The cardiofaciocutaneous syndrome

A Roberts

J Allanson

S Jadico

M Kavamura

A Roberts, Harvard Medical School, Partners Healthcare System, Center for Genetics and Genomics, Boston, Massachusetts, USA

J Allanson, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; University of Ottawa, Ottawa, Ontario, Canada

S K Jadico, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

M I Kavamura, Medical Genetics, Federal University of São Paulo, São Paulo, Brazil

J Noonan, Department of Pediatrics, University of Kentucy, Lexington, Kentucky, USA

J M Opitz, Departments of Pediatrics (Medical Genetics), University of Utah Medical School, Salt Lake City, Utah, USA

T Young, Departments of Ophthalmology and Pediatrics, Duke University Medical Center, Durham, North Carolina, USA

G Neri, Istituto di Genetica Medica, Facoltà di Medicina, A Gemelli, Università Cattolica del S Cuore, Roma, Italy

Correspondence to: G Neri
Istituto di Genetica Medica, Università Cattolica, Largo F Vito, 1, 00168 Roma, Italy; gneri@rm.unicatt.it

A Roberts, Harvard Medical School, Partners Healthcare System, Center for Genetics and Genomics, Boston, Massachusetts, USAJ Allanson, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada; University of Ottawa, Ottawa, Ontario, CanadaS K Jadico, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USAM I Kavamura, Medical Genetics, Federal University of São Paulo, São Paulo, BrazilJ Noonan, Department of Pediatrics, University of Kentucy, Lexington, Kentucky, USAJ M Opitz, Departments of Pediatrics (Medical Genetics), University of Utah Medical School, Salt Lake City, Utah, USAT Young, Departments of Ophthalmology and Pediatrics, Duke University Medical Center, Durham, North Carolina, USAG Neri, Istituto di Genetica Medica, Facoltà di Medicina, A Gemelli, Università Cattolica del S Cuore, Roma, ItalyCorrespondence to: G Neri
Istituto di Genetica Medica, Università Cattolica, Largo F Vito, 1, 00168 Roma, Italy; gneri@rm.unicatt.it

Received 2006 Mar 23; Revised 2006 May 30; Accepted 2006 Jun 17.

Abstract

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward‐slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain‐of‐function mutations in four different genes BRAF, KRAS, mitogen‐activated protein/extracellular signal‐regulated kinase MEK1 and MEK2, all belonging to the same RAS–extracellular signal‐regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP‐2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS–ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.

Abstract

The cardiofaciocutaneous (CFC) syndrome (OMIM 115150) is a syndrome where patients have multiple congenital anomalies or mental retardation, failure to thrive, psychomotor delay, a characteristic face, congenital heart defects, and abnormalities of the skin, eyes, gastrointestinal tract and central nervous system. Occurrence is sporadic, with men and women equally affected. The syndrome was first described 20 years ago by Reynolds et al¹ in eight children. Additional reports soon followed and, according to a recent review,² about 59 patients have been reported, providing the basis for an accurate delineation of the phenotypic spectrum of the syndrome. Nevertheless, a question has lingered for many years whether CFC is a unique and separate condition, or a variant of the Noonan syndrome (OMIM 163950)³⁴⁵⁶⁷⁸⁹ or of the Costello syndrome (OMIM 218040).¹⁰ These three conditions share several manifestations (table 11)¹¹¹²¹³ and “borderline” cases do exist, usually in infants, which defy a clear‐cut diagnosis. A useful diagnostic approach was provided with the creation of a CFC index based on 82 clinical traits and their frequencies in the population with the CFC syndrome.¹⁴ However, matters changed radically only with the discovery of different genes whose mutations cause each one of these syndromes: the protein tyrosine phosphatase SHP‐2 gene PTPN11 for Noonan syndrome,¹⁵HRAS for Costello syndrome,¹⁶ and KRAS, BRAF, mitogen‐activated protein/extracellular signal‐regulated kinase MEK1 and MEK2 for CFC.¹⁷¹⁸ These discoveries are doubly interesting for (a) finally allowing clarification of the nosology of these three syndromes and (b) explaining their similarities, given that the protein products of the causative genes interact in a common pathway.¹⁸ Therefore, it seems timely and appropriate to review the status of the CFC syndrome, providing a thorough clinical and molecular description and a nosological discussion with respect to the Noonan and Costello syndromes (table 11).

Table 1 Phenotypic overlap of the cardiofaciocutaneous, Noonan and Costello syndromes

	CFC	Noonan syndrome¹¹	Costello syndrome¹²¹³
Head	Relative macrocephaly	Yes	Yes
	Dolichocephaly	Yes	No

Hair	Sparse, curly, friable	Curly	Fine, sparse, curly, kinky
	Absent eyebrows	No	No

Face	Tall forehead	Yes	No
	Narrowed temples	No	No
	Small chin	Yes	No

Eye	Palpebral ptosis	Yes	Yes
	Hypertelorism	Yes	No
	Downward‐slanting palpebral fissures	Yes	Yes
	Epicanthal folds	Yes	Yes
	Exotropia	Strabismus	Strabismus

Ear	Earlobe creases	No	Fleshy lobes

Nose	Short	No	Yes
	Broad nasal base	No	Yes

Mouth	Deep philtrum	Yes	No
	Cupid's bow lip	No	No

Acknowledgements

We acknowledge the help and continued support of Brenda Conger, President of CFC International, and the families with members with the CFC syndrome who participated in the studies that form the basis of this review.

Acknowledgements

Abbreviations

ASD - atrial septal defect

CFC - cardiofaciocutaneous

ERK - extracellular signal‐regulated kinase

PTPN11 - protein‐tyrosine phosphatase nonreceptor type II encoding Tyrosine Phosphate SHP2

PVS - pulmonary valve stenosis

Abbreviations

Footnotes

Competing interests: None declared.

Footnotes

References

1. Reynolds J F, Neri G, Herrmann J P, Blumberg B, Coldwell J G, Miles P V, Opitz J M. New multiple congenital anomalies/mental retardation syndrome with cardio‐facio‐cutaneous involvement—the CFC syndrome. Am J Med Genet 198628413–427. [[PubMed]
2. Weiss G, Confino Y, Shemer A, Trau H. Cutaneous manifestations in the cardiofaciocutaneous syndrome, a variant of the classical Noonan syndrome. Report of a case and review of the literature. J Eur Acad Derm Vener 200418324–327. [[PubMed]
3. Fryer A E, Holt P J, Hughes H EThe cardio‐facio‐cutaneous syndrome and Noonan syndrome: are they the same? Am J Med Genet 199138548–551. [[PubMed][Google Scholar]
4. Neri G, Zollino M, Reynolds J FThe Noonan‐CFC controversy. Am J Med Genet 199139367–370. [[PubMed][Google Scholar]
5. Ward K A, Moss C, McKeown CThe cardio‐facio‐cutaneous syndrome: a manifestation of the Noonan syndrome? Br J Dermatol 1994131270–274. [[PubMed][Google Scholar]
6. Leichtman L GAre cardio‐facio‐cutaneous syndrome and Noonan syndrome distinct? A case of CFC offspring of a mother with Noonan syndrome. Clin Dysmorph 1996561–64. [[PubMed][Google Scholar]
7. Lorenzetti M E, Fryns J ‐ PRetinitis pigmentosa in a young man with Noonan syndrome: further evidence that Noonan syndrome (NS) and the cardio‐facio‐cutaneous syndrome (CFC) are variable manifestations of the same entity? Am J Med Genet 19966597–99. [[PubMed][Google Scholar]
8. Neri G, Zollino MMore on the Noonan‐CFC controversy. Am J Med Genet 199665100 [[PubMed][Google Scholar]
9. Legius E, Schollen E, Matthijs G, Fryns J PFine mapping of Noonan/cardio‐facio cutaneous syndrome in a large family. Eur J Hum Genet 1998632–37. [[PubMed][Google Scholar]
10. Wieczorek D, Majewski F, Gillessen‐Kaesbach GCardio‐facio‐cutaneous (CFC) syndrome—a distinct entity? Report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome. Clin Genet 19975237–46. [[PubMed][Google Scholar]
11. Tartaglia M, Gelb B DNoonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genom Hum Genet 2005645–68. [[PubMed][Google Scholar]
12. Johnson J B, Golabi M, Norton M E, Rosenblatt R M, Feldman G M, Yang S P, Hall B D, Fries M H, Carey JCostello syndrome: phenotype, natural history, differential diagnosis, and possible cause. J Pediatr 1998133441–448. [[PubMed][Google Scholar]
13. van Eeghen A M, van Gelderen I, Hennekam R C MCostello syndrome: report and review. Am J Med Genet 199982187–193. [[PubMed][Google Scholar]
14. Kavamura M I, Peres C A, Alchorne M M, Brunoni DCFC index for the diagnosis of cardiofaciocutaneous syndrome. Am J Med Genet 200211212–16. [[PubMed][Google Scholar]
15. Tartaglia M, Mehler E L, Goldberg R, Zampino G, Brunner H G, Kremer H, van der Burgt I, Crosby A H, Ion A, Jeffery S, Kalidas K, Patton M A, Kucherlapati R S, Gelb B DMutations in PTPN11, encoding the protein tyrosine phosphatase SHP‐2, cause Noonan syndrome. Nat Genet 200129465–468. [[PubMed][Google Scholar]
16. Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi G, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara YGermline mutations in HRAS proto‐oncogene cause Costello syndrome. Nat Genet 2005371038–1040. [[PubMed][Google Scholar]
17. Rodriguez‐Viciana P, Tetsu O, Tidyman W E, Estep A L, Conger B A, Santa Cruz M, McCormick F, Rauen K AGermline mutations in genes within the MAPK pathway cause cardio‐facio‐cutaneous syndrome. Science 20063111287–1290. [[PubMed][Google Scholar]
18. Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A, Okamoto N, Hennekam R C M, G Gillessen‐Kaesbach Wieczorek D, Kavamura M I, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, Kure S, Matsubara Y. Germline KRAS and BRAF mutations in cardio‐facio‐cutaneous syndrome. Nat Genet 200638294–296. [[PubMed][Google Scholar]
19. Somer M, Peippo M, Aalto‐Korte K, Ritvanen A, Niemi K MCardio‐facio‐cutaneous syndrome: three additional cases and review of the literature. Am J Med Genet 199244691–695. [[PubMed][Google Scholar]
20. Kavamura M I, Pomponi M G, Zollino M, Lecce R, Murdolo M, Brunoni D, Alchorne M M, Opitz J M, Neri GPTPN11 mutations are not responsible for the cardiofaciocutaneous syndrome. Eur J Hum Genet 20031164–68. [[PubMed][Google Scholar]
21. Herman T E, McAlister W HGastrointestinal and renal abnormalities in cardio‐facio‐cutaneous syndrome. Pediatr Radiol 200535202–205. [[PubMed][Google Scholar]
22. Manoukian S, Lalatta F, Selicorni A, Tadini G, Cavalli R, Neri GCardio‐facio‐cutaneous (CFC) syndrome: report of an adult without mental retardation. Am J Med Genet 199663382–385. [[PubMed][Google Scholar]
23. Drolet B A, Baselga E, Esterly N BWhat syndrome is this? Pediatr Dermatol 200017231–234. [[PubMed][Google Scholar]
24. Grebe T A, Clericuzio CNeurological and gastrointestinal dysfunction in cardio‐facio‐cutaneous syndrome: identification of a severe phenotype. Am J Med Genet 200095135–143. [[PubMed][Google Scholar]
25. Raymond G, Holmes L BCardio‐facio‐cutaneous (CFC) syndrome: neurological features in two children. Dev Med Child Neurol 199335727–741. [[PubMed][Google Scholar]
26. Sabatino G, Verrotti A, Domizio S, Angelozzi B, Chiarelli F, Neri GThe cardio‐facio‐cutaneous syndrome: a long‐term follow‐up of two patients, with special reference to the neurological features. Child Nerv Syst 199713238–241. [[PubMed][Google Scholar]
27. Ion A, Tartaglia M, Song X, Kalidas K, van der Burgt I, Shaw A C, Ming J E, Zampino G, Zackai E H, Dean J C, Somer M, Parenti G, Crosby A H, Patton M A, Gelb B D, Jeffery SAbsence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet 2002111421–427. [[PubMed][Google Scholar]
28. Neri G, Sabatino G, Bertini E, Genuardi MBrief clinical report: the CFC syndrome—report of the first two cases outside of the United States. Am J Med Genet 198727767–771. [[PubMed][Google Scholar]
29. Gross‐Tsur V, Gross‐Kieselstein E, Amir NCardio‐facio‐cutaneous syndrome: neurological manifestations. Clin Genet 199038382–386. [[PubMed][Google Scholar]
30. Allanson J, Opitz J M, Carey J C, Viskochil D, Noonan J, Kavamura M I, Neri GCardio‐facio‐cutaneous syndrome: a distinct entity. Proc Greenwood Genet Ctr 20022167 [PubMed][Google Scholar]
31. Verloes A, Le Merrer M, Soyeur D, Kaplan J, Pangalos C, Rigo J, Briard M LCFC syndrome: a syndrome distinct from Noonan syndrome. Ann Genet 198831230–234. [[PubMed][Google Scholar]
32. Pierard G E, Soyeur‐Broux M, Estrada J A, Pierard‐Franchimont C, Soyeur D, Verloes ACutaneous presentation of the cardio‐facio‐cutaneous syndrome. J Am Acad Dermatol 199022920–922. [[PubMed][Google Scholar]
33. Borradori L, Blanchet‐Bardon CSkin manifestations of the cardio‐facio‐cutaneous syndrome. J Am Acad Dermatol 199328815–819. [[PubMed][Google Scholar]
34. Tartaglia M, Kalidas K, Shaw A, Song X, Musat D L, van der Burgt I, Brunner H G, Bertola D R, Crosby A, Ion A, Kucherlapati R K, Jeffery S, Patton M A, Gelb B DPTPN11 mutations in Noonan syndrome: molecular spectrum, genotype‐phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002701555–1563. [Google Scholar]
35. Lin A E, Grossfeld P D, Hamilton R M, Smoot L, Gripp K W, Proud V, Weksberg R, Wheeler P, Picker J, Irons M, Zackai E, Marino B, Scott C I, Nicholson LFurther delineation of cardiac abnormalities in Costello syndrome. Am J Med Genet 2002111115–129. [[PubMed][Google Scholar]
36. Sarkozy A, Conti E, Deripa D, Digilio M C, Grifone M, Tandoi C, Fazio V M, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola BCorrelation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 200340704–708. [Google Scholar]
37. Bertola D R, Kim C A, Sugayama S M, Albano L M, Wagenfuhr J, Moyses R L, Gonzalez C HCardiac findings in 31 patients with Noonan's syndrome. Arq Bras Cardiol 200075409–412. [[PubMed][Google Scholar]
38. Marino B, Digilio M C, Toscano A, Gianotti A, Dallapiccola BCongenital heart disease in children with Noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr 1999135703–706. [[PubMed][Google Scholar]
39. Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze H U, Doerr H G, Hofbeck M, Singer H, Reis A, Rauch AGenotype‐phenotype correlations in Noonan syndrome. J Pediatr 2004144368–374. [[PubMed][Google Scholar]
40. Siwik E, Zahka K, Wiesner GCardiac disease in Costello syndrome. Pediatrics 1998101706–709. [[PubMed][Google Scholar]
41. Sarkozy A, Conti E, Digilio M C, Marino B, Morini E, Pacileo G, Wilson M, Calabro R, Pizzuti A, Dallapiccola BClinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet 200441e68 [Google Scholar]
42. Takahashi K, Kogaki S, Kuvotobi S, Nasuno S, Ohta M, Okabe H, Wada K, Sakai N, Taniike M, Ozono KA novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive cardiomyopathy. Eur J Pediatr 2005165497–500. [[PubMed][Google Scholar]
43. Noonan JNoonan syndrome and related disorders. Prog Pediatr Cardiol 200520177–185. [PubMed][Google Scholar]
44. Noonan J A, O'Connor WNoonan syndrome: a clinical description emphasizing the cardiac findings. Acta Paediatr Jpn 19963876–83. [[PubMed][Google Scholar]
45. Ostman‐Smith I, Wettrell G, Riesenfeld T AA cohort study of childhood hypertrophic cardiomyopathy. J Am Coll Cardiol 1999341813–1822. [[PubMed][Google Scholar]
46. Theirfelder L, Watkins H, MacRae C, Lamar R, McKenna W, Vosberg H ‐ P, Seidman J, Seidman CA tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 199477701–712. [[PubMed][Google Scholar]
47. Burch M, Mann J M, Sharland M, Shinebourne E A, Patton M A, McKenna W JMyocardial disarray in Noonan syndrome. Br Heart J 199268586–588. [Google Scholar]
48. Skinker D M, Cottrill C M, O'Connor W NRight ventricular biopsy findings of hypertrophic cardiomyopathy in a patient with Noonan syndrome. Cardiol Young 19988256–259. [PubMed][Google Scholar]
49. Sharland M, Patton M A, Talbot S, Chitolie A, Bevan D HCoagulation‐factor deficiencies and abnormal bleeding in Noonan syndrome. Lancet 199233919–21. [[PubMed][Google Scholar]
50. Young T L. Cardio‐facio‐cutaneous syndrome conference ophthalmic findings summary, Rockville Maryland—June 2003. http://www.cfcsyndrome.org/conference‐summary.htm
51. Young T L, Ziylan S, Schaffer D BThe ophthalmologic manifestations of the cardio‐facio‐cutaneous syndrome. J Pediatr Ophthalmol Strabismus 19933048–52. [[PubMed][Google Scholar]
52. McDaniel C H, Fujimoto AIntestinal malrotation in a child with cardio‐facio‐cutaneous syndrome. Am J Med Genet 199770284–286. [[PubMed][Google Scholar]
53. Nanda S, Rajpal M, Reddy B S NCardio‐facio‐cutaneous syndrome: report of a case with a review of thje literature. Int Soc Dermatol 200443447–450. [[PubMed][Google Scholar]
54. Estep A L, Tidyman W E, Teitell M A, Cotter P D, Rauen K AHRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy. Am J Med Genet A 20061408–16. [[PubMed][Google Scholar]
55. Tartaglia M, Cotter P D, Zampino G, Gelb B D, Rauen K AExclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio‐facio‐cutaneous and Costello syndromes. Clin Genet 200363423–426. [[PubMed][Google Scholar]
56. Troger B, Kutsche K, Bolz H, Luttgen S, Gal A, Almassy Z, Caliebe A, Freisinger P, Hobbiebrunken E, Morlot M, Stefanova M, Streubel B, Wieczorek D, Meinecke PExclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio‐facio‐cutaneous and Costello syndromes. Am J Med Genet A 200312182–84. [[PubMed][Google Scholar]
57. Schubbert S, Zenker M, Rowe S L, Boll S, Klein C, Bollag G, can der Burgt I, Musante L, Kalscheuer V, Wehner L K, Nguyen H, West B, Zhang K Y J, Sistermans E, Rauch A, Niemeyer C M, Shannon K, Kratz C PGermline KRAS mutations cause Noonan syndrome. Nat Genet 200638331–336. [[PubMed][Google Scholar]
58. Kerr B, Delrue M A, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M, Tang B, Eden T, O'Sullivan J, De Sandre‐Giovannoli A, Reardon W, Brewer C, Bennett C, Quarrell O, McCann E, Donnai D, Stewart F, Henekam R, Cave H, Verlos A, Philip N, Lacombe D, Levy N, Arveiler B, Black GGenotype‐phenotype correlation in Costello syndrome; HRAS mutation analysis in 43 cases. J Med Genet 2006 [Google Scholar]
59. Gripp K W, Lin A E, Stabley D L, Nicholson L, Scott C I, Doyle D, Aoki A, Matsubara Y, Zackai E H, Lapunzina P, Gonzalez‐Meneses A, Holbrook J, Agresta C A, Gonzalez I L, Sol‐Church KHRAS mutation analysis in Costello syndrome. Am J Med Genet A 20061401–7. [[PubMed][Google Scholar]
60. Jongmans M, Sistermans E A, Rikken A, Nillsen W M, Tamminga R, Patton M, Maier E M, Tartaglia M, Noordam K, van der Burgt IGenotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. Am J Med Genet A 2005134165–170. [[PubMed][Google Scholar]
61. Musante L, Kehl H G, Majewski F, Meinecke P, Schweiger S, Gillesen‐Kaesbach G, Wieczorek D, Hinkel G K, Tinschert S, Hoeltzenbein M, Ropers H H, Kalscheuer V MSpectrum of mutations in PTPN11 and genotype‐phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio‐facio‐cutaneous syndrome. Eur J Hum Genet 200211201–206. [[PubMed][Google Scholar]
62. Tartaglia M, Niemeyer, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht J D, Gelb B D. Somatic mutations in PTPN11 in juvenile myelomonocytoc leukaemia, myelodysplastic syndromes and acute myeloid leukaemia. Nat Genet 200334148–150. [[PubMed]
63. Bentires‐Alj M, Konmtaridis M I, Neel B GStops along the RAS pathway in human genetic disease. Nat Med 200612283–285. [[PubMed][Google Scholar]
64. Comstock J M, Putnam A R, Opitz J M, Pysher T J, Szakacs JPrenatal death in Fraser syndrome. Fetal Pediatr Pathol 200524223–238. [[PubMed][Google Scholar]
65. Navaratnam A E D, Hodgson G AUlerythema ophryogenes with mental retardation. Proc R Soc Med 107366233–234. [Google Scholar]
66. Baraitser M, Patton M AA Noonan‐like short stature syndrome with sparse hair. J Med Genet 198623161–164. [Google Scholar]