Pediatric Dermatology Vol. 32 No. 1 e18–e22, 2015
Large Multifocal Cutaneous Hemangioma Along Lines of Blaschko with Cardiac Failure Treated with Propranolol Deepshikha Khanna, M.D.,* Payal Chakravarty, D.V.D.,* Pooja Arora, M.D.,† Rahul Jain, M.D.,‡ and Medha Mittal, M.D.‡ *Department of Dermatology, Chacha Nehru Bal Chikitsalaya, Delhi, India, †Department of Dermatology, Hamdard Institute of Medical Sciences and Research, Delhi, India, ‡Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, Delhi, India
Abstract: Hemangiomas are classified as focal or segmental according to the morphology and distribution of lesions. Congestive cardiac failure is frequently encountered in diffuse hepatic hemangiomas due to high-volume shunting and rarely in hemangiomas confined to the skin. We report here the case of a large multifocal hemangioma along the lines of Blaschko with high-output cardiac failure, with improvement in cutaneous and hemodynamic symptoms after propranolol therapy. Presentation along the lines of Blaschko raises the possibility of hemangiomas arising as a result of mosaicism.
Hemangioma is the most common benign tumor in infancy and can occasionally lead to complications such as ulceration or interference with vital function or may rarely be associated with visceral hemangiomas or internal organ defects. Hemangiomas may be classified as focal, which are tumorlike lesions confined to small areas of the body, and segmental, which are plaque-like and are distributed over a specific cutaneous area. We report here the case of a large multifocal hemangioma along the lines of Blaschko with high-output cardiac failure with improvement in cutaneous and hemodynamic symptoms after propranolol therapy.
CASE REPORT A 3-month-old girl was brought to the pediatric dermatology department with complaints of a large red mass over the right arm, shoulder, hand, and left thigh. Soon after birth the parents noticed a small papule on the left thigh and subsequently one on the left arm that grew rapidly. On examination there was a large vascular plaque extending from the sternum to the right shoulder and covering the entire arm. The hemangioma was mixed and the deep component was felt clearly over the right axilla. Similar vascular plaques were also present over the dorsum of the right thumb extending to the palm of the right hand and
Address correspondence to Deepshikha Khanna, M.D., C-101 Narwana Apartments, 89 IP Extension, Patparganj, Delhi 110092, India, or e-mail: [email protected]. DOI: 10.1111/pde.12476
e18
© 2014 Wiley Periodicals, Inc.
Khanna et al: Mulifocal Blaschkoid Hemangioma
over the left thigh and left buttock. At all sites the hemangiomas were distributed along the lines of Blaschko and did not cross the midline (Fig. 1). Systemic examination revealed a heart rate of 166 beats/min. The apex beat was felt in the fifth intercostal space outside the midclavicular line and an external systolic murmur was heard at the lower midsternal border. The liver was palpable 3 cm below the costal margin; the spleen was not palpable. A radiograph of the chest showed cardiomegaly. Echocardiography did not reveal any abnormality. The hematologic profile was normal except for anemia (hemoglobin 8.3 mg/dL). Thyroid function tests were within normal limits. Ultrasonography of the abdomen did not reveal any visceral hemangioma. A diagnosis of large multifocal infantile hemangioma along the lines of Blaschko with high output cardiac failure was made. A possible diagnosis of PHACES syndrome was considered because of the presence of hemangiomas on the upper trunk, but we did not search extensively for any associated systemic finding since the patient had no symptoms or signs suggesting
e19
cerebral, cardiac, or ocular dysplasia, and the hemodynamic findings were secondary to the blood flow through the large cutaneous hemangioma. The infant was started on oral prednisolone at a dose of 3 mg/kg/ day accompanied by oral furosemide 5 mg and spironolactone 12.5 mg twice daily. Subsequently the mother reported increased appetite and frequent crying settled only by intake of milk. The infant gained weight rapidly and became cushingoid within the next few weeks, but no significant improvement was noted in the color, consistency, or extent of the hemangioma. A small area on the lower limb developed superficial ulceration during this time. Because of the poor response, oral steroids were tapered by 0.5 mg/kg of body weight every week and the patient was started on propranolol at a dose of 0.5 mg/kg/day gradually doubled every 3 days to reach the full dose of 2 mg/kg/day in 1 week’s time. Soon the deep bright red erythema and turgidity in the hemangioma began to settle, accompanied by marked improvement in tachycardia and high-output cardiac failure; spironolactone and furosemide were gradually tapered and stopped within 4 weeks. Over the next few months, the bulk of the lesion flattened and clear areas were also seen within. The patient was monitored for hypoglycemia, hypotension, bronchial spasm, and bradycardia initially daily during escalation of the propranolol dose and then weekly for 1 month followed by once in a fortnight. The patient tolerated the medication well, and no acute adverse event necessitating dose reduction was noted during the treatment period. Propranolol was continued for more than 18 months and led to complete clearance of the hemangioma over the lower limb and hand and almost 95% clearance of the chest and arm hemangioma (Figs. 2 and 3). The superficial and deep components of the hemangioma responded favorably, although the response was slower in the chest and arm lesion and the associated deep component. DISCUSSION
Figure 1. Complete body view of the infant showing the distribution of the multifocal hemangioma along the lines of Blashcko over the right sternum, shoulder, upper arm, thumb, palm, left thigh, buttock, and leg.
The case presented here has an atypical presentation of infantile hemangioma along the lines of Blaschko that has, to the best of our knowledge, not been reported earlier. Our patient presented with large hemangiomas along the broad lines of Blaschko, similar to the pigmentary changes in McAlbright syndrome (1). The individual lesions with large area involvement in our patient initially seemed like segmental hemangiomas corresponding to different embryologic segments, but unlike the plaque-type
e20 Pediatric Dermatology Vol. 32 No. 1 January/February 2015
A
B
C
D
Figure 2. Serial photographs showing resolution of the hemangioma over the chest and right upper limb after propranolol therapy: (A) baseline (arrow—deep underlying component in the hemangioma), (B) 3 months—decreased erythema and turgor and some flattening, (C) 9 months—marked flattening with clear areas, and (D) 18 months—more than 90% clearance with residual erythema and deep component.
A
B
C
D
Figure 3. Serial photographs showing resolution of the hemangioma over the left lower limb after propranolol therapy: (A) baseline, (B) 3 months—decreased erythema and turgor with flattening and clear areas, (C) 9 months—marked flattening with large areas of clearing, and (D) 18 months—complete clearance.
lesions in the segmental variety, the hemangioma in our patient was multifocal and lobular, with a definite deep component, especially in the upper limb, and individual lesions did not cross the midline (2). The anatomic segments classically used to describe seg-
mental hemangiomas do not correspond to the dermatomes or lines of Blaschko, which are mosaic expressions of embryonic neuroectodermal migration (2,3). The concept that skin disorders following Blaschko’s lines are manifestations of genetic mosaicism is
Khanna et al: Mulifocal Blaschkoid Hemangioma
widely accepted. Genetic mosaicism has been shown to be responsible for almost 15 skin diseases with monogenic etiology. Different cell clones can arise in different ways, including lyonization in X-linked disorders, postzygotic somatic mutations in sporadic conditions, and gametic half-chromatid mutations. The lines of Blaschko reflect the dorsoventral migratory pathways of two genetically different embryonic cell population pathways. It is believed that the earlier the mosaicism originates in the course of development, the more extensive the skin changes are (4). Mutations outside the germline, known as somatic mutations, are seen more frequently and result in circumscribed malformations, tumors, and nevi (5). Regarding the genetics of hemangioma, Blei et al (6) reported six family groups with the occurrence of infantile hemangioma and proposed autosomal dominant transmission with moderate to high penetrance. They subsequently tested the blood of individuals in five of these six families and demonstrated a loss of heterozygosity in the gene locus 5q in three of these groups. The authors mapped the three candidate genes as fibroblast growth factor receptor 4, plateletderived growth factor receptor b, and fms-related tyrosine kinase 4. They further proposed that genes and gene products associated with familial hemangiomas may be involved somatically in the more common sporadic cases (7). Subsequently Berg et al (8) demonstrated a loss of heterozygosity for markers on chromosome 5q in a proportion of sporadic hemangiomas that they studied. Different authors have proposed a polygenic etiology with different genes such as KDR (vascular endothelial growth factor receptor 2 [VEGFR2]) at 4q12, FLT4 (VEGFR-3) at 5q35.3, and ANTXR1 (TEM8) at 2p13.1 being involved in causing susceptibility to infantile hemangioma (9,10). The mutation may occur late during embryogenesis, and so the lesions remain confined to focal areas in the majority of cases. We hypothesize that our patient had a somatic mutation earlier in embryogenesis so that the affected cells presented with a more widespread Blaschkoid distribution. It was initially proposed that disorders following Blaschko’s lines were due to mutations in genes expressed in epidermal cells (keratinocytes and melanocytes) that are derived from the neuroectoderm (11), but there are other conditions such as focal dermal hypoplasia (Goltz syndrome) and atrophoderma of Moulin that present along the lines of Blaschko, with the main histopathologic abnormalities found in the dermis (12). A wide range of acquired conditions have been reported to present along the
e21
lines of Blaschko (13). Among these is linear morphea, which is believed to be a disease of the dermal fibroblasts (14). Whether mosaicism in other tissues such as endothelium and dermal fibroblasts can also manifest along the lines of Blaschko needs to be explored. Waner et al (3) demonstrated a concentration of focal, nonsegmental hemangiomas in the central part of the face, which contains the highest density of fusion lines between different mesenchymal growth centers and between different mesenchymal growth centres and the facial ectoderm. They have postulated that quantitative or qualitative abnormalities in the neural crest–derived tissues probably predispose local areas to hemangioma formation. They have further proposed that hemangiomas may occur in regions where neural crest–associated angioblast migration and proliferation is increased, such as sites of neuromesenchymal fusion (3). Congestive cardiac failure is usually seen in the setting of extensive hepatic hemangiomas due to highvolume shunting and only occasionally with large cutaneous hemangiomas (15). The large volume of cutaneous hemangioma in our patient probably resulted in a similar effect even in the absence of hepatic lesions. Successful treatment of hepatic hemangiomas with cardiac failure has been reported with propranolol (16). Mazereeuw-Hautier et al (17) used it successfully in three infants with neonatal hemangiomatosis and diffuse hepatic hemangiomas with congestive cardiac failure who had earlier failed steroid therapy. A decrease in the size of the hemangioma and subsequently reduced blood flow through the lesion may lead to cardiac improvement. A reduction in heart rate due to b-blockers and the subsequent decreased load on the heart may also be helpful. The atypical presentation in our patient leaves many questions unanswered. First, how does a condition with a possibly polygenic etiology present as mosaicism, or is infantile hemangioma actually a manifestation of mutation in an as yet undiscovered single gene? Second, if somatic mosaicism is the cause, why does infantile hemangioma occur more frequently in girls? Most cases of segmental hemangiomas also occur in girls, and even our atypical findings were seen in a girl. Lastly, distribution of a hamartoma of endothelial cells derived from the mesoderm along the lines of differentiation of neuroectoderm structures needs to be explained. Whether other tissue components are central to the pathogenesis and permit aberrant growth of blood vessels to produce a hemangioma remains to be seen. Further research and studies delineating the site of occurrence of hemangiomas may
e22 Pediatric Dermatology Vol. 32 No. 1 January/February 2015
provide vital information regarding their pathogenetic mechanisms and possible genetic origin. REFERENCES 1. Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet 1986;29:321– 324. 2. Haggstrom AN, Lammer EJ, Schneider RA et al. Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Paediatrics 2006;117:698–703. 3. Waner M, North PE, Scherer KA et al. The nonrandom distribution of facial hemangiomas. Arch Dermatol 2003;139:869–875. 4. Savin JA. Cutaneous mosaicism. QJM 1996;89:489– 491. 5. Itin P, Burger BJ. Mosaic manifestations of monogenic skin diseases. J Dtsch Dermatol Ges 2009;7:744–748. 6. Blei F, Walter J, Orlow SJ et al. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 1998;134:718– 722. 7. Walter JW, Blei F, Anderson JL et al. Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet 1999;82:77–83. 8. Berg JN, Walter JW, Thisanagayam U et al. Evidence for loss of heterozygosity of 5q in sporadic haemangiomas: are somatic mutations involved in haemangioma formation? J Clin Pathol 2001;54:249–252.
9. Walter JW, North PE, Waner M et al. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosom Cancer 2002;33:295–303. 10. Jinnin M, Medici D, Park L et al. Suppressed NFATdependent VEGFR1 expression and constitutive VEGFR2 signalling in infantile hemangioma. Nat Med 2008;14:1236–1246. 11. Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin of Blaschko lines. Am J Med Genet 1999;85:330–333. 12. Paller AS. Piecing together the puzzle of cutaneous mosaicism. J Clin Invest 2004;114:1407–1409. 13. Goldberg I, Sprecher E. Patterned disorders in dermatology. Clin Dermatol 2011;29:498–503. 14. Weibel L, Harper JI. Linear morphoea follows Blaschko’s lines. Br J Dermatol 2008;159:175–181. 15. Bruckner AL, Frieden IJ. Infantile hemangiomas and other vascular tumours. In: Harper J, Oranje A, Prose N, eds. Textbook of pediatric dermatology, 3rd ed., vol. 2. Oxford: Wiley-Blackwell, 2011: 113.1–113.28. 16. Bosemani T, Puttgen KB, Huisman TA et al. Multifocal infantile hepatic hemangiomas—imaging strategy and response to treatment after propranolol and steroids including review of the literature. Eur J Pediatr 2012;171:1023–1028. 17. Mazereeuw-Hautier J, Hoeger PH, Benlahrech S et al. Efficacy of propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. J Pediatr 2010;157:340–342.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Large Multifocal Cutaneous Hemangioma Along Lines of Blaschko with Cardiac Failure Treated with Propranolol Deepshikha Khanna, M.D.,* Payal Chakravarty, D.V.D.,* Pooja Arora, M.D.,† Rahul Jain, M.D.,‡ and Medha Mittal, M.D.‡ *Department of Dermatology, Chacha Nehru Bal Chikitsalaya, Delhi, India, †Department of Dermatology, Hamdard Institute of Medical Sciences and Research, Delhi, India, ‡Department of Pediatrics, Chacha Nehru Bal Chikitsalaya, Delhi, India
Abstract: Hemangiomas are classified as focal or segmental according to the morphology and distribution of lesions. Congestive cardiac failure is frequently encountered in diffuse hepatic hemangiomas due to high-volume shunting and rarely in hemangiomas confined to the skin. We report here the case of a large multifocal hemangioma along the lines of Blaschko with high-output cardiac failure, with improvement in cutaneous and hemodynamic symptoms after propranolol therapy. Presentation along the lines of Blaschko raises the possibility of hemangiomas arising as a result of mosaicism.
Hemangioma is the most common benign tumor in infancy and can occasionally lead to complications such as ulceration or interference with vital function or may rarely be associated with visceral hemangiomas or internal organ defects. Hemangiomas may be classified as focal, which are tumorlike lesions confined to small areas of the body, and segmental, which are plaque-like and are distributed over a specific cutaneous area. We report here the case of a large multifocal hemangioma along the lines of Blaschko with high-output cardiac failure with improvement in cutaneous and hemodynamic symptoms after propranolol therapy.
CASE REPORT A 3-month-old girl was brought to the pediatric dermatology department with complaints of a large red mass over the right arm, shoulder, hand, and left thigh. Soon after birth the parents noticed a small papule on the left thigh and subsequently one on the left arm that grew rapidly. On examination there was a large vascular plaque extending from the sternum to the right shoulder and covering the entire arm. The hemangioma was mixed and the deep component was felt clearly over the right axilla. Similar vascular plaques were also present over the dorsum of the right thumb extending to the palm of the right hand and
Address correspondence to Deepshikha Khanna, M.D., C-101 Narwana Apartments, 89 IP Extension, Patparganj, Delhi 110092, India, or e-mail: [email protected]. DOI: 10.1111/pde.12476
e18
© 2014 Wiley Periodicals, Inc.
Khanna et al: Mulifocal Blaschkoid Hemangioma
over the left thigh and left buttock. At all sites the hemangiomas were distributed along the lines of Blaschko and did not cross the midline (Fig. 1). Systemic examination revealed a heart rate of 166 beats/min. The apex beat was felt in the fifth intercostal space outside the midclavicular line and an external systolic murmur was heard at the lower midsternal border. The liver was palpable 3 cm below the costal margin; the spleen was not palpable. A radiograph of the chest showed cardiomegaly. Echocardiography did not reveal any abnormality. The hematologic profile was normal except for anemia (hemoglobin 8.3 mg/dL). Thyroid function tests were within normal limits. Ultrasonography of the abdomen did not reveal any visceral hemangioma. A diagnosis of large multifocal infantile hemangioma along the lines of Blaschko with high output cardiac failure was made. A possible diagnosis of PHACES syndrome was considered because of the presence of hemangiomas on the upper trunk, but we did not search extensively for any associated systemic finding since the patient had no symptoms or signs suggesting
e19
cerebral, cardiac, or ocular dysplasia, and the hemodynamic findings were secondary to the blood flow through the large cutaneous hemangioma. The infant was started on oral prednisolone at a dose of 3 mg/kg/ day accompanied by oral furosemide 5 mg and spironolactone 12.5 mg twice daily. Subsequently the mother reported increased appetite and frequent crying settled only by intake of milk. The infant gained weight rapidly and became cushingoid within the next few weeks, but no significant improvement was noted in the color, consistency, or extent of the hemangioma. A small area on the lower limb developed superficial ulceration during this time. Because of the poor response, oral steroids were tapered by 0.5 mg/kg of body weight every week and the patient was started on propranolol at a dose of 0.5 mg/kg/day gradually doubled every 3 days to reach the full dose of 2 mg/kg/day in 1 week’s time. Soon the deep bright red erythema and turgidity in the hemangioma began to settle, accompanied by marked improvement in tachycardia and high-output cardiac failure; spironolactone and furosemide were gradually tapered and stopped within 4 weeks. Over the next few months, the bulk of the lesion flattened and clear areas were also seen within. The patient was monitored for hypoglycemia, hypotension, bronchial spasm, and bradycardia initially daily during escalation of the propranolol dose and then weekly for 1 month followed by once in a fortnight. The patient tolerated the medication well, and no acute adverse event necessitating dose reduction was noted during the treatment period. Propranolol was continued for more than 18 months and led to complete clearance of the hemangioma over the lower limb and hand and almost 95% clearance of the chest and arm hemangioma (Figs. 2 and 3). The superficial and deep components of the hemangioma responded favorably, although the response was slower in the chest and arm lesion and the associated deep component. DISCUSSION
Figure 1. Complete body view of the infant showing the distribution of the multifocal hemangioma along the lines of Blashcko over the right sternum, shoulder, upper arm, thumb, palm, left thigh, buttock, and leg.
The case presented here has an atypical presentation of infantile hemangioma along the lines of Blaschko that has, to the best of our knowledge, not been reported earlier. Our patient presented with large hemangiomas along the broad lines of Blaschko, similar to the pigmentary changes in McAlbright syndrome (1). The individual lesions with large area involvement in our patient initially seemed like segmental hemangiomas corresponding to different embryologic segments, but unlike the plaque-type
e20 Pediatric Dermatology Vol. 32 No. 1 January/February 2015
A
B
C
D
Figure 2. Serial photographs showing resolution of the hemangioma over the chest and right upper limb after propranolol therapy: (A) baseline (arrow—deep underlying component in the hemangioma), (B) 3 months—decreased erythema and turgor and some flattening, (C) 9 months—marked flattening with clear areas, and (D) 18 months—more than 90% clearance with residual erythema and deep component.
A
B
C
D
Figure 3. Serial photographs showing resolution of the hemangioma over the left lower limb after propranolol therapy: (A) baseline, (B) 3 months—decreased erythema and turgor with flattening and clear areas, (C) 9 months—marked flattening with large areas of clearing, and (D) 18 months—complete clearance.
lesions in the segmental variety, the hemangioma in our patient was multifocal and lobular, with a definite deep component, especially in the upper limb, and individual lesions did not cross the midline (2). The anatomic segments classically used to describe seg-
mental hemangiomas do not correspond to the dermatomes or lines of Blaschko, which are mosaic expressions of embryonic neuroectodermal migration (2,3). The concept that skin disorders following Blaschko’s lines are manifestations of genetic mosaicism is
Khanna et al: Mulifocal Blaschkoid Hemangioma
widely accepted. Genetic mosaicism has been shown to be responsible for almost 15 skin diseases with monogenic etiology. Different cell clones can arise in different ways, including lyonization in X-linked disorders, postzygotic somatic mutations in sporadic conditions, and gametic half-chromatid mutations. The lines of Blaschko reflect the dorsoventral migratory pathways of two genetically different embryonic cell population pathways. It is believed that the earlier the mosaicism originates in the course of development, the more extensive the skin changes are (4). Mutations outside the germline, known as somatic mutations, are seen more frequently and result in circumscribed malformations, tumors, and nevi (5). Regarding the genetics of hemangioma, Blei et al (6) reported six family groups with the occurrence of infantile hemangioma and proposed autosomal dominant transmission with moderate to high penetrance. They subsequently tested the blood of individuals in five of these six families and demonstrated a loss of heterozygosity in the gene locus 5q in three of these groups. The authors mapped the three candidate genes as fibroblast growth factor receptor 4, plateletderived growth factor receptor b, and fms-related tyrosine kinase 4. They further proposed that genes and gene products associated with familial hemangiomas may be involved somatically in the more common sporadic cases (7). Subsequently Berg et al (8) demonstrated a loss of heterozygosity for markers on chromosome 5q in a proportion of sporadic hemangiomas that they studied. Different authors have proposed a polygenic etiology with different genes such as KDR (vascular endothelial growth factor receptor 2 [VEGFR2]) at 4q12, FLT4 (VEGFR-3) at 5q35.3, and ANTXR1 (TEM8) at 2p13.1 being involved in causing susceptibility to infantile hemangioma (9,10). The mutation may occur late during embryogenesis, and so the lesions remain confined to focal areas in the majority of cases. We hypothesize that our patient had a somatic mutation earlier in embryogenesis so that the affected cells presented with a more widespread Blaschkoid distribution. It was initially proposed that disorders following Blaschko’s lines were due to mutations in genes expressed in epidermal cells (keratinocytes and melanocytes) that are derived from the neuroectoderm (11), but there are other conditions such as focal dermal hypoplasia (Goltz syndrome) and atrophoderma of Moulin that present along the lines of Blaschko, with the main histopathologic abnormalities found in the dermis (12). A wide range of acquired conditions have been reported to present along the
e21
lines of Blaschko (13). Among these is linear morphea, which is believed to be a disease of the dermal fibroblasts (14). Whether mosaicism in other tissues such as endothelium and dermal fibroblasts can also manifest along the lines of Blaschko needs to be explored. Waner et al (3) demonstrated a concentration of focal, nonsegmental hemangiomas in the central part of the face, which contains the highest density of fusion lines between different mesenchymal growth centers and between different mesenchymal growth centres and the facial ectoderm. They have postulated that quantitative or qualitative abnormalities in the neural crest–derived tissues probably predispose local areas to hemangioma formation. They have further proposed that hemangiomas may occur in regions where neural crest–associated angioblast migration and proliferation is increased, such as sites of neuromesenchymal fusion (3). Congestive cardiac failure is usually seen in the setting of extensive hepatic hemangiomas due to highvolume shunting and only occasionally with large cutaneous hemangiomas (15). The large volume of cutaneous hemangioma in our patient probably resulted in a similar effect even in the absence of hepatic lesions. Successful treatment of hepatic hemangiomas with cardiac failure has been reported with propranolol (16). Mazereeuw-Hautier et al (17) used it successfully in three infants with neonatal hemangiomatosis and diffuse hepatic hemangiomas with congestive cardiac failure who had earlier failed steroid therapy. A decrease in the size of the hemangioma and subsequently reduced blood flow through the lesion may lead to cardiac improvement. A reduction in heart rate due to b-blockers and the subsequent decreased load on the heart may also be helpful. The atypical presentation in our patient leaves many questions unanswered. First, how does a condition with a possibly polygenic etiology present as mosaicism, or is infantile hemangioma actually a manifestation of mutation in an as yet undiscovered single gene? Second, if somatic mosaicism is the cause, why does infantile hemangioma occur more frequently in girls? Most cases of segmental hemangiomas also occur in girls, and even our atypical findings were seen in a girl. Lastly, distribution of a hamartoma of endothelial cells derived from the mesoderm along the lines of differentiation of neuroectoderm structures needs to be explained. Whether other tissue components are central to the pathogenesis and permit aberrant growth of blood vessels to produce a hemangioma remains to be seen. Further research and studies delineating the site of occurrence of hemangiomas may
e22 Pediatric Dermatology Vol. 32 No. 1 January/February 2015
provide vital information regarding their pathogenetic mechanisms and possible genetic origin. REFERENCES 1. Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet 1986;29:321– 324. 2. Haggstrom AN, Lammer EJ, Schneider RA et al. Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Paediatrics 2006;117:698–703. 3. Waner M, North PE, Scherer KA et al. The nonrandom distribution of facial hemangiomas. Arch Dermatol 2003;139:869–875. 4. Savin JA. Cutaneous mosaicism. QJM 1996;89:489– 491. 5. Itin P, Burger BJ. Mosaic manifestations of monogenic skin diseases. J Dtsch Dermatol Ges 2009;7:744–748. 6. Blei F, Walter J, Orlow SJ et al. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 1998;134:718– 722. 7. Walter JW, Blei F, Anderson JL et al. Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet 1999;82:77–83. 8. Berg JN, Walter JW, Thisanagayam U et al. Evidence for loss of heterozygosity of 5q in sporadic haemangiomas: are somatic mutations involved in haemangioma formation? J Clin Pathol 2001;54:249–252.
9. Walter JW, North PE, Waner M et al. Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosom Cancer 2002;33:295–303. 10. Jinnin M, Medici D, Park L et al. Suppressed NFATdependent VEGFR1 expression and constitutive VEGFR2 signalling in infantile hemangioma. Nat Med 2008;14:1236–1246. 11. Moss C. Cytogenetic and molecular evidence for cutaneous mosaicism: the ectodermal origin of Blaschko lines. Am J Med Genet 1999;85:330–333. 12. Paller AS. Piecing together the puzzle of cutaneous mosaicism. J Clin Invest 2004;114:1407–1409. 13. Goldberg I, Sprecher E. Patterned disorders in dermatology. Clin Dermatol 2011;29:498–503. 14. Weibel L, Harper JI. Linear morphoea follows Blaschko’s lines. Br J Dermatol 2008;159:175–181. 15. Bruckner AL, Frieden IJ. Infantile hemangiomas and other vascular tumours. In: Harper J, Oranje A, Prose N, eds. Textbook of pediatric dermatology, 3rd ed., vol. 2. Oxford: Wiley-Blackwell, 2011: 113.1–113.28. 16. Bosemani T, Puttgen KB, Huisman TA et al. Multifocal infantile hepatic hemangiomas—imaging strategy and response to treatment after propranolol and steroids including review of the literature. Eur J Pediatr 2012;171:1023–1028. 17. Mazereeuw-Hautier J, Hoeger PH, Benlahrech S et al. Efficacy of propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. J Pediatr 2010;157:340–342.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
