Kimberly Jett

Clinical and genetic aspects of neurofibromatosis 1

Neurofibromatosis 1 is an autosomal dominant disorder characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with neurofibromatosis 1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy. The diagnosis of neurofibromatosis 1 is usually based on clinical findings. Neurofibromatosis 1, one of the most common Mendelian disorders, is caused by heterozygous mutations of the NF1 gene. Almost one half of all affected individuals have de novo mutations. Molecular genetic testing is available clinically but is infrequently needed for diagnosis. Disease management includes referral to specialists for treatment of complications involving the eye, central or peripheral nervous system, cardiovascular system, spine, or long bones. Surgery to remove both benign and malignant tumors or to correct skeletal manifestations is sometimes warranted. Annual physical examination by a physician familiar with the disorder is recommended. Other recommendations include ophthalmologic examinations annually in children and less frequently in adults, regular developmental assessment in children, regular blood pressure monitoring, and magnetic resonance imaging for follow-up of clinically suspected intracranial and other internal tumors.

Quantification of aortic and cutaneous elastin and collagen morphology in Marfan syndrome by multiphoton microscopy.

In a mouse model of Marfan syndrome, conventional Verhoeff-Van Gieson staining displays severe fragmentation, disorganization and loss of the aortic elastic fiber integrity. However, this method involves chemical fixatives and staining, which may alter the native morphology of elastin and collagen. Thus far, quantitative analysis of fiber damage in aorta and skin in Marfan syndrome has not yet been explored. In this study, we have used an advanced noninvasive and label-free imaging technique, multiphoton microscopy to quantify fiber fragmentation, disorganization, and total volumetric density of aortic and cutaneous elastin and collagen in a mouse model of Marfan syndrome. Aorta and skin samples were harvested from Marfan and control mice aged 3-, 6- and 9-month. Elastin and collagen were identified based on two-photon excitation fluorescence and second-harmonic-generation signals, respectively, without exogenous label. Measurement of fiber length indicated significant fragmentation in Marfan vs. control. Fast Fourier transform algorithm analysis demonstrated markedly lower fiber organization in Marfan mice. Significantly reduced volumetric density of elastin and collagen and thinner skin dermis were observed in Marfan mice. Cutaneous content of elastic fibers and thickness of dermis in 3-month Marfan resembled those in the oldest control mice. Our findings of early signs of fiber degradation and thinning of skin dermis support the potential development of a novel non-invasive approach for early diagnosis of Marfan syndrome.

Internal tumor burden in neurofibromatosis Type I patients with large NF1 deletions

Neurofibromatosis Type 1 (NF1) is a frequent tumor suppressor gene disorder characterized by multiple benign tumors and high risk of malignancy. Internal tumor burden is a major disease‐associated manifestation and can be most adequately assessed by magnetic resonance imaging of the whole body. Approximately 5% of NF1 patients have constitutional large NF1‐deletions that are generally associated with more severe clinical manifestations. Here, we investigated whether these deletion patients also have more and/or larger internal tumors by assessing internal tumors and their total volume (exclusive of cutaneous and subcutaneous) in 38 NF1 deletion patients (including eight mosaic cases) and 114 age‐ and gender‐matched NF1 patients without deletions. The incidence of internal tumors was significantly lower in mosaic deletion patients (1/8 = 13%) but did not differ between the 30 nonmosaic deletion patients and the 90 age‐ and gender‐matched NF1 patients without large deletions used as controls. Neither the number nor the total volume of tumors per patient differed significantly between the latter two groups. However, extremely high tumor burden (>3,000 ml) was significantly more frequent among nonmosaic NF1 deletion patients than among NF1 patients without large deletions (13% vs. 1%, P = 0.014). Thus, as a group, patients with NF1 deletions do not exhibit a significantly higher internal tumor burden than NF1 patients without such deletions. However, deletion patients can frequently have extremely large internal tumors and thus demand special attention.

Cardiac characterization of 16 patients with large NF1 gene deletions

The aim of this study was to characterize cardiac features of patients with neurofibromatosis 1 (NF1) and large deletions of the NF1 gene region. The study participants were 16 patients with large NF1 deletions and 16 age‐ and sex‐matched NF1 patients without such deletions. All the patients were comprehensively characterized clinically and by echocardiography. Six of 16 NF1 deletion patients but none of 16 non‐deletion NF1 patients have major cardiac abnormalities (p = 0.041). Congenital heart defects (CHDs) include mitral insufficiency in two patients and ventricular septal defect, aortic stenosis, and aortic insufficiency in one patient each. Three deletion patients have hypertrophic cardiomyopathy. Two patients have intracardiac tumors. NF1 patients without large deletions have increased left ventricular (LV) diastolic posterior wall thickness (p < 0.001) and increased intraventricular diastolic septal thickness (p = 0.001) compared with a healthy reference population without NF1, suggestive of eccentric LV hypertrophy. CHDs and other cardiovascular anomalies are more frequent among patients with large NF1 deletion and may cause serious clinical complications. Eccentric LV hypertrophy may occur in NF1 patients without whole gene deletions, but the clinical significance of this finding is uncertain. All patients with clinical suspicion for NF1 should be referred to a cardiologist for evaluation and surveillance.

Effect of vitamin D3 treatment on bone density in neurofibromatosis 1 patients: A retrospective clinical study

OBJECTIVES We have previously demonstrated reduced bone density and an increased incidence of 25-hydroxy vitamin D3 (25-OH D3) deficiency in adults with neurofibromatosis 1 (NF1) compared to healthy controls. Vitamin D3 is a cheap, safe, and effective supplement in the general population, but its value in NF1 patients has not been demonstrated. This study investigates the therapeutic potential of oral vitamin D3 on bone mineral density (BMD) in NF1 patients with vitamin D3 deficiency. METHODS We measured serum 25-OH D3, parathyroid hormone, calcium, and bone alkaline phosphatase concentrations, urinary deoxypyridinoline concentrations, and BMD in 35 adults with NF1. Nineteen patients received vitamin D3 supplementation for 2 years, six patients received supplementation for 1 year and 10 patients received no supplementation. Supplementation was administered in a dose that maintained the serum 25-OH D3 level above 30 μg/l. BMD was measured again at 1 and 2 years, and biochemical assessments of bone metabolism were measured at least every half year during therapy. RESULTS Treated subjects had significantly reduced loss of BMD, as measured by T score at the hip (p=0.011) and lumbar spine (p=0.022). The effect on hip BMD was apparent at 1 year in comparison to baseline (p=0.02) and was greater at 2 years in comparison to measurements at 1 year (p=0.02). CONCLUSIONS Vitamin D3 supplementation improves BMD in adult NF1 patients. Further studies are needed to elucidate the mechanisms responsible for reduced BMD in NF1 patients.

Cerebrovasculopathy in NF1 associated with ocular and scalp defects

Vascular lesions are uncommon in children with neurofibromatosis 1 (NF1) but can cause serious complications. We report on a child with NF1 who presented at 18 months of age with symptomatic stenosis of the left middle cerebral artery and its branches, and associated moyamoya disease. She also had bilateral posterior embryotoxon, left corneal opacity (Peters anomaly), and cutis aplasia of the left scalp. All of these defects may have occurred as a result of disruption of the blood supply caused by NF1 vasculopathy prenatally. This constellation of vascular anomalies has not been previously reported in a patient with NF1.

The generalized bone phenotype in children with neurofibromatosis 1: A sibling matched case–control study

People with neurofibromatosis 1 (NF1) have low bone mineralization, but the natural history and pathogenesis are poorly understood. We performed a sibling‐matched case–control study of bone mineral status, morphology, and metabolism. Eighteen children with NF1 without focal bony lesions were compared to unaffected siblings and local population controls. Bone mineral content at the lumbar spine and proximal femur (dual energy X‐ray absorptiometry (DXA)) was lower in children with NF1; this difference persisted after adjusting for height and weight. Peripheral quantitative computed tomography (pQCT) of the distal tibia showed that trabecular density was more severely compromised than cortical. Peripheral QCT‐derived estimates of bone strength and resistance to bending and stress were poorer among children with NF1 although there was no difference in fracture frequencies. There were no differences in the size or shape of bones after adjusting for height. Differences in markers of bone turnover between cases and controls were in the directions predicted by animal studies, but did not reach statistical significance. Average serum calcium concentration was higher (although within the normal range) in children with NF1; serum 25‐OH vitamin D, and PTH levels did not differ significantly between cases and controls. Children with NF1 were less mature (assessed by pubertal stage) than unaffected siblings or population controls. Children with NF1 have a generalized difference of bone metabolism that predominantly affects trabecular bone. Effects of decreased neurofibromin on bone turnover, calcium homeostasis, and pubertal development may contribute to the differences in bone mineral content observed among people with NF1.

Quantitative associations of scalp and body subcutaneous neurofibromas with internal plexiform tumors in neurofibromatosis 1

Internal plexiform neurofibromas are a major cause of adverse outcomes in patients with neurofibromatosis 1 (NF1). We investigated the relationship of the numbers of subcutaneous neurofibromas of the scalp or body to internal plexiform tumor volume in 120 NF1 patients who had undergone whole body magnetic resonance imaging (MRI). We identified internal plexiform neurofibromas in 55% of patients, subcutaneous neurofibromas of the body in 75%, and subcutaneous neurofibromas of the scalp in 45%. The number of subcutaneous neurofibromas of the body and scalp were associated with each other (Spearmans Rho = 0.36; P < 0.001). The presence of internal tumors was associated with the presence (odds ratio [OR] = 4.38, 95% confidence interval [CI] 2.04–9.86, P < 0.001) and number (OR = 1.06 per neurofibroma, 95% CI 1.02–1.13, P < 0.001) of subcutaneous neurofibromas of the scalp. The total internal tumor volume was associated with the number of subcutaneous neurofibromas of the body (OR = 1.00086 per neurofibroma, 1.000089–1.0016, P = 0.029) and of the scalp (OR = 1.056 per neurofibroma, 1.029–1.083, P < 0.0001). Numbers of subcutaneous neurofibromas of the scalp and body are associated with internal plexiform tumor burden in NF1. Recognition of these associations may improve clinical management by helping to identify patients who will benefit most from whole body MRI and more intense clinical surveillance.