Proteus Syndrome: Successful Therapy of Severe Migraine Symptoms with low Molecular Weight Heparin

Symptoms with low Molecular Weight Heparin

V. Aumann, G. Lutze, A. Neumann, K. Mohnike and U. Mittler

Introduction

Proteus syndrome is a sporadically occurring dysplasia syndrome presumably caused by a lethal point mutation where only the carrier of a genetic mosaic is capable of surviving.

The clinical picture is characterized by a high variability. Symptoms include a partial or complete hemihyperthrophy of the body, partial gigantism of the hands or feet, ossification disorders of individual bones, subcutaneous and abdominal tumors (lipoma, hemangioma), pigmented moles and varicosis of the lower extre- mities with hardly any anomalies of the deep veins.

From the perspective of a differential diagnosis there is a close relationship to the Klippel-Trenaunay-Weber syndrome which is characterized by a triad of sym- ptoms consisting of hypertrophy of soft tissue and bones, cutaneous tumors and varicosis. The most important characteristics are anomalies of the deep venous system with atresia, hypoplasia, valvular incompetence, and aneurysmal dilatation.

Thrombophlebites and thromboembolic events such as pulmonary embolism have been frequently described.

Case report

A now 16-year-old boy shows a mostly right-sided partial hemihypertrophy with the feet, hand and shoulder being affected (Fig. 1). Naevus flammeus and superfici- al varices are also found on the lower legs and the distal upper legs. Syndactylia be- tween the 3 ^rd and 4 ^th left toe were removed surgically. Radiological tests (Fig. 2) con- firmed the varicosis and hypertrophies of the 1 ^st and 3 ^rd ray of hand and foot and of additional bone segments. MRT tests of the skull did not show any significant results. Since there were no anomalies of the deep veins, the Klippel-Trenaunay- Weber syndrome was considered unlikely and a Proteus syndrome was diagnosed instead.

The patient who attends high school with good credentials does not show acute symptoms of an illness. Severe migraine-like headaches have occurred since the age of seven with up to three attacks per week; this considerably impairs his life and his school attendance frequencies. An MRT excluded intracranial vascular malforma- tions (Fig. 2).

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Coagulation Diagnostics

Several coagulation tests did not reveal the presence of an inherited thrombophilia.

However, an increase in the prothrombin fragment 1+2 (F 1+2) and in D-dimer as well as elevated platelet aggregation indicated continuous coagulation activation.

Given an expected range of < 1.4 nmol/L, the prothrombin fragment 1+2 was per- manently elevated at a value of above 2.0 nmol/L (Fig. 3). The D-dimer levels were also constantly above 2.0 mg/L (expected value < 0.5 mg/L). Given the induced platelet aggregation with ADP at various concentrations, the pronounced effect of low ADP concentrations indicated an increased platelet aggregation or hyper-reac- tivity (Fig. 4).

Therapy

Under the assumption that the increased platelet aggregation may be considered the cause for the migraine-like pain attacks in addition to the existing vascular disturbances, acetyl salicylic acid (ASA) was first administered followed by a treat- ment with clopidogrel (Plavix). Both platelet aggregation inhibitors did not show any clinical success although the desired inhibition of the ADP-induced aggregation could be demonstrated under laboratory conditions. The treatment with Plavix was discontinued following a pain attack that lasted an entire day accompanied by vomiting and impaired vision. Treatment in a pain center and orthopedic, physio- therapeutic and paramedical treatment were not successful either.

Following a painful swelling of the right lower leg with a suspected venous thrombosis of the lower leg, low molecular weight heparin (Clexane) was adminis- tered since the thrombophilic situation had already been established. Surprisingly, the headache attacks disappeared almost completely. Currently the patient is admi- nistered Clexane 60 on a daily basis. Tests done before and after a Clexane 60 injec- tion show that the hypercoagulability largely disappears (Table 1).

Fig. 1. Clinical signs of the patient

Fig. 2. Radiological results

Phlebography: Varicosis without arteriovenous shunts and clot formation

X-ray examination of the hand and foot skeleton: Hypertrophic anomalies

Skull-MRT and Angio-MRT: no significant signs

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5

1 2 3 4 5 6 7 8

n m o l/l

Normal<1,4

Fig. 3. Prothrombin fragment 1+2 Course over time

3 2 1 µmol/l

Fig. 4. Induced platelet aggregation

Addition of ADP (final concentrations of 1, 2, and 3 mmol/L)

Table 1. Laboratory findings before and after Clexane 60 injections

Parameter Before injection 2 hours 4 hours

after injection after injection

F1+2 (nmol/L) 1.55 1.29 1.23

D-dimer (mg/L) 0.60 – 0.50

Clexane 60 (U/mL) < 0.10 0.48 0.56

Aggregation normal normal normal

Summary and Discussion

쐌 In addition to the partial hemihypertrophy, other changes which are also indi- cative of Proteus syndrome could be observed.

쐌 The patient has suffered from migraine-like headache attacks since the age of seven. Literature references mention in particular headache and thromboembo- lies when there are overlaps with the Klippel-Trenaunay-Weber syndrome.

쐌 Coagulation tests revealed in particular increased concentrations of the activati- on markers prothrombin fragment 1+2 and D-dimer and an increased platelet aggregation.

쐌 Following the administration of low molecular weight heparin, the patient was almost completely symptom-free. The reason for this may be that the pro- nounced varicosis caused an increased platelet activation together with an increase in plasmatic coagulation. The aggregate formation of the hyper-reactive platelets triggers the headache attacks. Since the effects of the drugs administered did not relieve the patient from his complaints, the increased plasmatic coagula- tion had to be considered the main cause. Heparin hence is currently the best- possible therapy option.

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