Pathology

In rickets, the primary disturbance is failure of mineralization of cartilage and osteoid tissue, which decreases longitudinal bone growth and weakens the mechanical properties of tubular bone. Thus the pathologic manifestations of the disease are most noticeable around growth plates and along long bones. Normal longitudinal growth of bone is the result of endochondral ossification. The key elements of the process are proliferation of chondrocytes in columns (zone of proliferation), cellular maturation to become hypertrophic chondrocytes, calcification of the cartilage matrix (zone of provisional calcification), vascular invasion of the terminal hypertrophic chondrocytes, and deposition of new bone. In rickets, failure of deposition of calcium along the matrix of the maturing chondrocyte columns is observed, along with a disorderly invasion of cartilage by blood vessels, lack of resorption at the zone of provisional calcification, and consequently increased thickness of the physis ( Fig. 42-2 ). The chondrocytes proliferate normally, but the normal process of endochondral ossification fails to take place.

Histologic appearance of rickets. A photomicrograph through the epiphyseal-metaphyseal junction shows uncalcified osteoid tissue, failure of deposition of calcium along the mature cartilage cell columns, and disorderly invasion of cartilage by blood vessels (×25, H & E).

Osteoblastic activity on the endosteal and periosteal surfaces of bone is normal, and abundant osteoid (nonmineralized bone matrix) is formed. With defective mineralization of osteoid, osteoclastic resorption of the osteoid does not take place. However, increased resorption of the mineralized bone because of secondary hyperparathyroidism occurs. Hence, the overly abundant osteoid produced by normal osteoblasts generates widened osteoid seams. Because of a lack of resorption of osteoids, the osteoid islets may even persist down into the diaphysis.

In rickets, an abnormality in the arrangement of bundles of collagen fibers in compact bone also exists. Instead of running parallel to the haversian canals, they course perpendicularly and are biomechanically inferior. Grossly, the rachitic bone is soft and becomes misshapen under the force of weight bearing. If the disease remains untreated, angular deformities of the lower extremities and deformities of the thoracic cage and pelvis may develop.

After treatment of rickets with vitamin D, calcium absorption increases and calcification of the cartilage columns and osteoid occurs. Osteoclasts resorb the calcified cartilage, and normal remodeling and improvement of bone follows.

Laboratory Findings

Vitamin D deficiency results in an inability to absorb calcium and phosphorus from the gut. Vitamin D status is best evaluated by measuring the level of serum 25(OH)D, which reflects the degree of deficiency. In contrast, the serum level of 1,25(OH) ₂ D is not helpful because it may be normal in most patients with vitamin D deficiency. The PTH level is elevated in response to hypocalcemia (secondary hyperparathyroidism), which attempts to ameliorate the serum calcium level. Serum calcium levels are normal to mildly decreased, but phosphate levels are low (hypophosphatemia) and alkaline phosphatase levels are high ( Table 42-1 ). Urinary excretion of calcium is low because of enhanced renal tubular reabsorption.

Clinical Features

The clinical features of nutritional rickets depend on the severity of the disease and may be subtle. Infants demonstrate generalized muscular weakness, lethargy, and irrita­bility. Sitting, standing, and walking are delayed. The abdomen may appear protuberant.

Early bone manifestations include a slight thickening of the ankles, knees, and wrists. Beading of the ribs, referred to as the rachitic rosary, is caused by enlargement of the costochondral junctions. As the disease continues, the pull of the diaphragm on the ribs produces a horizontal depression known as Harrison’s groove. Short stature results from insufficient longitudinal growth. Pectus carinatum is caused by forward projection of the sternum. Closure of the fontanelles is delayed and the sutures are thickened, which leads to a skull appearance described as resembling hot cross buns. The dentition is affected, with delays in appearance of the teeth and defects in the enamel.

As the child begins standing and walking, the softened long bones bow, and it is at this time that the child is usually brought to the orthopaedic surgeon for a diagnosis. In toddlers, bowleg, or genu varum, is one of the most common initial signs. In older children, genu valgum and coxa vara may be initial features. Stress fractures of the long bones may be present. Children may be seen acutely with unexplained fractures suggesting child abuse, tetany, and hypocalcemic seizures. Later, kyphoscoliosis may develop.

Radiographic Findings

Failure of the physeal cartilage to calcify and undergo normal endochondral ossification leads to an increased thickness of the physis and a hazy appearance of the provisional zone of calcification. The widened growth plate is particularly suspect for rickets, which differentiates this rare condition from the more common physiologic angular deformities of the lower extremities ( Fig. 42-3 ). The metaphysis abutting the physis is brushlike in appearance, with islands or columns of cartilage persisting well into the metaphysis ( Fig. 42-4 ). The metaphysis also appears cupped or flared. The bones have an osteopenic appearance overall, with thinning of the cortices. The bony trabeculae are indistinct. Looser’s lines, or radiolucent transverse bands (pseudofracture lines) that extend across the axes of the long bones, are evident on radiographs in 20% of patients with rickets.

Radiographs obtained in a 1-year-old black girl with nutritional rickets. A, Forearm. B, Knee. C, Pelvis. All physes are widened and the metaphyses are indistinct. Cupping is most prominent in the metaphysis of the distal radius and ulna and at the knee. See also Figure 42-6 .

A, Hazy metaphysis with cupping in a young boy with rickets. B, Accentuated genu varum is present. C, With vitamin D replacement therapy, the bony lesions healed in 6 months.

As the rickets continues, deformities of the long bones, ribs, pelvis, and spine develop. Thoracolumbar kyphosis—rachitic cat back—may be apparent on radiographs.

Although the diagnosis of nutritional rickets should be made on review of plain films, bone scintigraphy has been used in neonates to confirm the diagnosis and pick up areas of fractures. Increased uptake is seen. With treatment, mineralization occurs and radiographic abnormalities rapidly become normal. The physis thins, and bone density increases ( Fig. 42-5 ).

Radiographic appearance of the wrist of the girl whose radiographs (rickets) appear in Figure 42-3 after 4 months of treatment with vitamin D. The osteopenia has resolved and the physis is narrowed.

Treatment

Rickets is treated by the administration of vitamin D under the supervision of a pediatric specialist in metabolic bone disease. The usual course of treatment is 6 to 10 weeks. After 2 to 4 weeks, radiographs show improvement in mineralization. Tetracycline labeling shows response to therapy, with areas of new mineralization being labeled with the drug. Tetracycline should not be used in young children, however, because of staining of the teeth. If the child does not respond to vitamin D therapy, vitamin D–resistant rickets should be suspected. Because residual deformity is rare after medical treatment of nutritional rickets, there is no specific orthopaedic treatment of nutritional rickets.

Laboratory Findings

Laboratory studies reveal normal or almost normal levels of calcium. The serum phosphate concentration is significantly decreased, whereas the 1,25(OH) ₂ D level may be inappropriately low in response to the hypophosphatemia. The PTH level is normal. Urine assays for phosphate demonstrate an increased concentration of phosphate in the urine. The serum alkaline phosphatase concentration is elevated but not to the levels seen with nutritional rickets (see Table 42-1 ).

Clinical Features

The disease usually becomes apparent at a slightly older age than nutritional rickets, with most patients becoming symptomatic between 1 and 2 years of age. Severe hypophosphatemic rickets can be recognized in early infancy, and when the disease is suspected because of the family history, laboratory determination of phosphorus concentrations can lead to the diagnosis in infants as young as 3 months. The usual initial complaints are delayed walking and angular deformities of the lower extremities. In contrast to what is seen in nutritional rickets, systemic manifestations such as irritability and apathy are minimal.

Physical findings in hypophosphatemic rickets include skeletal deformities, which resemble those seen in nutritional rickets but, because of the chronicity of the disease, become much more severe. Once affected children begin to walk, genu varum develops, although genu valgum may occur in some children ( Fig. 42-6 ). Periarticular enlargement is present as a result of widening of the physes and metaphyses. The rachitic rosary may also occur.

A, Unilateral genu varum in a 12-year-old child with poorly controlled vitamin D–resistant rickets. B, Same child at 15 years of age after right medial hemiepiphysiodesis of the femur. Left genu varum is now apparent.

Short stature is a feature of hypophosphatemic rickets. Height is usually 2 standard deviations (SDs) below the mean for age in these patients.

Radiographic Findings

The radiographic changes are the same as those seen in nutritional rickets and include physeal widening and indistinct osteopenic metaphyses. In the lower extremities, genu varum is obvious, and the distal femoral and proximal tibial physes are particularly widened medially ( Fig. 42-7 ). Coxa vara is present, and there may be general anterior and lateral bowing of the entire femur. The varus of the tibia is also generalized, not only present proximally but also producing varus angulation of the ankle.

A and B, Anteroposterior radiographs of the left and right lower extremities of a standing 7-year-old child with familial hypophosphatemic rickets. Severe genu varum and anterolateral bowing of the femur are evident. The distal femoral and proximal tibial physes are widened medially. See Figures 42-8 and 42-9 .

The upper extremities are involved as well, but to a lesser degree because of absence of the influence of weight bearing ( Fig. 42-8 ).

Physeal widening and metaphyseal cupping of the distal end of the radius and ulna in a 7-year-old child (same as in Fig. 42-7 ) with vitamin D–resistant rickets.

Treatment

Orthopaedic Treatment

The orthotic management of vitamin D–resistant rickets has not been efficacious. If patients are experiencing increasing pain or difficulty walking, surgical correction of angular deformities should be performed. It is important to work closely with the nephrologist or endocrinologist who is managing the medical therapy because calcium levels can suddenly increase in a patient who is immobilized after surgery. Discontinuation of vitamin D before surgery should be discussed.

The deformity most commonly seen in patients with hypophosphatemic rickets is a gradual anterolateral bowing of the femur, combined with tibia vara. Multilevel osteotomy is generally required to satisfactorily correct the mechanical axis of the limb ( Fig. 42-9 ). The mechanical axis should be mildly overcorrected at surgery. The suggested fixation varies among reports. External fixation allows fine tuning of the alignment postoperatively, when the patient is able to stand ( Fig. 42-10 ). Others advocate the use of intramedullary fixation or plating ( Fig. 42-11 ). Regardless of the type of fixation used, careful preoperative planning of the surgical treatment of these multiplanar deformities is crucial to restoring alignment.

Postoperative radiographs of the child whose imaging findings are shown in Figures 42-7 and 42-8 . A, Appearance after distal femoral, proximal tibial, and distal tibial osteotomies for treatment of genu varum. B, Varus is recurring 1 year after surgery.

A, Clinical appearance of a 13-year-old girl with severe genu varum secondary to vitamin D–resistant rickets. Calluses on the knees were caused by crawling because of knee pain. B, Treatment consisted of distal femoral, proximal tibial, and distal tibial corticotomies and gradual correction with the Ilizarov device. Surgery on the two legs was staged because of the extent of the frame. C, Clinical appearance of the lower extremities at the end of treatment.

A, Coxa vara and genu varum in a 5-year-old boy with vitamin D–resistant rickets. B, Postoperative radiograph obtained after corrective osteotomy with plate fixation of the proximal femora and osteotomy with K-wire fixation of the proximal tibiae. C, Alignment remained satisfactory at 2-year follow-up.

Recurrent deformity is a common sequela of osteotomies in patients with hypophosphatemic rickets. Younger patients have a higher risk of recurrence. For this reason, milder deformities should not be corrected in early childhood. Some children have severe varus at a very young age that leads to thrust during gait. When gait is compromised or symptoms or pain is present, osteotomy should be performed and the alignment monitored for recurrent deformity.

Spinal deformity may be seen in patients with hypophosphatemic rickets. Kyphoscoliosis, Arnold-Chiari malformations, and spinal stenosis have all been described in patients with vitamin D–resistant rickets.

Adults with hypophosphatemic rickets are prone to the development of arthritis. Degradation of articular cartilage resembling osteochondritis dissecans has been described. Joint stiffness and bone pain are common complaints.

Pathophysiology

The pathophysiology of high-turnover renal osteodystrophy begins with the inability of the damaged glomerulus to excrete phosphorus, which results in hyperphosphatemia. Furthermore, advancing loss of nephrons and increased FGF23 levels decrease the production of dihydroxyvitamin D from the kidney. Calcium absorption from the small intestine is diminished in the absence of vitamin D. The serum calcium level is also diminished by the physiochemical binding of calcium to phosphate. Resulting hypocalcemia triggers the release of PTH, which increases osteoclast-mediated bone resorption in an attempt to normalize the serum calcium level. The hyperphosphatemia worsens with the release of minerals from bones, thereby leading to a cycle of bone resorption. PTH acts directly to stimulate osteoclast activity, which worsens the bony changes and leads to osteitis fibrosa.

High levels of serum phosphate are universal in renal failure. In the setting of elevated phosphate levels, calcium may precipitate out and lead to ectopic calcification in tissues. The usual areas for ectopic calcification are the corneas and conjunctivae, skin, blood vessels, and periarticular soft tissues.

Pathology

Features of rickets and hyperparathyroidism are present in renal osteodystrophy ( Fig. 42-12 ). The rachitic changes consist of failure to replace physeal chondrocytes by endochondral ossification. Physeal cartilage persists into the metaphysis. The physis is widened, and the zone of provisional calcification is irregular as a result of the lack of endochondral ossification occurring at the physis. Bony trabeculae have abundant osteoid and widened osteoid seams.

Histologic findings of osteodystrophy secondary to chronic renal insufficiency. A, Photomicrograph of a section through the widened physis showing extension of cartilage cells into the metaphysis (×25, ••). B, Higher magnification of the same area (×100, H & E). Note the uncalcified osteoid tissue and replacement of normal fatty bone marrow by hyperplastic fibrous tissue.

The histologic features of hyperparathyroidism include osteoclastic resorption of bone. Marrow is replaced by hyperplastic fibrous tissue. Patchy formation of new bone leads to areas of osteosclerosis, present in 20% of patients with renal osteodystrophy.

Laboratory Findings

The blood urea nitrogen level is high, as is the serum creatinine concentration. Levels of serum phosphate, alkaline phosphatase, and PTH are elevated. The serum calcium concentration is almost always low, as is the albumin level. Acidosis is present, and vitamin D levels are decreased (see Table 42-1 ).

Bone biopsy may be necessary for accurate diagnosis and can help guide treatment.

Clinical Features

Children with renal osteodystrophy resemble those with rickets. They are short for their age, and their bones are fragile. Because of the effects of weight bearing, lower extremity involvement is more severe than upper extremity involvement. Patients may complain of bone pain, and fractures occur easily. Skeletal deformities may consist of genu valgum, periarticular enlargement of the long bones, and slipped capital femoral epiphysis (SCFE). Gait may be abnormal because of muscular weakness, and a Trendelenburg gait is present in patients with SCFE. Enlargement of the costochondral cartilage may produce a rachitic rosary, as in nutritional rickets.

Radiographic Findings

Generalized osteopenia is notable, with thinning of the cortices and indistinct bony trabeculae. Overall, the bone looks blurry, like ground glass. The skull takes on a salt and pepper appearance because of the coarse granular pattern. The physes are increased in thickness, and the provisional zone of calcification looks uncalcified and indistinct ( Fig. 42-13 ). Cupping of the physes is not present, unlike the case in nutritional rickets.

Osteodystrophy secondary to chronic renal insufficiency in a young girl with progressive slipped capital femoral epiphyses. Anteroposterior ( A ) and lateral ( B ) radiographs of both ankles at the age of 12 years showed increased thickness of the physes and irregularity of the metaphysis at the zone of provisional calcification. C, Lateral view of the skull showing a ground-glass appearance. Note the absence of lamina dura of the teeth.

Changes of hyperparathyroidism develop with time. SCFE may be seen, even in young patients ( Fig. 42-14 ). The terminal tufts of the distal phalanges of the fingers resorb, as do the lateral end of the clavicle and the symphysis pubis. Subperiosteal resorption also occurs in the metacarpals and ulna.

A, Anteroposterior (AP) radiograph of a 7-year-old boy with hip pain. Slipped capital femoral epiphysis is present, osteopenia is obvious, and the physes are wide. AP ( B ) and lateral ( C ) radiographs of the hips after treatment of renal failure with dialysis. The proximal femoral physes have narrowed.

Osteosclerosis, when present, is most common at the base of the skull and in the vertebrae. The horizontal striped appearance of the spine is called a rugger jersey spine.

In severe and prolonged renal failure, peculiar, aggressive-appearing lytic areas may develop within the long bones, termed brown tumors. The surrounding cortex is thinned and then expands. The margins of a brown tumor are not well defined. Pathologic fracture may result. Radiographically, these lesions mimic malignancy. They are well visualized by magnetic resonance imaging (MRI).

Because many patients with renal failure, and all patients who have undergone kidney transplantation, are treated with steroids, the typical skeletal abnormalities seen with chronic steroid use may develop. Corticosteroid-associated osteonecrosis is common and develops most frequently in the femoral heads ( Fig. 42-15 ).

Avascular necrosis of the left hip in a 7-year-old boy after renal transplantation and steroid therapy.

Treatment

Orthopaedic Treatment

Patients with renal osteodystrophy are referred to the orthopaedic surgeon for the treatment of three problems: (1) angular deformity of the lower extremities; (2) SCFE; and (3) avascular necrosis. In the surgical correction of any of the orthopaedic deformities in renal osteodystrophy, the hazards and complications should be carefully weighed because of the increased risks in this patient population. Anemia, hypertension, bleeding tendencies, and electrolyte imbalances are all present in patients with renal failure. The risk for infection is also increased, particularly if the patient has received a transplant and is undergoing immunosuppressive therapy. Despite these potential risks, an osteotomy can be performed safely with careful coordination of surgery and perioperative management with the pediatric nephrologist.

Angular Deformity.

Angular deformity occurs in renal osteodystrophy because the bone is soft, undermineralized, and prone to bend with weight bearing. Genu valgum is the most common deformity, but genu varum may occur in some patients. It has been proposed that if the onset of renal osteodystrophy occurs before 4 years of age, varus deformity may develop because the normal alignment of the leg is in mild varus, which then is accentuated as the bone becomes weak. Similarly, older children are predisposed to the development of genu valgum because of the normal valgus alignment of the lower extremity. Valgus at the ankle may accompany the genu valgum.

Some milder deformities will correct with medical treatment of the renal osteodystrophy. Deformities do not respond well to bracing. If the patient is symptomatic and has had optimal medical management of the osteodystrophy without resolution of deformity, an osteotomy is performed. Preoperative assessment of the deformity with long-leg standing radiography will permit the surgeon to decide the location of the deformity and how many osteotomies will be needed to correct the mechanical axis most effectively. Usually the distal end of the femur is the site of greatest deformity, but some patients also need a proximal tibial osteotomy. Internal or external fixation may be used. Application of the Ilizarov device in metabolic bone disease has met with success, although healing was delayed. Recurrence is common in patients with continuing metabolic disease, so medical treatment should be optimized before osteotomy whenever possible. Elevation of the serum alkaline phosphatase concentration above 500 U/L is a good marker of ongoing metabolic bone disease. A bone biopsy may be needed to establish that the bone is metabolically healthy before osteotomy. Milder deformity may respond to physeal stapling.

A subset of patients with genu valgum shows evidence of a proximal tibial growth disturbance in the form of a physeal abnormality in the proximal lateral tibial physis. Oppenheim and associates compared the physeal widening of the lateral physis with that seen in the medial physis in Blount disease. These patients benefit from tibial osteotomy for realignment.

Slipped Capital Femoral Epiphysis.

SCFE is associated with renal osteodystrophy, but the clinical picture of a patient with renal slips differs from the usual clinical scenario. Often the patients are younger than those with idiopathic SCFE, and obesity is not commonly seen. Bilaterality is extremely common. Radiographs show more physeal widening than is usual in SCFE, and osteopenia and blurring of the metaphysis may be obvious. The orthopaedic surgeon should be aware of the radiographic appearance of renal SCFE because, on rare occasion, patients may seek treatment of hip or groin pain while being unaware of their renal disease. In such cases it is up to the orthopaedic surgeon to make the diagnosis of renal osteodystrophy, and promptly refer the child to a nephrologist for appropriate treatment.

There are inherent problems in the surgical treatment of SCFE in renal osteodystrophy. The goal of routine treatment of SCFE is to stop proximal femoral physeal growth and thus heal the slip. This may not be a desirable goal in a very young child with renal osteodystrophy. Also, physeal healing may be difficult to achieve in the presence of osteitis fibrosa and metabolic imbalance. Fortunately, in many patients, the hip pain resolves and the proximal femoral physis narrows with medical treatment of the renal osteodystrophy, so surgery is not necessary for every patient with renal SCFE. If the slip is displaced or if symptoms persist despite good medical control of the osteodystrophy, surgery may be needed. Fixation with special partially threaded screws to achieve stability by crossing the physis but not closing it has been performed in a small series of patients with renal slips. In an adolescent with SCFE secondary to renal disease, epiphyseal closure with in situ fixation is the treatment of choice once the metabolic bone disease is being treated appropriately ( Fig. 42-16 ).

A and B, Valgus slipped capital femoral epiphysis in an 11-year-old child after renal transplantation and hypothyroidism. C and D, In situ fixation was performed.

Physiolysis has been described in other physes in children with renal osteodystrophy. Sites at which physiolysis has occurred include the distal femur, proximal humerus, and distal radius and ulna ( Fig. 42-17 ). Treatment consists of medical management of the metabolic bone disease and cast immobilization.

Osteodystrophy secondary to chronic renal insufficiency in a young girl. An anteroposterior radiograph shows slipping of the humeral head.

Avascular Necrosis.

Another orthopaedic complication seen in patients with renal failure is avascular necrosis, usually of the femoral head. It may be unilateral or bilateral. Prolonged steroid use, commonly needed after renal transplantation, is the probable cause of avascular necrosis in most children, although it has been seen in the hips of some children with renal failure who were not taking steroids. Treatment is symptomatic.

Pathology

Histologically, wide osteoid seams are found around the trabeculae, similar to what is seen in rickets. The physis, however, is well calcified and normal in width and length. Metastatic calcification may be found in the kidneys, arteries, thyroid, pancreas, lungs, stomach, and brain. Deposition of calcium salts in the kidneys and degenerative changes in the arteries may produce significant morbidity.

Laboratory Findings

The hypercalcemia can be severe. The serum phosphate concentration is normal, with a diminished alkaline phosphatase concentration.

Clinical Features

Symptoms and signs of hypercalcemia are seen. Anorexia, constipation, nausea and vomiting, polyuria, thirst, and symptoms of dehydration are the early manifestations. The child feels very tired. With progression of the intoxication, mental depression and stupor develop. Renal failure and hypertension are common.

Radiographic Findings

Dense metaphyseal bands are seen in the long bones and result from an increase in the proximal zone of calcification. The diaphyses show osteopenia as a result of demineralization. Osteosclerosis is visible at the base of the skull, and there may be premature closure of the sutures. The vertebral end-plates are dense. Metastatic calcifications are seen in soft tissues ( Fig. 42-19 ).

Hypervitaminosis D in a 5-year-old boy who had taken 50,000 IU of vitamin D/day for the past 14 months. A, Lateral view of the skull showing metastatic calcification of the cerebral and cerebellar falces. B and C, Anteroposterior view of both hips and lower limbs. Note the increased radiopacity of the metaphyses.

Treatment

Treatment is medical and consists of the immediate cessation of vitamin D supplements. Diuretics are given, with replacement of volume with saline. Because dehydration can be fatal, serum electrolyte levels must be carefully monitored. Steroids inhibit calcium absorption in the kidney and gut and are helpful in correcting the calcium level. Bisphosphonates inhibit bone resorption and have been useful in treating vitamin D intoxication. Sodium phosphate should not be given because its administration leads to ectopic calcification.

Pathology

When vitamin C is deficient, collagen synthesis is impaired. Vitamin C is necessary for the hydroxylation of lysine and proline to hydroxylysine and hydroxyproline, two amino acids crucial to the proper cross-linking of the triple helix of collagen. The result is primitive collagen formation throughout the body, including the blood vessels, which predisposes to hemorrhage.

Osteoblasts become dysfunctional, with failure to produce osteoid tissue and form new bone. Chondroblasts, however, continue to function normally, and mineralization is unaffected. This leads to the persistence of cartilage cells, and calcified chondroid approaches the metaphysis. Radiographically, an opaque white line termed Frankel’s line is seen at the junction of the physis and metaphysis.

Generalized osteoporosis results from lack of osteoid and new bone. Osteoclasts are normal, but osteoblasts become flattened, with a resemblance to connective tissue fibroblasts. The bone trabeculae and cortices of the long bones are thin and fragile. Hemorrhage and fractures are common, but the body’s attempt to repair these injuries is disorderly. The provisional zone of calcification is weak, which leads to epiphyseal separations. In the teeth, dentin formation is abnormal because of the defective collagen.

Clinical Features

Scurvy develops after 6 to 12 months of dietary deprivation of vitamin C, so it is not seen in neonates. Early manifestations consist of loss of appetite, irritability, and failure to thrive. Hemorrhage of the gums is common, and they become bluish and swollen. Subperiosteal hemorrhage is a distinctive sign that usually occurs in the distal femur and tibia and proximal humerus. The limbs become exquisitely tender, so much so that the infant screams on movement of the affected areas. The child lies still in the frog-leg position to minimize pain, a posture called pseudoparalysis. The limbs are swollen and bruised. Beading of the ribs at the costochondral junctions may occur. Hemorrhage may also develop in the soft tissues, including the joints, kidneys, and gut, and petechiae may be seen. The hair takes on a coiled appearance. Anemia and impaired wound healing are common. Severe hypertension has been described.

Radiographic Findings

The changes of scurvy are best seen at the knees, wrists, and proximal humeri ( Fig. 42-20 ). Osteopenia is the first change seen, with thinning of the cortices. The zone of provisional calcification increases in width and opacity (Frankel’s line) because of failure of resorption of the calcified cartilaginous matrix, and it stands out in comparison to the severely osteopenic metaphyses. The margins of the epiphyses appear relatively sclerotic, a finding termed ringing of the epiphyses, or Wimberger sign. Lateral spur formation at the ends of the metaphysis is produced by outward projection of the zone of provisional calcification. The scurvy line or scorbutic zone is a radiolucent transverse band adjacent to the dense provisional zone. The corner or angle sign of scurvy is a peripheral metaphyseal cleft caused by a defect in the spongiosa and cortex adjacent to the provisional zone of calcification. Epiphyseal separation may occur.

Scurvy in a 10-month-old infant. A, Anteroposterior radiograph of both lower limbs demonstrates early changes in the scorbutic bones. Note the generalized osteoporosis with rarefaction of the spongiosa and atrophy of the cortex. There is relatively increased opacity of the provisional zones of calcification at the ends of the metaphyses and around the margins of the epiphyseal centers of ossification (ringing of the epiphyses). B, Two weeks after treatment with ascorbic acid, marked calcification of subperiosteal hematoma of the right femur has occurred. Such minimal calcification is also evident in the medial aspects of the distal left femoral shaft and proximal left tibia. Note the multiple metaphyseal spur formation. C, Three months later there are further radiographic signs of healing scurvy. The cortices have become thicker and the spongiosa has almost normal density. Note the persistence of rarefaction in the epiphyseal centers.

Subperiosteal hemorrhage usually occurs at the femur, tibia, or humerus and is initially seen as an increase in soft tissue density. The hemorrhage becomes radiodense as the scurvy is treated and the lesions calcify. The development of a physeal bar in a patient with scurvy has been described.

Differential Diagnosis

The most common entity for which scurvy is mistaken is osteomyelitis. The symptoms of pain, tenderness, subperiosteal soft tissue swelling, and pseudoparalysis resemble the symptoms of infection. Because infection is common and scurvy is extremely rare, the condition can be misdiagnosed initially. The sedimentation rate, C-reactive protein level, and white blood cell count are normal in scurvy, however. Other diagnoses to be considered for this clinical picture include polio, leukemia, and purpuric conditions, such as Henoch-Schönlein purpura and thrombocytopenic purpura. Syphilis may be suspected but usually occurs earlier.

Serum levels of vitamin C may be difficult to interpret in scurvy. A more reliable test is the absence of vitamin C in the buffy coat of centrifuged blood.

Treatment

Treatment is administration of vitamin C. Rapid recovery is usual, with the pain and tenderness resolving. Scurvy is prevented by adequate intake of vitamin C, defined as 25 mg/day for infants, 30 to 40 mg/day for children and 40 to 75 mg/day for adults. Intoxication does not occur.

Clinical Features

Clinically, the soft tissues overlying the hyperostotic bones are swollen and tender. Proliferation of basal cells and hyperkeratinization cause dry, itchy skin. Anorexia, vomiting, and lethargy are caused by increased intracranial pressure. The child fails to thrive. Hepatomegaly with cirrhosis-like liver damage or splenomegaly may be present.

Radiographic Findings

The development of bone changes in patients with hypervitaminosis A is slow, so radiographs are normal initially. For this reason, radiographs are normal in children younger than 1 year. Once changes do occur, there is periosteal hyperostosis and thickening of the cortex of the long bones. The ulna, radius, metacarpals, and metatarsals are particularly affected. The mandible is spared, a fact that distinguishes hypervitaminosis A from Caffey disease. Subperiosteal new bone formation is seen ( Fig. 42-21 ). Bone scintigraphy shows increased uptake. Premature partial or complete physeal closure may be present.

Hypervitaminosis A in a 2-year-old child. Note the subperiosteal new bone formation and cortical thickening of both tibiae and both ulnae. The mandible and other facial bones are not affected. A and B, Radiographs of the right and left forearms. C, Radiograph of both lower limbs.

Diagnosis

The diagnosis is made by determining the plasma level of vitamin A, which will be elevated 5 to 15 times the normal value. Hypercalcemia can be present. Hypervitaminosis A must be differentiated from infantile cortical hyperostosis (Caffey disease), scurvy, and congenital syphilis.

Treatment

Treatment entails total cessation of administration of vitamin A and eliminating all foods containing vitamin A from the diet. Because of the large body reserves of vitamin A, the hyperostosis will disappear only after a long period, although the systemic symptoms resolve quickly. Growth of the long bones should be monitored because premature physeal closure may not become apparent for years after the initial insult.

Inheritance

The gene for hypophosphatasia is the TNSALP gene ( TNSALP ), and many different mutations have been described within this gene. The transmission of lethal forms is autosomal recessive, whereas milder forms may have autosomal dominant or recessive transmission. Heterozygous carriers of hypophosphatasia can be detected by abnormally diminished alkaline phosphatase concentrations in plasma.

Pathology

The pathology seen in hypophosphatasia closely resembles that seen in patients with rickets. Osteoid production proceeds unharmed, but without alkaline phosphatase, mineralization of osteoid cannot occur. This leads to widening of the physis, with persistence of the provisional zone of calcification, which cannot calcify, and islands of cartilage continuing down into the metaphysis. The normal columnar arrangement of the chondrocytes of the growth plate is disturbed. If hypercalcemia is present, heterotopic calcification can occur, especially in the kidney.

Laboratory Findings

The hallmark of hypophosphatasia is a decrease or lack of alkaline phosphatase. The enzyme is decreased not only in serum but also in tissues such as the kidneys, bones, leukocytes, and spleen. Serum phosphorus, vitamin D, and PTH levels are normal, but hypercalcemia may be present, especially in young children. Characteristic findings in urine are elevated levels of phosphoethanolamine, which may be elevated in other endocrinopathies, and inorganic pyrophosphate. Pyridoxal-5′-phosphate levels are also increased in hypophosphatasia in relation to disease severity. Disease carriers have been found to have decreased serum alkaline phosphatase levels and increased urinary pyrophosphate levels.

Clinical Features and Radiographic Findings

Perinatal Hypophosphatasia

The clinical findings vary with the age at which the disease is manifested. In the perinatal lethal form, absence of skeletal mineralization is detected by prenatal ultrasound, and the infants may be stillborn. If they survive birth, they usually die from respiratory complications in early infancy because of hypoplastic lungs and chest wall deformities. A nonlethal, benign, prenatal form also exists and has been recognized. These patients have congenital limb bowing with a variable degree of hypomineralization, which improves postnatally, along with their limb bowing.

Radiographs of infants with the severe or lethal form of perinatal hypophosphatasia reveal diffuse, severe demineralization of the entire skeleton ( Fig. 42-22 ). Ossification of the skull is incomplete, and the suture lines are very wide. The ribs are unossified at the ends and slender in the middle. The pelvis is small, soft, and poorly mineralized. The vertebral bodies are paper thin and the neural arches cannot be seen. The long bones have jagged rarefied defects extending into the metaphysis.

Typical radiographic changes of hypophosphatasia in a 4-month-old infant. A and B, Both upper limbs. C, Lower limbs. D, Spine (see text for discussion). E, Skull. F, Femur, obtained at autopsy (see text for discussion).

Diagnosis

Treatment

Although there is no curative treatment for hypophosphatasia, a limited number of drugs have been reported to be effective in managing certain problems associated with hypophosphatasia. Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to improve pain in childhood hypophosphatasia. Recombinant human PTH 1-34 can improve and resolve metatarsal stress fractures in adult hypophosphatasia. A case report of bone marrow cell transplantation in a patient with severe infantile hypophosphatasia showing clinical and radiographic improvements has been reported. In another patient with infantile hypophosphatasia, successful transplantation of bone fragments and cultured osteoblasts, with improvement in the clinical severity of the disease, has also been reported. If the diagnosis of rickets is mistakenly made, treatment with vitamin D can worsen the heterotopic calcification and nephrocalcinosis. Enzyme replacement therapy is not yet available.

Fractures require orthopaedic referral. Healing of fractures is generally delayed in patients with hypophosphatasia. Occasionally, multiple osteotomies with intramedullary fixation, as would be done in cases of severe osteogenesis imperfecta, are needed to correct the bowing and lend structural support to the long bones.

Clinical Features

In congenital forms the infant is of normal size, but diminished growth is noted within the first 6 months in type IA deficiency. The limbs are of normal proportion in relation to the head and trunk. Intelligence is normal in most cases. The phenotypic feature of type IB deficiency is less severe in terms of growth disturbance than type IA. The condition can be associated with hypogonadism and a delay in or absence of sexual maturation.

In the acquired form caused by a pituitary lesion, signs of neurologic deficit, such as impaired vision, ocular disturbances, and pathologic sleepiness, are present.

Radiographic Findings

In congenital hypopituitarism, skeletal maturation is delayed. The ossification centers are late in both appearance and closure. Osteoporosis of the long bones and the skull is present. The fontanelles close later than normal.

Where there is a lesion in the pituitary, radiographs reveal enlargement of the sella turcica, the home of the pituitary. Intrasellar or suprasellar calcification suggests craniopharyngioma. MRI is especially useful for viewing the pituitary. Enlargement, hypoplasia, or tumor can be seen.

Diagnosis

Serum levels of growth hormone will be low or absent. Because low levels are normal in healthy children, a stimulatory test is usually needed to confirm the lack of growth hormone. Insulin or l -arginine is administered to produce hypoglycemia, which stimulates the release of growth hormone. Growth hormone levels do not increase in patients with pituitary dwarfism after the administration of these agents.

Treatment

Pituitary dwarfism is treated by the administration of synthetic growth hormone. This treatment stimulates growth and should be monitored by a pediatric endocrinologist. Patients with growth hormone deficiency after resection of craniopharyngiomas rarely have an isolated deficiency in growth hormone, so additional hormone replacement therapy is necessary, under the guidance of the endocrinologist. In some children with growth hormone deficiency, panhypopituitarism has developed in adulthood, with hypothyroidism and abnormalities in antidiuretic hormone. On rare occasion, referral to an orthopaedic surgeon is needed for the treatment of SCFE.

Causes

Congenital hypothyroidism can be caused by prenatal developmental defects of the thyroid gland producing a structural abnormality (thyroid agenesis or dysgenesis) or by defects in thyroid hormone biosynthesis (thyroid dyshormonogenesis). The former, structural causes of congenital hypothyroidism, are found in most cases (80%). Structural abnormalities range from aplasia of the thyroid, hypoplasia, and goiter to ectopic thyroid tissue. Defects in thyroid hormone synthesis are responsible for the remaining 20% of cases.

Clinical Features

Symptoms in early infancy include prolonged jaundice, lethargy, sleepiness, feeding difficulties, and constipation. Frequently these infants are overweight. Other features include dry skin, scanty coarse hair, an enlarged tongue, umbilical hernias, and an expressionless face ( Fig. 42-23 ). Developmental delay is noted. Associated congenital malformations, especially heart defects, are more likely to occur in children with congenital hypothyroidism.

Typical clinical appearance of congenital hypothyroidism.

In acquired hypothyroidism, which is manifested later in childhood, sluggishness, a slowdown in growth, and worsening school performance are noted. SCFE may occur and lead to groin, hip, or knee pain. Hypogonadism is present, and the children are often overweight.

Radiographic Findings

Thyroid hormone is very important in regulating bone growth and maturation. In patients with hypothyroidism, enchondral bone formation is disturbed. The skeleton is immature for the infant’s chronologic age. Appearance of the epiphyses is delayed, and they appear irregular and fragmented, which in childhood resembles what is seen in Perthes disease or multiple epiphyseal dysplasia. Epiphyseal dysgenesis was the term used by Reilly and Smyth to describe the ossific nuclei. The physis may be irregular and widened, similar to the radiographic picture in rickets.

The bone age of the patient is delayed. The long bones are abnormally widened as a result of normal intramembranous bone formation in the context of disturbed endochondral ossification.

The head appears large. Radiographically, ossification of the skull is retarded and the base of the skull is shortened. The sella turcica may be enlarged. Closure of the fontanelles is delayed. A delay in the development of normal dentition is common. Spinal radiographs show a tendency toward thoracolumbar kyphosis. The vertebral body of L2 is wedge-shaped and the anterior margin is beaked. L1 and L3 may have a similar appearance. The bony end-plates are convex. Osteosclerosis develops in some patients as a result of hypercalcemia. Radiographs in these patients show transverse radiopaque bands in the metaphyseal areas and thickened cortices. Metastatic calcification can occur. MRI has shown enlargement of the pituitary in children with congenital hypothyroidism.

Diagnosis

Great advances have been made in the diagnosis of congenital hypothyroidism. Screening programs are in place to measure TSH levels in the newborn nursery. An elevated TSH level is suggestive of congenital hypothyroidism. Further laboratory evaluation of thyroid hormone levels and further imaging studies consisting of radionuclide scintigraphy of the thyroid or thyroid ultrasound are then performed to ascertain the cause of the hormone deficiency.

Early diagnosis is mandatory because a delay in diagnosis can lead to irreversible mental retardation. The workup of a developmentally delayed child should include laboratory evaluation of thyroid function when the cause of the delay is unknown.

There is an association between Down syndrome and hypothyroidism. Studies have shown that 15% to 35% of infants with Down syndrome have congenital hypothyroidism, and annual screening of these children is recommended. Hypothyroidism should be especially considered in children with Down syndrome who have SCFE. In one study, six of eight patients with Down syndrome and slipped epiphyses had hypothyroidism.

Other laboratory findings in children with hypothyroidism may include high serum calcium levels. Patients with panhypopituitarism will have not only hypothyroidism but also the other hormonal deficiencies seen in this disorder, such as growth hormone deficiency.

Treatment

Treatment begins immediately on diagnosis. Hormone replacement therapy with thyroxine is initiated and carefully monitored. If treatment is begun by 24 months of age, subsequent growth has been shown to be normal by 5 years. With hormonal replacement therapy, the pubertal growth spurt is normal, and adult height is within normal limits. Long-term thyroxine replacement therapy has not been shown to decrease bone mass and lead to osteopenia. Prompt treatment results in normal intellectual development.

Prenatal diagnosis through cord blood sampling has been achieved, and prenatal treatment of hypothyroidism by means of thyroid hormone injected into amniotic fluid has been successful in experimental settings. If congenital hypothyroidism remains untreated, the mental retardation is progressive, and most children die early of respiratory infection.

Causes

The cause of idiopathic juvenile osteoporosis remains unknown. The disease is not genetically transmitted. The basic mechanism of disease is decreased bone remodeling activity and decreased bone formation. Bone histology generally shows a decreased cancellous bone volume and a very low bone formation rate on cancellous surfaces. Bone remodeling activity is less involved in the cortical bone surfaces than cancellous bone surfaces. In one study, secretion of synthesized collagen by cultured skin fibroblasts in some patients with idiopathic juvenile osteoporosis was reduced, whereas the range of collagen secretion in other patients with the disease overlapped the normal range. Another study found diminished levels of the carboxy-terminal propeptide of type I procollagen in patients with juvenile osteoporosis, again indicating abnormalities in collagen metabolism.

Biomechanical studies are conflicting. Serum calcium and phosphorus levels are normal in these patients. Calcium balance, however, is negative, with poor gastrointestinal absorption of calcium. Alkaline phosphatase and urinary hydroxyproline levels are usually normal as well. Although most studies reported normal vitamin D levels, two studies found low levels of calcitriol (1,25-dihydroxycholecalciferol). Therapy was then directed toward the vitamin deficiency, with improvement in the disease. It may be that different forms of the disease have different biochemical profiles.

Clinical Features

The mean age at onset is 7 years, with cases reported in children as young as 1 year. By definition, the disease is always manifested before puberty. There is no gender predilection.

The initial complaints in children with idiopathic juvenile osteoporosis are back and leg pain. Patients may refuse to walk or may have a slow gait or limp. The examining physician should always remember that a limp in children is a common orthopaedic problem, whereas idiopathic juvenile osteoporosis is an extremely rare condition.

Radiographic Findings

Diffuse generalized osteoporosis is seen on radiographs of the spine and limbs ( Fig. 42-25 ). The normal trabecular pattern is markedly decreased and the cortices of the bones are thinned. On lateral radiographs of the spine, a codfish appearance is seen. Increased thoracic or thoracolumbar kyphosis with anterior wedging of the vertebrae may develop. Vertebral compression fractures may be evident, and scoliosis may be present.

Idiopathic juvenile osteoporosis. Anteroposterior ( A ) and lateral ( B ) radiographs of the spine showing the severe osteoporosis. Note the compression fractures of the vertebrae in the lumbar region. C, AP radiograph of both tibiae. Note the plastic bowing of the fibulae and marked osteoporosis.

Another radiographic feature is the presence of long bone fractures in various stages of healing. The fractures are usually metaphyseal and tend to occur in areas of highest stress, such as the femoral neck. Other areas in which stress fractures are common are the distal femur and proximal tibia. The skull does not have a wormian appearance.

Diagnosis

The diagnosis is one of exclusion. The various known causes of osteoporosis in childhood are listed in Box 42-1 . The most difficult distinction to make is between idiopathic juvenile osteoporosis and mild osteogenesis imperfecta. Patients with a positive family history have osteogenesis imperfecta, yet individuals with no affected relatives may have either disease. Other distinguishing features of osteogenesis imperfecta that are not associated with idiopathic juvenile osteoporosis are blue sclerae, dentinogenesis imperfecta, ligamentous laxity, and easy bruising. Patients with juvenile osteoporosis do not sustain fractures in early infancy, which may help differentiate the two diseases in some patients. Finally, the fracture callus in juvenile osteoporosis is osteopenic.

Fibroblast studies may be of some help in establishing the diagnosis of osteogenesis imperfecta, but overlap of results with normal ranges and with results in idiopathic juvenile osteoporosis may occur in some children. Bone biopsy is not generally necessary to diagnose osteogenesis imperfecta or idiopathic juvenile osteoporosis but, when it is performed, increased woven immature bone is seen in osteogenesis imperfecta, whereas increased osteoclastic resorption of bone is seen in idiopathic juvenile osteoporosis.

Another very important clinical distinction to make is that between leukemia and idiopathic juvenile osteoporosis. A child with leukemia may have osteopenia and compression fractures, so urgent referral to a pediatric hematologist is wise in the evaluation of a patient with osteoporosis. Usually, a bone marrow aspirate will be required to rule out leukemia definitively.

Treatment

Treatment of idiopathic juvenile osteoporosis is controversial. Isolated reports of successful medical treatment with calcitonin, calcitriol, bisphosphonates, and estrogen have been published. All reported improved bone mineralization and decreased fractures. It appears that when a demonstrable deficiency is found through laboratory testing, treatment aimed toward correcting that deficiency is warranted.

Orthopaedic treatment of the spine is usually conservative. Bracing may relieve back pain and treat the kyphotic deformity. The Milwaukee brace has been used for this purpose, with reported success. The role of the brace in accelerating osteoporosis by stress shielding the spine is unknown. Use of the brace should be discontinued gradually as the osteoporosis resolves. Similarly, scoliosis should be managed orthotically when possible. Spinal fusion has been performed in isolated cases, but continued progression of the deformity because of bending of the fusion mass has been described.

Long bone fractures should be managed by conventional means. Immobilization should be kept to a minimum because prolonged immobilization leads to worsening osteoporosis and may result in a cycle of fractures.

Pathophysiology

The vast majority (at least 90%) of individuals with osteogenesis imperfecta have an identifiable genetic defect in one of the two chains that form the type I collagen. ^§

§ References .

Normal Type I Collagen Metabolism

Type I collagen is the major structural collagen of the bone, skin, tendons, dentin, and sclera. It is a triple-helix molecule made of two α ₁ chains and one α ₂ chain. In a normal fibroblast, precursor subunits for these two types of strands (pro-α ₁ [I] and pro-α ₂ [I] polypeptide chains) are synthesized in the rough endoplasmic reticulum. These two procollagen polypeptide chains are encoded by two separate genes, COL1A1 (encoding for pro-α ₁ [I]), located on the long arm of chromosome 17, and COL1A2 (encoding for pro-α ₂ [I]), located on the long arm of chromosome 7. Combining these three chains into the triple helix begins at the carboxy-terminal end and propagates toward the amino-terminal end. The process of alignment and assembly of the triple helix is supported by endoplasmic reticulum–resident molecular chaperones such as GRP78, Serpin H1, and the prolyl 3-hydroxylation complex, which consists of CRTAP, P3H1, and PPIB. An essential feature of the pro-α chains required for proper folding of the triple helix is a recurrent pattern of glycine residues at every third peptide position in the chain (Glycine-X-Y sequence). It is at these residues that cross-linking of the three chains occurs. The type I procollagen molecules are secreted from the cell and are processed extracellularly to form the type I collagen molecules ( Fig. 42-26, A ).

Schematic representation of normal and abnormal collagen formation. A, Normal type I collagen formation. Two pro-α ₁ (I) (encoded by COL1AI on chromosome 17) and one pro-α ₂ (I) (encoded by COL1A2 on chromosome 7) polypeptide chains form a left-handed triple helix, beginning at the carboxy end and continuing to the amino end. Cross-linking occurs at glycine residues located at every third position in the chains. The procollagen molecule is then secreted from the endoplasmic reticulum into the extracellular matrix, where coalescence into the complete type I collagen fiber continues. B, Quantitative defect typified by Sillence type IA osteogenesis imperfecta. There is a stop codon for one of the COL1AI genes, which results in no mRNA from that gene. As a result, normal pro-α ₁ polypeptide chains are produced in levels approximately 50% of normal, with the subsequent production of ≈50% of the normal amount of type I collagen. The collagen produced is electrophoretically normal, and no abnormal collagen is detectable. C, Formation of mutant type I collagen from some defect in COL1AI or COL1A2 . Skips or substitutions for glycine occur at some point along the polypeptide chains encoding for pro-α ₁ or pro-α ₂ . The mutant polypeptide chain results in poorer cross-linking. Defects closer to the carboxy terminal are potentially more serious because triple helix formation begins at this end. The mutant procollagen is usually produced in reduced amounts, so there is a qualitative and quantitative deficiency of type I collagen. This type of defect is typical of Sillence types II, III, and IV osteogenesis imperfecta.

Classification and Heredity

The identification of more than 280 specific locations of disruptions in genetic coding for type I collagen has improved our understanding of the nature and variability of the clinical manifestations but has not simplified the classification process. Variability in the natural history, time of onset, different patterns of inheritance, relatively high incidence of spontaneous mutations, and variability in clinical severity, even when the mode of inheritance is known, further compromise the effectiveness of classification schemes. Two classification schemes, those of Sillence and associates and Shapiro, are clinically useful despite their limitations.

In 1979, Sillence and Danks delineated four distinct types of osteogenesis imperfecta based on clinical and genetic characteristics ( Table 42-2 ). In their original description, four types were described and identified as autosomal dominant (types I and IV) or autosomal recessive (types II and III). More recent work on the nature of type I collagen disorders and the molecular genetic basis for these disorders has elucidated the nature of the genetic defect, and true autosomal recessive transmission is rare in this condition. Cole has recommended modification of the original Sillence classification based on an extensive review of the collagen defect in 200 patients with osteogenesis imperfecta. Discoveries of noncollagen gene defects causing osteogenesis imperfecta and histologic features dissimilar to those of the conventional types have led to the addition of types V to XI to osteogenesis imperfecta nosology. Type V has autosomal dominant transmission, whereas types VI to XI have recessive transmission. It is important to note that these latter types collectively account for approximately 5% of cases of osteogenesis imperfecta.

Osteogenesis Imperfecta Types X and XI

Types X and XI disease are caused by defects in SERPINH1 and FKBP10, respectively. These are so-called collagen chaperons that bind and accompany the procollagen molecule from the endoplasmic reticulum to the Golgi apparatus. Type X disease is associated with severe bone dysplasia, blue sclera, dentinogenesis imperfecta, transient skin bullae, pyloric stenosis, and renal stones. Type XI disease is associated with bone dysplasia, ligamentous laxity, platyspondyly, and scoliosis. Sclerae and teeth are normal.

One of the problems for the orthopaedic surgeon and the families of patients with osteogenesis imperfecta is the significant variability in the severity of long bone deformity and fracture frequency in the Sillence classification categories. Even within families, whose members presumably share the same genetic defect, one sibling may have only a few fractures whereas another may have repeated fractures, deformity requiring intramedullary rods, and difficulty ambulating without lower extremity bracing or an upper extremity aid. Because of this practical problem, clinical classifications based on the age at onset and severity of fractures still have prognostic relevance for orthopaedic surgeons and affected individuals.

Looser in 1906 classified osteogenesis imperfecta into two types, osteogenesis imperfecta congenita, characterized by the presence of numerous fractures at birth, and osteogenesis imperfecta tarda, in which the fracture(s) occur after the perinatal period. Shapiro recommended a further modification of Looser’s classification consisting of four categories—congenita A, congenita B, tarda A, and tarda B. This classification has excellent practical application for the orthopaedic surgeon and families of affected individuals in regard to prognosis for survival and ambulation. Shapiro classified patients as having osteogenesis imperfecta congenita if they had fractures in utero or at birth, whereas Looser and other authors used congenita only for in utero fractures. The distinction between the two congenita types is based on the timing of the fracture and radiographic features of the affected bones. Patients with congenita A sustain fractures in utero or at birth, with the additional radiographic features of crumpled long bones, crumpled ribs with rib cage deformity, and a fragile skull ( Fig. 42-27 ). These features are incompatible with life, and the patients are almost always stillborn or die shortly after birth from intracranial hemorrhage or respiratory insufficiency. Patients with congenita B have fractures at birth but are radiographically distinct from congenita A patients in that the long bones, as typified by the femur, are more tubular and have more normal funnelization in the metaphysis, the ribs are more normally formed (although there may be rib fractures), and there is no rib cage deformity. These patients are severely affected, but this type is compatible with survival. Patients with tarda A have an onset of fractures before walking. The age at onset of fractures was not prognostic for ambulation within this group in Shapiro’s study. Patients with tarda B suffer their first fracture after walking age; all these patients were ambulatory in Shapiro’s study.

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