Allanson et al. (1985) reported 4 unrelated patients with neurofibromatosis who had manifestations of Noonan syndrome (163950), including short stature, ptosis, midface hypoplasia, webbed neck, learning disabilities, and muscle weakness. Family history was negative in each case. Average ... Allanson et al. (1985) reported 4 unrelated patients with neurofibromatosis who had manifestations of Noonan syndrome (163950), including short stature, ptosis, midface hypoplasia, webbed neck, learning disabilities, and muscle weakness. Family history was negative in each case. Average paternal and maternal ages were 37 and 28 years, respectively, at the birth of the patients, suggesting new dominant mutation. The chromosomes, including prometaphase preparations in 3 of the 4, were normal. The authors suggested that this is a distinct entity. Opitz and Weaver (1985) likewise favored the distinctness of what they called the neurofibromatosis-Noonan syndrome. They suggested that males are more likely to have fusiform swelling of nerve strands, while females more often show the classic neurofibromata seen in von Recklinghausen disease (NF1). Lisch nodules of the iris were uncommon, whereas there was a strong tendency to develop retroperitoneal or visceral (ganglio-) neurofibromatosis. Abuelo and Meryash (1988) described an 18-year-old man with neurofibromatosis and classic manifestations of Noonan syndrome, including atrial septal defect of the secundum type and valvular and supravalvular pulmonic stenosis, for which cardiac surgery was performed. The father also had neurofibromatosis and was described by the authors as having 'some of the characteristics of Noonan syndrome,' which were only 'prominent nasolabial folds and apparently low-set ears.' The authors suggested several possibilities to explain the combination of features: (1) a mutation at a locus different from that of NF1 on chromosome 17; (2) an allele at the NF1 locus; (3) a coincidence of 2 relatively frequent conditions; or (4) associated disorders due to mutations at closely linked loci. In connection with the last possibility, it is of note that Abuelo and Meryash (1988) found no abnormality in the prophase chromosome analysis, performed with special attention to chromosome 17, in their propositus. Meinecke (1987) and Quattrin et al. (1987) concluded that it was uncertain whether neurofibromatosis with Noonan syndrome-like features was a distinct entity. Edman Ahlbom et al. (1995) reported a family in which 4 individuals spanning 2 generations had Noonan syndrome and cafe-au-lait spots. Dysmorphic features included hypertelorism, epicanthal folds, downslanting palpebral fissures, high peaks of the upper vermilion border, and low-set ears. They also had pulmonary stenosis, cardiac conduction defect, short stature, short neck, and widely spaced nipples. Intelligence was normal. Nystrom et al. (2009) reported follow-up of the family reported by Edman Ahlbom et al. (1995) and included additional affected family members. The Noonan syndrome facial phenotype was found in several family members but was less evident in others. All except 1 fulfilled the criteria for NF1, with cafe-au-lait spots, Lisch nodules, and axillary freckling. None had visible plexiform neurofibromas, but 2 had growing mandibles, suggestive of giant cell lesions. Upon reevaluation, Nystrom et al. (2009) concluded that the phenotype in this family was consistent with NFNS. Colley et al. (1996) examined 94 persons with neurofibromatosis for features of the Noonan syndrome and found that 12, including some familial cases, had diagnostic criteria of the Noonan syndrome. One of the families showed independent segregation of NF1 and Noonan syndrome; in other families, half of those affected with NF1 had manifestations of the Noonan syndrome. However, linkage of the Noonan syndrome gene to chromosome 12 (Jamieson et al., 1994) suggested that the genes for NF1 and Noonan syndrome are neither allelic nor contiguous. Colley et al. (1996) suggested that some alterations of the NF1 gene may predispose to the Noonan syndrome phenotype, but considered it unlikely that a neurofibromatosis-Noonan syndrome phenotype is a distinct disorder or occurs as part of classic Noonan syndrome. Bahuau et al. (1996, 1998) reported a 4-generation family in which 8 members had NF1/Noonan syndrome, 2 had NF1 only, and 2 had NS only. Linkage analysis showed tight linkage of the neurofibromatosis phenotype to the NF1 gene, whereas the Noonan phenotype was not linked to the NF1 gene. However, cosegregation of the 2 phenotypes suggested 2 genetically linked but distinct loci. Molecular analysis identified a heterozygous truncating mutation in the NF1 gene in all 10 patients with features of NF1, but not in the 2 patients with Noonan syndrome only. The findings suggested the presence of another locus for Noonan syndrome on 17q distinct from the NF1 gene. Klopfenstein et al. (1999) reported 2 unrelated boys with neurofibromatosis-Noonan syndrome who developed acute lymphoblastic leukemia. Stevenson et al. (2006) provided follow-up on the family reported by Carey et al. (1997) in which a mother and 4 of 5 offspring had NFNS. All 5 patients had multiple cafe-au-lait spots and relative macrocephaly consistent with NF1. None had neurofibromas. Variable features of Noonan syndrome included short stature (in 3 of 5 patients), speech delay (3), ptosis (5), downslanted palpebral fissures (2), telecanthus (3), malar hypoplasia (3), posteriorly angulated ears (4), broad neck (4), pectus anomaly (4), and pulmonic stenosis (3).
In affected members of a family with NFNS, Carey et al. (1997) identified a 3-bp deletion in exon 17 of the NF1 gene (162200.0033).
Baralle et al. (2003) used comparative sequence analysis to examine the NF1 ... In affected members of a family with NFNS, Carey et al. (1997) identified a 3-bp deletion in exon 17 of the NF1 gene (162200.0033). Baralle et al. (2003) used comparative sequence analysis to examine the NF1 gene in 6 patients with NFNS and identified mutations in 2: a 3-bp deletion in exon 25 (162200.0034) in 1 and a 2-bp insertion in exon 23-2 (162200.0035) in the other. The PTPN11 gene (176876), which had been recognized as the cause of more than 50% of Noonan syndrome cases, was also examined in 4 cases of NFNS, and no mutations were found. To answer the question of whether NFNS represents a variable manifestation of either NF1 or NS or is a distinct clinical entity, De Luca et al. (2005) screened a cohort with clinically well-characterized NFNS for mutations in the entire coding sequence of the NF1 and PTPN11 genes, which are responsible for classic neurofibromatosis and Noonan syndrome, respectively. Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects studied, thus providing evidence that mutations in NF1 represent the major molecular event underlying this condition. A particularly high prevalence of in-frame defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed. On the other hand, no defect in PTPN11 was observed and no lesion affecting exons 11 through 27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, providing further evidence that NFNS and NS are genetically distinct disorders. These results supported the view that NFNS is a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals. De Luca et al. (2005) pointed out that some of the mutations identified in patients with NFNS have also been reported in NF1 without any features suggestive of NS. From a molecular point of view, the clinical overlap between NFNS and NS is not surprising: the NF1 and PTPN11 gene products, neurofibromin and SHP2, elicit their modulatory role through a common pathway. Although Edman Ahlbom et al. (1995) excluded linkage to the NF1 locus in a family with Noonan syndrome and cafe-au-lait spots, Nystrom et al. (2009) used direct sequencing to identify a heterozygous NF1 mutation (L1390F; 613113.0045) in affected members of this family. - Cooccurrence of NF1 And PTPN11 Mutations Bertola et al. (2005) reported the occurrence of mutations in both NF1 (162200.0043) and PTPN11 (176876.0023) in a patient with neurofibromatosis type I and Noonan syndrome. This is probably a rare event accounting for a minority of these cases. Thiel et al. (2009) reported another patient with features of both neurofibromatosis I and Noonan syndrome who had mutations in both the NF1 (162200.0044) and PTPN11 (176876.0027) genes. The PTPN11 mutation occurred de novo, and the NF1 mutation was inherited from the patient's mother, who had mild features of neurofibromatosis I, including the absence of optic gliomas. The proband developed bilateral optic gliomas before age 2 years, suggesting an additive effect of the 2 mutations on the Ras pathway. The proband also had short stature, delayed development, sternal abnormalities, and valvular pulmonary stenosis.