Perinatal/Neonatal Case Presentation Cortical Hyperostosis in an Infant on Prolonged Prostaglandin Infusion: Case Report and Literature Review

Home , Osteomyelitis, Periosteal reaction

Sithembiso Velaphi, MBChB developed severe periosteal new bone formation as a consequence Antoinette Cilliers, MBBCh of the prolonged use of prostaglandins. Elaine Beckh-Arnold, MBBCh Mantoa Mokhachane, MBBCh CASE REPORT Ramatsimele Mphahlele, MBBCh John Pettifor, MBBCh, PhD The patient, a male infant born vaginally at 35 weeks gestation, weighed 2200 g at birth. The mother, a 20-year-old primigravida, had attended antenatal clinic, was rhesus positive, rapid plasma reagin (RPR) negative and the enzyme-linked immunosorbent The common side effects associated with the use of prostaglandins in antibody test for human immunodeficiency virus (HIV) was newborn infants include apnoea, hyperthermia, diarrhoea, skin flushing positive. Both the mother and infant received nevirapine and oedema. Periosteal reaction or cortical thickening of the bones, also peripartum to reduce maternal-to-child transmission of HIV. The known as cortical hyperostosis, is associated with a prolonged use of pregnancy and labour were uneventful. Apgar scores were 9 and 10 prostaglandins. This is a radiological diagnosis; therefore, its occurrence is at 1 and 5 minutes, respectively. On examination, the infant had most likely underestimated. We describe an infant who developed cortical no dysmorphic features. He was noted to be cyanosed in room air hyperostosis simulating osteomyelitis with elevated alkaline phosphatase. with pulse oximetry saturations of 83 to 85%. Cardiovascular The radiologic changes were initially attributed to congenital syphilis. This examination revealed dextrocardia, and 2/6 ejection systolic murmur over the third intercostal space along the left parasternal occurred after a prolonged infusion of prostaglandin E1 for a cyanotic congenital heart disease. border. The rest of the systemic examination was normal. Journal of Perinatology (2004) 24, 263–265. doi:10.1038/sj.jp.7211050 Echocardiography revealed a single ventricle, patent ductus arteriosus, pulmonary atresia and dextrocardia. The patient was started on intravenous infusion of prostaglandin E1, 0.1 mg/kg/ minute. He had a number of episodes of suspected sepsis requiring antibiotics. One of these episodes was confirmed to be candida INTRODUCTION albicans sepsis, which resolved on fluconazole. On day 43 of life, he was noted to have bilateral swelling of the lower limbs, which Prostaglandins are commonly used in neonates with cyanotic 1 was not pitting, tender and had a hard consistency and was congenital heart diseases to keep the ductus arteriosus patent. thought to be sclerema. The child was also irritable with a high Their use is often for a short period as the definite treatment for temperature of 381C. A clinical diagnosis of nosocomial sepsis was these conditions is surgery. Occasionally, a prolonged use of made and, after a sepsis work-up was done, he was started on prostaglandins is required for various reasons such as an infant antibiotics. The work-up revealed the following: full blood count: being too small for surgery, delays in surgery in developing white blood cell count F 17.3 Â 109/l, haemoglobin F 9.2 g/dl, countries because of inadequate facilities, and in developed platelets F 869 Â 109/l, neutrophils F 13.7 Â 109/l, countries because of delays in obtaining suitable donors for lymphocytes F 2.2 Â 109/l, monocytes F 1.4 Â 109/l; c-reactive transplantation. Complications related to a prolonged use of protein (CRP) F 125 mg/l, but the blood culture was negative. prostaglandins include gastric outlet obstruction, pretibial and soft He was continued on antibiotics, and repeat CRP on day 45 had tissue swelling of the extremities, and reversible cortical 2–4 fallen to 39 mg/l. On day 49, he had another temperature spike proliferation of the bones. We wish to report a neonate who and the swelling of the legs had not improved. X-rays of the tibia and fibula in both limbs were performed to exclude osteomyelitis. These X-rays revealed periosteal reaction or cortical thickening of

Department of Paediatrics, University of the Witwatersrand, South Africa. the diaphyses (Figure 1). Further skeletal survey revealed extensive involvement of the bones of the upper limbs and clavicles Address correspondence and reprint requests to Sithembiso Velaphi, Department of Paediatrics, University of the Witwatersrand, Chris Hani Baragwanath Hospital, P. O. Bertsham 2013, (Figure 2). On reviewing chest X-rays performed at birth, these Johannesburg, South Africa. changes were not present. Congenital syphilis was considered a

considered to be less common within the few days after commencing prostaglandins. Histological examination of bones with cortical hyperostosis due to prostaglandin shows rapid formation of primitive bone, extensive resorption of the outer cortical surface and bone formation of the inner surface.5 These changes are associated with an increase in serum alkaline phosphatase concentrations.6–8 Prostaglandin-induced cortical thickening seems to be related to duration or dosage of continuous PGE1 infusion.3,5,6,8 The percentage of infants on continuous PGE1 infusion, who develop hyperostosis, increases with duration of PGE infusion from 42% at <30 days to 100% at >60 days.8 These changes can be seen as early as 9 to 11 days on PGE infusion.4,6,7 The outcome of this hyperostosis is good in that it has been shown to be reversible after 5,9 Figure 1. X-rays of the lower extremities showing cortical thickening stopping PGE. of the femur and tibia on both sides. The differential diagnosis of generalized cortical thickening in infants includes congenital syphilis, infantile cortical hyperostosis, prostaglandin osteopathy, scurvy and hypervitaminosis A.10 Generalized periosteal reaction or cortical thickening can also be found incidentally in asymptomatic patients, and is usually due to physiologic changes. In contrast, cortical thickening of a single bone is always pathologic due to conditions such as infection (osteomyelitis), trauma and tumour. The cortical thickening seen with scurvy occurs during the healing process of subperiosteal haematomas and is unlikely in this patient because of the very young age. The same applies for hypervitaminosis A, which appears only after many months of excessive ingestion of vitamin A. Infantile cortical hyperostosis, which is also called Caffey disease, is a disorder affecting the skeleton and some of its contiguous fasciae and muscles, whose cause is unknown. Common presentation is hyperirritability, swelling of the soft tissues and cortical thickening Figure 2. X-ray of the chest showing cortical thickening (white of the underlying bone. The swelling appears clinically before arrows) of the clavicles and the humerus. cortical thickening becomes visible radiologically. It may be associated with thrombocytosis, increased erythrocyte sedimentation possible aetiology despite the mother’s RPR being negative; rate and alkaline phosphatase. The average age at onset is about 9 however, RPR performed on the child was also negative. Alkaline weeks, although it can also be recognized in utero.10 phosphatase was raised at 808 IU/l and the rest of the liver function This patient’s presentation would fit the diagnosis of infantile tests were normal; serum calcium and phosphate were 2.6 and cortical hyperostosis. However, the history of a prolonged use 1.46 mmol/l, respectively. A final diagnosis of prostaglandin of prostaglandin suggests prostaglandin osteopathy rather osteopathy was made. The cardiothoracic surgeons considered that than infantile cortical hyperostosis and one would not like to the cardiac lesion had a poor prognosis, and therefore decided not suggest dual pathology. Since syphilis is relatively common to attempt corrective surgery. The prostaglandins were stopped and in our institution, the initial work-up included repeating the infant was discharged home to spend time with the family, RPR. follow-up X-rays were not taken as the patient did not come back In conclusion, in patients who are on continuous infusions of for review. prostaglandins in addition to the common side effects like apnoea, fever and skin flushing with oedema that are often looked for in these patients, cortical hyperostosis needs to be considered. This may be confused with osteomyelitis clinically, especially if some of DISCUSSION the above side effects such as fever and oedema are also present. Compared to the other side effects of prostaglandins like apnoea, Although this is commonly seen with a prolonged use of PGE, it hyperthermia, skin flushing and bradycardia, cortical thickening is can present as early as 9 days after initiation of therapy. Isolated

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increase in serum measurement of alkaline phosphatase might be 5. Jorgensen HR, Svanholm H, Host A. Bone formation induced in an infant by helpful in making a diagnosis of cortical hyperostosis. systemic prostaglandin-E2 administration. Acta Orthop Scand 1988;59:464– 6. 6. Nadroo AM, Shringari S, Garg M, al-Sowailem AM. Prostaglandin induced cortical hyperostosis in neonates with cyanotic heart disease. J Perinat Med References 2000;28:447–52.

1. Donahoo JS, Roland JM, Kan J, Gardner TJ, Kidd BS. Prostaglandin E1 as an 7. Kalloghlian AK, Frayha HH, deMoor MM. Cortical hyperostosis simulating adjunct to emergency cardiac operation in neonates. J Thorac Cardiovasc osteomyelitis after short-term prostaglandin E1 infusion. Eur J Pediatr Surg 1981;81:227–31. 1996;155:173–4. 2. Babyn P, Peled N, Manson D, Dagan O, Silver MM, Koren G. Radiologic 8. Woo K, Emery J, Peabody J. Cortical hyperostosis: a complication of features of gastric outlet obstruction in infants after long-term prolonged prostaglandin infusion in infants awaiting cardiac transplanta- prostaglandin administration. Pediatr Radiol 1995;25:41–4. tion. Pediatrics 1994;93:417–20. 3. Jureidini S, Chase NA, Alpert BS, Vanderzalm T, Sheneﬂet RE. Soft tissue 9. Host A, Halken S, Andersen Jr PE. Reversibility of cortical hyperostosis swelling in two neonates during prostaglandin E1 therapy. Pediatr Cardiol following long-term prostaglandin E1 therapy in infants with ductus- 1986;7:157–60. dependent congenital heart disease. Pediatr Radiol 1988;18:149–53. 4. Kaufman MB, El-Chaar GM. Bone and tissue changes following 10. Silverman FN, Kuhn JP. Caffey’s Pediatric X-ray Diagnosis: An Intergrated prostaglandin therapy in neonates. Ann Pharmacother 1996;30:269–77. Imaging Approach. St. Louis: CV Mosby; 1993. p. 1855–67.

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