This month, our discussion continues about the newly released American College of Medical Genetics and Genomics (ACMG) clinical practice resource for adults with NF1.  The resource, written for general practitioners and other healthcare professionals, summarizes current knowledge of clinical care and proposes an approach to management for general practitioners and other healthcare professionals providing care to individuals with NF1.  I’d like to focus on a review of the ACMG recommendations in three areas: hypertension and vasculopathy; osteoporosis; and cutaneous neurofibromas.

Hypertension and Vasculopathy

The most common reason for hypertension, or high blood pressure, in individuals with NF1 is essential hypertension, which means that there is no known cause for why the high blood pressure is occurring.  This is similar to hypertension occurring in the general population.  Another cause of hypertension in individuals with NF1 is pheochromocytoma, a tumor of the adrenal gland discussed in last month’s blog that affects fewer than 5% of people with NF1. The tumor causes the irregular and excessive release of the hormones epinephrine and norepinephrine, causing symptoms of high blood pressure as well as rapid heart rate and palpitations, flushing, and excessive sweating. 

An important cause of hypertension in children and young adults with NF1 is renal artery stenosis, which is a narrowing of the artery that carries blood to the kidney. The kidneys control blood pressure by regulating the amount of water excreted from the body, and restriction in blood flow causes the kidneys to misinterpret this as low blood pressure in the body. In response, the kidneys release hormones that raise blood pressure and result in hypertension. It’s important to monitor blood pressure in people with NF1 beginning in childhood. If blood pressure is elevated, a vascular imaging study such as MRA (magnetic resonance arteriogram) is performed to diagnose the problem. If renal artery stenosis is found, it is treated with medication and sometimes surgery or stenting of the vessel to increase blood flow.

Vascular problems can occur in other areas of the body in people with NF1.  Moyamoya disease is a rare vascular disorder in which the internal carotid artery to the brain becomes blocked or narrowed, reducing blood flow to the brain.  In response to the blockage, which develops very slowly, tiny blood vessels open up in the brain in an attempt to restore blood flow. The word “moyamoya” means “puff of smoke” in Japanese (the condition was first described in Japan, among children who did not have NF1), which describes the appearance on an angiogram (where dye is injected into the artery and it is visualized by X-ray) of the cluster of blood vessels formed that compensate for the carotid artery blockage. Moyamoya disease significantly increases the risk of stroke and transient ischemic attack (TIA), a temporary reduction of blood flow to the brain.  Moyamoya occurs with increased frequency in individuals – usually children – with NF1, and is especially common among children exposed to radiation therapy to the brain for treatment of a brain tumor.

Other blood vessels can be narrowed in individuals with NF1, causing a weakening of the arterial wall and an increased risk of hemorrhage. However, screening for vascular problems in people with NF1 isn’t routinely performed unless there are instances of high blood pressure or TIA.  In these cases, a vascular imaging study would be performed to locate the vascular abnormality. 

Osteoporosis

Decreased bone mineral density and osteoporosis are more common in people with NF1 than the general population. Some studies have shown vitamin D deficiencies in people with NF1, which increases the risk of osteoporosis. A possible contributing factor to vitamin D deficiency may be that individuals with skin neurofibromas tend to cover up more often and not be exposed to enough sunlight as a result. Vitamin D deficiency is also common in the general population, and the practice resource recommends vitamin D supplementation to maintain regular levels. It’s important to note that supplementation should be done under the supervision of a physician to avoid toxicity that can occur with taking too much of the vitamin.  If osteoporosis is diagnosed, the treatments are the same as those for the general population, including the administration of medications to increase bone mineral density.

Cutaneous Neurofibromas

Cutaneous neurofibromas, benign tumors in or on the skin, are common in adults with NF1.  Numbers of tumors can be highly variable, with some individuals having very few and others having a wide distribution covering a large portion of the body. Cutaneous neurofibromas typically increase in number during puberty and continue to progress during adulthood. A substantial proportion of women develop them during pregnancy, and the neurofibromas typically don’t regress when the pregnancy is over. Studies indicate that quality of life for people with cutaneous neurofibromas can be significantly impaired, with major cosmetic concerns often arising in those with a large number and wide distribution of neurofibromas due to the potentially disfiguring aspect of the tumors. Also, the tumors may itch, cause pain, and can sometimes bleed. 

There is no known prevention of cutaneous neurofibromas, and the recommended treatment is surgical removal by a physician who has experience removing cutaneous neurofibromas.  Treatment with a specialized laser called the COlaser has also shown success in removing cutaneous neurofibromas. Another treatment called electrodessication uses heat generated from electricity to remove the tumors. Anesthesia is often required if a large number of tumors are being removed at one time.  The risks of these treatments include scarring and regrowth of the neurofibromas.  Studies have shown that individuals treated with these approaches tend to be satisfied over a period of months following the procedure, but we do not have long term follow-up studies to know how long lasting the benefit might be.  

Here at UAB we are continuing our clinical trial targeting cutaneous neurofibromas using the investigational drug selumetinib, which has been shown to often be effective in reducing the growth of plexiform neurofibromas.  The trial is actively recruiting study participants at two study locations, UAB and the National Cancer Institute in Bethesda, Maryland. More information regarding the trial can be found at: www.clinicaltrials.gov(study number NCT02839720).