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
     1.  Alagille D.  Alagille syndrome today. Clinical 
Invest Med 1996;19:325-330.
     2.  Hodson CJ.  Metabolic and endocrine induced 
bone disease.  In:  Shanks.  Textbook of X-ray 
Diagnosis, 4th Edition.  Philadelphia, PA, W.B. 
Saunders Co., 1971, pp. 685-695.
     3.  Krantz I, Piccoli D, Spinner N.  Alagille syndrome. 
J Med Genet 1997;34:152-157.
     4.  Mimouni F, Tsang RC.  Parathyroid and vitamin 
D-related disorders.  In:  Kaplan S.  Clinical Pediatric 
Endocrinology.  Philadelphia, PA, W.B. Saunders Co., 
1990, pp. 427-452.
     5.  Pitt M.  Rickets and osteomalacia are still around.  
Radiologic Clinics of North America 1991;29:97-118.
     6.  Silverman F, Kuhn J.  Metaholic abnormalities of 
the skeleton.  In:  Caffey.  Caffey's Pediatric Xray 
Diagnosis, 9th Edition. St. Louis, MO, 1993, pp. 
1746-1783.
     7.  Smith R.  The pathophysiology and management 
of rickets.  Orthopedic Clinics of North America 
1972;3:601-621.