Comparative analysis of arteriovenous malformation grading ...
Capillary malformation–arteriovenous malformation syndrome: Identification of a family with a...
Transcript of Capillary malformation–arteriovenous malformation syndrome: Identification of a family with a...
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clinical and histopathologic features in this letter. Apossible mechanism for this eruption may be drug-induced activation of downstream pERK in wild-typeBRAF follicular epithelial cells.6
Although this eruption does not seem to result indose limitation or discontinuation of therapy, itsrecognition is important. Guidelines for treatmentare likely to gain significant attention as we enter aperiod of BRAF inhibitor monotherapy for metastaticmelanoma. There appears to be a lack of an inflam-matory component to this entity suggesting thattherapies for acne with anti-inflammatory mecha-nisms will not be efficacious. Topical therapies forkeratosis pilaris are also likely to be of little benefitgiven the depth at which the infundibular changesoccur. Trials of systemic retinoid therapy are beingconsidered for our patients.
Of note, an impressive reduction in the incidenceof this eruption has been observed in a number ofresearch patients enrolled in a BRAF kinase inhibitorand MEK inhibitor combination therapy trial. Weanticipate that this phenomenon will be well de-scribed in forthcoming literature.
Kaisa van der Kooi, MD,a L. Frank Glass, MD,b
Jane L. Messina, MD,b,c and James S. Trimble,MDc
Kent Pathology Laboratory, Grand Rapids, Michi-gana; Moffitt Cancer Center and Research Insti-tute, Tampa, Floridab; and Department ofDermatology and Cutaneous Surgery, Universityof South Florida, Tampac
Funding sources: None.
Conflicts of interest: None declared.
Correspondence to: James S. Trimble, MD, 202 SMelville Ave, Tampa, FL 33606
E-mail: [email protected]
Fig 1. Capillary malformation (CM)earteriovenous mal-formation (AVM) syndrome. CMs in the proband on the leftproximal arm (top), right forearm (middle), and right thirdfinger (bottom).
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1. Hong DS, Reddy SB, Prieto VG, Wright JJ, Tannir NM, Cohen PR,
et al. Multiple squamous cell carcinomas of the skin after
therapy with sorafenib combined with tipifarnib. Arch Dermatol
2008;144:779-82.
2. Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, et al.
Cutaneous side effects of kinase inhibitors and blocking anti-
bodies. Lancet Oncol 2005;6:491-500.
3. Marquez CB, Smithberger EE, Bair SM, Wenham RM, Fenske NA,
Glass LF, et al. Multiple keratoacanthomas arising in the setting
of sorafenib therapy: novel chemoprophylaxis with bexarotene.
Cancer Control 2009;16:66-9.
4. Kwon EJ, Kish LS, Jaworsky C. The histologic spectrum of
epithelial neoplasms induced by sorafenib. J Am Acad Dermatol
2009;61:522-7.
5. Pickert A, Hughes M, Wells M. Chloracne-like drug eruption
associated with sorafenib. J Drugs Dermatol 2011;10:1331-4.
6. Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S,
et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, acti-
vates the ERK pathway and enhances cell migration and
proliferation of BRAF melanoma cells. Pigment Cell Melanoma
Res 2010;23:190-200.
http://dx.doi.org/10.1016/j.jaad.2012.06.043
Capillary malformationearteriovenousmalformation syndrome: Identification of afamily with a novel mutation
To the Editor: Capillary malformation (CM)earterio-venous malformation (AVM) syndrome is anautosomal dominant condition resulting from loss-of-function mutations in RASA1 and is characterizedby multiple CMs with or without AVMs.1 RASA1encodes a Ras-GTPase activating protein,p120RasGAP, that negatively regulates Ras activityand influences angiogenesis via modulation ofendothelial cell proliferation, organization, and
Fig 2. Pedigree of capillary malformation (CM )earteriovenous malformation (AVM ) syndrome kindred (K100). Presenceof CM or AVM is denoted by black fill on left or right side of each symbol, respectively. Family members from whom DNAwas available for study are numbered. Sequence traces depict wild-type (wt) RASA1 sequence and heterozygousGln503Stop (Q503X) mutation (*) found in the proband (arrow; subject 3) and her affected mother (subject 1) but not in herunaffected brother (subject 2). Encoded amino acid sequences are shown at the top of each trace; the mutant terminationcodon is shown in red.
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migration.2 The CMs are characteristically multifocal,rarely solitary, round or oval pinkmacules or patchesranging in size from less than 1 cm up to 3 cm. It isestimated that up to one third of patients withCM-AVM syndrome have AVMs, many of which areintracranial or spinal and have the potential for poorclinical outcomes.1,3-5
Here we report a family with a novel mutation inthe RASA1 gene. The proband, a 30-year-old woman,presented for skin cancer screening andwas found tohave numerous pink, 0.5- to 3-cm round and oval
macules and patches scattered over her trunk, ex-tremities, and face (Fig 1). By report, many lesionswerepresent at birth,while others appeared later. Hersister, mother, maternal aunt, and maternal grand-mother had similar lesions, but her father, brother,and maternal uncles did not (Fig 2, top). In addition,her sister had asymptomatic enlargement of the loweraspect of her right leg present since early childhood,and imaging revealed an AVM in her right thigh (videinfra) consistent with Parkes Weber syndrome. Noother family members had known AVMs.
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The coding sequence and splice junctions ofRASA1 were screened for mutation in the proband,her mother, and her brother via polymerase chainreaction and Sanger sequencing, demonstrating thatthe proband and her affected mother had the sametruncating mutation in exon 11 of RASA1 (Q503X)(Fig 2, bottom), while the unaffected brother did not.This novel heterozygous mutation introduces a pre-mature termination codon and causes a truncation inthe pleckstrin homology domain of p120RasGAP.This mutation is similar in effect to other dominant,loss-of-function mutations in RASA1 that have beendescribed in CM-AVM syndrome.1,3
The proband reported new-onset headachesaround the time of her presentation. Given concernfor an intracranial AVM, magnetic resonance (MR)imaging, MR angiography, and MR venography wereperformed and revealed normal findings.
Both sisters conceived and gave birth to childrenduring the period of genetic analysis. Early in theirpregnancies, they were evaluated by MR imagingfor both spinal and uterine AVMs; the latter havenot been described in CM-AVM syndrome.Although MR imaging did not reveal spinal orintra-abdominal AVMs in either patient, an AVM inthe hamstring muscles of the proximal right thighwas noted in the sister with presumed ParkesWeber syndrome. Both sisters carried their preg-nancies to term without complication and deliveredhealthy female infants, one with multiple CMswithout clinical evidence of AVM, and the otherwithout evidence of CMs or AVM at birth but withsubsequent development of CMs (Fig 2, top).Screening imaging for intracranial and spinalAVMs in the infants was recommended but wasdeferred by their parents.
Although none of the family members describedhere are known to have intracranial or spinal AVMs,the incidence among individuals with RASA1 muta-tions is not insignificant.1 Dermatologists will oftenbe the physicians identifying CM-AVM syndrome andneed to be cognizant of the risk for clinically signif-icant intracranial and spinal AVMs in this disorder.1,3-5
Lynn M. Boyden, PhD,a Charisse M. Orme, MD,PhD,b Richard J. Antaya, MD,c Keith A. Choate,MD, PhD,c and Brett A. King, MD, PhDc
Departments of Genetics,a Cell Biology,b andDermatology,c Yale University School of Medi-cine, New Haven, Connecticut
Funding sources: None.
The first two authors contributed equally to thiswork.
Conflicts of interest: None declared.
Correspondence to: Brett A. King, MD, PhD, De-partment of Dermatology, Yale University Schoolof Medicine, PO Box 208059, New Haven, CT06520-8059
E-mail: [email protected]
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1. Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR,
Burrows PE, et al. Parkes Weber syndrome, vein of Galen
aneurysmal malformation, and other fast-flow vascular anom-
alies are caused by RASA1 mutations. Hum Mutat
2008;29:959-65.
2. Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R,
Scheppke L, et al. MicroRNA-132-mediated loss of p120RasGAP
activates the endothelium to facilitate pathological angiogen-
esis. Nat Med 2010;16:909-14.
3. Thiex R, Mulliken JB, Revencu N, Boon LM, Burrows PE, Cordisco
M, et al. A novel association between RASA1 mutations
and spinal arteriovenous anomalies. Am J Neuroradiol
2010;31:775-9.
4. Chee D, Phillips R, Maixner W, Southwell BR, Hutson JM. The
potential of capillary birthmarks as a significant marker for
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J Pediatr Surg 2010;45:2419-22.
5. Wooderchak-Donahue W, Stevenson DA, McDonald J, Grimmer
JF, Gedge F, Bayrak-Toydemir P. RASA1 analysis: clinical and
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Genet 2012;55:91-5.
http://dx.doi.org/10.1016/j.jaad.2012.07.004
Minocycline-induced Sweet syndrome (acutefebrile neutrophilic dermatosis)
To the Editor: A 49-year-old woman presented withacute onset of multiple raised, erythematous, viola-ceous nodules and plaques over her cheeks andforehead. Minocycline had been started for treat-ment of rosacea and the cutaneous eruption devel-oped 8 days later. The lesions later spread to theupper aspect of her back, chest, and upper and lowerlimbs. The painful skin lesions were well circum-scribed, bluish-red in color, and of variable sizemeasuring between 1 and 5 cm in diameter, withsome lesions showing areas of central ulceration,pseudovesiculation, and pustulation (Fig 1). Shereported recent good health with no malaise, fever,or systemic symptoms and had no significant med-ical history. After extensive investigation, no endog-enous cause for Sweet syndrome was found,however, the patient demonstrated transient liverdysfunction. Table I shows significant elevation ofliver enzymes.
Histopathologic examination showed irregularacanthosis, focal excoriation, and intact basal layer