Early-onset hypertension associated with extensive capillary malformations: A new worry to raise dermatologists’ blood pressure
By Warren R. Heymann, MD, FAAD
Jan. 31, 2024
Vol. 6, No. 5
The recent passing of Mikhail Gorbachev reminded me of the teaching value of his port wine stain. The following brief article published in the Washington Post in 1987 reflects the state of knowledge 36 years ago. (1)
Q. I can’t help but notice the red blemish on Mr. Gorbachev’s forehead. Do you know what caused it? Is it a sign of any other condition?
A. The Soviet leader has a birthmark on his forehead called a port wine stain. Named for its red-wine color, this skin blemish usually is present from birth, most often affecting the face or arms. It is caused by a malformation of blood vessels and appears either as a flat or pebbly patch of purplish-red skin. Port wine stains usually last for life, although they may fade a little. Until recently, there was no good treatment for this type of birthmark, except for wearing a masking make-up like Covermark. Now, various laser techniques — the newest being the “tunable” laser — use special wavelengths of light to obliterate the abnormal blood vessels, leaving a more natural-looking skin surface. But even laser therapy is often unsatisfactory, and in most cases it may be best to get along without any treatment. Most of the time, port wine stains are simple birthmarks and not a sign of any other abnormality. Occasionally, port wine stains on the face are accompanied by malformations of blood vessels in the brain — a serious condition known as Sturge-Weber syndrome that can cause mental retardation, blindness, strokes and seizures. Port wine stains are somewhat different from a related birthmark known as strawberry hemangiomas (blood vessel growths). Named for their raised, bumpy, dark red appearance, these birthmarks generally get larger during the first six to 12 months of life. After that, they gradually clear, usually from the center outward. Most disappear in early childhood, so treatment — with surgery or lasers — is usually not needed.
Just as President Reagan implored General Secretary Gorbachev to “tear down this wall,” so has the molecular revolution torn down the wall of uncertainty regarding the etiology of capillary malformations (CMs, aka port wine stains [PWS] or nevus flammeus). Histologically, CMs demonstrate hyperdilation of capillaries and postcapillary venules in the dermis or subcutaneous tissue. Somatic mosaic mutations in the GNAQ, GNA11, and PIK3CA genes are pathogenic. CMs are associated with physical and functional effects, and often lead to decreased emotional and social overall health-related quality of life. (2)
Vascular malformations (VM) are congenital lesions that occur in lymphatic vessels, arteries, veins, capillaries, or in combinations thereof. As Rose and Cathey state, “Normal vascular system development and ongoing regulation require continual choreography of positive and negative drivers. The RAS-MAPK and PI3K-AKT-mTOR signaling pathways have emerged as major influencers in the formation of vascular malformations.” CMs can be isolated or observed as part of syndromes, such as Sturge-Weber syndrome (SWS). Widespread CMs can also be associated with underlying soft tissue overgrowth termed diffuse capillary malformation with overgrowth (DCMO). The authors assert, “The same pathogenic somatic variant, R183Q, in the GNAQ gene is identified in approximately 90% of CMs (both isolated PWS and those in SWS or DCMO). GNAQ encodes the Gαq subunit of heterotrimeric G-protein. G-proteins are involved in a wide range of signaling cascades, and heterotrimeric G-protein is specifically involved in the activation of the RAS-MAPK signaling pathway… A closely related gene, GNA11, encodes a different subunit of the heterotrimeric G-protein; GNA11 mutations have also been reported in patients with isolated CMs, SWS, and DCMO. In both isolated CMs and SWS or DCMO, variants in GNAQ and GNA11 occur as mosaic somatic variants, present only in affected cells. Genetic diagnosis requires biopsy of affected tissue and testing designed to identify somatic mutations present at low levels.” Additionally, mosaic pathogenic variants in GNAQ and GNA11 have been identified in dermal melanocytosis with or without phakomatosis pigmentovascularis lesions. (3)
CMs are the most common type of VM. They are slow-flow lesions that occur in approximately 0.3% to 0.5% of the population with an equal sex distribution. CMs are also observed in other syndromes, including Klippel–Trenaunay syndrome (KTS), CLOVES syndrome, among others. Please see the excellent article by Escobar et al for further details. (4)
Dermatologists are intimately familiar with complications that may accompany syndromic PWS, such as glaucoma and seizures in SWS, limb overgrowth in DCMO and KTS, and asymmetric lipomatous lesions in CLOVES.
A newly reported association demanding attention is early-onset hypertension (defined as hypertension before the age of 55 years) associated with extensive cutaneous CMs harboring postzygotic variations in GNAQ and GNA11. Davies et al identified 29 patients with confirmed GNAQ/11 postzygotic variants and documented their past medical history from a multi-institutional vascular anomalies study. Five of the 29 patients identified as having GNAQ/11 postzygotic variants had documented early-onset hypertension. Three individuals harbored a GNAQ p.R183Q variant, and two patients displayed a GNA11 p.R183C variant. All individuals had extensive cutaneous CMs involving the trunk and covering 9%-56% of their body surface area. The median age of hypertension diagnosis was 15 years (range 11-24 years), with 3 individuals having renal abnormalities on imaging. Three patients required medical management of their hypertension. The etiology of hypertension in patients with extensive CMs is unknown — hypotheses include disruption of embryonic vessel morphogenesis, calcium homeostasis, activation of phospholipase C, mediation of the adrenal aldosterone response to angiotensin II, and G-protein effects on vascular smooth muscle. The authors recommend serial blood pressure measurements in patients with extensive CMs on the trunk and extremities with a referral to nephrology if early-onset hypertension is identified. (5)
Point to Remember: Patients presenting with extensive capillary malformations (port wine stains) on the trunk and extremities should be routinely screened for early-onset hypertension.
Our expert’s viewpoint
Jim Treat, MD, FAAD
Professor of Clinical Pediatrics and Dermatology
Associate Chair for IT for the Dept. of Pediatrics
Fellowship Director, Pediatric Dermatology
Education Director, Pediatric Dermatology
Children’s Hospital of Philadelphia
When patients have post-zygotic mutations in genes that lead to abnormal vasculature in the skin (such as capillary malformations), it seems reasonable that there may be an association with hypertension. The discovery of the genes that lead to capillary malformations has allowed for clearer delineation of various different associations such as overgrowth in the case of DCMO or Wilms tumor in the case of CLOVES syndrome. We often have patients with widespread capillary malformations follow up every few years even if entirely stable because new associations may be found. The association between widespread CMs and hypertension is important clinically and has changed my practice to make sure that as children transition to adult care, I educate them on what to follow.
Siwak J. Gorbachev’s birthmark. Washington Post, December 8, 1987. https://www.washingtonpost.com/archive/lifestyle/wellness/1987/12/08/gorbachevs-birthmark/4cccf8b1-b256-44fc-b5a3-475b795cdeff/. Accessed December 29, 2022.
Langbroek GB, Wolkerstorfer A, Horbach SER, Spuls PI, Kelly KM, Robertson SJ, van Raath MI, Al-Niaimi F, Kono T, Boixeda P, Laubach HJ, Badawi AM, Rubin AT, Haedersdal M, Manuskiatti W, van der Horst CMAM, Ubbink DT; COSCAM study group. A core outcome domain set for clinical research on capillary malformations (the COSCAM project): an e-Delphi process and consensus meeting. Br J Dermatol. 2022 Nov;187(5):730-742. doi: 10.1111/bjd.21723. Epub 2022 Jul 31. PMID: 35762296; PMCID: PMC9796083.
Rose AL, Cathey SS. Genetic Causes of Vascular Malformations and Common Signaling Pathways Involved in Their Formation. Dermatol Clin. 2022 Oct;40(4):449-459. doi: 10.1016/j.det.2022.07.002. PMID: 36243432.
Escobar K, Pandher K, Jahnke MN. Capillary Malformations. Dermatol Clin. 2022 Oct;40(4):425-433. doi: 10.1016/j.det.2022.06.005. Epub 2022 Sep 16. PMID: 36243429.
Davies OMT, Ng AT, Tran J, Blumenthal S, Arkin LM, Nopper AJ, Cottrell CE, Garzon M, Siegel DH, Frieden IJ, Drolet BA. Early-onset hypertension associated with extensive cutaneous capillary malformations harboring postzygotic variants in GNAQ and GNA11. Pediatr Dermatol. 2022 Nov;39(6):914-919. doi: 10.1111/pde.15103. Epub 2022 Aug 10. PMID: 36440997.
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