Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in man, affecting 1 in 3500 people. NF1 is a complex neurocutaneous disorder with an increased susceptibility to develop both benign and malignant tumors but with a wide spectrum of inter and intrafamilial clinical variability. The most prominent clinical hallmarks of the disorder are café-au-lait macules, neurofibromas, Lisch nodules of the iris, and axillary freckling. Other clinical manifestations are abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems, facial and body disfigurement, cognitive deficit, and malignancies of the peripheral nerve sheath and central nervous system. About 25% of people with neurofibromatosis type 1 develop one or more of these clinical complications, which together cause significant morbidity and mortality. The tumors that occur in neurofibromatosis type 1 are dermal and plexiform neurofibromas, optic gliomas, malignant peripheral nerve sheath tumors, pheochromocytomas, and rhabdomyosarcomas. Children with neurofibromatosis type 1 have an increased risk of developing myeloid disease, particularly juvenile chronic myeloid leukemia.
Neurofibromatosis type I is caused by mutation in the neurofibromin gene, NF1. The NF1 gene on chromosome 17q11.2 spans more than 350 kb of genomic DNA and contains 60 exons. The 8,457 bp open reading frame predicts a protein of 2,818 amino acids with an estimated mass of 327 kDa. The NF1 gene product, neurofibromin, contains a 360 amino acid region with homology to the catalytic domain of the mammalian guanosine triphosphatase activating protein. Over 70% of NF1 germline mutations cause truncation or loss of the encoded protein.
Approximately 5-20% of all NF1 patients carry a heterozygous deletion of usually 1.5 Mb involving the NF1 gene and contiguous genes lying in its flanking regions, which is caused by unequal homologous recombination of NF1 repeats. To date, several children with some features of neurofibromatosis type 1 and hematologic malignancies have been identified with homozygous mutations in the mismatch repair genes MLH1 and MSH2. The establishment of genotype-phenotype associations in NF1 is potentially useful for targeted therapeutic intervention but has generally been unsuccessful, apart from small subsets of molecularly defined patients.
Al-Gazali et al. (2010) reported an Iraqi child, living in the United Arab Emirates, with Neurofibromatosis type 1. A novel frameshift deletion was identified in NF1 gene.
Nanda (2008) described two patients of neurofibromatosis type 1 having an association with vitiligo in one, and alopecia areata and autoimmune thyroiditis in another.
Tarrass (2008) described a patient with an association of Neurofibromatosis Type I with Focal and Segmental Glomerulosclerosis. The 58-year-old male patient with known NF1 presented with deteriorating renal function. He had no family history of NF or kidney disease. Upon examination, he was found to be hypertensive, and had café au lait spots and multiple neurofibromas scattered all across his chest, back, and arms. Serum creatinine was high at 6.5 mg/dl, and urinalysis showed proteinuria of 4 g/day, with microscopic hematuria. Renal biopsy revealed FSGS with severe interstitial fibrosis and tubular atrophy. Tarrass (2008) suggested linkage investigation to assess whether the co-occurrence of these two evidences was coincidental or linked to the same gene defect.
Jacob and Chand (1995) reported massive cerebral infarction in an Omani man aged 32-years with neurofibromatosis type 1. This patient was not known to be hypertensive or diabetic and was not a smoker. He was brought to the emergency with one day history of altered consciousness and left sided weakness. Clinically, he was found to have high blood pressure of 170/125 mmHg, although his cardiovascular system was normal. He was noticed to have multiple skin lesions (measured 2cm by 3cm) of café au lait spots and freckles all over his chest, abdomen and hips, as well as soft subcutaneous neurofibromas on the extremities and trunk, and osteoma on the sternum. Neurologically, he was drowsy, inattentive, obeying simple commands, had dense left hemiplegia and hemianesthesia, but there were no signs of meningeal irritation. Investigations revealed evidence of renal failure with elevation of blood urea and serum creatinine, normal blood counts, and normal blood biochemistry. Chest x-ray was normal, but abdominal ultrasound revealed a small right kidney (hypoplastic or ischemic). CT scan of the brain showed extensive infarction due to internal carotid artery occlusion which manifested as large non-enhancing hypodense areas on the right frontal, temperol and occipital lobes. Other investigations were planned (carotid Doppler studies, echocardiogram and carotid angiogram) but the patient's condition deteriorated and he became unresponsive and then died. The patient's family refused autopsy. Jacob and Chand (1995) concluded by mentioning that neurofibromatosis could cause cerebral infarction in the young.
Koul et al. (2000) reported the diagnosis of neurofibromatosis type 1 in monozygotic twins with Dandy-Walker syndrome. The twins, both males, were born at term vaginally to non-consanguineous parents and at delivery they were noted to be monozygotic twins as there was a single placenta. There were no antenatal or perinatal complications. As motor and mental developmental delay was noticed by the parents, these children at the age of 32-months were referred to the authors' care for neurological evaluation, which revealed marked motor delay (head control at nine months, sitting at one year, and just standing with support when seen) and no speech development. Examination revealed head circumference at the 50th percentile but both weight and height were below the third percentile. Both children had dysmorphic features which were not descriptive of any syndrome, including prominent forehead, hypotelorism, low set ears and prominent occiput. In addition to these features, they had café-au-lait spots seen more on their trunks with few of 5 cm2 in size, along with few depigmented spots. A diagnosis of neurofibromatosis type 1 was made on the bass of the presence of the features of café-au-lait, microcephaly and short stature. Routine investigations, including blood count, liver and renal function tests, nerve conduction studies and brainstem auditory evoked potential, and karyotyping were normal. In both children, CT scan of the brain revealed typical features of Dandy-Walker syndrome which were cerebellar aplasia, cystic dilatation of the fourth ventricle and enlarged posterior fossa. In addition, one twin had hydrocephalus as well. Koul et al. (2000) suggested an underlying genetic basis for this unique association of neurofibromatosis type 1 with Dandy-Walker syndrome in monozygotic twins.
Alkindy et al. (2012) evaluated the clinical phenotype associated with the specific types of NF1 mutation in a retrospectively recorded clinical dataset comprising 149 NF1 mutation-known individuals from unrelated families. Each patient was assessed for 10 NF1-related clinical features, including the number of café-au-lait spots, cutaneous and subcutaneous neurofibromas and the presence/absence of intertriginous skin freckling, Lisch nodules, plexiform and spinal neurofibromas, optic gliomas, other neoplasms (in particular CNS gliomas, malignant peripheral nerve sheath tumors (MPNSTs), juvenile myelomonocytic leukemia, rhabdomyosarcoma, phaechromocytoma, gastrointestinal stromal tumors, juvenile xanthogranuloma, and lipoma) and evidence of learning difficulties. Patients were subcategorized according to their associated NF1 germ line mutations: frame shift deletions (52), splice-site mutations (23), nonsense mutations (36), missense mutations (32) and other types of mutation (6). A significant association was apparent between possession of a splice-site mutation and the presence of brain gliomas and MPNSTs (p?=?0.006).
Alorainy (2006) reviewed and analyzed the MRI studies on 808 pediatric patients (aged 3 days to 15 years) over a 3-year period. A total of 114 congenital cerebral malformations were identified in 86 of these patients via MRI. Nine patients were identified with neurofibromatosis.
Bin Amer and Al-Khenaizan (2007) described a patient with Neurofibromatosis in association with malignant melanoma. The 21-month old Saudi boy presented with fever, cough, respiratory distress, and progressive bone pain in the right leg. He was found to have hepatosplenomegaly, and decreased air entry with coarse crepitations. CT chest showed large opacities in both lungs. There was severe tenderness over the right femur, and CT showed bone destruction in the proximal right femur. The patient had major pigmentary changes on the skin; multiple café-au-lait macules on the trunk and extremities, skin-colored firm neurofibromas on the back, and a giant speckled lentiginous nevus extending from the waist to mid-thighs studded with multiple hairy giant congenital melanocytic nevi. Biopsy results of the skin and bone were consistent with a diagnosis of invasive malignant melanoma. A week after the diagnosis, the patient died of respiratory failure.
Gouider et al. (1994) conducted a multidisciplinary transversal descriptive study (June-October 1992) to determine the clinical manifestations and laboratory findings observed in 66 patients from Tunisia with type 1 neurofibromatosis. All patients over the age of 25 had café-au-lait spots, neurofibromas, lentigines and nodules. Occurrence of lesions of the central nervous system was significantly earlier than peripheral nervous manifestations. The optic glioma was the most frequent lesion of the central nervous system. Complications were observed during the first twenty years of the disease.
Hamza el al. (1996) reported a 45-year old woman with neurofibromatosis type 1 presented with the third largest plexiform neuroma described and the first from the Middle East of such dimension. The woman consulted for massive swelling of both buttocks almost reaching to the mid thighs, increasing in size steadily since birth. Clinical examination revealed café-au-lait spots, neurofibromas, plexiform neuromas, axillary and inguinal freckling. Two of her children showed signs of the disease including skin freckling and café-au-lait spots. Genetic studied revealed all the family members carrying the NF1 gene on chromosome 17.
[See also: Iraq > Al-Gazali et al., 2010].
Ben-Salem et al. (2013) studied 12 neurofibromatosis type I patients, of which 7 belonged to 4 different families and 5 were sporadic cases. Genetic analysis of the cohort helped unveil 9 heterozygous mutations in the NF1 gene. These included a large novel 9.2 kb deletion in three members of a family, a novel missense mutation (c.6374T>C, p.Leu2125Pro) in two members of another family, and a novel frameshift (c.1846delC, p.Gln616ArgfsX15) in another family. Sporadic mutations included 3 novel frameshift mutations (c.4065_4066delAG, p.Glu1356IlefsX17; c.5346delT, p.Ile1782MetfsX60; c.3291delA, p.Ala1098ProfsX14), a known nonsense mutation (c.6546C>G, p.Tyr2182X), a known missense mutation (c.2540T>C, p.Leu847Pro) and a known splice site mutation (c.1062+2T>C). Both missense mutations found in the study occurred at highly conserved residues and were predicted by in-silico analysis to be pathogenic. It was noted that no obvious genotype-phenotype correlations were observed in the cohort. Also, the analysis indicated the absence of hotspots in the NF1 gene.
Mandani et al. (1996) reported the case of a boy aged just over five years with neurofibromatosis type 1, who developed precocious puberty at the age of four years. The latter disorder appeared to have a CNS origin.
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