Neurofibromatosis type 1 associated with systemic vasculopathy

ARTICLE

Neurofibromatosis (NF) is a multisystemic, neurocutaneous syndrome with high phenotypic heterogeneity.

Riccardi [1] has proposed a classification system that distinguishes NF1, the most common type of NF (with an incidence of approximately 1:3000), from the central, acoustic type and from at least six rarer forms of NF. Patients suffering from NF1 may present a wide variety of lesions. However, the diagnosis of NF1 can be presumed by the presence of a few hallmarks: "café au lait" spots, neurofibromas, axillary freckling, optic glioma, Lisch nodules. Mesodermal tissues involved in NF1 include the musculo-skeletal system (kyphoscoliosis, thining of the long bone cortex, bone cysts, pseudoarthrosis) and cardiovascular tissues (arterial dysplasia or vascular NF) [2].

In 1988, the NIH Consensus Development Conference Statement for the diagnostic criteria for NF1 established that none of these lesions by itself is pathognomic for NF1. In addition, the prevalence of these major manifestations varies with the age of the patient, so that for example, neurofibromas are rarely seen in infants but are almost always present in older patients with the disease [3].

Vascular manifestations are uncommon [2-4] but are usually found in extracranial locations, particularly in the renal arteries, which results in renovascular hypertension, in about 1% of NF1 patients [5]. They have also been noted in the heart and in the carotid and vertebral arteries [6]. Cerebral vascular disease associated with NF1 is rare, with only 18 cases described up to 1994, all of which were of an occlusive nature [7].

Reubi, in 1945, was the first to describe and classify vascular lesions in small and large vessels [8]. In small vessels (less than 1mm diameter) Salyer and Salyer [9] distinguished four types of involvements: pure intimal, advanced intimal, intimal aneurysmal and nodular. Both stenotic and aneurysmal formations may be due to intimal proliferation, medial thinning, and/or elastic tissue fragmentation [10].

The pathogenesis of these lesions is totally obscure. The absence of adjacent neurofibromas suggests that one or more cell types of the arterial wall are capable of expressing an NF1 gene mutation [2].

Recently [11], some authors have studied mRNA expression of the NF1 gene in blood vessels and they found some alterations. At the moment, the functional significance of these variants and their effects on neurofibrinomina, the NF1 gene product, is not known.

Here we report the case of a young woman affected by NF1, having numerous clinical features, including hypertension of a renovascular origin, which is the most common clinical manifestation of systemic vasculopathy. We believe that this is a case of vascular neurofibromatosis [6].

Case report

A 29 year-old woman was admitted to our hospital after dematological and general examinations that had revealed multiple, subcutaneous neurofibromas, axillary freckles and "café au lait" spots exceeding 5 mm in diameter. They were distributed over the head, trunk and arms (Figs. 1 and 2).

The young woman also presented speech impediments, including excessive nasality and imprecise consonants, and a recurrent hiccup.

Her father was affected by NF1. She had no brothers or sisters.

At 15 years of age, a mild mental retardation had been demonstrated and a diagnosis of NF1 was made.

At the same time, the girl developed mild renal hypertension and underwent surgery involving aorto-aortic, aorto-right renal and aorto-mesenteric by-pass and with multiple prosthesic revascularization. At 25 years of age, additional surgery was performed as a consequence of a pseudoaneurism and re-stenosis of the right renal artery.

At 27 she suffered an ischemic attack as a result of anterior cerebral arterial occlusive disease. On that occasion there was a subtotal occlusion of the carotid syphon in the intracavernous tract of the sylvian artery. It was at this time, that the patient first reported a loss of consciousness, which was subsequently followed by many similar episodes.

During her numerous hospitalizations, laboratory data included hemograms that were all lower than normal (R.G.: 3.90 x 10 ⁶/microl; Hb: 7.3 g/dl; HCT: 23.10%), the platelet counts were normal (PLT: 308 x 10 ³/microl). The prothrombin time and the partial thromboplastin time were within normal limits.

Her mean blood pressure was found to be 180/100 mmHg. Creatinine levels and serum and urinary levels of vanillimandelic acid and homovanillic acid were normal.

At the time of our observation, the brain CT scan showed frontal and bilateral parietal areas of abnormal uptake in the area of a previous infarct and dilatation of the cisterna magna (Figs. 3 and 4).

Doppler analysis of epiaortic arteries showed partially obliterated flow in the common carotid arteries, bilaterally, and a few other alterations in cerebral flow.

Ocular findings showed the presence of multiple, bilateral, iris Lisch nodules, which are diagnostic features of NF1. Moreover, the patient presented severe bilateral retinal hypertension.

The renovascular situation was clinically defined by the presence of a peri-namel puff. The arteriographic findings for the abdominal aorta, at the time of our observation, showed the presence of the previous aorto-aortic by-pass, with evidence of collateral circulation between mesenteric and renal arteries (Fig. 5). A subsequent CT scan of the abdomen revealed the dilatation and displacement of the abdominal aorta. Nephroscintigraphy with 99m Tc showed hypoperfusion and reduced glomerular filtration in the right kidney (Fig. 6).

During hospitalization, the patient began therapy with anti-epileptic, anti-hypertensive and anti-aggregant drugs. The blood pressure was lowered to 120/80 mmHg.

She died about one year later, not during hospitalization but in her home, at the age of 30, as a consequence of another cerebral ischemic attack. Unfortunately, histopathological material was not made available.

Discussion

NF1-associated arterial dysplasia is characterized by an accumulation of mucoid substance in the intima and in myointimal tissues, which may result in stenosis, occlusions, ruptures, arteriovenous (A-V) fistulae or aneurysms involving large and medium-sized arteries [12].

The frequency of arterial involvement in NF1 has probably been understimated because many of these lesions are clinically silent or are not considered to be a part of the disease [2].

The entire arterial tree, from the proximal aorta to the small arteries, may be subject to involvement by the NF1 gene mutation. Neverthless, the renal arteries, that contain a large concentration of nerve endings of Schwann cell origin, represent the most common area of involvement of vascular disease [13]. In the presence of hypertension and normal catecholamine levels, particularly in young patients, renal artery disease should be suspected. The frequency of cerebral vascular disease in NF1 patients is more difficult to estimate. It should be suspected in young NF1 patients with convulsions and/or hemiparesis [14]. It usually involves the carotid, the middle cerebral and the anterior cerebral arteries [15, 16]. Collateral flow is usually present around the occlusive cerebral lesion. It can have the appearance of a puff of smoke (Moya-Moya disease).

Our young patient presented a fatal cerebral symptomatology that was the suggestive sign of a severe systemic vasculopathy, although it was not confirmed by histologic specimens.

We hope that further studies on the functional consequences of the loss of NF1 gene expression will explain the pathogenesis of the arterial dysplasias seen in NF1 [3, 10].

REFERENCES

1. Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981; 305: 1617-27.

2. Riccardi VM, Eichner JE. Neurofibromatrosis. The John Hopkins University press, Baltimore, 1986; 115-8.

3. Von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1: pathology, clinical features and molecular genetics. Brain Pathol 1995; 5: 153-62.

4. Lehrnbecher T, Gassel AM, Rauch V, Kirchner T, Huppertz HI. Neurofibromatosis presenting as a severe systemic vasculopathy. Eur J Pediatr 1984; 153: 107-9.

5. Finley JL, Dabbs DJ. Renal vascular smooth muscle proliferation in neurofibromatosis. Hum Pathol 1988; 19: 107-10.

6. Greene JF, Fitzwater JE, Burgess J. Arterial lesions associated with neurofibromatosis. Am J Clin Pathol 1974; 62: 481-7.

7. Steel TR, Bentivoglio PB, Garrick R. Vascular neurofibromatosis affecting the internal carotid artery: a case report. Br J Neurosurg 1994; 8: 233-7.

8. Reubi F. Neuromatosis et lesions vasculaires. Schw Med Wochens, 1945; 75: 463.

9. Salyer WR, Salyer DC. The vascular lesions of neurofibromatosis. Angiology 1974; 25: 510-9.

10. Schievink WI, Michels VV, Piepgras DG. Neurovascular manifestations of heritable connective tissue disorders. A review. Stroke 1994; 25: 889-903.

11. Ahlegren-Beckendorf JA, Maggio WW, Chen F, Kent TA. Neurofibromatosis 1 mRNA expression in blood vessels. Bioch Biophys Res Com 1993; 197 (2): 1019-24.

12. Deans WR, Bloch S, Leibrock L, Berman BM, Skultety FM. Arteriovenous fistula in patients with neurofibromatosis 1. Neurorad 1982; 144 (1): 103-7.

13. Nopajaroonsri C, Lurie AA. Venous aneurism, arterial dysplasia and near-fatal hemorrages in neurofibromatosis type 1. Hum Pathol 1996; 27 (9) : 982-5.

14. Taboada D, Alonso A, Moreno J, Muro D, Mulas F. Occlusion of the cerebral arteries in Recklinghausen's disease. Neurorad 1979; 18: 281-4.

15. Tomsick TA, Lukin RR, Chambers AA, Benton C. Neurofibromatosis and intracranial arterial occlusive disease. Neurorad 1979; 11: 229-34.

16. Cluzel P, Pierot L, Leung A, Gaston A, Kieffer E, Chiras J. Vertebral arteriovenous fistula in neurofibromatosis: report of two cases and review of the literature. Neurorad 1994; 36: 321-5.