InternalMed_Harrison

InternalMed_Harrison. body habitus includes thin limbs with little muscle mass yet prominent and palpable bones and, when the skull is involved, large head with prominent forehead and proptosis. Patients may also display signs of cranial nerve palsies, hydrocephalus, central hypogonadism, and Raynaud’s phenomenon. Radiographically, patchy progressive endosteal and periosteal new bone formation is observed along the diaphyses of the long bones. Bone scintigraphy shows increased radiotracer uptake in involved areas.


InternalMed_Harrison

InternalMed_Harrison. Treatment with low-dose glucocorticoids relieves bone pain and may reverse the abnormal bone formation. Intermittent bisphosphonate therapy has produced clinical improvement in a limited number of patients.


InternalMed_Harrison

InternalMed_Harrison. This is also known as van Buchem’s disease; it is an autosomal recessive disorder characterized by endosteal hyperostosis in which osteosclerosis involves the skull, mandible, clavicles, and ribs. The major 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 assigned to the same region of the chromosome 17q12-q21. It is possible that both conditions may have deactivating mutations in the BEER (bone-expressed equilibrium regulator) gene.


InternalMed_Harrison

InternalMed_Harrison. 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. No specific etiology is known. There is no specific treatment. Surgical interventions to correct contractures are often unsuccessful.


InternalMed_Harrison

InternalMed_Harrison. 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 426e-5 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. Histologic inspection reveals thickened but otherwise normal trabeculae and islands of normal cortical bone. No treatment is indicated.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 about 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,


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 CHAPTER 426e Paget’s Disease and Other Dysplasias of Bone detect loss-of-function mutation(s) within the ALPL gene that encodes TNSALP.


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 426e Paget’s Disease and Other Dysplasias of Bone detect loss-of-function mutation(s) within the ALPL gene that encodes TNSALP. There is no established medical therapy. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. This is a rare condition of unknown etiology. It presents in both sexes; in middle age or later; and with progressive, intractable skeletal pain and fractures; worsening immobilization; and a debilitating course. Radiographic evaluation reveals generalized osteomalacia, osteopenia, and occasional pseudofractures. Histologic features include a tangled pattern of collagen fibrils with abundant osteoblasts and osteoclasts. There is no effective treatment. Spontaneous remission has been reported in a small number of patients. Calcium and vitamin D have not been beneficial.


InternalMed_Harrison

InternalMed_Harrison. 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 (Gsα). 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 Gsα regulatory protein and mutations in regions of Gsα that selectively inhibit GTPase activity, which results in constitutive stimulation of the cyclic AMP–protein kinase A signal transduction pathway. Such mutations of the Gsα protein–coupled receptor


InternalMed_Harrison

InternalMed_Harrison. that selectively inhibit GTPase activity, which results in constitutive stimulation of the cyclic AMP–protein kinase A signal transduction pathway. Such mutations of the Gsα 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 426e-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.


InternalMed_Harrison

InternalMed_Harrison. FIGurE 426e-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. 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. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 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. 427.


InternalMed_Harrison

InternalMed_Harrison. Achondrodysplasia This is a relatively common form of short-limb 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. Pseudoachondroplasia clinically resembles


InternalMed_Harrison

InternalMed_Harrison. lordosis. Severe spinal deformity may lead to cord compression. The homozygous disorder is more serious than the sporadic form and may cause neonatal death. Pseudoachondroplasia clinically resembles achondrodysplasia but has no skull abnormalities.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Multiple Exostoses This is also called diaphyseal aclasis or osteochon-426e-7 dromatosis; 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 regulate processing of chondrocyte cytoskeletal proteins. The products of the EXT gene likely function as tumor suppressors, with the loss-of-function mutation resulting in abnormal proliferation of growth-plate cartilage. Solitary or multiple lesions are located in the metaphyses of long bones. Although usually asymptomatic, the lesions may interfere with


InternalMed_Harrison

InternalMed_Harrison. resulting in abnormal proliferation of growth-plate cartilage. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 426e-2.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Therapy with vitamin D and phosphate CHAPTER 426e Paget’s Disease and Other Dysplasias of Bone


InternalMed_Harrison

InternalMed_Harrison. 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, while 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 primary defect responsible for the metastatic calcification appears to be hyperphosphatemia resulting from the increased capacity of the renal tubule to reabsorb filtered phosphate. Spontaneous soft tissue calcification is related to the elevated serum phosphate,


InternalMed_Harrison

InternalMed_Harrison. to be hyperphosphatemia resulting from the increased capacity of the renal tubule to reabsorb filtered phosphate. Spontaneous soft tissue calcification is related to the elevated serum phosphate, which, along with normal serum calcium, exceeds the concentration product of 75.


InternalMed_Harrison

InternalMed_Harrison. All of the North American patients reported have been African American. 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 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 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.


InternalMed_Harrison

InternalMed_Harrison. There is no effective medical therapy. Bisphosphonates, glucocorticoids, and a low-calcium diet have largely been ineffective in halting progression of the ossification. 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. Thus, CT imaging of the mandible should be undertaken to detect early sites of soft tissue ossification before they are appreciated by standard radiography.


InternalMed_Harrison

InternalMed_Harrison. Heritable Disorders of Connective Tissue Darwin J. Prockop, John F. Bateman CLASSIFICATION OF CONNECTIVE TISSUE DISORDERS Some of the most common conditions that are transmitted genetically 427 SEC Tion 5 Endocrinology and Metabolism in families are disorders that produce clinically obvious changes in the skeleton, skin, or other relatively acellular tissues that have been loosely defined as connective tissues. Because of their heritability, the disorders were recognized as potentially traceable to mutated genes soon after the principles of genetics were introduced into medicine. In the last several decades, many of these disorders have been linked to mutations in several hundred different genes. However, classifying the disorders on the basis of either their clinical presentations or the mutations causing them presents a challenge for both the clinician and the geneticist.


InternalMed_Harrison

InternalMed_Harrison. A major development in the field was made by McKusick, who suggested that a group of disorders that included brittle bones in children (osteogenesis imperfecta), hyperextensible skin (Ehlers-Danlos syndrome), and characteristic distortions of skeleton (Marfan’s syndrome) be considered as “heritable disorders of connective tissue” and that mutations causing the disorders would be found in the genes coding for proteins of the tissues.


InternalMed_Harrison

InternalMed_Harrison. The information on the disorders has continued to develop on two levels. The initial clinical classifications suggested by McKusick, and others, had to be refined as additional patients were examined. For example, some patients had skin changes similar to those commonly seen in Ehlers-Danlos syndrome, 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, and each has been divided into a series of subtypes. For example, a recent effort to classify all the heritable disorders that alter the skeleton defined 456 distinctive conditions that were divided into 40 major groups.


InternalMed_Harrison

InternalMed_Harrison. 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, the most abundant protein in bones, skin, tendons, and several other tissues. Some of the first assays in patients with osteogenesis imperfecta (OI) revealed mutations in type I collagen genes. Biochemical data developed using cultures of skin fibroblasts from affected patients demonstrated that the mutations dramatically altered the synthesis or 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 are particularly vulnerable to a large number different


InternalMed_Harrison

InternalMed_Harrison. in different connective tissues and the collagen genes were readily isolated by their unique signature sequences. Also, the collagen genes are particularly vulnerable to a large number 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, in some patients with dwarfism, and in patients with other disorders, including Alport’s syndrome, that were not initially classified as disorders of connective tissue. Also, mutations in collagen genes were found in subset of patients with a diagnosis of osteoarthritis and a subset of patients with the diagnosis of osteoporosis. However, the search for mutations quickly expanded to hundreds of other genes that included those for other structural proteins, for the posttranslational processing of structural proteins, and for growth factors and their receptors, and other


InternalMed_Harrison

InternalMed_Harrison. to hundreds of other genes that included those for other structural proteins, for the posttranslational processing of structural proteins, and for growth factors and their receptors, and other genes whose functions are still not fully understood.


InternalMed_Harrison

InternalMed_Harrison. In many instances, the mutations helped to define the clinical subtype of the disorder. In others, however, they did not. Some patients with the same clinical presentations were found to have mutations in different genes. Also, some patients with different manifestations were found to have mutations in the same genes. In addition, it was difficult to establish whether a change in the structure of a gene caused the phenotypic changes in patients and was not 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 genetic abnormalities. As an illustration of the problem, mutations in 226 genes have been found to be associated with the 456 defined disorders of the skeleton, but the latest nosology remains a “hybrid” between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum pro-2505 duced by


InternalMed_Harrison

InternalMed_Harrison. latest nosology remains a “hybrid” between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum pro-2505 duced by mutations in a given gene. A simpler system of classification proved feasible for one rare heritable disorder of skin, epidermolysis bullosa. The disorder was first defined by the presence of friction-induced blister. It was then divided into subtypes that were defined by the ultrastructural layers of the skin that cleaved and blistered. Most patients in each subtype were subsequently shown to have mutations in genes expressed in the corresponding layer of skin. Even with these patients, however, the strength of the genotype-phenotype correlation varies, and mutations have not yet been found in every patient.


InternalMed_Harrison

InternalMed_Harrison. In the end, consensus reports by experts in the field and sources such as the Online Mendelian Inheritance in Man database provide valuable resources for physicians searching for diagnoses of patients with unusual clinical features. However, patients with the most common forms of the disorders have mutations in a limited number of genes. This chapter will focus primarily on these more common disorders.


InternalMed_Harrison

InternalMed_Harrison. Connective tissues such as skin, bone, cartilage, ligaments, and tendons are the critical structural frameworks of the body important for development and function. They consist of a complex interacting extracellular matrix network of collagens, proteoglycans, and a large number of noncollagenous glycoproteins and proteins. Although 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 427-1). The most abundant components are three similar fibrillar collagens (types I, II, and III). They have a similar tensile


InternalMed_Harrison

InternalMed_Harrison. Heritable Disorders of Connective Tissue aOver 30 proteoglycans have been identified. They differ in the structures of their core proteins and their contents of glycosaminoglycan side chains of chondroitin-4-sulfate, chondroitin6-sulfate, dermatan sulfate, and keratin sulfate. Basal lamina contains a proteoglycan with a side chain of heparan sulfate that resembles heparin. 2506 strength as 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.


InternalMed_Harrison

InternalMed_Harrison. 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 strength and 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


InternalMed_Harrison

InternalMed_Harrison. 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. 97). In both osteoarthritis and rheumatoid arthritis, there is extensive degradation of articular cartilage collagen. Glucocorticoids weaken most tissues by decreasing collagen synthesis. In many 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. The deposition of the fibrils is largely irreversible and prevents regeneration of normal tissues in hepatic cirrhosis, pulmonary fibrosis, atherosclerosis, and nephrosclerosis.


InternalMed_Harrison

InternalMed_Harrison. 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 post-translational 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 diseases of connective tissues.


InternalMed_Harrison

InternalMed_Harrison. 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 about 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


InternalMed_Harrison

InternalMed_Harrison. (-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 in a sterically restricted space in the middle of the helix where the three chains come together. The requirement for a glycine residue at every third position explains the severe effects of mutations that convert any of the glycine residues to an amino acid with a bulkier side chain (see below). Many of the Xand Y-position amino acids are proline and hydroxyproline, which, because of their ring structures, provide additional rigidity to the triple helix. Other Xand 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 Xand Y-positions can, in rare instances, also produce genetic diseases.


InternalMed_Harrison

InternalMed_Harrison. 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 Xand Y-positions of the α chains and therefore in some of their physical properties. Type I collagen is composed of two identical α1(I) chains and a third α2(I) chain that differs slightly in its amino acid sequence. Type II collagen is composed of three identical α(II) chains. Type III collagen is composed of three identical α1(III) chains.


InternalMed_Harrison

InternalMed_Harrison. 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. 427-1). The monomer, first synthesized as a soluble precursor called procollagen, contains an additional globular domain at each end. As the proα chains of procollagen are synthesized on ribosomes, the free N-terminal ends move into the cisternae of the rough endoplasmic reticulum. Signal peptides at the N-termini are cleaved, and additional posttranslational reactions begin. Proline residues in the Y-position of the repeating -Gly-X-Ysequences are converted to hydroxyproline by the enzyme prolyl hydroxylase. The hydroxylation of prolyl residues is essential for the three α chains of the monomer to fold into a triple helix at body temperature. The enzyme requires ascorbic acid as one of its essential cofactors, an observation that explains why wounds fail to heal in scurvy (Chap. 96e). In scurvy, some


InternalMed_Harrison

InternalMed_Harrison. a triple helix at body temperature. The enzyme requires ascorbic acid as one of its essential cofactors, an observation that explains why wounds fail to heal in scurvy (Chap. 96e). In scurvy, some of the underhydroxylated and unfolded protein accumulates in the cisternae of the rough endoplasmic reticulum and is degraded. Lysine residues in the Y-position are also hydroxylated to hydroxylysine by a separate lysyl hydroxylase. Many of the hydroxylysine residues are glycosylated with galactose or with galactose and glucose. 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


InternalMed_Harrison

InternalMed_Harrison. 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 ancillary proteins. The fully folded protein is then secreted. After secretion, procollagen is processed to collagen by cleavage of the N-propeptides and C-propeptides by two specific proteinases. The release of the propeptides decreases the solubility of the protein about 1000-fold. The entropic energy that is released drives the self-assembly of the collagen into fibrils. Self-assembled collagen fibers have considerable tensile strength, but their strength is


InternalMed_Harrison

InternalMed_Harrison. about 1000-fold. The entropic energy that is released drives the 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.


InternalMed_Harrison

InternalMed_Harrison. Although the assembly of collagen monomers into fibers is 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. 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. The unique properties of the triple helix are used to define a family of at least 28 collagens that contain repetitive -Gly-X-Ysequences and form triple helices of varying length and complexity. The proteins are


InternalMed_Harrison

InternalMed_Harrison. O-Gal-Glc-Gal-GlcOHOHOHOHOHOHOHOHOHOH OH OH OH OH OH OH OHOH Glc Gal O OH OH OHOH OH OH OH OH OH O Gal (Man)n GlcNAc S S S S Glc Gal O OH OH OHOH 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 Endoplasmic reticulum Late transport vesicles and extracellular matrix FIGURE 427-1 Schematic summary of biosynthesis of fibrillar collagens. (Modified and reproduced with permission from J Myllyharju, KI Kivirikko: Trends in Genetics 20:33, 2004.) Cleavage of propeptides


InternalMed_Harrison

InternalMed_Harrison. Cleavage of propeptides Formation of covalent cross-links 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 any of the six genes can cause Alport’s syndrome.


InternalMed_Harrison

InternalMed_Harrison. 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’s 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). The principles whereby the fibrils provide elasticity to tissue and their biosynthetic


InternalMed_Harrison

InternalMed_Harrison. variable amounts of elastin, bone morphogenic proteins (BMPs), and microfibril-associated glycoproteins (MAGPs). The principles whereby the fibrils provide elasticity to tissue and their biosynthetic assembly are still under investigation. As well as contributing to extracellular matrix structure, the fibrillins play a major role in TGF-β signaling.


InternalMed_Harrison

InternalMed_Harrison. 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 about 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. The central feature of OI is a severe decrease in bone mass that makes bones brittle. The disorder is frequently associated with blue sclerae, dental abnormalities (dentinogenesis imperfecta), progressive hearing loss, and a positive family history. Most patients have mutations in one of the two genes coding for type I collagen. Classification OI was originally classified into two subtypes of congenita and tarda depending on the age of onset of the symptoms. Sillence suggested a series of subtypes based on clinical and radiologic findings and mode of inheritance. As with the other disorders discussed here, the description of rare recessive forms of OI and discovery of mutations in new genes have opened a debate as to whether the disorders should be classified by the clinical phenotypes or by the genes at fault. For the near term, the classification based on the clinical presentations seems the most useful (Table 427-2).


InternalMed_Harrison

InternalMed_Harrison. Type I is the mildest subtype and can produce either mild or no apparent deformities of the skeleton. Most patients have distinctly blue sclerae. Type II produces bone so brittle that it is lethal in utero or shortly after birth; it can be subclassified into types IIA, IIB, and IIC, depending on radiologic findings. Of the nonlethal forms, type III is progressively deforming with moderate to severe bone deformity, and type IV (common variable OI with normal sclerae) has mild to moderate bone fragility. The classifications of patients by types of OI do not consistently predict the clinical course of the disease. Some patients appear normal at birth and become progressively worse; others have multiple fractures in infancy and childhood, improve after puberty, and fracture more frequently later in life. Women are particularly prone to fracture during Heritable Disorders of Connective Tissue Nondeforming OI with I blue sclerae Common variable OI IV with normal sclerae


InternalMed_Harrison

InternalMed_Harrison. Heritable Disorders of Connective Tissue Nondeforming OI with I blue sclerae Common variable OI IV with normal sclerae OI with calcification of V the interosseous membranes Bruck syndrome type 2 Mild to moderate bone fragility, AD normal or near-normal stature, blue sclerae, normal dentition in most, hearing loss in ~50% Extreme bone fragility, short stature, AD long bone bowing, blue sclerae Normal/pale blue sclerae, normal AR Moderate to severe bone deformity, AD blue sclerae at birth, hearing loss and abnormal dentition common Mild to moderate, bone fragility, AD normal sclerae, variable dentition, hearing loss in <10% Calcification of the interosseous AD membranes in forearm and legs and/or hypertrophic callus; variable bone deformity, normal sclerae and dentition Contractures with pterygia, fractures AR in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis


InternalMed_Harrison

InternalMed_Harrison. Contractures with pterygia, fractures AR in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis Abbreviations: AD, autosomal dominant; AR, autosomal recessive. Note: Predominant OI gene mutations (>90%) are in COL1A1 and COL1A2 (in bold typeface). pregnancy and after menopause. A few women from families with mild variants of OI do not develop fractures until after menopause, and their disease may be difficult to distinguish from postmenopausal osteoporosis. Incidence Type I OI has a frequency of about 1 in 15,000–20,000 births. Type II OI has a reported incidence of about 1 in 60,000. Only a limited number of patients with the severe forms of OI have been reported, and the combined incidence of the severe forms that are recognizable at birth (types II, III, and IV) may be higher than 1 in 60,000.


InternalMed_Harrison

InternalMed_Harrison. Skeletal Effects In type I OI, the fragility of bones may be severe enough to limit physical activity or be so mild that individuals are unaware of any disability. Radiographs of the skull in patients with mild disease may show a mottled appearance because of small islands of irregular ossification. In type II OI, ossification of many bones is frequently incomplete. Continuously beaded or broken ribs and crumpled long bones (accordina femora) may be present. For reasons that are not apparent, the long bones may be either thick or thin. In types III and IV, multiple fractures from minor physical stress can produce severe deformities. Kyphoscoliosis can impair respiration, cause cor pulmonale, and predispose to pulmonary infections. The appearance of “popcorn-like” deposits of mineral in x-rays of the ends of long bones is an ominous sign. Progressive neurologic symptoms may Proteolytic removal of procollagen N-propeptide PEDF growth factor signaling? Cation channel, Ca2+ release


InternalMed_Harrison

InternalMed_Harrison. Proteolytic removal of procollagen N-propeptide PEDF growth factor signaling? Cation channel, Ca2+ release Transcription factor, bone formation defect Transcription factor, bone formation defect Collagen posttranslational modification of lysine result from basilar compression and communicating hydrocephalus. Type V OI is recognized by the presence of dislocated radial heads and hyperplastic callus formation. In all forms of OI, bone mineral density is decreased. However, the degree of osteopenia may be difficult to evaluate because recurrent fractures limit exercise and thereby diminish bone mass. Surprisingly, fractures appear to heal normally. Ocular Features The sclerae can be normal, gray, slightly bluish, or bright blue. The color is probably caused by a thinness of the collagen layers of the sclerae that allows the choroid layers to be seen. Blue sclerae, however, are an inherited trait in some families who do not have increased bone fragility.


InternalMed_Harrison

InternalMed_Harrison. Dentinogenesis The teeth may be normal, moderately discolored, or grossly abnormal. The enamel generally appears normal, but the teeth may have a characteristic amber, yellowish brown, or translucent bluish gray color because of a deficiency of dentin that is rich in type I collagen. The deciduous teeth are usually smaller than normal, whereas permanent teeth are frequently bell-shaped and restricted at the base. In some patients, the teeth readily fracture and need to be extracted. Similar tooth defects, however, can be inherited without any evidence of OI. Hearing Loss Hearing loss usually begins during the second decade of life and occurs in more than 50% of individuals over age 30. The loss can be conductive, sensorineural, or mixed, and it varies in severity. The middle ear usually exhibits maldevelopment, deficient ossification, persistence of cartilage in areas that are normally ossified, and abnormal calcium deposits.


InternalMed_Harrison

InternalMed_Harrison. Other Features Changes in other connective tissues can include thin skin that scars extensively, joint laxity with permanent dislocations indistinguishable from those of Ehlers-Danlos syndrome (EDS), and occasionally, cardiovascular manifestations such as aortic regurgitation, floppy mitral valves, mitral incompetence, and fragility of large blood vessels. For unknown reasons, some patients develop bouts of a hypermetabolic state with elevated serum thyroxine levels, hyperthermia, and excessive sweating. Molecular Defects Of the ~1360 unique gene mutations now described in OI, more than 90% are heterozygous mutations in either COL1A1 or COL1A2, the genes coding for the proα1 or proα2 chain of type I procollagen (Table 427-2). Most patients with type I OI and blue sclerae have mutations that reduce the synthesis of proα1 chains to about one-half. Mutations that reduce the synthesis of proα2 chains produce slightly more severe phenotypes and skin defects similar to EDS.


InternalMed_Harrison

InternalMed_Harrison. In contrast to the null mutations found in type I OI, most of the severe variants (types II, III, and IV) are caused by mutations that produce structurally abnormal proα chains that have compromised assembly or abnormal folding of the triple helix. As with collagen mutations in other connective tissue diseases, these structural mutations generally fall into two functional categories. First, the relatively rare mutations in the C-propeptide domain can prevent or seriously impair initial assembly of the procollagen trimers. These misfolded chains are retained in the endoplasmic reticulum (ER) and targeted for degradation by the ER-associated proteasomal pathway. Because these mutations induce an ER stress response, the unfolded protein response (UPR) may have many downstream effects on cells. ER stress is a new concept in the pathophysiology of connective tissue disease and has been best characterized for chondrodysplasias (see below).


InternalMed_Harrison

InternalMed_Harrison. The most common type I collagen mutations, however, are single base substitutions that introduce an amino acid with a bulky side chain for one of the glycine residues that appear as every third amino acid in the triple 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. These mutations compromise the structural integrity of the triple helix, causing disruption to helix folding, retention of the mutant trimers in the ER, and increased posttranslational hydroxylation and glycosylation of lysines. Collagen-containing helix mutations can form insoluble aggregates in the ER that are degraded by the autophagosome-endosome system, rather than the proteasomes.


InternalMed_Harrison

InternalMed_Harrison. A similar sequence of events occurs with less common mutations that produce partial gene deletions, partial gene duplications, and splicing mutations. In addition to their intracellular effects, the structurally abnormal mutant-containing collagen that is secreted by the cell can also have important extracellular affects. For example, the presence of one abnormal proα chain in a procollagen molecule can interfere with cleavage of the N-propeptide from the protein. The persistence of the N-propeptide on a fraction of the molecules interferes with the self-assembly of normal collagen so that thin and irregular collagen fibrils are formed. Furthermore, if structurally abnormal collagens are incorporated into fibrils, they may have a destabilizing effect and be selectively degraded, or they may alter the interactions of collagen with other connective tissue components, disturbing architecture and stability.


InternalMed_Harrison

InternalMed_Harrison. Several generalizations can be made about mutations in type I collagen genes. One is that unrelated patients rarely have the same mutation in the same gene. Glycine substitutions in the N-terminal region of the triple helix tend to produce milder phenotypes, apparently because they have less effect on the zipper-like propagation of the triple-helical conformation from the C terminus. Rare substitutions 2509 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.


InternalMed_Harrison

InternalMed_Harrison. The search for mutations causing the less common and autosomal recessive forms of OI identified mutations in genes for a series of proteins that are essential for the timely folding of the procollagen monomer: cartilage-associated protein (CRTAP), prolyl-3-hydroxylase (LEPRE1/P3H1), cyclophilin B (PPIB), collagen chaperone-like protein HSP47 (SERPINH1), and the procollagen chaperone protein FKBP65 (FKBP10). Recently, mutations have been characterized in additional downstream components of the collagen fibrillogenesis pathway: BMP1, the gene coding for a metalloproteinase that cleaves the C-propeptide of type I procollagen, and PLOD2 (LH2, lysyl oxidase 2), which is involved in establishing collagen cross-links. In addition to these mutations that affect the collagen assembly pathway, mutations have been characterized in genes involved in the regulation of bone formation and mineralization such as SP7 (osterix), IFITM5, WNT1, and TMEM38B (Table 427-2).


InternalMed_Harrison

InternalMed_Harrison. Inheritance and Mosaicism in Germline Cells and in Somatic Cells Type I OI is inherited as an autosomal dominant trait. However, some patients with type I OI appear to represent sporadic new mutations or a diagnosis that was missed in earlier generations. Most lethal OI is the result of sporadic mutations that occur in the germ line in one of the parents. Because of the possibility for germline mosaicism for newly generated mutations, there is about a 7% probability that a second child could inherit a severe variant of OI.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis OI is usually diagnosed on the basis of clinical criteria. The presence of fractures together with blue sclerae, dentinogenesis imperfecta, or family history of the disease is usually sufficient to make the diagnosis. Other causes of pathologic fractures must be excluded, including battered child syndrome, nutritional deficiencies, malignancies, and other inherited disorders such as chondrodysplasias and hypophosphatasia that can have overlapping presentations. The absence of superficial bruises can be helpful in distinguishing OI from battered child syndrome. X-rays usually reveal a decrease in bone density that can be verified by photon or x-ray absorptiometry. Bone microscopy can be helpful in the diagnosis. The diagnosis, as in other genetic disorders, is now routinely determined using targeted candidate gene sequencing and exome sequencing, but whole-genome sequencing may be used in the future.


InternalMed_Harrison

InternalMed_Harrison. Many patients with OI lead productive and successful lives despite severe deformities. Those with mild forms of the disease may need little treatment when fractures decrease after puberty, but women require special attention during pregnancy and after menopause, when fractures again increase. More severely affected children require a comprehensive program of physical therapy and surgical management of fractures and skeletal deformities.


InternalMed_Harrison

InternalMed_Harrison. Many fractures are only slightly displaced and have little soft tissue swelling and, therefore, can be treated with minimal support or traction for a week or two followed by a light cast. If fractures are relatively painless, physical therapy can be initiated early. A judicious amount of exercise prevents loss of bone mass secondary to physical inactivity. Some physicians advocate insertion of steel rods into long bones to correct limb deformities; the risk/benefits and cost/benefits of such procedures are difficult to evaluate. Aggressive conventional intervention is usually warranted for pneumonia and cor pulmonale. For severe hearing loss, stapedectomy or replacement of the stapes with a prosthesis may be successful. Moderately to severely affected patients should be evaluated periodically to anticipate possible neurologic problems. About half of children have a substantial increase in growth when given growth hormone. Treatment with bisphosphonates to decrease bone loss has been


InternalMed_Harrison

InternalMed_Harrison. to anticipate possible neurologic problems. About half of children have a substantial increase in growth when given growth hormone. Treatment with bisphosphonates to decrease bone loss has been introduced for moderate to severe forms of OI. Improvements in bone mineral


InternalMed_Harrison

InternalMed_Harrison. Heritable Disorders of Connective Tissue 2510 density are consistently seen in patients. Some clinical trials observed improvements in bone pain and fracture incidence; however, there are still unresolved questions about the best delivery protocols and the risks associated with long-term use in OI patients. For these reasons, the current consensus is that bisphosphonate therapy should be restricted to moderate to severe OI, where the possible benefits outweigh risks. Also, a clinical trial was performed in which patients were treated by intravenous infusion of cells from bone marrow referred to as mesenchymal stem cells, or multipotential stromal cells (MSCs; see Chap. 90e). Promising results were obtained, but the trial required a prior bone marrow transplant with marrow from a normal donor who subsequently was used as a source of normal MSCs. As a result, the procedure has not been widely adopted. However, the results raise the possibility that it may be possible in the future to


InternalMed_Harrison

InternalMed_Harrison. donor who subsequently was used as a source of normal MSCs. As a result, the procedure has not been widely adopted. However, the results raise the possibility that it may be possible in the future to develop effective stem cell therapies for OI. Counseling and emotional support are important for patients and their parents; lay organizations in some countries provide help in these areas. Prenatal ultrasonography will detect severely affected fetuses at about 16 weeks of pregnancy. Diagnosis is routinely performed on DNA from blood.


InternalMed_Harrison

InternalMed_Harrison. EDS is characterized by hyperextensible skin and hypermobile joints, but the category includes rare patients with other distinctive features. Mutations in different types of collagen are found in many patients, but other genes are at fault in rare forms. Contrary to initial expectations, no patients have been found with mutations in the gene for elastin in EDS.


InternalMed_Harrison

InternalMed_Harrison. Classification Several types of EDS have been defined, based on the extent to which the skin, joints, and other tissues are involved, mode of inheritance, and molecular and biochemical analysis (Table 427-3). Classical EDS includes a severe form of the disease (type I) and a milder form (type II), both characterized by joint hypermobility and skin that is velvety in texture, hyperextensible, and easily scarred. In hypermobile EDS (type III), joint hypermobility is more prominent than skin changes. In vascular-type EDS (type IV), the skin changes are more prominent than joint changes, and the patients are predisposed to sudden death from rupture of large blood vessels or other hollow organs. EDS type V is similar to EDS type II but is inherited as an X-linked trait. The ocular-scoliotic type of EDS (type VI) is characterized by scoliosis, ocular fragility, and a cone-shaped deformity of the cornea (keratoconus). The arthrochalasic type of EDS (type VIIA and VIIB) is characterized by


InternalMed_Harrison

InternalMed_Harrison. type of EDS (type VI) is characterized by scoliosis, ocular fragility, and a cone-shaped deformity of the cornea (keratoconus). The arthrochalasic type of EDS (type VIIA and VIIB) is characterized by marked joint hypermobility that is difficult to distinguish from EDS III except by the specific molecular defects in the processing of type I procollagen to collagen. The periodontotic-type EDS (type VIII) is distinguished by prominent periodontal changes. EDS types IX, X, and XI were defined on the basis of preliminary biochemical and clinical data. EDS due to tenascin X deficiency has not been assigned a type; it is an autosomal recessive form of the syndrome similar to EDS II. The cardiac valvular form of EDS has similar features to EDS II, but also involves severe changes to the aorta. The progeroid form of EDS displays features of both EDS and progeria. Because of overlapping signs and symptoms, many patients and families with some of the features of EDS cannot be assigned to any of


InternalMed_Harrison

InternalMed_Harrison. progeroid form of EDS displays features of both EDS and progeria. Because of overlapping signs and symptoms, many patients and families with some of the features of EDS cannot be assigned to any of the defined types.


InternalMed_Harrison

InternalMed_Harrison. Incidence The overall incidence of EDS is about 1 in 5000 births, with a higher rate for blacks. Classical and hypermobile types of EDS are the most common. Patients with milder forms frequently do not seek medical attention. Skin Skin changes vary from thin and velvety to skin that is either dramatically hyperextensible (“rubber person” syndrome) or easily Classic (EDS I—severe and Skin hyperextensibility and fragility, joint hypermobil-EDS II—mild) ity, tissue fragility manifested by widened atrophic scarring Hypermobile (EDS III) Joint hypermobility, moderate skin involvement, absence of tissue fragility Vascular (EDS IV) Markedly reduced life span due to spontaneous rupture of internal organs such as arteries and intestines; skin is thin, translucent, and fragile, with extensive bruising; hypermobile minor joints; characteristic facial appearance X-linked EDS (EDS V) Similar to classic type Ocular-scoliotic EDS VI (EDS Features of classic EDS as well as severe muscular


InternalMed_Harrison

InternalMed_Harrison. X-linked EDS (EDS V) Similar to classic type Ocular-scoliotic EDS VI (EDS Features of classic EDS as well as severe muscular VIA and EDS VIB) hypotonia after birth, progressive kyphoscoliosis, a Marfanoid habitus, osteopenia, occasionally rupture of the eye globe and great arteries Arthrochalasic EDS VII (EDS Congenital bilateral hip dislocation, hypermobile VIIA and EDS VIIB) joints, moderate skin involvement, osteopenia Dermatosparactic EDS VII C Redundant and fragile skin, prominent hernias, joint laxity, dysmorphic features Periodontotic EDS VIII Absorptive periodontosis with premature loss of permanent teeth, fragility of the skin, skin lesions EDS due to tenascin X Similar to EDS II deficiency EDS, progeroid form Abbreviations: AD, autosomal dominant; AR, autosomal recessive. AD, AR AD AD AR AD AR AR? COL1A1 Proα1 (I) and proα2 (I) chains of procollagen I PLOD1 Deficiency of procollagenlysine 5-dioxygenase activity (EDS VIA)


InternalMed_Harrison

InternalMed_Harrison. AD, AR AD AD AR AD AR AR? COL1A1 Proα1 (I) and proα2 (I) chains of procollagen I PLOD1 Deficiency of procollagenlysine 5-dioxygenase activity (EDS VIA) COL1A1 Mutations that prevent cleavage of the N propeptides ADAMTS2 Deficiency of procollagen I N-terminal proteinase B4GALT7 Deficiency of galactosyltransferase 7 (defective synthesis of dermatan sulfate proteoglycans) torn or scarred. Patients with classical EDS develop characteristic “cigarette-paper” scars. In vascular-type EDS, extensive scars and hyperpigmentation develop over bony prominences, and the skin may be so thin that subcutaneous blood vessels are visible. In the periodontotic type of EDS, the skin is more fragile than hyperextensible, and it heals with atrophic, pigmented scars. Easy bruisability occurs in several types of EDS.


InternalMed_Harrison

InternalMed_Harrison. Ligament and Joint Changes Laxity and hypermobility of joints vary from mild to unreducible dislocations of hips and other large joints. In mild forms, patients learn to avoid dislocations by limiting physical activity. In more severe forms, surgical repair may be required. Some patients have progressive difficulty with age. Other Features Mitral valve prolapse and hernias occur, particularly with type I. Pes planus and mild to moderate scoliosis are common. Extreme joint laxity and repeated dislocations may lead to degenerative arthritis. In the ocular-scoliotic type of EDS, the eye may rupture with minimal trauma, and kyphoscoliosis can cause respiratory impairment. Also, sclerae may be blue.


InternalMed_Harrison

InternalMed_Harrison. Molecular Defects Subsets of patients with different types of EDS have mutations in the structural genes for collagens (Table 4273). These include mutations in the COL1A1 gene in a few patients with moderately severe classical EDS (type I); mutations in COL1A2 in rare patients with an aortic valvular form of EDS; mutations in two of the three genes (COL5A1 and COL5A2) for type V collagen, a minor collagen found in association with type I collagen, in about half the patients with classical EDS (types I and II); and mutations in the COL3A1 gene for type III collagen, which is abundant in the aorta in patients with the frequently lethal vascular EDS (type IV). Some of the type I collagen-related mutations alter processing of the protein or genes for the processing enzymes. Arthrochalasic EDS (type


InternalMed_Harrison

InternalMed_Harrison. VII) is caused by mutations in the amino acid sequence that make type I procollagen resistant to cleavage by procollagen N-proteinase or by mutations that decrease the activity of the enzyme. The persistence of the N propeptide causes the formation of collagen fibrils that are thin and irregular. Some of the patients have fragile bones and therefore a phenotype that overlaps with OI. The ocular-scoliotic type of EDS (type VI) is caused by homozygous or compound heterozygous mutations 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.


InternalMed_Harrison

InternalMed_Harrison. Some patients with the hypermobile EDS (type III) and a few with mild EDS (type II) have mutations in the TNXB gene, which encodes tenascin X, another minor component of connective tissue that appears to regulate the assembly of collagen fibers. Mutations in proteoglycans have been found in a few patients. The progeroid form of EDS results from autosomal recessive mutations in B4GALT7, the gene for β-1,4-galactosyltransferase 7, a key enzyme in the addition of glycosaminoglycan chains to proteoglycans. Diagnosis The diagnosis is based on clinical criteria and increasingly on DNA sequencing. Correlations between genotype and phenotype can be challenging, but gene or biochemical tests are particularly useful for the diagnosis of vascular type IV EDS with its dire prognosis.


InternalMed_Harrison

InternalMed_Harrison. 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. Some patients have increased fractures and are difficult to distinguish from OI. A few families with heritable aortic aneurysms have mutations in the gene for type III collagen without any evidence of EDS or OI. Surgical repair and tightening of joint ligaments require careful evaluation of individual patients, as the ligaments frequently do not hold sutures. Patients with easy bruisability should be evaluated for bleeding disorders. Patients with type IV EDS and members of their families should be evaluated at regular intervals for early detection of aneurysms, but surgical repair may be difficult because of friable 2511 tissues. Also, women with type IV EDS should be counseled about the increased risk of uterine rupture, bleeding, and other complications of pregnancy.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 426e) Chondrodysplasias (CDs), also referred to as skeletal dysplasias, are heritable skeletal disorders that are characterized by dwarfism and abnormal body proportions. The category also includes some individuals with normal stature and body proportions who have features such as ocular changes or cleft palate, which are common in more severe CDs. Many patients develop degenerative joint changes, and mild CD in adults may be difficult to differentiate from primary generalized osteoarthritis. An undefined number of patients have mutations in either the most abundant collagen in cartilage (type II) or the less abundant collagens (types X or XI). Other patients have mutations in genes that code for other components of cartilage or for proteins required for the embryonic development of cartilage, including a common mutation in a gene for a fibroblast growth factor receptor.


InternalMed_Harrison

InternalMed_Harrison. Classification Over 200 distinct types and subtypes have been defined based on criteria such as “bringing death” (thanatophoric), causing “twisted” bones (diastrophic), affecting metaphyses (metaphyseal), affecting epiphyses (epiphyseal), affecting spine (spondylo-), and producing histologic changes such as an apparent increase in the fibrous material in the epiphyses (fibrochondrogenesis). Also, a number of eponyms are based on the first or most comprehensive case reports. Severe forms of the diseases produce dwarfism with gross distortions of most cartilaginous structures and of other structures including the eye. Mild forms are more difficult to classify. Among the features are cataracts, degeneration of the vitreous, retinal detachment, high forehead hypoplastic facies, cleft palate, short extremities, and gross distortions of the epiphyses, metaphyses, and joint surfaces. Patients with Stickler’s syndrome (hereditary arthro-ophthalmopathy) have been classified into three types


InternalMed_Harrison

InternalMed_Harrison. short extremities, and gross distortions of the epiphyses, metaphyses, and joint surfaces. Patients with Stickler’s syndrome (hereditary arthro-ophthalmopathy) have been classified into three types based on a combination of the ocular phenotype and mutated genes.


InternalMed_Harrison

InternalMed_Harrison. 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’s syndrome is 1 in 10,000. Therefore, the disease is probably among the more common heritable disorders of connective tissue.


InternalMed_Harrison

InternalMed_Harrison. Molecular Defects Mutations in the COL2A1 gene for the type II collagen of cartilage are found in a fraction of patients with both mild and severe CDs. For example, a mutation in the gene substituting a cysteine residue for an arginine was found in three unrelated families with spondyloepiphyseal dysplasia (SED) and precocious generalized osteoarthritis (OA). Mutations in the gene, often glycine substitution mutations with the collagen II triple helix, were also found in some lethal CDs characterized by gross deformities of bones and cartilage, such as those found in spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia congenita, hypochondrogenesis/achondrogenesis type II, and Kniest’s syndrome. The highest incidence of COL2A1 mutations, however, occurs in patients with the distinctive features of Stickler’s syndrome, which is characterized by skeletal changes, orofacial abnormalities, and auditory abnormalities. Most of the mutations in COL2A1 are premature stop


InternalMed_Harrison

InternalMed_Harrison. the distinctive features of Stickler’s syndrome, which is characterized by skeletal changes, orofacial abnormalities, and auditory abnormalities. Most of the mutations in COL2A1 are premature stop codons that produce haploinsufficiency. In addition, some patients with Stickler’s syndrome or a closely related syndrome have mutations in two genes specific for type XI collagen, which is an unusual heterotrimer formed from α chains encoded by the gene for type II collagen (COL2A1) and two distinctive genes for type XI collagen (COL11A1 and COL11A2). Mutations in the COL11A1 gene are also found in patients with Marshall’s syndrome, which is similar to classic Stickler’s 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.


InternalMed_Harrison

InternalMed_Harrison. Heritable Disorders of Connective Tissue 2512 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, network-forming 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. In type X collagen, all the structural mutations detected occur in the C-terminal NC1 domain that coordinates the formation of the trimers. This NC1 domain is functionally equivalent to the C-propeptide of the fibrillar collagens. These mutations disturb the structure of the NC1 domain, leading to misfolding and initiation of cellular ER stress via the unfolded protein response (UPR). While the


InternalMed_Harrison

InternalMed_Harrison. of the fibrillar collagens. These mutations disturb the structure of the NC1 domain, leading to misfolding and initiation of cellular ER stress via the unfolded protein response (UPR). While the UPR evolved to allow cells to adjust their ER folding capacity to differing protein folding loads, it is deployed by cells when mutant misfolded proteins accumulate in the ER. Activation of the UPR attenuates protein translation and activates mutant protein degradation pathways such as ER-associated degradation. If these strategies do not sufficiently reduce the stress response, cell death may occur. In Schmid metaphyseal CD, mutant misfolded type X collagen induces the UPR, resulting in downstream consequences that contribute to the pathophysiology. This general mechanism may also contribute to pathology in other CDs (and in other connective tissues disorders) where gene mutations lead to protein structural abnormalities. Some patients have mutations in genes for proteins that interact with


InternalMed_Harrison

InternalMed_Harrison. pathology in other CDs (and in other connective tissues disorders) where gene mutations lead to protein structural abnormalities. 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. With misfolding mutations in COMP and matrilin-3, the activation of the UPR has been described, providing further evidence that the UPR is a component of pathology of these conditions. Some CDs are caused by mutations in genes that affect early development of cartilage and related structures. The most common form of


InternalMed_Harrison

InternalMed_Harrison. that the UPR is a component of pathology of these conditions. Some CDs are caused by mutations in genes that affect early development of cartilage and related structures. The most common form of short-limbed dwarfism, achondroplasia, is caused by mutations in the gene for a receptor for a fibroblastic growth factor (FGFR3). The mutations in the FGFR3 gene causing achondroplasias are unusual in several respects. The same single-base mutation in the gene that converts glycine to arginine at position 380 in the FGFR3 gene is present in over 90% of patients. Most patients harbor sporadic new mutations, and therefore, this nucleotide change must be 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


InternalMed_Harrison

InternalMed_Harrison. 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 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 the proteoglycan posttranslational sulphation pathway (DTDST, PAPSS2, and CHST3). Mutations in more than 45 other genes have been defined


InternalMed_Harrison

InternalMed_Harrison. of cartilage, aggrecan (AGC1), and perlecan (HSPG2) and the proteoglycan posttranslational sulphation pathway (DTDST, PAPSS2, and CHST3). Mutations in more than 45 other genes have been defined in chondrodysplasias.


InternalMed_Harrison

InternalMed_Harrison. 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. Evaluation of patients by specialists in the field is usually required for a diagnosis. Targeted gene and exome sequencing or more global sequencing strategies are used for molecular diagnosis. Given the wide spectrum of CD phenotypes, these gene tests are becoming critical diagnostic tools. For Stickler’s 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 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. The treatment 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, and support groups have formed in many countries. MFS includes features that primarily affect the skeleton, the cardiovascular system, and the eyes. Most patients have mutations in the gene for fibrillin-1.


InternalMed_Harrison

InternalMed_Harrison. MFS includes features that primarily affect the skeleton, the cardiovascular system, and the eyes. Most patients have mutations in the gene for fibrillin-1. Classification 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. Incidence and Inheritance The incidence of MFS is among the highest of any heritable disorder: about 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 one-fourth of patients have sporadic new mutations.


InternalMed_Harrison

InternalMed_Harrison. Skeletal Effects Patients have long limbs and are usually tall compared to other members of the same family. 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 two standard deviations below mean for age, race, and sex. The fingers and hands are long and slender and have a spider-like appearance (arachnodactyly). Many patients have severe chest deformities, including depression (pectus excavatum), protrusion (pectus carinatum), or asymmetry. Scoliosis is frequent and usually accompanied by kyphosis. High-arched palate and high pedal arches or pes planus are common. A few patients have severe joint hypermobility similar to EDS. Computed tomography or magnetic resonance imaging examinations of the lumbar sacral region frequently reveal enlargement of the neural canal, thinning of the pedicles and laminae, widening of the foramina, or anterior meningocele (dural ectasia).


InternalMed_Harrison

InternalMed_Harrison. Cardiovascular Features Cardiovascular abnormalities are the major source of morbidity and mortality (Chap. 301). Mitral valve prolapse develops early in life and 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 the disease 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. Patients usually differ from those with familial aortic aneurysms who tend to develop aneurysms in the abdominal aorta. The location of the aneurysms, however, is somewhat variable, and the high incidence of aortic aneurysms in the general population (1 in 100) makes the differential diagnosis difficult unless other features of MFS are clearly present.


InternalMed_Harrison

InternalMed_Harrison. Ocular Features Upward displacement of the lens is common. It is usually not progressive but may contribute to the formation of cataracts. The ocular globe is frequently elongated, and most patients are myopic, but with adequate vision. Retinal detachment can occur. Other Features Striae may occur over the shoulders and buttocks. A number of patients develop spontaneous pneumothorax. Inguinal and incisional hernias are common. Patients are typically thin with little subcutaneous fat, but adults may develop centripetal obesity.


InternalMed_Harrison

InternalMed_Harrison. 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. Also, a few MFS patients without mutations in the FBN1 gene have mutations in the gene for TGF-β receptor 2 (TGFBR2). In addition, mutations in either TGFBR2 or TGFBR1 are found in the related Loeys-Dietz syndrome, which is characterized by aortic aneurysms, cleft palate, and hypertelorism. Mutations in the FBN2 gene, which is structurally similar to the FBN1 gene, are found in patients with MFS-like syndrome of congenital contractual arachnodactyly.


InternalMed_Harrison

InternalMed_Harrison. FBN1 gene mutations are scattered throughout its 65 coding exons. Most are private mutations, but about 10% are recurrent new mutations that are largely located in CpG sequences known to be “hot spots.” Most severe mutations are located in the central codons (24–32). 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 nature of the mutation.


InternalMed_Harrison

InternalMed_Harrison. The discovery that syndromes similar to MFS are caused by mutations in TGFBR1 and TGFBR2 refocused attention on structural similarity between fibrillin-1 and TGF-β binding proteins that sequester TGF-β in the extracellular matrix. As a result, some of the manifestations of MFS have been shown to arise from alterations in binding sites that modulate TGF-β bioavailability during development of the skeleton and other tissues. Likewise, TGFBR1 and TGFBR2 mutations in Loeys-Dietz syndrome alter TGF-β signaling. In both MFS and Loeys-Dietz syndrome, the pathogenic mechanisms involve increased TGF-β signaling, which contributes to aneurysm formation.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis All patients with a suspected diagnosis of MFS should have a slit-lamp examination and an echocardiogram. Also, homocystinuria should be ruled out by amino acid analysis of plasma (Chap. 434e). The diagnosis of MFS according to the international Ghent standards places emphasis on major criteria that include presence of at least four skeletal abnormalities: ectopia lentis; dilation of the ascending aorta with or without dissection; dural ectasia; and a blood relative who meets the same criteria, with or without a DNA diagnosis. A final diagnosis is based on a balanced assessment of the major criteria together with several minor criteria. The absence of ocular changes suggests the Loeys-Dietz syndrome, and the presence of contractures with some of the signs of OI suggests congenital contractual arachnodactyly.


InternalMed_Harrison

InternalMed_Harrison. Diagnostic tests based on gene sequencing or detection of protein defects are available. These results are unlikely to alter the treatment or prognosis but are helpful to inform the patients and families and to rapidly exclude the diagnosis in unaffected family members. Propranolol or other β-adrenergic blocking agents are used to lower blood pressure and thereby delay or prevent aortic dilation. Surgical correction of the aorta, aortic valve, and mitral valve has been successful in many patients, but tissues are frequently friable. Patients should be advised that the risks are increased by severe physical exertion, emotional stress, and pregnancy.