Editorial Comment

Neurofibromatosis-Noonan Syndrome

John C. Carey*Departments of Pediatrics, University of Utah, School of Medicine, Salt Lake City, Utah

The topic of the so-called Neurofibromatosis-Noonansyndrome (NFNS) has fascinated those of us interestedin the individual disorders since the report by Allansonet al. [1985]. In this seminal paper, Allanson et al. de-scribed 4 individuals with the co-occurrence of theNoonan syndrome and manifestations of neurofibroma-tosis. Since this report, more than 30 cases, including afew multigenerational families with linkage analysis,have been described (for a summary of the references,see Bahuau et al., 1996).

Despite the volume of work and number of cases andfamilies, controversy and conflict still surround thistopic. Whether or not NFNS represents a true syn-drome or simply variable expressivity of NF1 is stilldebated. For example, in an editorial, Riccardi [1989]characterized the discussion of this topic as ‘‘syndro-mology gone awry’’ and concluded that NFNS merelyrepresents the variability of NF1. In contrast, at the1994 David W. Smith meetings on malformations andmorphogenesis, we summarized the existing literatureand indicated that probably only 7 of the reported casesup to that time actually manifested a convincingNoonan phenotype [Carey et al., 1995]. We went on topoint out that the presence of a consistent patternamong the most convincing cases of NFNS suggestedthat this combination represented a discrete and dis-tinctive entity: the 7 most convincing patients withNFNS lacked Lisch nodules (a consistent finding inmost older patients with NF1), had a small number ofdermal neurofibromas, and lacked internal tumors.These descriptive observations of the pattern and thepresence of 3 families in which the NFNS ‘‘ran true’’within the kindred supported the notion that this wasa true syndrome, either a variant of NF1 (like the Wat-son syndrome) or its own separate entity [Carey et al.,1995].

Various possibilities have been proposed to explainthe coexistence of the Noonan syndrome and NF1 inthe same patients. I present each of these possibilitiesand the existing evidence for each hypothesis. This dis-cussion represents an update of the editorial presentedby Opitz and Weaver [1985].

Coincidence of two common autosomal domi-nant disorders. Colley et al. [1996] documented a

convincing family (family 1) in which the gene for NF1and Noonan syndrome were cosegregating separately.Thus, they provided evidence for a chance associationof the two conditions. Bahuaua et al., in this issue ofthe Journal, document another such family.

Manifestations of NF1, specifically the cafe-au-lait spots, occur as a component of the classicalNoonan syndrome. Edman Ahlbom et al. [1995]demonstrated a family with Noonan syndrome andcafe-au-lait spots in which a linkage analysis showedno linkage of this disease phenotype to the NF1 locus.Linkage analysis of the Noonan syndrome locus onchromosome 12 was not reported. (However, the au-thors indicated that ‘‘further molecular studies will beundertaken’’ regarding this linkage on 12 and, to ourknowledge, results of that are still unknown.) More-over, the literature occasionally mentions that patientswith Noonan syndrome can have multiple cafe-au-laitspots [Pernot et al., 1989].

Manifestations of Noonan syndrome in these pa-tients are simply a variable manifestation of clas-sic NF1. In this hypothesis, the signs of Noonan syn-drome are part of the variability of the NF1 syndrome,just like optic glioma or scoliosis, etc. The family re-ported by Stern et al. [1992] included a grandfatherwho had signs of NF1 and Noonan syndrome and agrandchild who also exhibited these manifestations.The child’s parent and the 3 other sibs in the secondgeneration of this kindred had no signs of Noonan syn-drome. In addition, families 2, 4, and 5 in the paper byColley et al. [1996] showed discordance of NF1 andNoonan manifestations in various generations; al-though all of the affected patients had NF1, only somehad signs of a Noonan phenotype. These findings sup-port the notion that in some families the Noonan mani-festations are simply a variable component of classicNF1.

NFNS represents a discrete entity. By thisstatement, I am referring to the concept that the phe-notype is distinct and relatively well delineated interms of its natural history. The essence of this conceptis illustrated by the distinction between the Crouzonand Pfeiffer syndromes or between the Hurler andScheie syndromes: in both examples, the same or simi-lar molecular or biochemical basis is present, but thedifferent phenotypes ‘‘run true’’ in the family and arewell characterized. The notion of a discreet entity couldbe explained by the following mechanisms: (a) an au-tosomal dominant gene located on a chromosome otherthan 17 (locus of NF1) or 12 (locus of some of the fami-

*Correspondence to: John C. Carey, M.D., Department of Pedi-atrics, Division of Medical Genetics, 50 North Medical Drive, Rm.413 MREB, Salt Lake City, UT 84112.

Received 12 September 1997; Accepted 15 September 1997

American Journal of Medical Genetics 75:263–264 (1998)

© 1998 Wiley-Liss, Inc.

lies with Noonan syndrome; the family of Edman Ahl-bom et al. [1995] could represent this idea); (b) NFNSrepresents a true variant or allele of NF1. This mecha-nism could be explained by allelism, i.e., a differentmutation producing this discrete phenotype or by acontiguous gene syndrome (however, the cases withwhole gene deletion do not typically have a Noonanphenotype [Wu et al., 1995]).

The most convincing evidence that NFNS representsa discrete and distinctive entity is the observation thatthe entire pattern runs true in some kindreds. Thefamilies reported by Abuello and Meryash [1988] andthose observed by Carey et al. [1995] substantiate thisnotion. In addition, we reported on a 2-generation fam-ily with NFNS who had a 3-bp deletion in exon 17 of theNF1 gene, thus deleting a methionine from the neuro-fibromin peptide. The presence of an apparently dis-ease-causing mutation of the NF1 gene in a family whohad NFNS (and not classic NF1) supports this hypoth-esis [Carey et al., 1997].

In this issue of the Journal, Bahuau et al. rediscussan interesting family reported previously [Bahuau etal., 1996]. In this paper, the authors identified a non-sense mutation causing NF1. What they show convinc-ingly is that the patients who have signs of Noonansyndrome but not NF1 lack this nonsense mutation.They then provide evidence for a second family inwhich the gene for NF1 and Noonan syndrome are co-segregating. Moreover, the Noonan phenotype in thisfamily also mapped to chromosome 17, which providesanother candidate locus for those families with Noonansyndrome that does not link to chromosome 12.

What is quite fascinating about the NFNS story isthat cases with NFNS have now been demonstrated tohave the phenotype based on all of the mechanismsoriginally proposed in the Opitz and Weaver editorial.It appears that the NFNS phenotype really is hetero-geneous at a clinical and molecular level. Although the

recent advances in molecular biology have certainlyprovided new insights into disease pathogenesis, com-prehensive phenotype analysis and thorough documen-tation of cases still remain essential for making infer-ences about their cause.

REFERENCES

Abuelo DN, Meryash DL (1988): Neurofibromatosis with fully expressedNoonan syndrome. Am J Med Genet 29:937–941.

Allanson JE, Hall JG, Van Allen MI (1985): Noonan phenotype associatedwith neurofibromatosis. Am J Med Genet 21:457–462.

Bahuau M, Flintoff W, Assouline B, Lyonnet S, Le Merrer M, Prieur M,Guilloud-Bataille M, Feingold, N, Munnich A, Vidaud M, Vidaud D(1996): Exclusion of allelism of Noonan syndrome and neurofibroma-tosis type 1 in a large family with Noonan syndrome-neurofibromatosisassociation. Am J Med Genet 66:347–355.

Carey JC, Hall BD, Allanson JE, Witt D (1995): Is there a ‘‘neurofibroma-tosis-Noonan syndrome’’? Proc Greenwood Genet Center 14:82–83.

Carey JC, Stevenson DA, Ota, Neil S, Viskochil DH (1997): Is there anNF/Noonan syndrome: Part 2: Documentation of the clinical and mo-lecular aspects of an important family. Proc Greenwod Genet Center, inpress.

Colley A, Donnai D, Evans DGR (1996): Neurofibromatosis/Noonan phe-notype: A variable feature of type 1 neurofibromatosis. Clin Genet 49:59–64.

Edman Ahlbom B, Dahl N, Zetterqvist P, Anneren G (1995): Noonan syn-drome with cafe-au-lait spots and multiple lentigines syndrome are notlinked to the neurofibromatosis type 1 locus. Clin Genet 48:85–89.

Opitz JM, Weaver DD (1985): Editorial comment: The Neurofibromatosis-Noonan syndrome. Am J Med Genet 21:477–490.

Pernot C, Worms A-M, Marxon F, Gilgenkrantz S, Leheup B (1989): Lesyndrome de Noonan et sa dysplasie cardio-vasculaire: A propos de 64observations. Pediatrie 44:437–447.

Riccardi VM (1989): Editorial. Syndromology gone awry–The phenotypicoverlap of NF1 with the Noonan syndrome. Neurofibromatosis 2:249–250.

Stern HJ, Saal HS, Lee JS, Fain PR, Goldgar DE, Rosenbaum KN, BarkerDF (1992): Clinical variability of type 1 neurofibromatosis: Is there aneurofibromatosis-Noonan syndrome? J Med Genet 29:184–187.

Wu B-L, Austin MA, Schneider GH, Boles RG, Korf BR (1995): Deletion ofthe entire NF1 gene detected by FISH: Four deletion patients associ-ated with severe manifestations. Am J Med Genet 59:528–535.

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