0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Observation |

Hydroxyurea-Induced Leg Ulceration in a Patient With a Homozygous MTHFR Polymorphism Misdiagnosed as Pyoderma Gangrenosum FREE

Sunita C. Crittenden, MD1; Juliana E. Gilbert, MD1; Jeffrey P. Callen, MD1
[+] Author Affiliations
1Division of Dermatology, University of Louisville, Louisville, Kentucky
JAMA Dermatol. 2014;150(7):780-781. doi:10.1001/jamadermatol.2013.7198.
Text Size: A A A
Published online

Both hydroxyurea, an antimetabolite used to treat chronic myeloproliferative diseases, and methylene tetrahydrofolate reductase (MTHFR) polymorphisms have been associated with cutaneous ulceration.1,2 We present a case of a severe leg ulcer that likely occurred from hydroxyurea use in a patient with a MTHFR polymorphism.

REPORT OF A CASE

A woman in her 70s with a history of myelodysplastic syndrome, well controlled with hydroxyurea for 14 years, presented with an extensive right leg ulcer of 10 months’ duration. The ulcer began after cryotherapy and enlarged despite oral antibiotic treatment for Staphylococus aureus infection and local wound care. A wedge biopsy showed papillary dermal fibrinoid necrosis of vessel walls with mild leukocytoclasia, and tissue culture findings were negative. The patient was then treated with clobetasol ointment for presumed pyoderma gangrenosum. Hydroxyurea treatment was discontinued owing to concern for impaired wound healing but was restarted 2 months later when her thrombocytosis significantly worsened.

With the addition of prednisone and azathioprine to her treatment regimen, the ulcer continued to progress. When the patient was seen in our office, her ulcer measured 20 × 12 cm with exposed muscle and tendons (Figure, A). She was admitted to the hospital, and hydroxyurea, prednisone, and azathioprine were permanently removed from her drug regimen. Vascular assessment failed to reveal significantly reduced arterial flow. After undergoing extensive surgical debridement and receiving intravenous antibiotics, she was discharged with a wound vacuum-assisted closure (VAC) device. Three months later, she underwent a split-thickness skin graft closure of the ulcer leading to complete resolution (Figure, B).

Place holder to copy figure label and caption
Figure.
Clinical Images From the Present Case

A, Large ulceration on the right distal leg with exposed muscle and tendons. B, The ulcer completely healed after discontinuation of hydroxyurea and full-thickness skin graft closure.

Graphic Jump Location

A full coagulopathy workup was later performed to investigate impaired wound healing. The patient was found to be homozygous for the C677T polymorphism of the MTHFR gene. She was treated with a vitamin B complex–vitamin C–biotin–folic acid supplement, which led to cessation of new ulcer development.

DISCUSSION

The prevalence of hydroxyurea-induced cutaneous ulceration is approximately 8%.1,3 These ulcers commonly occur on the legs and may take months to develop. In most cases, ulcers attributed to hydroxyurea slowly heal after discontinuation of the drug treatment, although it can take several months. Our patient was without hydroxyurea for 2 months and showed no improvement. Only after the hydroxyurea therapy was discontinued permanently was her ulcer finally able to resolve with medical and surgical intervention. Another complicating factor in our patient’s wound healing was the immunosuppressive effects of the prednisone and azathioprine, which likely led to intermittent superinfection and prevented the ulcer from healing on its own.

Why does hydroxyurea cause cutaneous ulceration? Almost all patients taking hydroxyurea develop megaloblastic erythrocytes within 24 hours, causing decreased susceptibility to deformation that impairs capillary blood flow to the skin.4,5 The result is cutaneous anoxia followed by ulceration. This mechanism may explain why the malleolus, a frequent site of trauma, is a common location for these ulcers. In our patient, the ulcer developed after cryotherapy, which led to skin breakdown and ultimately ulceration.

MTHFR polymorphisms, such as the homozygous C→T substitution at nucleotide 677 found in our patient and in 10% to 13% of the white population, can lead to arterial occlusive disease and ulceration. This results from decreased enzyme activity, which causes an increased total homocysteine level in the presence of suboptimal folate intake.6

The concurrent existence of an MTHFR polymorphism or other thrombophilic genetic mutation in a patient taking hydroxyurea could be the complicating insult that leads to cutaneous ulceration. Therefore, we recommend screening for an array of coagulation abnormalities that predispose to thrombophilia (including MTHFR polymorphisms) in patients with ulcers unresponsive to standard therapy as well as the use of B vitamin supplementation in patients with a MTHFR polymorphism. Future studies looking at MTHFR polymorphisms in patients with hydroxyurea-induced ulcers may solidify this association.

ARTICLE INFORMATION

Corresponding Author: Sunita C. Crittenden, MD, Division of Dermatology, University of Louisville, Louisville, Kentucky, 310 E Broadway, Floor 2A, Louisville, KY 40202 (sunitacrittenden@gmail.com).

Published Online: March 5, 2014. doi:10.1001/jamadermatol.2013.7198.

Conflict of Interest Disclosures: None reported.

REFERENCES

Montefusco  E, Alimena  G, Gastaldi  R, Carlesimo  OA, Valesini  G, Mandelli  F.  Unusual dermatologic toxicity of long-term therapy with hydroxyurea in chronic myelogenous leukemia. Tumori. 1986;72(3):317-321.
PubMed
New  D, Eaton  P, Knable  A, Callen  JP.  The use of B vitamins for cutaneous ulcerations mimicking pyoderma gangrenosum in patients with MTHFR polymorphism. Arch Dermatol. 2011;147(4):450-453.
PubMed   |  Link to Article
Latagliata  R, Spadea  A, Cedrone  M,  et al; Gruppo Laziale SMPC Ph1 neg.  Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer. 2012;118(2):404-409.
PubMed   |  Link to Article
Boyd  AS, Neldner  KH.  Hydroxyurea therapy. J Am Acad Dermatol. 1991;25(3):518-524.
PubMed   |  Link to Article
Sirieix  ME, Debure  C, Baudot  N,  et al.  Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol. 1999;135(7):818-820.
PubMed   |  Link to Article
Hankey  GJ, Eikelboom  JW.  Homocysteine and vascular disease. Lancet. 1999;354(9176):407-413.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Clinical Images From the Present Case

A, Large ulceration on the right distal leg with exposed muscle and tendons. B, The ulcer completely healed after discontinuation of hydroxyurea and full-thickness skin graft closure.

Graphic Jump Location

Tables

References

Montefusco  E, Alimena  G, Gastaldi  R, Carlesimo  OA, Valesini  G, Mandelli  F.  Unusual dermatologic toxicity of long-term therapy with hydroxyurea in chronic myelogenous leukemia. Tumori. 1986;72(3):317-321.
PubMed
New  D, Eaton  P, Knable  A, Callen  JP.  The use of B vitamins for cutaneous ulcerations mimicking pyoderma gangrenosum in patients with MTHFR polymorphism. Arch Dermatol. 2011;147(4):450-453.
PubMed   |  Link to Article
Latagliata  R, Spadea  A, Cedrone  M,  et al; Gruppo Laziale SMPC Ph1 neg.  Symptomatic mucocutaneous toxicity of hydroxyurea in Philadelphia chromosome-negative myeloproliferative neoplasms: the Mister Hyde face of a safe drug. Cancer. 2012;118(2):404-409.
PubMed   |  Link to Article
Boyd  AS, Neldner  KH.  Hydroxyurea therapy. J Am Acad Dermatol. 1991;25(3):518-524.
PubMed   |  Link to Article
Sirieix  ME, Debure  C, Baudot  N,  et al.  Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol. 1999;135(7):818-820.
PubMed   |  Link to Article
Hankey  GJ, Eikelboom  JW.  Homocysteine and vascular disease. Lancet. 1999;354(9176):407-413.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

487 Views
1 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature
How Serious Is the Risk of Bias?

Users' Guides to the Medical Literature

×