title: Tegumentary manifestations of Noonan and Noonan-related syndromes.
abstract: OBJECTIVE
  Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement.
  
  
  METHODS
  A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF.
  
  
  RESULTS
  The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients.
  
  
  CONCLUSIONS
  We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11).
authors.affiliation: Genetics Unit, Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São PauloSP, Brazil.
authors.forename: Caio Robledo D'Angioli Costa
authors.initials: CR
authors.lastname: Quaio
authors.forename: Tatiana Ferreira
authors.initials: TF
authors.lastname: de Almeida
authors.forename: Amanda Salem
authors.initials: AS
authors.lastname: Brasil
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.forename: Alexsandra C
authors.initials: AC
authors.lastname: Malaquias
authors.forename: Chong Ae
authors.initials: CA
authors.lastname: Kim
authors.forename: Débora Romeo
authors.initials: DR
authors.lastname: Bertola
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics / Q000473:pathology*; D011446:Prospective Studies; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D012737:Sex Factors; D012867:Skin / Q000473:pathology*; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology*; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
references.citation: Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):161-79
references.pmid: 21396583
references.citation: Pediatr Dermatol. 2000 Nov-Dec;17(6):440-6
references.pmid: 11123774
references.citation: Am J Med. 1976 Mar;60(3):447-56
references.pmid: 1258892
references.citation: Acta Oncol. 2013 May;52(4):874-7
references.pmid: 22998476
references.citation: J Neurosci. 1999 Nov 1;19(21):9426-35
references.pmid: 10531446
references.citation: J Hum Genet. 2007;52(6):521-526
references.pmid: 17468812
references.citation: Am J Med Genet. 2002 Sep 15;112(1):12-6
references.pmid: 12239713
references.citation: Am J Med Genet. 1994 Nov 1;53(2):187-91
references.pmid: 7856646
references.citation: Am J Med Genet C Semin Med Genet. 2011 May 15;157C(2):129-35
references.pmid: 21495173
references.citation: J Med Genet. 2006 Nov;43(11):833-42
references.pmid: 16825433
references.citation: Hum Mutat. 2008 Aug;29(8):992-1006
references.pmid: 18470943
references.citation: J Cell Biol. 2002 Oct 14;159(1):103-12
references.pmid: 12370245
references.citation: Actas Dermosifiliogr. 2011 Jul-Aug;102(6):402-16
references.pmid: 21536246
references.citation: Biochem Soc Trans. 2006 Nov;34(Pt 5):858-61
references.pmid: 17052215
references.citation: Clin Immunol. 2007 Dec;125(3):215-23
references.pmid: 17913587
references.citation: Cell Signal. 2008 Mar;20(3):453-9
references.pmid: 17993263
references.citation: Br J Dermatol. 2011 Mar;164(3):521-9
references.pmid: 21062266
references.citation: Br J Dermatol. 2012 Mar;166(3):601-7
references.pmid: 22098123