized as potentially

traceable to mutated genes soon after the principles of genetics were

introduced into medicine by Garrod and others. About half a century

later, McKusick emphasized the specificity of many of the diseases

for selective connective tissues and suggested that they were probably

caused by mutations in genes coding for the major proteins found in

those tissues. In the past several decades, mutations in several hundred

different genes expressed in connective tissues have been identified as

the cause of many connective tissue disorders. However, classifying

the disorders on the basis of either their clinical presentations or the

mutations causing them continues to present a challenge for both the

clinician and the molecular biologist.

Information on the disorders has continued to develop on two

levels. The initial clinical classifications suggested by McKusick and

3218 PART 12 Endocrinology and Metabolism

many others had to be refined as more patients were examined. For

example, some patients had skin changes similar to those commonly

seen in Ehlers-Danlos syndrome (EDS), but this feature was overshadowed by other features such as extreme hypotonia or sudden rupture

of large blood vessels. To account for the full spectrum of presentations

in patients and families, many of the disorders have been reclassified

several times, dividing each into a series of subtypes.

The identification of mutations causing the diseases has developed

on a parallel track. The first genes cloned for connective tissues were

the two genes coding for type I collagen (COL1A1 and COL1A2),

the most abundant protein in bones, skin, tendons, and several other

tissues. This facilitated early studies in patients with osteogenesis

imperfecta (OI) that revealed mutations in type I collagen genes. Biochemical data, developed primarily with cultures of skin fibroblasts

from affected individuals, demonstrated that the mutations dramatically altered the synthesis of collagen α-chains or the structure of

collagen fibers. The results stimulated efforts to identify additional

mutations in genes coding for structural proteins. Genes for collagens

provided an attractive paradigm to search for mutations, since a series

of different types of collagens were found in different connective tissues

and the collagen genes were readily isolated by their unique signature

sequences. Also, the collagen genes were vulnerable to a large number

of different mutations because of unusual structural requirements of

the protein. The search for mutations in collagen genes proved fruitful in that mutations were found in most patients with OI, in many

patients with hyperextensible skin and hypermobile joints, in some

patients with dwarfism, and in patients with other disorders, including

some such as Alport syndrome (AS) that were not initially classified

as disorders of connective tissue. Also, mutations in collagen genes

were found in subset of patients presenting with osteoarthritis (OA)

or osteoporosis, likely representing the mildest end of the syndromic

spectrum. However, the search for mutations quickly expanded to hundreds of other genes that included genes for other structural proteins,

for the posttranslational modification and processing of the structural

proteins, for chaperones, and for growth factors and their receptors and

other genes whose functions are still not fully understood.

In many instances, the mutations helped to define the clinical subtype

of the disorder, while in others, they revealed the genetic heterogeneity

of the same clinical presentations. Conversely, some patients with different manifestations were found to have mutations in the same genes.

In noncollagenous genes, it was sometimes difficult to establish whether

a change in the structure of a gene caused the phenotypic changes in

the patients or was simply a neutral polymorphism. Therefore, there

has been a continuing debate as to whether the disorders should be

classified by their clinical presentations or by the causative genes. As an

illustration of the problems, mutations in 437 genes have been found

associated with the 461 defined disorders of the skeleton. The latest

nosology for the disorders remains “hybrid” in nature in the sense that

the classification is not always based on the same criteria. Some diseases

are grouped based on the causal gene, others are listed together, because

they share common radiographic features, and still others are brought

together because of a similar clinical course (lethality) or involvement

of similar parts of the skeleton. A simpler system of classification proved

feasible for one rare heritable disorder of skin, epidermolysis bullosa.

The disorder was first defined clinically into subtypes based on the

layers of the skin that were cleaved in friction-induced blisters. Most

patients in each subtype were subsequently shown to have mutations

in genes expressed in the corresponding layer of skin. Even with these

patients, the strength of the genotype-phenotype correlation varies and

mutations have not yet been found in every patient.

The best pathway through this maze of information is probably to

begin by matching the signs and symptoms in a patient with the presentations that define each clinical classification. A major focus should be

on the most common disorders, recognizing that the signs and symptoms may vary among different individuals and family members with

the same diagnosis. Then, attempt to reach a decision, in consultation

with the patient, parents, and specialist, as to whether a DNA analysis

for the probable mutation is indicated. Among the considerations are

the cost, the rigor with which the clinical classification has been linked

to mutated genes, the reassurance the diagnosis can bring to patients

and their families, the use of the information for prenatal diagnosis, and

the possibility that mutation-specific therapies may be developed in the

future. For patients with the most severe forms, it is probably best to

consult a specialist in the disease to determine a multidisciplinary program for management and therapy. Patient support groups have formed

for many of the diseases and are an important source of information.

Patients with the most common forms of the disorders have mutations in a limited number of genes. This chapter will focus primarily

on these. Also, it will provide a brief summary of biosynthesis and

structure of connective tissues that may help guide the physician from

the nature of the mutations to their clinical presentations.

■ COMPOSITION OF CONNECTIVE TISSUES

Connective tissues such as skin, bone, cartilage, ligaments, and tendons are the critical structural frameworks of the body. They consist

of a complex interacting extracellular matrix network of collagens,

proteoglycans, and a large number of noncollagenous glycoproteins

and proteins. While these precise combinations of up to ~500 potential extracellular matrix building blocks provide tissue-specific function, there are many overarching similarities in composition such as

the role of composite collagen fibrils in providing strength and form,

elastin fibrils and proteoglycans and other interacting proteins, and

glycoproteins that fine-tune function (Table 413-1). The most abundant components of many connective tissues are three similar fibrillar

collagens (types I, II, and III). They have a similar tensile strength that

is comparable to that of steel wires. The three fibrillar collagens are

distributed in a tissue-specific manner: type I collagen accounts for

most of the protein of dermis, ligaments, tendons, and demineralized

bone; type I and type III are the most abundant proteins of large blood

vessels; and type II is the most abundant protein of cartilage.

■ BIOSYNTHESIS AND TURNOVER OF

CONNECTIVE TISSUES

Connective tissues are among the most stable components in living

organisms, but they are not inert. During embryonic development,

connective tissue membranes appear as early as the four-cell blastocyst

to provide a structural scaffold for the developing embryo. With the

development of blood vessels and skeleton, there is a rapid increase

in the synthesis, degradation, and resynthesis of connective tissues.

The turnover continues at a slower, but still rapid pace throughout

postnatal development and then spikes during the growth spurt of

puberty. During adulthood, the metabolic turnover of most connective

tissues is slow, but it continues at a moderate pace in bone. With age,

malnutrition, physical inactivity, and low gravitational stress, the rate

of degradation of most connective tissues, especially in bone and skin,

begins to exceed the rate of synthesis and the tissues shrink. In starvation, a large fraction of the collagen in skin and other connective tissues

is degraded and provides amino acids for gluconeogenesis (Chap. 334).

In both OA and rheumatoid arthritis, there is extensive degradation of

articular cartilage collagen. Glucocorticoids weaken most tissues by

decreasing collagen synthesis. In some pathologic states, however, collagen is deposited in excess. With most injuries to tissues, inflammatory and immune responses stimulate the deposition of collagen fibrils

in the form of fibrotic scars. In humans, as distinct from many other

species, the deposition of the fibrils is largely irreversible and prevents

regeneration of normal tissues in diseases such as hepatic cirrhosis,

pulmonary fibrosis, atherosclerosis, and nephrosclerosis.

Structure and Biosynthesis of Fibrillar Collagens The tensile

strength of collagen fibers derives primarily from the self-assembly of

protein monomers into large fibril structures in a process that resembles crystallization. The self-assembly requires monomers of highly

uniform and relatively rigid structure. It also requires a complex series

of posttranslational processing steps that maintain the solubility of the

monomers until they are transported to the appropriate extracellular

sites for fibril assembly. Because of the stringent requirements for correct self-assembly, it is not surprising that mutations in genes for fibrillar collagens cause many of the heritable diseases of connective tissues.

3219Heritable Disorders of Connective Tissue CHAPTER 413

TABLE 413-1 Constituents of Connective Tissues and Their Associated Heritable Conditions

PROTEIN TISSUE DISTRIBUTION DISEASE KEY MANIFESTATIONS

Collagen I Bone, cornea, dermis,

tendon

Osteogenesis imperfecta Bone fragility with fractures and deformity; blue sclerae; dentinogenesis

imperfecta; hearing loss

EDS (various rare subtypes) Joint hypermobility; skin hyperextensibility; skin fragility; soft connective

tissue fragility

Caffey disease Subperiosteal new bone formation; irritability; soft tissue swelling

Collagen II Cartilage, vitreous Various chondrodysplasias Skeletal dysplasia; ocular manifestations; hearing loss; orofacial

findings

Collagen III Dermis, aorta, uterus,

intestine

Vascular EDS Arterial, intestinal, and uterine fragility; thin translucent skin; easy

bruising

Collagen IV Basement membranes Alport syndrome (COL4A3/A4/A5) Hematuria; hearing loss; ocular abnormalities

Brain small-vessel disease

(COL4A1/A2)

Porencephaly; intracerebral hemorrhage; retinal arteriolar tortuosity;

congenital cataract; hematuria; renal cysts; muscle cramps

Collagen V Placental tissue, bone,

dermis, cornea

Classical EDS Joint hypermobility; skin hyperextensibility; atrophic scarring

Collagen VI Uterus, dermis, cornea,

cartilage

Bethlem myopathy and Ullrich

congenital muscular dystrophy

Muscle weakness; joint contractures; joint hypermobility

Collagen VII Skin, amniotic membrane,

mucosal epithelium

Epidermolysis bullosa Skin blistering; oral and esophageal blistering; corneal erosions

Collagen VIII Descemet’s membrane,

endothelial cells

Corneal dystrophy Corneal endothelial dystrophy; stromal edema

Collagen IX Cartilage, vitreous Stickler syndrome Spondyloepiphyseal dysplasia; early-onset osteoarthritis; high myopia;

vitreoretinal abnormalities; hearing loss; cleft palate; midfacial

hypoplasia

Collagen X Calcifying cartilage Multiple epiphyseal dysplasia Epiphyseal dysplasia; early-onset osteoarthritis

Collagen XI Cartilage, intervertebral disk Various chondrodysplasias Skeletal dysplasia; ocular manifestations; hearing loss; orofacial

findings

Collagen XII Dermis, tendon, cartilage Myopathic EDS Joint hypermobility; congenital muscle hypotonia and/or atrophy;

proximal joint contractures

Cartilage oligomeric

matrix protein

(COMP)

Cartilage, tendon, ligament,

bone

Pseudoachondroplasia Short-limb dwarfism; early-onset osteoarthritis

Multiple epiphyseal dysplasia Mildly short stature; early-onset osteoarthritis

Elastin Dermis, arterial wall, lung Cutis laxa Wrinkled, redundant, sagging inelastic skin

Williams syndrome Cardiovascular disease (especially supravalvular aortic stenosis);

orofacial features; intellectual deficit; connective tissue abnormalities;

endocrine abnormalities

Fibrillin 1 Dermis, arterial wall, lung Marfan syndrome Aortic root aneurysm or dissection; ectopia lentis; marfanoid habitus

Weill-Marchesani-syndrome Short stature; joint stiffness; lens abnormalities; cardiovascular features

Stiff skin syndrome Progressive rock-hard skin; flexion contractures; hypertrichosis

Geleophysic dysplasia Short stature; joint stiffness; thickened skin; progressive cardiac

valvular disease; orofacial features

Fibronectin Dermis, tendons, ligaments Glomerulopathy with fibronectin

deposits

Glomerulopathy with fibronectin deposits

Spondylometaphyseal dysplasia,

corner fracture type

Spondylometaphyseal dysplasia characterized by flake-like, triangular,

or curvilinear ossification centers at the edges of irregular metaphyses

that simulate fractures; short stature

Aggrecan Cartilage Spondyloepiphyseal dysplasia,

Kimberley type

Short stature; habitus; progressive osteoarthropathy;

spondyloepiphyseal dysplasia

Short stature; advanced bone

age, with or without early-onset

osteoarthritis and/or osteochondritis

dissecans

Short stature and advanced bone age, with or without early-onset

osteoarthritis and/or osteochondritis dissecans

Spondyloepimetaphyseal dysplasia,

aggrecan type

Severe short stature; spondyloepimetaphyseal dysplasia

Decorin Dermis, tendons, ligaments,

cornea

Congenital stromal corneal dystrophy Corneal stromal opacification; visual loss; increased corneal thickness

Biglycan Bone, cartilage, tendons Meester-Loeys syndrome Aortic aneurysm or dissection; orofacial features; joint hypermobility;

ventricular dilatation on brain imaging; relative macrocephaly; hip

dislocation; platyspondyly; phalangeal dysplasia; dysplastic epiphyses

of the long bones

X-linked spondyloepimetaphyseal

dysplasia

Severe short-trunked dwarfism; brachydactyly; spondyloepimetaphyseal

dysplasia

Abbreviation: EDS, Ehlers-Danlos syndrome.