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Sirolimus for diffuse intestinal infantile hemangioma with PHACE features: systematic review

Abstract

Background

We report a 3-month-old female with cardiovascular anomalies and diffuse intestinal infantile hemangioma (IIH) of the small bowel suggesting possible diagnosis of PHACE syndrome (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies). The GI symptoms persisted under treatment with propranolol, whereas the addition of sirolimus led to regression of the IIH.

Methods

A systematic review was conducted using PubMed, EMBASE, and Ovid MEDLINE databases between 1982 and 2021.

Results

A total of 4933 articles were identified; 24 articles met inclusion criteria with 46 IIH cases. The most common GI presentations were unspecified GI bleed (40%) and anemia (38%). The most common treatments were corticosteroids (63%), surgical resection (32.6%), and propranolol (28%). Available outcomes were primarily bleeding arrest (84%). Nine cases (19.5%) were diagnosed with definite PHACE, 5 (11%) with possible PHACE, and 32 (69.5%) no PHACE. Our case presented with symptoms most consistent with those of possible PHACE and definite PHACE. No cases in this review underwent treatment with sirolimus.

Conclusions

This is the first reported case of successful treatment of IIH with sirolimus. Our case, along with other patients who present with IIH and PHACE features, suggests consideration of IIH as a diagnostic criterion for PHACE syndrome.

Impact

  • This is the first reported case in which sirolimus showed regression of an intestinal infantile hemangioma.

  • This study serves to demonstrate the presentation, treatment, outcomes of intestinal infantile hemangioma, and correlation with PHACE.

  • The potential correlation between intestinal infantile hemangioma and PHACE deserves more study in consideration of intestinal infantile hemangioma as a diagnostic criterion of PHACE.

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Fig. 1: Diagnostic MRI of our 3-month-old patient's intestinal hemangioma prior to treatment.
Fig. 2: PRISMA search strategy.

Data availability

The dataset generated and analyzed in this study are included in Tables 2 and 3 of this published article with appropriate citations to the original articles.

References

  1. Bandera, A. I. R., Sebaratnam, D. F., Wargon, O. & Wong, L. C. F. Infantile hemangioma. Part 1: Epidemiology, pathogenesis, clinical presentation and assessment. J. Am. Acad. Dermatol. 85, 1379–1392 (2021).

    Article  Google Scholar 

  2. Anderson, K. et al. Increasing incidence of infantile hemangiomas (IH) over the past 35 years: correlation with decreasing gestational age at birth and birth weight. J. Am. Acad. Dermatol. 74, 120–126 (2016).

    Article  PubMed  Google Scholar 

  3. Metry, D. W., Hawrot, A., Altman, C. & Frieden, I. J. Association of solitary, segmental hemangiomas of the skin with visceral hemangiomatosis. Arch. Dermatol. 140, 591–596 (2004).

    Article  PubMed  Google Scholar 

  4. Frieden, I. J., Reese, V. & Cohen, D. PHACE syndrome: the association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch. Dermatol. 132, 307–311 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Metry, D. et al. Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics 124, 1447–1456 (2009).

    Article  PubMed  Google Scholar 

  6. Garzon, M. C. et al. PHACE syndrome: consensus-derived diagnosis and care recommendations. J. Pediatr. 178, 24–33 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Moher, D. et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 4, 1–9 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ouzzani, M., Hammady, H., Fedorowicz, Z. & Elmagarmid, A. Rayyan—a web and mobile app for systematic reviews. Syst. Rev. 5, 1–10 (2016).

    Article  Google Scholar 

  9. Maruani, A. et al. Sirolimus (Rapamycin) for slow-flow malformations in children: the observational-phase randomized clinical PERFORMUS trial. JAMA Dermatol. 157, 1289–1298 (2021).

    Article  PubMed  Google Scholar 

  10. Dávila‐Osorio, V. L., Iznardo, H., Roé, E., Puig, L. & Baselga, E. Propranolol‐resistant infantile hemangioma successfully treated with sirolimus. Pediatr. Dermatol. 37, 684–686 (2020).

    Article  PubMed  Google Scholar 

  11. Greenberger, S. et al. Rapamycin suppresses self-renewal and vasculogenic potential of stem cells isolated from infantile hemangioma. J. Investig. Dermatol. 131, 2467–2476 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Hutchins, K. K., Ross, R. D., Kobayashi, D., Martin, A. & Rajpurkar, M. Treatment of refractory infantile hemangiomas and pulmonary hypertension with sirolimus in a pediatric patient. J. Pediatr. Hematol. Oncol. 39, e391–e393 (2017).

    Article  PubMed  Google Scholar 

  13. Sebaratnam, D. F., Rodríguez Bandera, A. L., Wong, L. F. & Wargon, O. Infantile hemangioma. Part 2: Management. J. Am. Acad. Dermatol. 85, 1395–1404 (2021).

    Article  PubMed  Google Scholar 

  14. Enjolras, O., Riche, M. C., Merland, J. J. & Escande, J. P. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics 85, 491–498 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Enjolras, O. & Gelbert, F. Superficial hemangiomas: associations and management. Pediatr. Dermatol. 14, 173–179 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Ezekowitz, R. A., Mulliken, J. B. & Folkman, J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N. Engl. J. Med. 326, 1456–1463 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Ge, Z. Z. et al. Clinical application of wireless capsule endoscopy in pediatric patients for suspected small bowel diseases. Eur. J. Pediatr. 166, 825–829 (2007).

    Article  PubMed  Google Scholar 

  18. Metry, D. W. et al. A comparison of disease severity among affected male versus female patients with PHACE syndrome. J. Am. Acad. Dermatol. 58, 81–87 (2008).

    Article  PubMed  Google Scholar 

  19. Metry, D. W. et al. A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am. J. Med. Genet. A 140, 975–986 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Papparella, A. et al. Laparoscopic approach to Meckel’s diverticulum. World J. Gastroenterol. 20, 8173–8178 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Al-Musalhi, B. & Al-Balushi, Z. PHACES syndrome with intestinal hemangioma causing recurrent intussusceptions: a case report and literature review of associated intestinal hemangioma. Oman Med. J. 35, e204 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bank, E. R., Hernandez, R. J. & Byrne, W. J. Gastrointestinal hemangiomatosis in children: demonstration with CT. Radiology 165, 657–658 (1987).

    Article  CAS  PubMed  Google Scholar 

  23. Chattopadhyay, A., Kumar, V., Maruliah, M. & Rao, P. L. N. G. Duodenojejunal obstruction by a hemangioma. Pediatr. Surg. Int. 18, 501–502 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Coleman, J., Phillips, R. & Steiner, R. Small bowel hemangioma in a 2-year-old female with recurrent anemia. Ochsner J. 18, 428–432 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Destro, F., Maestri, L., Vella, C., Baraldini, V. & Riccipetitoni, G. Infantile hemangioma as cause of neonatal gastrointestinal bleeding. J. Pediatr. Surg. Case Rep. 31, 71–76 (2018).

    Article  Google Scholar 

  26. Drolet, B. A. et al. Gastrointestinal bleeding in infantile hemangioma: a complication of segmental, rather than multifocal, infantile hemangiomas. J. Pediatr. 160, 1021–1026 (2012).

    Article  PubMed  Google Scholar 

  27. Ghandour, R. M. et al. Prevalence and treatment of depression, anxiety, and conduct problems in US children. J. Pediatr. 206, 256–267 (2019).

    Article  PubMed  Google Scholar 

  28. Fishman, S. J., Burrows, P. E., Leichtner, A. M. & Mulliken, J. B. Gastrointestinal manifestations of vascular anomalies in childhood: varied etiologies require multiple therapeutic modalities. J. Pediatr. Surg. 33, 1163–1167 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Fu, J. X., Zou, Y. N., Han, Z. H., Yu, H. & Wang, X. J. Small bowel racemose hemangioma complicated with obstruction and chronic anemia: a case report and review of literature. World J. Gastroenterol. 26, 1674 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hayek, S., Amin, M. B. & Trupiano, J. K. Diffuse neonatal hemangiomatosis with gastrointestinal involvement in a 4-month-old infant [Abstract]. Pediatr. Dev. Pathol. 13, 132–168 (2010).

    Google Scholar 

  31. Jarvi, K. et al. Successful treatment of extensive infantile hemangiomatosis of the small bowel in a 3-month-old with thalidomide and somatostatin analog. J. Pediatr. Gastroenterol. Nutr. 46, 593–597 (2008).

    Article  PubMed  Google Scholar 

  32. Kella, N., Rathi, P. K., Rathi, S. & Qureshi, M. A. Small bowel haemangioma. A rare cause of intestinal obstruction in infant. Pak. J. Med. Sci. 24, 629–631 (2008).

    Google Scholar 

  33. Krick, J., Riehle, K., Chapman, T. & Chabra, S. Recurrent bloody stools associated with visceral infantile haemangioma in a preterm twin girl. BMJ Case Rep. 11, bcr-2018 (2018).

    Article  Google Scholar 

  34. Madan, V., Lloyd, I. C., Wakefield, R. M., Kaleem, M. & Judge, M. R. PHACE syndrome. Clin. Exp. Dermatol. 34, 651–652 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Metry, D. et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: collective experience in 32 infants. Pediatr. Dermatol. 30, 71–89 (2013).

    Article  PubMed  Google Scholar 

  36. Morris, G. A., Stratchko, L. & Sabri, M. Intestinal hemangioma presenting as recurrent hematochezia in a 6-week-old male. J. Pediatr. Surg. Case Rep. 3, 280–282 (2015).

    Article  Google Scholar 

  37. September 10-14 Munich, Germany CIRSE 2011. Cardiovasc Intervent Radiol. 34 331 https://doi.org/10.1007/s00270-011-0216-9 (2011).

  38. Patel, S. D., Cohen, B. A. & Kan, J. S. Extensive facial hemangioma associated with cardiac and abdominal anomalies. J. Am. Acad. Dermatol. 36, 636–638 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Peterman, C. M., Gibson, R. S., Lillis, A. P., Fishman, S. J. & Liang, M. G. Clinical and radiological characteristics of patients with retroperitoneal infantile hemangiomas. Pediatr. Dermatol. 36, 823–829 (2019).

    Article  PubMed  Google Scholar 

  40. Rao, A. B., Pence, J. & Mirkin, D. L. Diffuse infantile hemangiomatosis of the ileum presenting with multiple perforations: a case report and review of the literature. J. Pediatr. Surg. 45, 1890–1892 (2010).

    Article  PubMed  Google Scholar 

  41. Scafidi, D. E., McLeary, M. S. & Young, L. W. Diffuse neonatal gastrointestinal hemangiomatosis: CT findings. Pediatr. Radiol. 28, 512–514 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Shukri, N., Amara, R., Malik, S., Taher, H. & Kilany, M. Neonatal intestinal perforation-a rare complication of small bowel hemangioma. Eur. J. Pediatr. Surg. Rep. 1, 30–31 (2013).

    Article  Google Scholar 

  43. Soukoulis, I. W. et al. Gastrointestinal infantile hemangioma: presentation and management. J. Pediatr. Gastroenterol. Nutr. 61, 415–420 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Stillman, A. E., Hansen, R. C., Hallinan, V. & Strobel, C. Diffuse neonatal hemangiomatosis with severe gastrointestinal involvement. Favorable response to steroid therapy. Clin. Pediatr. 22, 589–591 (1983).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge Tali Mualem, MD in management of this patient.

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Correspondence to Elana P. Kleinman.

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Kleinman, E.P., Blei, F., Adams, D. et al. Sirolimus for diffuse intestinal infantile hemangioma with PHACE features: systematic review. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02325-z

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