Laboratory Data

Epidermal necrosis. Many small vessels in dermis and subcutis occluded by fibrin thrombus. Fibrinoid necrosis in vessel walls and extensive red cell extravasation. No active vasculitis.

Conclusion - Epidermal infarction secondary to small vessel thrombosis most in keeping with atrophie blanche.

Direct IF negative

The presumed diagnosis in this case is atrophie blanche, a disorder of cutaneous microvascular occlusion. Onset in childhood is extremely rare. There has only been one previous report of an underlying systemic disease (cryoglobulinaemia) in this age group. The clinical relevance of the Factor V Leiden mutation in our patient is uncertain. Many different therapies have been used with variable success rates in the literature of atrophie blanche including pentoxifylline, heparin, warfarin, tissue plaminogen activator, iloprost, danazol and PUVA although the evidence is limited to case reports and small case series mostly from adult patients.

Atrophie blanche is “…a cutaneous vascular disorder characterised by grouped and reticulated purpuric macules and papules that usually progress into painful ulcerations of the lower extremities…” It is due to progressive thrombotic occlusion of dermal vessels Aetiology uncertain – end-result of several possible pathological proceses v. multifactorial? Usually idiopathic. Very rare in children especially prepubescent boys

As physicians, we always strive to gain a diagnosis but in this case we are struggling to find an underlying cause to account for this lad's significant pathology. He has been an "orphan patient" in that he has a challenging problem without an easy solution and he has been seen by many different specialists - paediatrics, dermatology, haematology, rheumatology. Although it has been frustrating for us in terms of his care, it has been challenging and this is the sort of clinical case that most of us learn by and "enjoy" and is why we chose a career in medicine.
We would greatly appreciate any comments from members of the faculty re. similar experience and further management.

What is the diagnosis?
Is it primary/idiopathic atrophie blanche or secondary atrophie blanche ?
Have we missed a leucocytoclastic vascultis or cutaneous PAN?
What further investigations are indicated?
Is the Factor V Leiden mutation in our patient clinically relevant?
What treatment is indicated?

Suarez SM, Paller AS. Atrophie blanche with onset in childhood. J Pediatr
1993; 123: 753-5.

Calamia K, Balabanova M, Perniciaro C, Walsh J. Livedo (livedoid) vasculitis
and the factor V Leiden mutation: Additional evidence for abnormal
coagulation. J Am Acad Dermatol 2002; 46: 133-7.

Maessen-Visch MB, Koedam MI, Hamulyak K and Neumann HAM. Atrophie blanche.
Int J Dermatol 1999; 38: 161-172.

John Fenyk MD, Clinical Professor, Department of Dermatology, University of Minnesota, USA, on June 11, 2006

Is there history of trauma to the contralateral limb? Is there history of prior thermal injury to this foot/limb? Reflex sympathetic dystrophy (RSD) and chillblains need to be considered. The treatment of RSD, though quite difficult might require beta-blockers, physical therapy etc. in addition to aspirin therapy. While clearly atypical, Raynaud's and a livido vasculitis should be considered.

Robert Rudolph MD, FACP, Clinical Professor of Dermatology, University of Pennsylvania, Philadelphia, PA, USA on June 12, 2006

My diagnosis would simply have been "a vasculitis", and this entity would not have been in my differential list.

I worry about some undefined hematologic process or clotting factor problem, some kind of peculiar enzyme deficiency, and also worry about an occult drug ingestion, and even (I shudder in a kid this age!) smoking.

If this kid really has this disease, then a "tip of the hat" to all who made the diagnosis. I would not have, even in the face of the pathologic findings.

Khalifa Shaquie MD, PhD, Professor of Dermatology, College of Medicine, University of Baghdad, Baghdad, Iraq on June 17, 2006

It is not easy to differentiate between vasculitis and atrophie blanche even by histopathology.There many overlapping features

T C Satish MD, Dubai, UAE on June 17, 2006

I think there is a prothrombotic phenomenon and Factor V Leiden mutation could be significant in this boy. I also would think about a fixed eruption due to the ingestion of some food or drug.

Jag Bhawan, MD, Professor of Dermatology & Pathology, Head, Dermatopathology Section, Director, Skin Pathology Laboratory, Boston University School of Medicine, Boston, MA., USA

Therese el Helou, MD Fellow, Dermatopathology, Boston University School of Medicine, Boston, MA., USA on July 4, 2006

The clinical presentation and the histologic findings are consistent with the diagnosis of Atrophie blanche / livedoid vasculitis.

Suggestions:
The patient was found to have Factor V Leiden gene heterozygous G1691A mutation, which was interpreted as probably non significant. Factor V G1691A gene mutation is listed among the most common inherited prothrombotic risk factors in children (1). There is an increased risk of venous thromboembolism for factor V Leiden deficiency in both heterozygous (7-fold) and homozygous (80-fold) phenotypes (4). The patient should be checked if he is only heterozygote for factor V Leiden deficiency or also is pseudohomozygote. Pseudohomozygotes are Factor V Leiden heterozygotes who carry a null mutation on the counterpart (non-Leiden) Factor V allele. Factor V Leiden pseudohomozygotes are exposed to the same risk for thrombosis as homozygotes (4).

Thrombophilia is a multifactorial disorder. The simultaneous occurrence of hereditary thrombophilias and prothrombotic polymorphisms was shown to substantially increase the risk of venous thromboembolism (5). Coexistence of established and potentially inherited conditions predisposing for thrombosis are found for Factor V:Q506 in association with protein C, protein S, antithrombin and heparin cofactor II deficiencies, and Lp (a) and histidine-rich glycoprotein levels increase( 2).
Coincidence of elevated Lp (a) with factor V:Q506 mutation or deficiencies of protein C or antithrombin increases the risk for thromboembolic events to 8.4 ( 3). The common occurrence of heterozygous factor V G1691A and homozygous 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T leads to hyperhomocysteinemia which was shown to confer a greater risk of venous thromboembolism than factor V G1691A alone ( 5).

More work up is suggested:
Factor II G20210A gene mutation (if not done, because it was listed as non detected), same for cryoglobulins (listed as not detected), apolipoprotein (a), homozygous C677T polymorphism in the methylenetetrahydrofolate reductase gene, antithrombin-deficiency, heparin cofactor II-deficiency, and levels of histidine-rich glycoprotein.

Treatment:
In addition to what he has already received more options mentioned in the literature (6, 7, 9) include warfarin, niacin, pentoxifylline, beraprost sodium (a synthetic Prostaglandin I2 analogue), IV immunoglobulin, hyperbaric oxygen therapy, tissue plasminogen activator (t-PA). If there is a deficiency of homocysteine metabolism, vitamin supplementation with folate, vitamin B12 and B6 is helpful (8).

References:

1- Nowak-Gottl U, Duering C, Kempf-Bielack B, Strater R. Thromboembolic diseases in neonates and children. Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec; 33(5-6):269-74. Review.
2- Ehrenforth S, Junker R, Koch HG, Kreuz W, Munchow N, Scharrer I, Nowak-Gottl U. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr. 1999 Dec; 158 Suppl 3:S97-104.
3- Nowak-Gottl U, Junker R, Hartmeier M, Koch HG, Munchow N, Assmann G, von Eckardstein A. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation. 1999 Aug 17; 100(7):743-8.
4- Simioni P, Castoldi E, Lunghi B, Tormene D, Rosing J, Bernardi F. An underestimated combination of opposites resulting in enhanced thrombotic tendency. Blood. 2005 Oct 1; 106(7):2363-5. Epub 2005 Jun 16.
5- Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, Berliner S, Inbal A, Many A, Lubetsky A, Varon D, Martinowitz U, Seligsohn U. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol. 1999 Mar; 19(3):511-8.
6- Juan WH, Chan YS, Lee JC, Yang LC, Hong HS, Yang CH. Livedoid vasculopathy: long-term follow-up results following hyperbaric oxygen therapy. Br J Dermatol. 2006 Feb; 154(2):251-5.
7- Calamia KT, Balabanova M, Perniciaro C, Walsh JS. Livedo (livedoid) vasculitis and the factor V Leiden mutation: additional evidence for abnormal coagulation. J Am Acad Dermatol. 2002 Jan; 46(1):133-7. Review.
8- Gibson GE, Li H, Pittelkow MR. J Am Acad Dermatol. 1999 Feb; 40(2 Pt 1):279-81. Homocysteinemia and livedoid vasculitis.
9- Carolyn Bryant Lyde. Atrophie blanche: a review from the perspective of a 31 patient cohort. Dermatologic Therapy, Vol.14, 2001, 111-116.