Evaluation of bleeding disorders in patients with Noonan syndrome: a systematic review

Figures & data

Figure 1 Prisma figure of studies for inclusion.

Note: *Key search terms included: Noonan; bleed*3; hemorrhag*3; thrombocytop*enia; h*emostatic; h*emostasis; bleed* diathesis; platelet* disorder*.

Table 1 Factor deficiencies and other bleeding disorders reported in patients with NS

Type of deficiency	Single factor deficiency	Multiple factor deficiency	Total
FI	2	1	3
FII	0	1	1
FV	0	5	5
FVII	6	6	12
FVIII	18	12	30
FIX	4	7	11
FX	0	5	5
FXI	57	30	87
FXII	19	16	35
FXIII	1	0	1
vWD	4	6	10
Platelet-relateda	42	5	47
Totalb	153	42	195

Notes:

a Thrombocytopenia: 20 (two were transient after birth); ITP + cyclooxygenase deficiency: 1; Bernard–Soulier syndrome: 1; platelet aggregation abnormality: 19; platelet storage pool deficiency: 1.

b Total is the number of patients with factor deficiencies, and for multiple factor deficiencies patients could have more than one deficiency type.

Abbreviations: ITP, idiopathic thrombocytopenia; FI, factor I; FII, factor II; FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor IX; FX, factor X; FXI, factor XI, FXII, factor XII; FXIII, factor XIII; NS, Noonan syndrome; vWD, von Willebrand disease.

Table 2 Multiple factor deficiencies and platelet-related disorders reported in patients with NS

Multiple factor deficiency	Number of patients
FI + FXI + FXII	1
FII + FXI	1
FV + FVII + FX	1
FV + FVIII	3
FV + FIX + FX	1
FVII + FIX + FXI + vWD	2
FVII + FX	2
FVII + FXII + platelet-related disorder	1
FVIII + FXI + FXII	1
FVIII + vWD	1
FVIII + FXI	7
FIX + FX	1
FIX + FXII + platelet-related disorder	1
FIX + FXI	2
FXI + FXII	11
FXI + vWD	2
FXI + platelet-related disorder	3
FXII + vWD	1
Total	42

Notes:

a Platelet-related disorders included: thrombocytopenia; idiopathic thrombocytopenic purpura + cyclooxygenase deficiency; Bernard–Soulier syndrome, platelet aggregation abnormality; platelet storage pool deficiency.

Abbreviations: FI, factor I; FII, factor II; FV, factor V; FVII, factor VII; FVIII, factor VIII; FIX, factor IX; FX, factor X; FXI, factor XI, FXII, factor XII; FXIII, factor XIII; NS, Noonan syndrome; vWD, von Willebrand disease.

Table S1 Case reports/series on bleeding disorders in patients with NS

Reference	Number of patients
Argyrou A, et al. Arch Hell Med, 2010^Citation1	1
Artoni A, et al. Pediatrics, 2014^Citation2	39
Bertola DR, et al. Rev Hosp Clin Fac Med Sao Paulo, 2003^Citation3	30
González Casado I, et al. Horm Res Paediatr. 2011^Citation4	27
de Haan M, et al. Am J Med Genet. 1988^Citation5	12
Flick JT, et al. Am J Clin Pathol. 1991^Citation6	1
Gamba G, et al. Horm Res Paediatr. 2011^Citation7	19
Kitchens CS, et al. J Pediatr. 1983^Citation8	4
Koc A, et al. Turk J Haematol. 2001^Citation9	1
Massarano AA, et al. Acta Paediatr. 1996^Citation10	18
Nunes P, et al. BMJ Case Rep. 2012^Citation11	1
Patrick K, et al. Br J Haematol. 2010^Citation12	1
Sharland M, et al. Arch Dis Child. 1992^Citation13	151a
Sharland M, et al. Lancet. 1992^Citation14	72a
Staudt JM, et al. Scand J Plast Reconstr Surg Hand Surg. 2005^Citation15	1
Stoffman JM, et al. Blood. 2004^Citation16	28
Tanaka Y, et al. Am J Med Genet. 1999^Citation17	2
Troiano M, et al. Horm Res Paediatr. 2011^Citation18	13
Vortia E, et al. Am J Gastroenterol. 2011^Citation19	2
Waespe N, et al. Hämostaseologie. 2013^Citation20	15
Witt DR, et al. Am J Med Genet. 1988^Citation21	19
Caralis DG, et al. Johns Hopkins Med J. 1974^Citation22	1
Evans DG, et al. Clin Genet. 1991^Citation23	1
Grange CS, et al. Can J Anaesth. 1998^Citation24	1
Humbert JA, et al. Lancet. 1970^Citation25	1
Komp DM, et al. Pediatr Res. 1975^Citation26	2
Phillips WG, et al. Br J Dermatol. 1993^Citation27	1
Sgouros SN, et al. J Gastroenterol Hepatol. 2004^Citation28	1
Sharland M, et al. J Med Genet. 1990^Citation29	31a
Singer ST, et al. J Pediatr Hematol Oncol. 1997^Citation30	3
Sugar AW, et al. J Oral Maxillofac Surg. 1994^Citation31	1

Note:

a Substudies (31 and 72 of 151 patients from Sharland et al. Arch Dis Child. 1992).⁶³

Abbreviation: NS, Noonan syndrome.

ArgyrouAMarinakisTKalofoliasNPapazoglouSThrombotic thrombocytopenic purpura in a young patient with Noonan syndrome and systemic lupus erythematosusArch Hell Med2010273545548

 Google Scholar

ArtoniASelicorniAPassamontiSMHemostatic abnormalities in Noonan syndromePediatrics20141335e1299e130424753526

 PubMed Web of Science ®Google Scholar

BertolaDRCarneiroJDD’AmicoEAHematological findings in Noonan syndromeRev Hosp Clin Fac Med Sao Paulo20035815812754583

 PubMedGoogle Scholar

González-CasadoIBarreda BonisASalamanca FresnoLNoonan syndrome and hemato-oncological anomaliesHorm Res Paediatr201176Suppl 2167168

 Google Scholar

de HaanMVd KampJJBriëtEDubbeldamJNoonan syndrome: partial factor XI deficiencyAm J Med Genet19882922772823354599

 PubMed Web of Science ®Google Scholar

FlickJTSinghAKKizerJLazarchickJPlatelet dysfunction in Noonan’s syndrome. A case with a platelet cyclooxygenase-like deficiency and chronic idiopathic thrombocytopenic purpuraAm J Clin Pathol19919557397421902619

 PubMed Web of Science ®Google Scholar

GambaGMarabottoFLosaLCo-agulation factor deficiencies and abnormal bleeding in Noonan’s syndromeHorm Res Paediatr201176Suppl 232121952409

 PubMed Web of Science ®Google Scholar

KitchensCSAlexanderJAPartial deficiency of coagulation factor XI as a newly recognized feature of Noonan syndromeJ Pediatr198310222242276822926

 PubMed Web of Science ®Google Scholar

KoçAKösecikMTatlıMMAtasAEmiroğluHHBernard-Soulier Syndrome like platelet defect in a patient with noonan syndrome; a case reportTurk J Haematol200118319119327264256

 PubMedGoogle Scholar

MassaranoAAWoodATaitRCStevensRSuperMNoonan syndrome: coagulation and clinical aspectsActa Paediatr19968510118111858922080

 PubMed Web of Science ®Google Scholar

NunesPAguilarSPradoSNPalaréMJFerrãoAMoraisASevere congenital thrombocytopaenia − first clinical manifestation of Noonan syndromeBMJ Case Rep20122012bcr1020114940

 Google Scholar

PatrickKMakrisMImages in haematology. Noonan syndrome associated with bleeding disordersBr J Haematol2010151211720738302

 PubMedGoogle Scholar

SharlandMBurchMMcKennaWMPatonMAA clinical study of Noonan syndromeArch Dis Child19926721781831543375

 PubMed Web of Science ®Google Scholar

SharlandMPattonMATalbotSChitolieABevanDHCoagulation-factor deficiencies and abnormal bleeding in Noonan’s syndromeLancet1992339878419211345952

 PubMed Web of Science ®Google Scholar

StaudtJMvan der HorstCMPetersMMelisPBleeding diathesis in Noonan syndromeScand J Plast Reconstr Surg Hand Surg200539424724816208790

 PubMed Web of Science ®Google Scholar

StoffmanJMChodirkerBNIsraelsSJCoagulation abnormalities in patients with Noonan Syndrome − a single centre case seriesBlood20041041110351035

 Google Scholar

TanakaYMasunoMIwamotoHNoonan syndrome and cavernous hemangioma of the brainAm J Med Genet199982321221410215542

 PubMed Web of Science ®Google Scholar

TroianoMGottliebSReyRNoonan Syndrome: assessment of bleeding disordersHorm Res Paediatr201176Suppl 221

 Google Scholar

VortiaEMahajanLKaplanBDuodenal hematoma complicating upper endoscopy with biopsy in two pediatric patients with Noonan’s syndrome: what pediatric gastroenterologists need to knowAm J Gastroenterol2011106Suppl 2S400

 Google Scholar

WaespeNPraderSKroissSKnirschWSpeerOSchmugeMClinical and laboratory manifestations of bleeding diathesis in Noonan syndromeHämostaseologie2013331A74

 Google Scholar

WittDRMcgillivrayBCAllansonJEBleeding diathesis in Noonan syndrome: a common associationAm J Med Genet19883123053173232698

 PubMed Web of Science ®Google Scholar

CaralisDGCharFGraberJDVoigtGCDelineation of multiple cardiac anomalies associated with the Noonan syndrome in an adult and review of the literatureJohns Hopkins Med J197413463463554427400

 PubMedGoogle Scholar

EvansDGLonsdaleRNPattonMACutaneous lymphangioma and amegakaryocytic thrombocytopenia in Noonan syndromeClin Genet19913932282322036745

 PubMed Web of Science ®Google Scholar

GrangeCSHeidRLucasSBRossPLDouglasMJAnaesthesia in a parturient with Noonan’s syndromeCan J Anaesth19984543323369597207

 PubMed Web of Science ®Google Scholar

HumbertJAHammondKBHathawayWETrimethylaminuria: the fish-odour syndromeLancet1970276767707714195988

 PubMed Web of Science ®Google Scholar

KompDM“Car. factor” deficiency revisited”Pediatric Res197594184189

 Web of Science ®Google Scholar

PhillipsWGDunnillMGKurwaARBlackMMOrbital oedema: an unusual presentation of Noonan’s syndromeBr J Dermatol199312921901927654583

 PubMed Web of Science ®Google Scholar

SgourosSNKaramanolisGPapadopoulouEPostbiopsy intramural hematoma of the duodenum in an adult with Noonan’s syndromeJ Gastroenterol Hepatol200419101217121915377306

 PubMed Web of Science ®Google Scholar

SharlandMPattonMAChitolieATalbotSBevanDCoagulation factor abnormalities in Noonan syndromeJ Med Genet19902710646

 Web of Science ®Google Scholar

SingerSTHurstDAddiegoJEBleeding disorders in Noonan syndrome: three case reports and review of the literatureJ Pediatr Hematol Oncol19971921301349149742

 PubMed Web of Science ®Google Scholar

SugarAWEzsiasABloomALMorcosWEOrthognathic surgery in a patient with Noonan’s syndromeJ Oral Maxillofac Surg19945244214258133379

 PubMed Web of Science ®Google Scholar

SgourosSNKaramanolisGPapadopoulouEPostbiopsy intramural hematoma of the duodenum in an adult with Noonan’s syndromeJ Gastroenterol Hepatol200419101217121915377306

 PubMed Web of Science ®Google Scholar