Volume 6, Case 5
Donna Mendez, MD
Children's Medical Center of Dallas
University of Texas Southwestern School of Medicine
This is a 2 year old male, with a history of Alagille's syndrome (a chronic liver condition), who presents to the ED with elbow swelling 3 days after a fall, hitting his head on the edge of a door. There was no loss of consciousness or neurological symptoms. He has normal activity and is eating and drinking as usual. He has a one day history of a stuffy nose and cough. There are no other complaints.
Exam: T 38.0 (tympanic). His other vital signs are normal. He is noted to have a contusion with mild swelling and ecchymosis over his right forehead. There are no palpable skull deformities or areas of significant tenderness. He is also noted to have yellow nasal discharge, icteric sclera and a swollen right elbow with decreased range of motion. There is no erythema, warmth or tenderness on palpation in the area of swelling. There is no hepatosplenomegaly, and the remainder of the exam is unremarkable.
Because he has evidence of a systemic disease, a CBC, ESR, CRP and a chemistry panel are ordered. His CBC is normal. His electrolytes are normal. His phosphorous is slightly low at 2.9 mg/dL (normal 3-6 mg/dL). His serum calcium is normal at 8.5 mg/dL. His liver enzymes are elevated (ALT 288, AST 198, total bilirubin 4.3, GGT 1204, alkaline phosphatase 2323 mg/dL). His ESR and CRP are normal.
Radiographs of his right elbow and forearm are obtained.
View his forearm radiographs.
The radiograph demonstrates a healing right radial midshaft fracture. Also noted are multiple lytic lesions with cortical scalloping along the metaphysis and diaphysis of the forearm bones with generalized severe demineralization. A long bone survey is obtained.
View his lower extremity radiographs.
View femur radiographs.
View tibia radiographs.
These radiographs demonstrate epiphyseal and metaphyseal flaring at the ends of the femur and tibia. Lytic lesions are noted throughout the long bones. These bony abnormalities are not primarily due to the Alagille syndrome. What bony abnormality is present?
Teaching Points:
1) Alagille syndrome (arteriohepatic dysplasia) is characterized by a paucity of intrahepatic bile ducts. Clinical manifestations include chronic cholestasis, characteristic facies, cardiovascular abnormalities, vertebral arch defects and posterior embryotoxin (an ocular accumulation of pigmentary material). Cholestasis usually develops in the first few months of life. Episodes of jaundice, are interspersed with periods of anicteric remission. The characteristic facies is observed in 95% of patients, consisting of a prominent forehead, moderate hypertelorism with deep set eyes, a small pointed chin, and a saddle or straight nose. These features are usually not fully apparent until 5-10 years of age.
The most common cardiovascular abnormality is isolated and nonprogressive pulmonary stenosis of the peripheral pulmonary vascular tree. The vertebral arch defect seen is "butterfly-like" appearance of the dorsal vertebrae. The accumulation of embryotoxin occurs in more than 80% of patients with this syndrome. Embryotoxin, a pigmentary material, accumulates in the inner aspects of the cornea near its junction with the iris. It is best observed with a slit lamp examination. Other clinical manifestations include growth retardation, renal abnormalities, mental retardation and voice changes.
Chronic cholestasis can lead to malabsorption of fat soluble vitamins due to lack of bile salts. Vitamin D deficiency can result from this malabsorption as well being due to a deficiency of 25-hydroxylation secondary to destruction of liver parenchyma.
Diagnosis of Alagille syndrome is made by liver biopsy and histological examination of the interlobular bile ducts. This syndrome can be transmitted in an autosomal dominant mode. Management includes a high energy diet with adequate protein intake. Fat soluble vitamins may need to be supplemented. There is no way of predicting which patients (15%) will progress to end stage liver disease and require transplantation.
2) Our patient has severe demineralization and pathologic fractures due to vitamin D deficiency resulting in rickets. Rickets can be caused by dietary deficiency, inadequate exposure to sunlight, malabsorption and/or failure of metabolic activation of vitamin D to the active form. Provitamin D3, is a prohormone that eventually is converted to the active form of vitamin D, 1,25-dihydroxyvitamin D3. This active form increases intestinal calcium and phosphorous absorption, mobilizes calcium and phosphorous from bone to the bloodstream, and retains calcium and phosphorous through its renal effect. This renal effect moves calcium and phosphorous out of older bone and also promotes the maturation and mineralization of newly formed organic bone matrix.
In rickets, the main effect of vitamin D deficiency results in a disorganization of the maturation and calcification of the cartilage and its cells at the growing ends of long bones. These abnormalities can be correlated with radiographic findings. The widening and lengthening of the physis represents the area of disorganized mineralization in the zone of hypertrophy. Widening and cupping of the metaphysis represents the bulky mass of the hypertrophied zone placing abnormal inward stress on the poorly mineralized metaphysis, particularly on the more central areas.
3) The radiographic abnormalities seen in children with rickets depend on the age of onset and duration of illness.
a) Craniotabes: The head is particularly affected during the first months of life. During this period, the skull must accommodate the most rapidly growing organ, the brain. The rapid accommodation by the skull is associated with excess osteoid formation, particularly at the central margins and outer table, while resorption at the inner table continues. The thin calvarium is less rigid and subject to supine postural influences, resulting in posterior flattening. Continued accumulation of osteoid in the frontal and parietal regions results in the squared configuration known as craniotabes.
b) Long bone findings: During infancy and early childhood, the long bones show the greatest deformity. The metaphysis is widened, cupped and has a ragged edge. There is a wide gap between the metaphysis and the epiphysis corresponding to the area of disordered mineralization. In mild cases the first radiologic sign is a widening of the gap between the epiphysis and the metaphysis. The characteristic bowing deformities of the arms and legs are related to the sitting position assumed by the child. Often, the child with severe rickets will sit with his legs crossed. Bowing may also result from asymmetric, musculotendinous forces that displace the weakened growth plate. For example, the Achilles tendon on the calcaneus displaces the distal tibial growth plate resulting in the bowed tibia. The shafts of long bones may also become less dense caused by the loss of mineral content.
c) Rachitic rosary: Lumps develop at the costochondral junctions, particularly those of the middle ribs forming the characteristic rachitic rosary. The costochondral junctions are the most active growth plates and is the reason you see these changes here.
d) Harrison's groove: The distal end of the ribs are weak and may be depressed by the negative intrathoracic pressure developed during respiration with a resultant semicoronal impression being found at the costal attachment of the diaphragm, leading to the formation of Harrison's groove.
e) Scoliosis: With increasing age, the effects of weight bearing become prominent with scoliosis frequently developing.
f) Looser's zones (pseudofractures): Rickets, later in childhood, may have pseudofractures present. Looser's zones are composed of focal accumulations of osteoid, which is uncalcified bone matrix. They often occur at sites where major arteries cross the bone and have been thought to be secondary to the mechanical stress of the pulsating vessel.
g) Fractures: Greenstick fractures of the cortex are not uncommon.
4) Laboratory findings: In rickets, patients will have an increased alkaline phosphatase >200, as in this case. This is because of the active release of its stores in bone. There are 3 stages of rickets. Stage I is the early phase where serum calcium is low but serum phosphorous is normal. In stage II, which occurs later, serum calcium concentrations are restored to normal ranges because of compensatory hyperparathyroidism, but serum phosphorous levels are low. In stage III, both serum calcium and phosphorous levels are low and bone disease is florid because of the combined effect of mineral deficiency and hyperparathyroidism. This patient presented in stage II with a normal serum calcium and low serum phosphorous.
5) Treatment of rickets requires vitamin D, 50-150 micrograms once daily or 0.5-2.0 micrograms of 1,25-dihydroxycholecalciferol daily.
6) Secondary hyperparathyroidism occurs in response to hypocalcemia which occurs in rickets. PTH acts on the bone, kidney and intestine to have a net effect of increasing serum calcium and decreasing serum phosphorous. PTH acts to increase serum calcium by releasing it directly from the bone. This involves removal of bone and replacing it with osteoid tissue, and in more advanced cases osteoid plus fibrous tissue. Cystic degeneration later occurs within this fibrous tissue; the cystic spaces being irregular at first, but later becoming well defined. Conglomerations of osteoclasts may eventually develop into large tumours (osteoclastomata); so called "brown tumours." Other radiographic findings are resorption of subperiosteal bone, best seen along the margins of the phalanges of the hands. In the skull there may be gross trabeculations or a granular appearance resulting from lytic skull lesions. Fractures can also occur. About 10% of patients with hyperparathyroidism have radiographic findings of rickets.
Refer to the forearm radiograph again.
Click on [Forearm]
As noted before, a right radial fracture is noted with generalized severe demineralization, which can occur solely due to rickets or secondary hyperparathyroidism. Metaphyseal fraying and cuffing are noted, consistent with rickets. Multiple lytic lucent lesions within the diaphyses consistent with brown tumors are indicative of secondary hyperparathyroidism.
References