Derm2014:
Diffuse capillary malformation with overgrowth (DCMO) is a subset of [[capillary malformations]] (CM) associated with [[hypertrophy]], i.e. increased size of body structures. CM can be considered an umbrella term for various [[vascular anomalies]] caused by increased diameter or number of capillary blood vessels. It is commonly referred to as “port-wine stain”, and is thought to affect approximately 0.5% of the population. <ref name=" ref 1"> Colletti G, Valassina D, Bertossi D, et al. Contemporary management of vascular malformations. J Oral Maxillofac Surg. Mar 2014; 72: 510-28</ref> Typically capillaries in the papillary dermis are involved, and this gives rise to pink or violaceous colored lesions. <ref name="ref 2"> Happle R. What is a capillary malformation? J Am Acad Dermatol. Dec 2008; 59: 1077-9.</ref> Majority of DCMO lesions are diffuse, reticulated pale-colored stains. <ref name="ref 3"> Lee MS, Liang MG, Mulliken JB. Diffuse capillary malformation with overgrowth: a clinical subtype of vascular anomalies with hypertrophy. J Am Acad Dermatol. Oct 2013; 69: 589-94</ref>
DCMO is a unique entity from previously described vascular syndromes including: [[Klippel-Trenaunay Syndrome]], macrocephaly-capillary malformation syndrome
, [[cutis marmorata telangiectatica congenita]], [[CLOVES syndrome]] and [[Proteus Syndrome]]. <ref name="ref 4"> Moore CA, Toriello HV, Abuelo DN, et al. Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. Am J Med Genet. May 2 1997; 70: 67-73.</ref><ref name="ref 5"> Toriello HV, Mulliken JB. Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM). Am J Med Genet A. Dec 15 2007; 143A: 3009</ref><ref name="ref 6"> Wright DR, Frieden IJ, Orlow SJ, et al. The misnomer "macrocephaly-cutis marmorata telangiectatica congenita syndrome": report of 12 new cases and support for revising the name to macrocephaly-capillary malformations. Arch Dermatol. Mar 2009; 145: 287-93.</ref><ref name="ref 7"> Cohen MM, Jr. Proteus syndrome review: molecular, clinical, and pathologic features. Clin Genet. Feb 2014; 85: 111-9.</ref><ref name="ref 8"> Bloom J, Upton J, 3rd. CLOVES syndrome. J Hand Surg Am. Dec 2013; 38: 2508-12.</ref> Careful evaluation must be made to rule out these vascular-complex syndromes from the differential diagnosis, as DCMO is considered a more common and benign condition.
==Signs and Symptoms==
CM in DCMO is characteristically present at birth or during infancy. Appearance of the CM can be categorized into reticulate or homogenous pattern and pale or dark in color. <ref name="ref 2" /> Reticulate is defined as a non-uniform, mottled stain with indistinct demarcations, and homogenous is a uniform, solid color with distinct borders. Commonly, it affects multiple regions of the body. Lesions are pink or violaceous in color because capillaries in the papillary dermis are involved. Lesions are commonly diffuse, meaning that they extend contiguously greater than 2-3cm beyond a region of involvement. <ref name="ref 3" /> Midline demarcations commonly affect the abdomen, but can also involve the back and buttocks. <ref name= "ref 9" >García-Rodrigo CG, Jimenez LM, Martín, RL, et al. Diffuse capillary malformation with overgrowth: a new and unusual case of a recent entity. Journal of Dermatological Case Reports. Dec 31 2014; 8: 118-9.</ref>
There is usually overgrowth of at least one extremity, with possible overgrowth of face and body. Soft tissue and bony overgrowth proportionate to patient growth are the most common associated changes in DCMO. <ref name="ref 3" /> Typically there are no bone abnormalities on imaging. However, leg length discrepancy is observed in approximately half of patient cases. There have been cases of [[hemihypertrophy]], which are associated with diffuse CM appearance. Although rare, there are reports of limb hypotrophy. [[Syndactyly]] and [[macrodactyly]] are observed in approximately one third of patients. DCMO is not commonly associated with developmental delay. Knowledge of diseases associated with DCMO in the fetus is limited. However, there is a reported case of a fetus with DCMO and a pleural effusion. <ref name=" ref 10 ">Rork JF, Alomari AI, Mulliken JB, et al. Diffuse Capillary Malformation in Association with Fetal Pleural Effusion: Report of Five Patients. Pediatric Dermatology. Jan-Feb 2015; 32(1), 70-75.</ref>
==Classification==
Limb complex-combined vascular abnormalities have been categorized based on underlying vascular defects, namely slow-flow capillary malformation and fast-flow capillary malformations. <ref name="ref 11"> Enjolras O, Chapot R, Merland JJ. Vascular anomalies and the growth of limbs: a review. J Pediatr Orthop B. Nov 2004; 13: 349-57.</ref> Fast-flow vascular malformations comprise of arterial malformations, [[arteriovenous fistulae]] and [[arteriovenous malformations]]. Slow-flow vascular malformations include venous malformations, microcystic and macrocytic lymphatic malformations and [[capillary malformation]]. In this classification system, DCMO would fall under the slow-flow vascular malformation.
==Etiology==
There is a somatic mosaic mutation in sporadic and syndromic capillary malformations in the GNAQ gene. Capillary malformations are comprised of endothelial cells that have a missense mutation in this gene at p.R183L and p.R183G. GNAQ gene encodes an alpha subunit of heterotrimeric G proteins that activates phospholipase. It is postulated that the underlying etiology in capillary malformations is due to the abnormal interaction between the mutated endothelial cells and non-mutated perivascular cells. Disease severity is thought to correlate with GNAQ mutant allele frequency. This could potentially be used as a prognostication of the disease. <ref name= " ref 12 ">Couto JA, Huang L, Vivero MP, et al. Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plastic and Reconstructive Surgery. Jan 2016; 137(1).</ref> GNA11 is a mutation associated with capillary malformations causing overgrowth present on the extremities. <ref name= " ref 13 ">Couto JA, Ayturk UM, Konczyk DJ, et al. A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis. Jan 2017; 20: 303-6. </ref> Understanding the genetic basis may help establish and further improve current treatment modalities.
==Differential Diagnosis==
According to the International Society for Study of Vascular Anomalies (ISSVA), diagnosis and classification of vascular anomalies is made by clinical, radiological, pathological and hemodynamic characteristics. <ref name="ref 14"> Takahashi K, Mulliken JB, Kozakewich HP, et al. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest. Jun 1994; 93: 2357-64.</ref>
There are various conditions that present as vascular malformation and hypertrophy of soft tissue or bone. These include [[Klippel-Trenaunay Syndrome]], macrocephaly-capillary malformation syndrome, [[cutis marmorata telangiectatica congenita]], [[CLOVES syndrome]] (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis), and [[Proteus Syndrome]]. <ref name="ref 4" /><ref name="ref 5" /><ref name="ref 6" /><ref name="ref 7" /><ref name="ref 8" /> DCMO is a unique entity, and thus must be differentiated from these syndromes.
==Medical Management==
An interprofessional approach should be used for the medical management of DCMO patients.
Small CMs are typically benign and require no treatment. <ref name="ref 15"> Zheng JW, Zhou Q, Yang XJ, et al. Treatment guideline for hemangiomas and vascular malformations of the head and neck. Head Neck. Aug 2010; 32: 1088-98.</ref> Large CMs should be treated due to esthetic reasons and societal exclusion, as they have a higher tendency to hypertrophy. Pulse-dye laser photocoagulation should be used for large CM. Therapy should be initiated before the age of 6 months. <ref name="ref 16"> Chapas AM, Eickhorst K, Geronemus RG. Efficacy of early treatment of facial port wine stains in newborns: a review of 49 cases. Lasers Surg Med. Aug 2007; 39: 563-8.</ref> Surgery is the last resort for non-responding hypertrophied CM. However, redarkening after laser treatment and recurrence of overgrowth after surgical excision are common.
Differences in leg length observed in DCMO can lead to problems with gait, joint pain and scoliosis. An orthopedic consultation should be made for patients with overgrowth involving bone. In [[Parkes-Weber syndrome]], leg discrepancies > 2cm require orthopedic evaluation. <ref name="ref 11"/> Similar recommendations can be assumed for the limb overgrowth in DCMO. Orthodontic evaluation can be made in presence of facial hypertrophy.
DCMO patients do not typically present with lymphatic malformations, therefore MRI studies or lymphangiography are not necessary. MRI is indicated if there is presence of lymphatic vessels, edema, or large veins. Similarly, AVMs are not present with DCMO, thus ultrasound/Doppler or arteriographies are not required. Patients with DCMO have not been reported to have developmental or neurological abnormalities, thus neuroimaging is not necessary. However, head circumference and neurologic development should be serially examined. Presence of neurological abnormality or macrocephaly can suggest macrocephaly-capillary malformation syndrome.
Hemihypertrophy-multiple lipomatosis or [[Beckwith-Wiedemann syndrome]] are diseases with total hypertrophy and are associated with an increased risk of Wilms tumor. <ref name="ref 17"> Hoyme HE, Seaver LH, Jones KL, et al. Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet. Oct 2 1998; 79: 274-8.</ref><ref name="ref 18"> Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet. Aug 15 2005; 137C: 53-71. </ref> About 10% of DCMO cases present with total hemihypertrophy. <ref name="ref 3" /> Because of this, screening of Wilms tumor is recommended in DCMO patients with total hemihypertrophy. However, vascular anomaly and soft tissue hypertrophy in the absence of hemihypertrophy have a low risk of Wilms Tumor. <ref name="ref 19"> Kundu RV, Frieden IJ. Presence of vascular anomalies with congenital hemihypertrophy and Wilms tumor: an evidence-based evaluation. Pediatr Dermatol. May-Jun 2003; 20: 199-206.</ref>
References:
DCMO is a unique entity from previously described vascular syndromes including: [[Klippel-Trenaunay Syndrome]], macrocephaly-capillary malformation syndrome
, [[cutis marmorata telangiectatica congenita]], [[CLOVES syndrome]] and [[Proteus Syndrome]]. <ref name="ref 4"> Moore CA, Toriello HV, Abuelo DN, et al. Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. Am J Med Genet. May 2 1997; 70: 67-73.</ref><ref name="ref 5"> Toriello HV, Mulliken JB. Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM). Am J Med Genet A. Dec 15 2007; 143A: 3009</ref><ref name="ref 6"> Wright DR, Frieden IJ, Orlow SJ, et al. The misnomer "macrocephaly-cutis marmorata telangiectatica congenita syndrome": report of 12 new cases and support for revising the name to macrocephaly-capillary malformations. Arch Dermatol. Mar 2009; 145: 287-93.</ref><ref name="ref 7"> Cohen MM, Jr. Proteus syndrome review: molecular, clinical, and pathologic features. Clin Genet. Feb 2014; 85: 111-9.</ref><ref name="ref 8"> Bloom J, Upton J, 3rd. CLOVES syndrome. J Hand Surg Am. Dec 2013; 38: 2508-12.</ref> Careful evaluation must be made to rule out these vascular-complex syndromes from the differential diagnosis, as DCMO is considered a more common and benign condition.
==Signs and Symptoms==
CM in DCMO is characteristically present at birth or during infancy. Appearance of the CM can be categorized into reticulate or homogenous pattern and pale or dark in color. <ref name="ref 2" /> Reticulate is defined as a non-uniform, mottled stain with indistinct demarcations, and homogenous is a uniform, solid color with distinct borders. Commonly, it affects multiple regions of the body. Lesions are pink or violaceous in color because capillaries in the papillary dermis are involved. Lesions are commonly diffuse, meaning that they extend contiguously greater than 2-3cm beyond a region of involvement. <ref name="ref 3" /> Midline demarcations commonly affect the abdomen, but can also involve the back and buttocks. <ref name= "ref 9" >García-Rodrigo CG, Jimenez LM, Martín, RL, et al. Diffuse capillary malformation with overgrowth: a new and unusual case of a recent entity. Journal of Dermatological Case Reports. Dec 31 2014; 8: 118-9.</ref>
There is usually overgrowth of at least one extremity, with possible overgrowth of face and body. Soft tissue and bony overgrowth proportionate to patient growth are the most common associated changes in DCMO. <ref name="ref 3" /> Typically there are no bone abnormalities on imaging. However, leg length discrepancy is observed in approximately half of patient cases. There have been cases of [[hemihypertrophy]], which are associated with diffuse CM appearance. Although rare, there are reports of limb hypotrophy. [[Syndactyly]] and [[macrodactyly]] are observed in approximately one third of patients. DCMO is not commonly associated with developmental delay. Knowledge of diseases associated with DCMO in the fetus is limited. However, there is a reported case of a fetus with DCMO and a pleural effusion. <ref name=" ref 10 ">Rork JF, Alomari AI, Mulliken JB, et al. Diffuse Capillary Malformation in Association with Fetal Pleural Effusion: Report of Five Patients. Pediatric Dermatology. Jan-Feb 2015; 32(1), 70-75.</ref>
==Classification==
Limb complex-combined vascular abnormalities have been categorized based on underlying vascular defects, namely slow-flow capillary malformation and fast-flow capillary malformations. <ref name="ref 11"> Enjolras O, Chapot R, Merland JJ. Vascular anomalies and the growth of limbs: a review. J Pediatr Orthop B. Nov 2004; 13: 349-57.</ref> Fast-flow vascular malformations comprise of arterial malformations, [[arteriovenous fistulae]] and [[arteriovenous malformations]]. Slow-flow vascular malformations include venous malformations, microcystic and macrocytic lymphatic malformations and [[capillary malformation]]. In this classification system, DCMO would fall under the slow-flow vascular malformation.
==Etiology==
There is a somatic mosaic mutation in sporadic and syndromic capillary malformations in the GNAQ gene. Capillary malformations are comprised of endothelial cells that have a missense mutation in this gene at p.R183L and p.R183G. GNAQ gene encodes an alpha subunit of heterotrimeric G proteins that activates phospholipase. It is postulated that the underlying etiology in capillary malformations is due to the abnormal interaction between the mutated endothelial cells and non-mutated perivascular cells. Disease severity is thought to correlate with GNAQ mutant allele frequency. This could potentially be used as a prognostication of the disease. <ref name= " ref 12 ">Couto JA, Huang L, Vivero MP, et al. Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plastic and Reconstructive Surgery. Jan 2016; 137(1).</ref> GNA11 is a mutation associated with capillary malformations causing overgrowth present on the extremities. <ref name= " ref 13 ">Couto JA, Ayturk UM, Konczyk DJ, et al. A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis. Jan 2017; 20: 303-6. </ref> Understanding the genetic basis may help establish and further improve current treatment modalities.
==Differential Diagnosis==
According to the International Society for Study of Vascular Anomalies (ISSVA), diagnosis and classification of vascular anomalies is made by clinical, radiological, pathological and hemodynamic characteristics. <ref name="ref 14"> Takahashi K, Mulliken JB, Kozakewich HP, et al. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest. Jun 1994; 93: 2357-64.</ref>
There are various conditions that present as vascular malformation and hypertrophy of soft tissue or bone. These include [[Klippel-Trenaunay Syndrome]], macrocephaly-capillary malformation syndrome, [[cutis marmorata telangiectatica congenita]], [[CLOVES syndrome]] (congenital lipomatous overgrowth, vascular malformation, epidermal nevus, scoliosis), and [[Proteus Syndrome]]. <ref name="ref 4" /><ref name="ref 5" /><ref name="ref 6" /><ref name="ref 7" /><ref name="ref 8" /> DCMO is a unique entity, and thus must be differentiated from these syndromes.
==Medical Management==
An interprofessional approach should be used for the medical management of DCMO patients.
Small CMs are typically benign and require no treatment. <ref name="ref 15"> Zheng JW, Zhou Q, Yang XJ, et al. Treatment guideline for hemangiomas and vascular malformations of the head and neck. Head Neck. Aug 2010; 32: 1088-98.</ref> Large CMs should be treated due to esthetic reasons and societal exclusion, as they have a higher tendency to hypertrophy. Pulse-dye laser photocoagulation should be used for large CM. Therapy should be initiated before the age of 6 months. <ref name="ref 16"> Chapas AM, Eickhorst K, Geronemus RG. Efficacy of early treatment of facial port wine stains in newborns: a review of 49 cases. Lasers Surg Med. Aug 2007; 39: 563-8.</ref> Surgery is the last resort for non-responding hypertrophied CM. However, redarkening after laser treatment and recurrence of overgrowth after surgical excision are common.
Differences in leg length observed in DCMO can lead to problems with gait, joint pain and scoliosis. An orthopedic consultation should be made for patients with overgrowth involving bone. In [[Parkes-Weber syndrome]], leg discrepancies > 2cm require orthopedic evaluation. <ref name="ref 11"/> Similar recommendations can be assumed for the limb overgrowth in DCMO. Orthodontic evaluation can be made in presence of facial hypertrophy.
DCMO patients do not typically present with lymphatic malformations, therefore MRI studies or lymphangiography are not necessary. MRI is indicated if there is presence of lymphatic vessels, edema, or large veins. Similarly, AVMs are not present with DCMO, thus ultrasound/Doppler or arteriographies are not required. Patients with DCMO have not been reported to have developmental or neurological abnormalities, thus neuroimaging is not necessary. However, head circumference and neurologic development should be serially examined. Presence of neurological abnormality or macrocephaly can suggest macrocephaly-capillary malformation syndrome.
Hemihypertrophy-multiple lipomatosis or [[Beckwith-Wiedemann syndrome]] are diseases with total hypertrophy and are associated with an increased risk of Wilms tumor. <ref name="ref 17"> Hoyme HE, Seaver LH, Jones KL, et al. Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet. Oct 2 1998; 79: 274-8.</ref><ref name="ref 18"> Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet. Aug 15 2005; 137C: 53-71. </ref> About 10% of DCMO cases present with total hemihypertrophy. <ref name="ref 3" /> Because of this, screening of Wilms tumor is recommended in DCMO patients with total hemihypertrophy. However, vascular anomaly and soft tissue hypertrophy in the absence of hemihypertrophy have a low risk of Wilms Tumor. <ref name="ref 19"> Kundu RV, Frieden IJ. Presence of vascular anomalies with congenital hemihypertrophy and Wilms tumor: an evidence-based evaluation. Pediatr Dermatol. May-Jun 2003; 20: 199-206.</ref>
References:
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