Prostaglandin-induced cortical hyperostosis in infants with cyanotic congenital heart disease

Last revised by Daniel J Bell on 9 Sep 2020

Prostaglandin-induced cortical hyperostosis in infants is a well-known side-effect from the treatment of cyanotic congenital heart diseases. Prostaglandin-E1 (injectable form), and prostaglandin-E2 (oral form) are E-type prostaglandins (PGE), that are commonly used in newborns with cyanotic congenital heart disease to maintain the patency of the ductus arteriosus 1-4. Prostaglandins (PG) are often used for the short term as surgery is the definitive curative treatment of these conditions; however, occasionally, they can be used for a longer duration in preterm neonates 1,2

Rough texture skin, thickened skin and subcutaneous tissues, coarse facial features with prominent supraorbital ridges, and hypertrichosis (excessive hair growth) 1.

The degradation of prostaglandins is catalyzed by the enzymes (prostaglandin 15-OH dehydrogenase and prostaglandin-13 reductase) that are largely dispersed in vascular beds of many organs, including lungs 1. Normally, E-type prostaglandins (PGE) are promptly mollified by these enzymes, especially during passage through the lungs; however, newborns with cyanotic congenital heart diseases have diminished pulmonary blood flow which leads to decreased alleviation of PGE 1,3. Furthermore, these babies generally receive pharmacologic doses of PGE to keep the ductus arteriosus patent, and both these factors (reduced clearance and higher doses) lead to greater PGE concentration in the circulation, which may lead to the osseous complications 1,3. Cortical hyperostosis may be a dose-related, direct provocation of the osteoblasts, however, its exact mechanism is not yet known 1

Histological evaluation of the afflicted bones shows the accelerated primitive bone formation, protracted absorption of the outer cortical surface, and bone formation of the inner surface 2,5.

PGE1 is generally used as an intravenous infu­­­­­­sion at a dose of 0.05-0.1 µg/kg/minute for a brief duration (6 hours-20 days), preoperatively 1. However, it is used for a longer duration (weeks-months) in certain circumstances like preterm neonates (to allow the growth of pulmonary arteries to a reasonable size for surgery), infection, low birth weight, or lack of specialized cardiac surgery services 1-3,5.

Common complications of short-term prostaglandin use are apnea, abdominal distension, bradycardia, fever, skin flushing, rash, hypotension, convulsions, diarrhea, necrotizing enterocolitis, and gastric outlet obstruction 1,2,5. Important sequelae associated with prolonged use of prostaglandin are reversible cortical hyperostosis (predominantly affecting the long bones) and soft tissue swelling 1,2.

Prostaglandin-induced cortical hyperostosis appears to be linked to the duration (mainly) or dosage of the prostaglandin therapy 1-3,5. The percentage of patients developing hyperostosis increases from 42% at <30 days to 100% at >60 days of continuous PGE1 infusion 1-3,5. However, sometimes these changes can be encountered as early as 9-11 days after PGE infusion 1,2,5.

Laboratory investigations show isolated elevation of serum alkaline phosphatase (ALP) level, which correlates well with the extent of periostitis as well as with the duration of PGE1 therapy 1,2,5.  This elevated serum ALP level may not only help in making a diagnosis but can also be used as a follow-up marker of cortical hyperostosis 1,6.

The long bones of upper and lower extremities are the most commonly affected bones 1. Ribs and to a lesser extent, clavicles and scapula are among the other affected bones 1. The long bones are always symmetrically (but not uniformly) affected. Periosteal elevation of the diaphysis without any destructive changes and sparing of the metaphysis are classical radiological features 1. Pseudowidening of the cranial sutures (due to an unossified zone at the margins of the sutures) without any abnormal increase in head size had also been mentioned 1. The mandible is not affected (cf. Caffey disease where it is invariably affected) 1.

Generally, it is a reversible, benign, self-limiting process and often disappears after discontinuation of the prostaglandins but can persist for months 1-3. It has no effects on the subsequent bone growth, after PGE discontinuation 1.

The clinical history, physical examination, and radiological features are usually sufficient to elucidate the diagnosis. The differential diagnosis of generalized cortical thickening in infants includes:

Clinicians and radiologists must be aware of the late side-effects associated with prolonged prostaglandin treatment. Early suspicion and detection may avoid unnecessary laboratory investigations or inaccurate diagnoses such as child abuse or osteomyelitis, during the resolution phase.

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