HISTORY OF MEDICINE

NOONAN SYNDROME A HISTORICAL PERSPECTIVE

Jacqueline A. Noonan, M.D. Professor Emeritus, University of Kentucky, Department of Pediatric Cardiology Lexington, Kentucky, USA

   Introduction
   Genetics of Noonan syndrome
   Associated clinical findings: new insights
   Short stature
   Mental development
   Non-cardiac findings
   Cardiovascular abnormalities
   Differential diagnosis
   CONCLUSION
   References

Introduction

The eponym, Noonan syndrome, was first proposed by Dr. John Opitz in 1965 (1). He had been a senior medical student and then a first year pediatric resident in the Department of Pediatrics in Iowa City where Dr. Noonan was a new faculty member from 1959 –1961 (2). She presented at the Midwest Society for Pediatric Research in 1962 (3) a clinical study of associated non-cardiac malformations in children with congenital heart disease and described nine patients who shared a phenotype suggestive of Turner syndrome, all of whom had valvular pulmonary stenosis. She felt this represented a new syndrome because it occurred in both males and females, had normal chromosomes, was associated with a congenital cardiac defect and could be inherited. When Dr. Opitz moved to Madison, Wisconsin to complete his training, he soon noted a number of children, similar to the ones he had seen with Dr. Noonan. In 1965 he published an abstract “Noonan Syndrome in Girls: A Genocopy of the Ullrich-Turner syndrome” (1). In 1968 Dr. Noonan published her report of 19 patients (4). Four other papers appeared in the same issue describing similar patients. Although three of the papers used the term “Turner phenotype” (4, 5, 6), two (7,8) used the term Noonan syndrome. Finally in 1972, Dr. Noonan used the term Noonan syndrome for the first time at the March of Dime Conference on the cardiovascular system (9). A number of authors have suggested the first reported patient with what is now called Noonan syndrome was a 20-year-old male reported by Kobylinski in 1883 (10). This young man had marked webbing of the neck. It was this feature, which seemed to prompt most of the early reports. Funke (11) in 1902 reported a patient with Pterygium colli (webbed neck) as well as short stature, micronathia, cubitus vagus, and other minor abnormalities. Ullrich (12) in 1930 reported an eight-year-old girl with similar features. In 1938 Turner (13) reported seven older females with similar facies as well as short stature who had sexual infantilism. Unfortunately, in 1943 before Turner syndrome was shown to be a sex chromosome abnormality, Flavell (14) introduced the term “male Turner syndrome” which subsequently led to considerable confusion in the literature. In the meantime, Ullrich (15) reported a series of patients in 1949 whom he had noted over the past two decades. He noted a 4:1 predominance of females over males and suggested the similarity between his patients and mice that had been bred by Bonnevie. Bonnevie was a mouse geneticist who had bred a mutant strain of mice with webbed neck and swelling of the limbs. The term Bonnevie-Ullrich syndrome became popular, particularly in Europe. This term was used to describe children, some of whom would now be recognized as having Noonan syndrome, while others would be recognized as having Turner syndrome. In 1959 Ford (16) demonstrated that Turner syndrome patients had a 45 XO chromosome pattern. Throughout the 1960s a number of reports of “male Turner syndrome” or “Turner phenotype” in males were reported. Heller in 1965 (17) reported five cases of his own and reviewed 43 cases from the literature. These reports were mainly by endocrinologists who began to use this term for patients with a variety of testicular problems with or without short stature. There was a vigorous attempt to find a chromosomal abnormality in the “male Turner syndrome”, but these attempts were unsuccessful. From review of the literature it is apparent that these “male Turner syndrome” represented a heterogeneous group of patients. Some of these, but not all, would be considered Noonan syndrome today. As chromosome studies became more widely available, it became clear that all girls with the Turner phenotype did not have Turner syndrome, but in reality, were Noonan syndrome. Some of the earlier reports of the cardiac lesions in Turner syndrome suggested pulmonary stenosis was a rather frequent abnormality. We now know true Turner syndrome have left-sided lesions with bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome among the more frequently reported. To my knowledge, pulmonary stenosis has never been observed in a patient with proven Turner syndrome. Early reports of Noonan syndrome suggested cardiac lesions to occur in about 50% (18), but more recent studies by Sharland (19) and Marino (20) reveal an incidence of over 80% when cardiac ultrasound is used as part of the work-up. Almost every type of cardiac defect has been reported, but valvular pulmonary stenosis is the most frequent. The valve is often quite dysplastic. Dysplasia of all four valves has been reported (21). It is of interest to note that the renowned cardiologist, Paul Wood (22), mentioned the association of hypertelorism with valvular pulmonary stenosis in the second edition of his textbook, but did not comment on any other associated abnormalities. In the third edition (23), published after his death, there are two children who are referred to as Turner syndrome with pulmonary stenosis who, clearly, are really Noonan syndrome patients.

Genetics of Noonan syndrome

Noonan syndrome was recognized early on as an autosomal dominantly inherited disorder, but the majority of cases appeared to be sporadic. Dr. Allanson in 1985 (24) made the important observation that the phenotype of Noonan syndrome changes significantly over time. She found if photographs of parents taken at the same age as their affected child and compared they would frequently suggest one of the parents also had Noonan syndrome. As is common in autosomal dominantly inherited disorders, there is often great variability in expression and mild cases may go unrecognized. In 1994 Jamison et. al (25) studied some familial cases of Noonan syndrome and were able to map the gene for Noonan syndrome to the long arm of chromosome 12. Not all families with Noonan syndrome showed linkage to this chromosome suggesting that there was more than one genetic cause for Noonan syndrome. Recently, using new information provided by the human genome project, the group headed by Dr. Bruce Gelb (26), identified the Noonan syndrome gene on chromosome 12. This gene is called PTPN-11 and regulates the product of a protein named SHP-2. This is a protein essential in several intracellular single transduction pathways that control a number of developmental processes including cardiac semilunar valvular genesis. Valvular pulmonary stenosis with a dysplastic pulmonary valve is the most common lesion found in Noonan syndrome. This suggested that the PTPN-11 gene would be a likely candidate since mice with a mutated gene often had aortic and pulmonary stenosis. Patient studies included two moderate size families who had shown linkage to chromosome 12. All affected members showed missence mutations in the PTPN-11 gene.

Child with Noonan syndrome characterized by slight irides, hypertelorism and fleshy posteriorly rotated ears.The syndrome is commonly associated with valvular pulmonary stenosis. The gene PTPN-11 on chromosome 12 is responsible for the abnormality.

An additional 22 unrelated individuals with Noonan syndrome representing sporadic or small families were also studied. Half of these had missence mutations in PTPN-11 similar to the family studies. A more recent report (27) now includes studies in 119 individuals with Noonan syndrome. 54 of the 119 or 45% were demonstrated to have mutations. There was a higher prevalence of mutations in familial cases than in sporadic. Among those patients with Noonan syndrome and pulmonary valve stenosis, PTPN-11 mutations were found in 70.6% while those with Noonan syndrome and hypertrophic cardiomyopathy showed a lower incidence of 5.9%. In the not too distant future, it should be possible to screen for PTPN-11 in other Noonan syndrome like conditions such as Cardio-facio-cutaneous, Leopard and Noonan-neurofibromatosis syndromes. It is also likely that in the future linkage studies in other families with Noonan syndrome will map to a specific chromosome and other genes will be identified that are responsible for those cases of Noonan syndrome not due to a mutation of the PTPN-11 gene. For the first time, there is hope that a genetic test will be available to make a firm diagnosis of Noonan syndrome. Up to the present time the diagnosis relies on clinical findings alone.

Associated clinical findings: new insights

Since the first reports of Noonan syndrome, there have been a number of subsequent, important observations. For example, although the majority of Noonan syndrome patients have an unremarkable prenatal history; in at least a third, the pregnancy is complicated by polyhydramnios. With the advent of fetal ultrasound, a number of fetuses later diagnosed with Noonan syndrome have been reported to show increased nuchal fluid as well as hydrops as early as 14 weeks (28). Early development of a cystic hygroma in the fetus, on follow-up, frequently shows the cystic hygroma to regress (29). It is likely that fetal edema may be quite common since excessive weight loss is common in the first weeks of life. The cystic hygromas present in fetal life in Noonan syndrome, Turner syndrome, and a number of other conditions, are partly responsible for the similar facial features among these syndromes. The antimongoloid slant, micrognathia and broad chest may all be the result of the cystic hygroma in fetal life. Although there is some resemblance between Turner and Noonan syndrome, the facies of Noonan syndrome are actually quite different. The characteristic slight irides, hypertelorism and fleshy posteriorly rotated ears are actually distinctive from Turner syndrome.

Short stature

The cause of short stature noted in over 80% of Noonan syndrome is unknown. Weight and length are usually normal at birth, but the height drops within the first few months. In general, there is a two-year or longer delay between bone age and chronological age. This results in the delay of onset of puberty. Short stature is of concern to both patients and families. The availability of growth hormone prompted a number of studies to evaluate the effect of growth hormone therapy. There are no consistent abnormalities in the secretory dynamics of growth hormone and there has been no consistent relationship between growth hormone studies and the response to growth hormone therapy. A number of studies have shown a positive effect of growth hormone treatment on the linear growth. Studies by Romano et al (30) and Noordam et al (31) demonstrated a positive effect of growth hormone on the linear growth, but unfortunately, both studies demonstrated an advance in bone age relative to height age. It is clear that children treated with growth hormone reach final growth earlier, but it is not clear whether their final height has been significantly increased by the use of growth hormone therapy. Unfortunately, there is still very limited data on the final height in patients with Noonan syndrome who have been followed serially.

Mental development

Developmental delay is frequent. Part of this motor delay may be attributed to muscular hypotonia. In a study by van der Burgt (32) individual IQ scores varied between 48 –130. Some children clearly have some learning disability. Although the overall mean IQ is reduced, severe mental retardation is uncommon. Graduation from college and achievement of Ph.D. degrees have been reported.

Non-cardiac findings

Hepatosplenomegaly, usually unexplained, is found in about 25%. Skin problems and easy bruising have been noted frequently. A variety of abnormal clotting factors, which include low levels of factor 11, factor 8 as well as thrombocytopenia and platelet function defects are frequent (33). Low levels of a wide variety of clotting factors with no specific patterns have also been reported. Lymphatic abnormalities occur (34) in less than 20% of patients with Noonan syndrome, but may cause serious problems. Both intestinal (35) and pulmonary lymphagectasia (36) have been reported as well as spontaneous chylothorax (37). Persistent pleural effusions following cardiac surgery is a known risk in patients with Noonan syndrome.

Cardiovascular abnormalities

Over 80% of patients with Noonan syndrome have some kind of a cardiovascular abnormality. Pulmonary stenosis is the lesion most characteristic of Noonan syndrome. The valve is often dysplastic. Virtually, every kind of cardiac defect has been described, although to my knowledge there have been no cases of complete transposition. Atrial septal defect, branch pulmonary artery stenosis, ventricular septal defect, tetralogy of Fallot as well as ostium primum have all been reported. In addition, left sided obstructive lesions, such as valvar aortic stenosis, subaortic stenosis, coarctation of the aorta as well as patent ductus arteriosus are seen. Ehlers (38) was the first to report hypertrophic cardiomyopathy. Both obstructive and non-obstructive hypertrophic cardiomyopathy occurs in 20-30%. This hypertrophy may be noted at birth or may develop in later infancy or childhood (39). Unlike the non-syndromic, familial hypertrophic cardiomyopathy, patients with Noonan syndrome often have involvement of both the right and left ventricle. The microscopic findings are similar to those seen in the non-syndromic form and include muscle disarray and thick walled coronary arteries.

Still unexplained is the unusual electrocardiogram with an indeterminate left axis deviation and a dominant S wave over the entire precordium. Although this may be seen with hypertrophic cardiomyopathy, it may occur as an isolated finding and is a helpful sign in supporting the diagnosis of Noonan syndrome.

Differential diagnosis

There are a number of conditions, which must be included in the differential diagnosis. Certainly a female with a left-sided cardiac lesion should be evaluated for Turner syndrome. Cardio-facio-cutaneous syndrome and Costello syndrome are often difficult to differentiate from Noonan syndrome in early infancy, although with time differences become more apparent. It is possible that both Watson syndrome and Leopard syndrome are indistinguishable from Noonan syndrome. We will not know until a specific diagnostic test becomes available. An interesting group of patients with both neurofibromatosis and a Noonan phenotype are still poorly understood. A careful history to eliminate alcohol abuse or other tetragons as well as chromosome studies may be necessary to distinguish Noonan syndrome from other conditions that might resemble Noonan syndrome.

CONCLUSION

Since Noonan syndrome was described 40 years ago, much has been learned about associated problems that may occur with this syndrome. It is exciting that a gene has been discovered and there is hope that other genes may soon be recognized. We will soon have a specific diagnostic test for this syndrome. We still know little about the long-term natural history of Noonan syndrome and what long-term risks are faced by patients with Noonan syndrome. Sporadic reports of leukemia (40) and other malignancies in Noonan syndrome have been reported. An interesting report on the first patient reported by Dr. Noonan (42) suggests that progressive left ventricular disease may occur many years after apparent successful pulmonary valvotomy surgery. I have tried to present a brief history of Noonan syndrome to the present time. Delineation of the genetic defect in a variety of syndromes will help us to understand better the role of mutant genes in development. As we learn more about the natural history of Noonan syndrome, there is hope that we will develop therapies to prevent long-term adverse effects.

References

1. Opitz JM, Summitt RL, Smith DW, Sarto GE Noonan’s syndrome in girls: 
    A genocopy of the Ullrich-Turner syndrome. J Pediatr 67/ 5(2):968 (Abstract).

2. Opitz JM. Editorial comment: the Noonan syndrome. Am J Med Genet. 
    1985;21:515-518.

3. Noonan JA, Ehmke DA. Associated noncardiac malformations in children with 
    congenital heart disease. J Pediatr. 1963;31:150-153.

4. Noonan JA. Hypertelorism with Turner phenotype. Am J Dis Child.1968;116:373-380.

5. Celermajer JM, Bowdler JD, Cohen DH (1968): Pulmonary stenosis in patients with 
    the Turner phenotype in the male. Am J Dis Child 116:351-358.

6. Nora JJ, Sinha AK (1968): Direct familial transmission of the Turner phenotype. 
    Am J Dis Child 116:343-350.

7. Wright NL, Summitt RL, Ainger LE (1968): Noonan’s syndrome and 
    Ebstein’s malformation of the tricuspid valve. Am J Dis Child 116:367-372.

8. Kaplan MS, Opitz JM, Gosset FR. Noonan’s syndrome: 
    a case with elevated serum alkaline phosphatase levels and malignant schiwannoma 
    of the left forearm. Am J Dis Child. 1968;116:359-366.

9. Noonan JA (1972): Noonan syndrome (comments). In Bergsma D (ed): 
   “the Cardiovascular System, Part V.” Baltimore: Williamson and Wilkins for The
    National Foundation-March of Dimes, BD:OAS VIII (5):122-123.

10. Kobylinski O. Ueber Eine Flughoutahnibiche Ausbreitung. 
      Am Hals Arch Anthoropol. 1883;14:342-348.

11. Funke O, Pterygium colli. Dtsch Zeitschr Chir 1902;63:163-167.

12. Ullrich O. Uber typische kombination-bilder multiyear abanturgen. 
      Z Kinderheilkd. 193;49:271-276.

13. Turner HH. A syndrome of infantilism, congenital webbed neck, and 
      cubitus valgus. Endocrinology. 1938;25:566- 574.

14. Flavell G. Webbing of the neck with Turner’s syndrome in the male. 
      Br J Surg. 1943;31:150-153.

15. Ullrich O. Turner’s syndrome and status Bonnevie-Ullrich; synthesis of 
      animal phenogenetics and clinical observations on a typical complex of 
      developmental anomalies. Am J Hum Genet. 1949;1:179-202.

16. Ford CE, Jones KW, Polani PE et al. A sec chromosomal anomaly in 
      a case of gonadal dysgenesis (Turner’s syndrome). Lancet. 1959;7:11-13.

17. Heller RH. The Turner phenotype in the male. J Pediatr. 1965;66:48-63.

18. Noonan JA. Noonan syndrome: An update and review for the primary pediatrician. 
      Clin Pediatr. 1994;9:548- 555.

19. Sharland M, Burch M, McKenna WM, Patton MA. 
      A clinical study of Noonan syndrome. Arch Dis Child. 1992;67:178- 183.

20. Marino B, Digilio C, Toscano A, Giannotti A Dallapiccola B.
      Congenital heart diseases in children with Noonan syndrome: 
      An expanded cardiac spectrum with high prevalence of atrioventricular canal. 
      J Pediatr. 1999;135:703-706.

21. Sreeram N, Kitchiner D, Smith A. Spectrum of valvar abnormalities in
      Noonan’s syndrome: A pathological study. Cardiol Young 1994;4:62-66.

22. Wood P. Diseases of the heart and circulation, ed 2 Philadelphia: J.P. 
      Lippincott Co. 1956, p318.

23. Wood P. Disease of the heart and circulation, ed 3 Philadelphia: J.P.
      Lippincott Co. 1968, p357-358.

24. Allanson JE, Hall JG, Hughes M. Noonan syndrome: The changing phenotype. 
      Am J Med Genet. 1985;21:507-514.

25. Jamieson CR, et al. Mapping a gene for Noonan syndrome to the long arm 
      of chromosome 12. Nature Genetics. 1994;8:357-360.

26. Tartaglia M, et al. Mutations in PTPN11, encoding the protein tyrosine 
      phosphatase SHP-2, cause Noonan syndrome. Nature Genetics, 2001;29:465-468.

27. Tartaglia M, et al. PTPN11 Mutations in Noonan syndrome:
       Molecular spectrum genotype-phenotype correlation and 
       phenotypic teterogensity Am J Hum Genet. 2002;70.

28. Bowle EV, Black V. Non-immune hypdrops fetalis in Noonan’s syndrome. 
      Am J Dis Child. 1986;140:758-760.

29. Donnenfeld AE, Nazir MA, Sindoni F, Libviggi RJ. 
      Prenatal sonographic documentation of cystic hygroma regression in
       Noonan syndrome. Am J Med Genet. 1991;39:461- 465.

30. Romana AA, et al. Growth hormone treatment in Noonan syndrome:
      The National Cooperative Growth Study experience. J Pediatr. 1996;128:S18-21.

31. Noordam C, van der Burgt I, Sengers RCA, Delemane- van de Waal HA, 
      Otten BJ. Growth hormone treatment in children with Noonan’s syndrome:
      4 year results of a partly controlled trial. Activa Paed. 2001;90:889-894.

32. van der Burgt I, Thoonet G, Roosenboom N, Assman- Hulsmans C, Gabreels F,
      Otten B, Brunner H. Patterns of cognitive functioning in school-aged children 
      with Noonan syndrome associated with variability in phenotypic expression.
      J Pediatr.1999;135:707-713.

33. Witt DR, McGillioray BC, Allanson JE, et al. Bleeding diathesis in Noonan syndrome: 
      a common association. Am J Med Genet. 1988;31:305-317.

34. Hoeffel JC, Juncker P, Remy J. Lymphatic vessel dysplasia in Noonan syndrome. 
      Am J Roentgenol. 1980;134:399-401.

35. Vallet HL, Holtzapple PG, Eberlein WR, et al.
      Noonan syndrome with intestinal lymphangiectasisa.
      J Pediatr. 1972;80:269-274.

36. Baltaxe HA, Lee JG, Ehlers KH, Engle MA. 
      Pulmonary lymphangiectasia demonstrated by lymphangiography in 2 patients
       with Noonan syndrome. Radiology. 1975;115:149-153.

37. Goens MB, Campbell D, Wiggins JW. 
      Spontaneous chylothorax Noonan syndrome. Treatment with prednisone. 
      Am J Dis Child. 1992;146:1453-1456.

38. Ehlers KH, Engle MA, Levin AR, Delly WJ.
      Eccentric ventricular hypertrophy in familial and sporadic instances of
      46XX, XY Turner phenotype. Circulation. 1972;45:639- 652.

39. Noonan JA, O’Connor W. Noonan syndrome, a clinical descriptionemphasizing
      the cardiac findings. Acta Paed Jap 1996;38:76-83.

40. Piombo M, Rosanda C, Pasino M, et al. Acute l ymphoblastic leukemia in 
      Noonan syndrome: report of two cases. Med Pediatr Oncol. 1993;21:454-455.

41. Danetz JS, Donofri MT, Embrey RP. Multiple left sided cardiac lesion in one 
      of Noonan’s origins patient. Cardiology in the Young. 999;6:610-612.

Dr. Jacqueline Noonan and an adult patient with Noonan syndrome