NF1 is an autosomal dominant condition caused by heterozygous mutations of the NF1 gene, which is located on chromosome 17.4
NF1 has approximately 100% penetrance and variable phenotypic expression with 50% of cases being sporadic.14
This disorder mainly involves the skin (café-au-lait macules, intertriginous freckling), peripheral nervous system (neurofibromas) and iris (Lisch nodules).3 4
Furthermore, NF1 patients may develop learning disabilities, central nervous system abnormalities, plexiform neurofibromas, gastrointestinal tumours and bony dysplasia.1 3 4
Our patient met the National Institutes of Health consensus criteria for the diagnosis of NF115
because she had (1) more than six café-au-lait macules >15 mm in greatest diameter, (2) multiple cutaneous neurofibromas and (3) axillary and inguinal freckling.
NF1 can also cause arterial vasculopathies but the frequency and pathogenesis of this serious complication of the disease remains not well-known.2 4 16
NF1 vasculopathy mainly involves the cerebral, renal, coronary and peripheral vascular beds2 4 6
and may produce stenosis, occlusion, aneurysm, rupture or arteriovenous fistula formation.4 16
In addition to malignant peripheral nerve sheath tumours, vasculopathies are the most relevant causes of early death in NF1 individuals.4
Neurofibromin, the NF1 gen-encoded protein, has a role in both tumour suppression and regulation of cell growth and proliferation.3 16
Since neurofibromin is expressed in endothelial and smooth muscle cells of blood vessels,2 16
it has been hypothesised that its deficient function could originate a vasculopathy by impairing the response of these cells to growth suppressor signals.16
Pulmonary arteriopathy and secondary PAH have been recognised in NF1 patients and the long-term prognosis of such association is poor.2
To our knowledge, as of January 2010, this association (NF1-PAH) has been described in 12 patients2 5–10
(female/male ratio 9/3; mean age 53.8 y (16–72)). All patients suffered from gradually progressive dyspnoea. The presence of a pulmonary vasculopathy may be suspected on the basis of the mosaic pattern of lung attenuation seen on the chest CT or high resolution CT. The mosaic pattern is defined as sharply demarcated areas of heterogeneous attenuation in the pulmonary parenchyma and it can arise from cardiac, lung and vascular disease.2
Therefore, such radiological findings could not be considered as a specific or pathognomonic sign of pulmonary vasculopathy. The mosaic pattern has been observed in 4 of the 12 cases of NF1-associated PAH previously reported. In our patient, pulmonary vasculature appeared normal and mosaic pattern was not detected.
In the 12 previous cases, like in ours, extensive workup revealed no evidence of diseases or findings to explain PAH other than NF itself. Pathological study was performed in only three patients,2 9
which revealed increased intimal and medial thickness and plexiform (or angiomatoid) lesions in the pulmonary arterial bed.
The bone morphogenic protein receptor 2 (BMPR2) gene is mutated in 70% of patients with familial PAH and 20–25% of patients with idiopathic PAH.2 17
BMPR2 gene analysis is very important to exclude a heritable or idiopathic PAH when the familial history of the patient is unsure. BMPR2 gene analysis has been performed in 5 of the 12 previous cases of NF1-associated PAH and no mutations or rearrangements were found in them. We did not perform BMPR2 gene testing in the present case but the patient had no familial history of PAH or NF1.
Despite the adverse outcome, some improvement in symptoms and pulmonary pressures can be achieved by both supportive and specific treatment for pulmonary hypertension—calcium channel blockers, endothelin receptor antagonists, prostanoids and phosphodiesterase type-5 inhibitors.2 13 18–20
Therefore, when dealing with NF1 patients with progressive dyspnoea and/or syncope, clinicians should do not forget the possible presence of NF1-associated PAH.
- NF1 is one of the most common inherited disorders. People with NF1 can develop a characteristic vasculopathy, which may affect vessels ranging in size from the proximal aorta to small arterioles.
- PAH has been described in NF1 patients and is thought to be caused by a NF1-related vasculopathy.
- NF1 patients with progressive dyspnoea and/or syncope should be investigated to rule out the presence of PAH. However, NF1-associated PAH is a diagnosis of exclusion and patients need proper workups to exclude secondary causes of PAH.
- Patients with NF1 and PAH have a generally poor long-term prognosis but some improvement can be achieved using supportive and specific treatment.