American Journal of Medical Genetics 39367-370 (1991)
Editorial Cornment The Noonan-CFC Controversy Giovanni Neri, Marcella Zollino, and James F. Reynolds Istituto di Genetica Umana, Facoltadi Medicina “A. Gemelli”, U.C.S.C., Roma, Italy (G.N., M.Z.) and Department of Medical Genetics, Shodair Children’s Hospital, Helena, Montana The Noonan syndrome and the cardio-faciocutaneous (CFC) syndrome have been described as phenotypically and genetically distinct entities. However, the resemblance between them led some authors to question the validity of this separation. We review available clinical evidence to support the opposite view, namely,that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype.
KEY WORDS: multiple congenitalanomalies/ mental retardation syndrome, congenital lymphedema, skin abnormalities,congenital heart defects THE NOONAN SYNDROME The Noonan syndrome was first identified by Noonan and Ehmke [1963], who described a group of nine patients with valvular pulmonary stenosis, short stature, mild mental retardation, unusual face, and testicular and skeletal abnormalities. Subsequent reports, as well as retrospective analyses, established a high prevalence of the syndrome. Nora and Fraser [1981] assumed a frequency among liveborn infants as high as 1/1,0001/2,500.Mendez and Opitz [19851estimated a frequency of 1/1,000 of severely affected individuals and 1/100 of partial expression of the syndrome. As reported in two recent reviews [Mendez and Opitz, 1985; Allanson, 19871,the main manifestations of the Noonan syndrome are: peculiar face (hypertelorism, epicanthus, ptosis, downslanting palpebral fissures, high cranial vault, hypoplasia of the supraorbital ridges), neck abnormalities (short or webbed neck or pterygium colli), testicular abnormalities, short stature, congenital heart defects, cubitus valgus, ear abnormalities, highly arched palate, low posterior hairline, abnormalities of skin and appendages, and mental retardation. Skin and appendage Received for publication July 20,1990; revision received September 24, 1990. Address reprint requests to Giovanni Neri, M.D., Istituto di Genetica Umana, Universita Cattolica, Largo F. Vito 1, 00168 Rome, Italy.
0 1991 Wiley-Liss, Inc.
abnormalities include hyperelastic skin, lymphedema, nevi, moles, cafe-au-lait spots, “dystrophic” nails, and curly hair. With the exception of the peculiar face and neck abnormalities, detected in about 95% of cases, the other manifestations are less common. A congenital heart defect has been detected in 50-66% of cases, mental retardation in 24-35%, skin and appendage abnormalities in 27-35%. In addition, familial cases have been frequently reported [Nora et al., 1974; Collins and Turner, 1973; Levy et al., 19701. Mendez and Opitz [19851found familial occurrence in 33 of 148 patients. Allanson [1987] found a parent to child transmission in 30-75% of published cases. The family data so far collected are compatible with autosomal dominant inheritance of the syndrome.
THE NOONAN PHENOTYPE A large number of observations have established the existence of great phenotypic variability in the Noonan syndrome, even if some of the changes clearly appear to be age-related [Allanson et al., 1985al. Such clinical heterogeneity is likely t o reflect genetic heterogeneity, with different causes acting through a common pathogenetic mechanism. Mendez [19851 suggested that intrauterine lymphedema could be an important pathogenetic factor. Therefore, it is probably appropriate to speak in terms of the Noonan phenotype as a broad category containing a number of different genetic conditions. In reviewing the literature dealing with such genotype-phenotype correlations, we were able to identify at least seven non-chromosomal conditions that fall within the Noonan phenotype: Cardio-facio-cutaneous (CFC) syndrome [Reynolds et al., 19861 Noonan syndrome Neurofibromatosis-Noonan syndrome [Allanson et al., 1985b; Mendez, 1985; Opitz and Weaver, 19851 Trimethylaminuria LHumbert et al., 1970; Calvert, 19731 The cardio-cutaneous syndromes [Sanchez-Cascos, 19721 A new entity reported by Baraitser and Patton [1986] A new entity reported by Cantalamessa et al. [1989] All of these conditions share some phenotypic commonalities, at least with respect to facial appearance. For
368
Neri et al.
this reason a Noonan syndrome has been almost always considered as a possible diagnosis.
THE CFC SYNDROME The CFC syndrome was first described by Reynolds et al. [19861 as a genetic condition different from Noonan syndrome. It includes growth failure, psychomotor delay, congenital heart defects, characteristic facial appearance, ectodermal abnormalities, and splenomegaly. Since then, a total of 19 cases has been reported [Reynolds et al., 1986; Neri et al., 1987; Verloes et al., 1988; Chrzanowska et al., 1989; Mucklow, 1989; Sorge et al., 1989; Corsello and Giuffre, 19901. Recently, Fryer e t al. [1990] raised some doubts about the legitimacy of separating the CFC syndrome from the Noonan syndrome, based on the many phenotypic similarities between the two conditions. We wish to defend the opposite view, namely, that they are clinically distinguishable and genetically different. In a n attempt to gather elements that would be valuable for settling the controversy, we analyzed in detail the 19 cases of CFC syndrome so far reported, with special emphasis on their most typical manifestations. The summary data are reported in Table I. This analysis led us to identify six constant or very frequent characteristics of the CFC syndrome, which, when present simultaneously, make the diagnosis almost obligatory: 1) distinctive, “Noonan-like’’ face; 2) mental retardation, mostly severe; 3) hyperkeratotic skin lesions; 4) sparse, thin, and curly hair, often associated with absence of eyebrows; 5) congenital heart defects; 6) sporadic occurrence. The frequency of these manifestations in the CFC syndrome was compared with that found in the Noonan
syndrome, calculated from the Mendez and Opitz [19851 and Allanson [1987] reviews. This comparison is reported in Table 11. Two traits were found in the CFC syndrome only: 1) hyperkeratotic skin lesions; and 2) sparse, thin, curly hair. With regard to the skin lesions, two reports in the Noonan literature seem to contradict the above statement. Pierini and Pierini (1979) reported follicular hyperkeratosis in five patients with Noonan syndrome. Unfortunately, the authors did not provide phenotypic details, or photographs of the patients. However, based on the report of hyperkeratotic skin lesions, mental retardation, and sparse andlor curly hair with sparse eyebrows, one can argue that these patients may have had the CFC syndrome rather than the Noonan syndrome. Dry ichthyotic skin, particularly of the palms of the hands, was reported by Collins and Turner [19731 in two of four subjects with familial Noonan syndrome. This report represents the sole description of hyperkeratosis in Noonan syndrome known to us, and chance concurrence cannot be excluded. The other skin lesions in the CFC syndrome are different from those in the Noonan syndrome. Hemangiomatosis is the primary manifestation in the CFC syndrome, whereas in the Noonan syndrome cafe-au-lait spots and nevi are primary. The second manifestation, exclusively present in the CFC syndrome is sparse, thin, curly hair. Sparse and thin hair (but not curly) has been reported by ReforzoMembrives et al. [ 19491in a patient considered “a posteriori” to have the Noonan syndrome. This patient, who most likely represents a bona fide case of Noonan syndrome, also lacks hyperkeratotic skin lesions. Recently, Baraitser and Patton [ 19861 described four unrelated cases with Noonan phenotype and sparse (but not thin
TABLE I. Main Clinical Manifestations of the CFC Syndrome Case
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Reference
%pica1 face
MR”
Suarse
Hair Thin
Curlv
Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Neri et al., 1987 Neri et al., 1987 Chrzanowska et al., 1989 Mucklow, 1989 Sorge et al., 1989 Sorge et al., 1989 Sorge et al., 1989 Corsello and Giuffre, 1990 Corsello and GiuffrB, 1990 Verloes et al., 1988 Verloes et al., 1988
+ + + + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + +
+ + + + + + ++ + + + + + + + + +
+ + + + + + ++ + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + +
. ~
*Mental retardation. bcongenital heart defect. c Skin hemangiomata present. dEndocardia1 cushion defect, suspected. e Protomesosystolic murmur at birth subsequently disappeared.
~
~
Absent evebrows
Hyperkeratotic skin lesions
+-
++ + + + + + + + + + + + + + + + +
-
+ + + +-
+ +-
+ + + + +
CHDb
+ + + + +d -
+ + + ke + ++ + + + +
Noonan-CFC
369
TABLE 11. Comparison Between CFC and Noonan Syndrome With Respect to Five Characteristics (percentage positive cases) CFC syndrome (n = 19)
-~
Mental retardation Sparse, thin, curly hair Hyperkeratotic skin lesions Congenital heart defect Familial occurrence
100 100 95 84 0
Noonan syndrome __ ---___ Mendez and Optiz, Allanson, 1985 1987 (n = 121) ( n = ?) _____ 24
35 Oa
Oa Ob
Ob
50 Frequent
66 30-75
‘Only one report of thin and sparse hair, without skin hyperkeratosis (see text). bCollins and Turner (1973) report excluded (see text).
and curly) hair. In reviewing pictures and clinical description, we agree with the authors that this is not Noonan syndrome. These particular patients may rather have a new condition, falling within the Noonan phenotype. Additional distinctive elements between CFC and Noonan syndrome seem to be the frequency and severity of mental retardation and the frequency of congenital heart defects. Mental retardation, varying from mild to severe, was always present in CFC patients. On the other hand, i t is reported in only one-third of Noonan patients, where it is usually of milder degree. Congenital heart defects are also distinctly more frequent in CFC than in Noonan patients. Finally, CFC cases were always sporadic. In only one case, reported by Verloes e t al. [lSSS], was a father to daughter transmission suspected, based on supposedly mild phenotypic expression in the father. However, simple family resemblance should also be considered as a possible explanation. The facial characteristics were not considered in the comparison in Table 11,because their evaluation is likely to be more subjective. However, we wish to emphasize that the high forehead, bitemporal constriction, downslanting eyes, and bulbous nose give the CFC syndrome face a “gestalt”that the majority of authors expert in the field seem capable of distinguishing easily from that of
the Noonan syndrome face. The overall “gestalt”is often that of a large molecular weight storage disease with visceroptosis, accentuated lumbar lordosis, and coarse appearance. As opposed to most Noonan syndrome patients, CFC patients have often had extensive evaluation for metabolic disorders based on this “gestalt.” In summary, the CFC syndrome phenotype appears to be quite distinct, based on the simultaneous presence of peculiar face, mental retardation, hyperkeratotic skin lesions, sparse, thin, curly hair, congenital heart defect, and sporadic occurrence. In addition to these major manifestations, there are in CFC patients a constellation of minor anomalies, shared by Noonan patients. A list of these anomalies is reported in Table 111. Fig. 1 presents a comparison between CFC and Noonan syndrome in the form of a histogram, using those signs for which we had percentual values available from the Mendez and Opitz [1985] review. In addition to the characteristics mentioned above, the histogram shows that some manifestations, such a s low posterior hairline, cubitus valgus, neck abnormalities, and familial occurrence, are distinctive of the Noonan syndrome and are seldom present in the CFC syndrome.
CONCLUSIONS Based on available evidence, we conclude that it is correct to speak in terms of Noonan phenotype, which is
TABLE 111. Percentage of CFC and Noonan Syndrome Cases Sharing Common Phenotypic Manifestations -~Noonan syndrome _ _
Phenotype
Mendez and Opitz, 1985
Allanson, 1987-
95 68 47 42 37 33 26 11 11 10 5
95 44 34 94 53 69 20 28 22 47 32
90 90 45 NR 60 60 20 NR 25 50 55
~~~~~~
Eye abnormalities E a r abnormalities Highly arched palate Neck abnormalities Short stature Testicular abnormalities Delayed hone age Skeletal abnormalities Micrognathia Cuhitus valgus Low posterior hairline
~
CFC syndrome
~
-
370
Neri et al.
n
Fig. 1. Comparison between CFC and Noonan syndromes based on 16 characteristic features. Stippled bars, CFC syndrome; white bars, Noonan syndrome.
frequent, wide, and causally heterogeneous, and includes different genetic conditions. Among them, the CFC and Noonan syndromes must be considered as two distinct, specific entities, whose diagnosis is not interchangeable. This seems to be the safest and most productive conclusion until the time when a “Noonan syndrome gene” is isolated.
REFERENCES Allanson J E , Hall JG, Hughes HE, Preus M, Witt RD (1985a):Noonan syndrome: changing phenotype. Am J Med Genet 21:507-514. Allanson J E , Hall J G , Van Allen MI (198513):Noonan phenotype associated with neurofibromatosis. Am J Med Genet 21:457-462. Allanson J E (1987): Noonan syndrome. J Med Genet 24:9-13. Baraitser M, Patton MA (1986):A Noonan-like short stature syndrome with sparse hair. J Med Genet 23:161-164. Calvert GD (1973): Trimethylaminuria and inherited Noonan’s syndrome. Lancet 1:320-321. Cantalamessa L, Baldini M, Ambrosi B, Fraccaro M (1989): A syndrome of primary gonadal failure, short stature, mitral valve prolapse and mental retardation. Am J Med Genet 33:117-120. Chrzanowska K , Fryns JP, Van den Berghe H (1989): Cardio-faciocutaneous (CFC) syndrome: report of a new patient. Am J Med Genet 33:471-473. Collins E, Turner G (1973): The Noonan syndrome-a review of the clinical and genetic features of 27 cases. J Pediatr 83:941-950. Corsello G, Giuffre L (1990): Letter to the Editor: cardio-facio-cutaneous syndrome: notes on clinical variability and natural history. Am J Med Genet 39:OOO-000. Fryer AL, Holt PJ, Hughes HE (1990): The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same? Am J Med Genet 39:OOO-000. Humbert JR, Hammond KB, Hathaway WE, Marcoux J G , O’Brien D (1970): Trimethylaminuria: the fish-odour syndrome. Lancet 2:770-771.
Levy EP, Pashayan H, Fraser FC, Pinsky L (1970):XX and XY Turner phenotypes in a family. Am J Dis Child 120:36-43. Mendez HMM (1985):The Neurofibromatosis-Noonan syndrome. Am J Med Genet 21:471-476. Mendez HMM, Opitz J M (1985):Noonan syndrome: areview. Am J Med Genet 21:493-506. Mucklow ES (1989):Brief clinical report. A case of cardio-facio-cutaneous syndrome. Am J Med Genet 33:474-475. Neri G, Sabatino G, Bertini E, Genuardi M (1987):Briefclinical report: the CFC syndrome-report of the first two cases outside the United States. Am J Med Genet 27:767-771. Noonan JA, Ehmke DA (1963): Associated noncardiac malformations in children with congenital heart disease. J Pediatr 63:468-470. Nora JJ, Fraser FC (1981):“Medical Genetics: Principles and Practice,” 2nd ed. Philadelphia: Lea & Febiger. Nora J J , Nora AH, Sinha AK, Spangler RD, Lubs HA (1974): The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child 127:48-55. Opitz J M , Weaver DD (1985): Editorial comment: the neurofibromatosis-Noonan syndrome. Am J Med Genet 21:477-490. Pierini DO, Pierini AM (1979): Keratosis pilaris atrophicans faciei (Ulerythema ophryogenes): a cutaneous marker in the Noonan syndrome. B r J Dermatol 100:409-416. Reforzo-Membrives J, Trabucco A, Escardo F (1949):A case ofrudimentary testes, delayed growth and congenital malformations. J Clin Endocrinol 9:1333-1347. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz J M (1986): New multiple congenital anomaliesimental retardation syndrome with cardio-facio-cutaneous involvementthe CFC syndrome. Am J Med Genet 29:413-427. Sanchez-Cascos A (1972): Genetics of pulmonic stenosis. Acta Cardiol (Brux) 27:316-330. Sorge G, Di Forti F, Scarano G, Ventruto V, Zelante L, Dallapiccola B (1989):CFC syndrome: report on three additional cases. Am J Med Genet 33:476-478. Verloes A, Le Merrer M, Soyeur D, Kaplan J, Pangalos C, Rig0 J, Briard ML (1988):CFC syndrome: a syndrome distinct from Noonan syndrome. Ann Genet 31:230-234.
Editorial Cornment The Noonan-CFC Controversy Giovanni Neri, Marcella Zollino, and James F. Reynolds Istituto di Genetica Umana, Facoltadi Medicina “A. Gemelli”, U.C.S.C., Roma, Italy (G.N., M.Z.) and Department of Medical Genetics, Shodair Children’s Hospital, Helena, Montana The Noonan syndrome and the cardio-faciocutaneous (CFC) syndrome have been described as phenotypically and genetically distinct entities. However, the resemblance between them led some authors to question the validity of this separation. We review available clinical evidence to support the opposite view, namely,that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype.
KEY WORDS: multiple congenitalanomalies/ mental retardation syndrome, congenital lymphedema, skin abnormalities,congenital heart defects THE NOONAN SYNDROME The Noonan syndrome was first identified by Noonan and Ehmke [1963], who described a group of nine patients with valvular pulmonary stenosis, short stature, mild mental retardation, unusual face, and testicular and skeletal abnormalities. Subsequent reports, as well as retrospective analyses, established a high prevalence of the syndrome. Nora and Fraser [1981] assumed a frequency among liveborn infants as high as 1/1,0001/2,500.Mendez and Opitz [19851estimated a frequency of 1/1,000 of severely affected individuals and 1/100 of partial expression of the syndrome. As reported in two recent reviews [Mendez and Opitz, 1985; Allanson, 19871,the main manifestations of the Noonan syndrome are: peculiar face (hypertelorism, epicanthus, ptosis, downslanting palpebral fissures, high cranial vault, hypoplasia of the supraorbital ridges), neck abnormalities (short or webbed neck or pterygium colli), testicular abnormalities, short stature, congenital heart defects, cubitus valgus, ear abnormalities, highly arched palate, low posterior hairline, abnormalities of skin and appendages, and mental retardation. Skin and appendage Received for publication July 20,1990; revision received September 24, 1990. Address reprint requests to Giovanni Neri, M.D., Istituto di Genetica Umana, Universita Cattolica, Largo F. Vito 1, 00168 Rome, Italy.
0 1991 Wiley-Liss, Inc.
abnormalities include hyperelastic skin, lymphedema, nevi, moles, cafe-au-lait spots, “dystrophic” nails, and curly hair. With the exception of the peculiar face and neck abnormalities, detected in about 95% of cases, the other manifestations are less common. A congenital heart defect has been detected in 50-66% of cases, mental retardation in 24-35%, skin and appendage abnormalities in 27-35%. In addition, familial cases have been frequently reported [Nora et al., 1974; Collins and Turner, 1973; Levy et al., 19701. Mendez and Opitz [19851found familial occurrence in 33 of 148 patients. Allanson [1987] found a parent to child transmission in 30-75% of published cases. The family data so far collected are compatible with autosomal dominant inheritance of the syndrome.
THE NOONAN PHENOTYPE A large number of observations have established the existence of great phenotypic variability in the Noonan syndrome, even if some of the changes clearly appear to be age-related [Allanson et al., 1985al. Such clinical heterogeneity is likely t o reflect genetic heterogeneity, with different causes acting through a common pathogenetic mechanism. Mendez [19851 suggested that intrauterine lymphedema could be an important pathogenetic factor. Therefore, it is probably appropriate to speak in terms of the Noonan phenotype as a broad category containing a number of different genetic conditions. In reviewing the literature dealing with such genotype-phenotype correlations, we were able to identify at least seven non-chromosomal conditions that fall within the Noonan phenotype: Cardio-facio-cutaneous (CFC) syndrome [Reynolds et al., 19861 Noonan syndrome Neurofibromatosis-Noonan syndrome [Allanson et al., 1985b; Mendez, 1985; Opitz and Weaver, 19851 Trimethylaminuria LHumbert et al., 1970; Calvert, 19731 The cardio-cutaneous syndromes [Sanchez-Cascos, 19721 A new entity reported by Baraitser and Patton [1986] A new entity reported by Cantalamessa et al. [1989] All of these conditions share some phenotypic commonalities, at least with respect to facial appearance. For
368
Neri et al.
this reason a Noonan syndrome has been almost always considered as a possible diagnosis.
THE CFC SYNDROME The CFC syndrome was first described by Reynolds et al. [19861 as a genetic condition different from Noonan syndrome. It includes growth failure, psychomotor delay, congenital heart defects, characteristic facial appearance, ectodermal abnormalities, and splenomegaly. Since then, a total of 19 cases has been reported [Reynolds et al., 1986; Neri et al., 1987; Verloes et al., 1988; Chrzanowska et al., 1989; Mucklow, 1989; Sorge et al., 1989; Corsello and Giuffre, 19901. Recently, Fryer e t al. [1990] raised some doubts about the legitimacy of separating the CFC syndrome from the Noonan syndrome, based on the many phenotypic similarities between the two conditions. We wish to defend the opposite view, namely, that they are clinically distinguishable and genetically different. In a n attempt to gather elements that would be valuable for settling the controversy, we analyzed in detail the 19 cases of CFC syndrome so far reported, with special emphasis on their most typical manifestations. The summary data are reported in Table I. This analysis led us to identify six constant or very frequent characteristics of the CFC syndrome, which, when present simultaneously, make the diagnosis almost obligatory: 1) distinctive, “Noonan-like’’ face; 2) mental retardation, mostly severe; 3) hyperkeratotic skin lesions; 4) sparse, thin, and curly hair, often associated with absence of eyebrows; 5) congenital heart defects; 6) sporadic occurrence. The frequency of these manifestations in the CFC syndrome was compared with that found in the Noonan
syndrome, calculated from the Mendez and Opitz [19851 and Allanson [1987] reviews. This comparison is reported in Table 11. Two traits were found in the CFC syndrome only: 1) hyperkeratotic skin lesions; and 2) sparse, thin, curly hair. With regard to the skin lesions, two reports in the Noonan literature seem to contradict the above statement. Pierini and Pierini (1979) reported follicular hyperkeratosis in five patients with Noonan syndrome. Unfortunately, the authors did not provide phenotypic details, or photographs of the patients. However, based on the report of hyperkeratotic skin lesions, mental retardation, and sparse andlor curly hair with sparse eyebrows, one can argue that these patients may have had the CFC syndrome rather than the Noonan syndrome. Dry ichthyotic skin, particularly of the palms of the hands, was reported by Collins and Turner [19731 in two of four subjects with familial Noonan syndrome. This report represents the sole description of hyperkeratosis in Noonan syndrome known to us, and chance concurrence cannot be excluded. The other skin lesions in the CFC syndrome are different from those in the Noonan syndrome. Hemangiomatosis is the primary manifestation in the CFC syndrome, whereas in the Noonan syndrome cafe-au-lait spots and nevi are primary. The second manifestation, exclusively present in the CFC syndrome is sparse, thin, curly hair. Sparse and thin hair (but not curly) has been reported by ReforzoMembrives et al. [ 19491in a patient considered “a posteriori” to have the Noonan syndrome. This patient, who most likely represents a bona fide case of Noonan syndrome, also lacks hyperkeratotic skin lesions. Recently, Baraitser and Patton [ 19861 described four unrelated cases with Noonan phenotype and sparse (but not thin
TABLE I. Main Clinical Manifestations of the CFC Syndrome Case
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Reference
%pica1 face
MR”
Suarse
Hair Thin
Curlv
Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Reynolds et al., 1986 Neri et al., 1987 Neri et al., 1987 Chrzanowska et al., 1989 Mucklow, 1989 Sorge et al., 1989 Sorge et al., 1989 Sorge et al., 1989 Corsello and Giuffre, 1990 Corsello and GiuffrB, 1990 Verloes et al., 1988 Verloes et al., 1988
+ + + + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + +
+ + + + + + ++ + + + + + + + + +
+ + + + + + ++ + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + +
. ~
*Mental retardation. bcongenital heart defect. c Skin hemangiomata present. dEndocardia1 cushion defect, suspected. e Protomesosystolic murmur at birth subsequently disappeared.
~
~
Absent evebrows
Hyperkeratotic skin lesions
+-
++ + + + + + + + + + + + + + + + +
-
+ + + +-
+ +-
+ + + + +
CHDb
+ + + + +d -
+ + + ke + ++ + + + +
Noonan-CFC
369
TABLE 11. Comparison Between CFC and Noonan Syndrome With Respect to Five Characteristics (percentage positive cases) CFC syndrome (n = 19)
-~
Mental retardation Sparse, thin, curly hair Hyperkeratotic skin lesions Congenital heart defect Familial occurrence
100 100 95 84 0
Noonan syndrome __ ---___ Mendez and Optiz, Allanson, 1985 1987 (n = 121) ( n = ?) _____ 24
35 Oa
Oa Ob
Ob
50 Frequent
66 30-75
‘Only one report of thin and sparse hair, without skin hyperkeratosis (see text). bCollins and Turner (1973) report excluded (see text).
and curly) hair. In reviewing pictures and clinical description, we agree with the authors that this is not Noonan syndrome. These particular patients may rather have a new condition, falling within the Noonan phenotype. Additional distinctive elements between CFC and Noonan syndrome seem to be the frequency and severity of mental retardation and the frequency of congenital heart defects. Mental retardation, varying from mild to severe, was always present in CFC patients. On the other hand, i t is reported in only one-third of Noonan patients, where it is usually of milder degree. Congenital heart defects are also distinctly more frequent in CFC than in Noonan patients. Finally, CFC cases were always sporadic. In only one case, reported by Verloes e t al. [lSSS], was a father to daughter transmission suspected, based on supposedly mild phenotypic expression in the father. However, simple family resemblance should also be considered as a possible explanation. The facial characteristics were not considered in the comparison in Table 11,because their evaluation is likely to be more subjective. However, we wish to emphasize that the high forehead, bitemporal constriction, downslanting eyes, and bulbous nose give the CFC syndrome face a “gestalt”that the majority of authors expert in the field seem capable of distinguishing easily from that of
the Noonan syndrome face. The overall “gestalt”is often that of a large molecular weight storage disease with visceroptosis, accentuated lumbar lordosis, and coarse appearance. As opposed to most Noonan syndrome patients, CFC patients have often had extensive evaluation for metabolic disorders based on this “gestalt.” In summary, the CFC syndrome phenotype appears to be quite distinct, based on the simultaneous presence of peculiar face, mental retardation, hyperkeratotic skin lesions, sparse, thin, curly hair, congenital heart defect, and sporadic occurrence. In addition to these major manifestations, there are in CFC patients a constellation of minor anomalies, shared by Noonan patients. A list of these anomalies is reported in Table 111. Fig. 1 presents a comparison between CFC and Noonan syndrome in the form of a histogram, using those signs for which we had percentual values available from the Mendez and Opitz [1985] review. In addition to the characteristics mentioned above, the histogram shows that some manifestations, such a s low posterior hairline, cubitus valgus, neck abnormalities, and familial occurrence, are distinctive of the Noonan syndrome and are seldom present in the CFC syndrome.
CONCLUSIONS Based on available evidence, we conclude that it is correct to speak in terms of Noonan phenotype, which is
TABLE 111. Percentage of CFC and Noonan Syndrome Cases Sharing Common Phenotypic Manifestations -~Noonan syndrome _ _
Phenotype
Mendez and Opitz, 1985
Allanson, 1987-
95 68 47 42 37 33 26 11 11 10 5
95 44 34 94 53 69 20 28 22 47 32
90 90 45 NR 60 60 20 NR 25 50 55
~~~~~~
Eye abnormalities E a r abnormalities Highly arched palate Neck abnormalities Short stature Testicular abnormalities Delayed hone age Skeletal abnormalities Micrognathia Cuhitus valgus Low posterior hairline
~
CFC syndrome
~
-
370
Neri et al.
n
Fig. 1. Comparison between CFC and Noonan syndromes based on 16 characteristic features. Stippled bars, CFC syndrome; white bars, Noonan syndrome.
frequent, wide, and causally heterogeneous, and includes different genetic conditions. Among them, the CFC and Noonan syndromes must be considered as two distinct, specific entities, whose diagnosis is not interchangeable. This seems to be the safest and most productive conclusion until the time when a “Noonan syndrome gene” is isolated.
REFERENCES Allanson J E , Hall JG, Hughes HE, Preus M, Witt RD (1985a):Noonan syndrome: changing phenotype. Am J Med Genet 21:507-514. Allanson J E , Hall J G , Van Allen MI (198513):Noonan phenotype associated with neurofibromatosis. Am J Med Genet 21:457-462. Allanson J E (1987): Noonan syndrome. J Med Genet 24:9-13. Baraitser M, Patton MA (1986):A Noonan-like short stature syndrome with sparse hair. J Med Genet 23:161-164. Calvert GD (1973): Trimethylaminuria and inherited Noonan’s syndrome. Lancet 1:320-321. Cantalamessa L, Baldini M, Ambrosi B, Fraccaro M (1989): A syndrome of primary gonadal failure, short stature, mitral valve prolapse and mental retardation. Am J Med Genet 33:117-120. Chrzanowska K , Fryns JP, Van den Berghe H (1989): Cardio-faciocutaneous (CFC) syndrome: report of a new patient. Am J Med Genet 33:471-473. Collins E, Turner G (1973): The Noonan syndrome-a review of the clinical and genetic features of 27 cases. J Pediatr 83:941-950. Corsello G, Giuffre L (1990): Letter to the Editor: cardio-facio-cutaneous syndrome: notes on clinical variability and natural history. Am J Med Genet 39:OOO-000. Fryer AL, Holt PJ, Hughes HE (1990): The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same? Am J Med Genet 39:OOO-000. Humbert JR, Hammond KB, Hathaway WE, Marcoux J G , O’Brien D (1970): Trimethylaminuria: the fish-odour syndrome. Lancet 2:770-771.
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