Novel phenotypes of NF1 patients from unrelated Chinese families with tibial pseudarthrosis and anemia

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant, multi-system, neurocutaneous disorder, manifested with neurofibromas and Cafe´-au-lait spots. Germline mutations in NF1 gene are associated with Neurofibromatosis type 1. NF1 gene encodes neurofibromin, a RAS-specific GTPase activating protein. In our study, we present a clinical molecular study of four Chinese probands with NF1 from four unrelated families, showing extreme phenotypic variation with rare phenotype. In family 1, the proband is a 16 months old girl with multiple café-au-lait spots throughout her whole body. In family 2, the proband is a 6 months old girl with several café-au-lait spots mostly in her trunk and in lower limbs. In family 3, the proband is a 4 months old boy with several café-au-lait spots, tibial pseudarthrosis, and chronic iron deficiency anemia. In family 4, the proband is a 14 years old boy with multiple café-au-lait spots of variable sizes. Targeted exome capture based next generation sequencing and Sanger sequencing identified a novel mutation and three previously reported mutations in these four probands. These four mutations in NF1 gene were causing disease phenotypes in these four probands and was absent in unaffected family members and in healthy controls. According to the variant interpretation guideline of American College of Medical Genetics and Genomics (ACMG), these four mutations, are classified as “likely pathogenic”. Our result expands the mutational spectrum of the NF1 gene associated with neurofibromatosis type1.

Clinical and molecular characterization of 112 single-center patients with Neurofibromatosis type 1

“…The underlying pathogenic mechanisms of the skeletal defects are not fully understood and could have a multifactorial etiology. Recent studies showed that during ossification, one of the most important functions of neurofibromin is to regulate osteoprogenitors as well as composition of the bone matrix [ 5 ]. Additionally, haploinsufficiency of neurofibromin leads to premature apoptosis of osteoblasts and alteration in proliferation/differentiation of osteoprogenitor cells.…”

“…All patients were clinically evaluated following the National Institutes of Health (NIH) criteria for NF1 [ 5 , 9 ], revised by Gutmann et al 1997 [ 10 ], integrated for 67 of them by molecular testing. According to these references, 112 of 168 patients were diagnosed as NF1.…”

“…NF1 is a relatively common neurogenetic disorder [ 4 ]. Its incidence is about 1:2500–1:3000 individuals worldwide, with no differences in sex or ethnic origin [ 5 ]. It is caused by mutations of the NF1 gene on chromosome 17ql1.2, which encodes neurofibromin.…”

Next generation sequencing identified a novel multi exon deletion of the NF1 gene in a Chinese pedigree with neurofibromatosis type 1

“…Recently, in their two studies, Banerjee et al . [1,6] reported that clinical manifestations for NF1 patients are extremely heterogenous, even associated with astrocytoma, tibial pseudarthrosis and anemia. In this study, we showed that the proband and his mother presented with severe and mild phenotypes, respectively, although they carry the same mutation.…”

NF1 germline mutation in a Chinese family with colon cancer

“… 7 Hence, a germline mutation in the NF1 gene results in the formation of a truncated or non-functional neurofibromin that can activate or up-regulate the Ras-mediated signaling pathway, leading to the formation of benign or malignant tumors. 8 Germline mutations in the NF1 gene have been identified in several tumors including gliomas, malignant peripheral nerve sheath tumors, neurofibromas, pheochromocytomas, and breast cancer. 4 , 9 – 12 Here, we report two cases of colon cancer in a brother and sister with NF1 germline mutations.…”