Authors: Daniela Perez-Velasco DO, Chinwe Unegbu MD, and Christopher Busack MD – Children’s National Hospital
An 8-year-old male child with a history of Noonan syndrome and mild supravalvar pulmonary stenosis presents for dental rehabilitation surgery. Which of the following is the MOST LIKELY hematologic abnormality seen in patients with Noonan syndrome?
Correct!
Wrong!
Question of the Week 397
Noonan syndrome (NS) was first described in 1963 and has an estimated prevalence of 1 in 1000 to 2500 live births. Initially considered to be a type of “male Turner syndrome”, Dr. Jaqueline Noonan then described NS as clinically and etiologically unique from Turner syndrome and occurring in both males and females. Patients with NS have a normal karyotype, and most cases are likely secondary to de novo mutations, which are inherited in an autosomal dominant manner. Patients with NS demonstrate a wide range of phenotypic features including short stature, hypertelorism, ptosis, undescended testes, skeletal malformations, mild cognitive impairment, and congenital cardiac malformations. The incidence of congenital cardiac defects in NS is approximately 60%, of which the most common is pulmonary valve stenosis (50%).
Bleeding disorders are common in patients with NS and represent a serious, yet poorly defined, complication of NS. In her first report, Dr. Noonan described a NS patient with persistent thrombocytopenia. The estimated frequency of bleeding diatheses in NS is between 20-65%. There are reports in the literature of cases of decreased coagulation factor levels (factors II and XI), von Willebrand disease (vWD), thrombocytopenia, and abnormal platelet function. A study published in 1997 by Singer et al. described findings of a literature review of bleeding disorders in NS citing multiple types of hemostatic abnormalities with a wide range of clinical presentations. The most frequently described hemostatic abnormality was low Factor XI levels but thrombocytopenia and abnormal platelet function were also common. NS patients with hemostatic abnormalities may present with easy bruising and prolonged bleeding. Since there is no consistent pattern of hemostatic defects in this patient population, a definitive coagulation abnormality may not be identified in some NS patients. One potential factor leading to increased bleeding tendency may be shear stress due to pulmonary valve stenosis, resulting in reduced quality of functional von Willebrand factor.
The increased likelihood of hemostatic abnormalities in NS patients has important clinical implications. Anesthesiologists need to be aware of the increased risk of bleeding since NS patients often present for cardiac catheterization, open heart surgery, and noncardiac surgical procedures. Given the increased risk of perioperative bleeding, it may be advisable that NS patients have a full hematology workup and screening prior to invasive procedures. Evaluation should include a careful history of bleeding tendencies (i.e. bruising, epistaxis), a complete blood count, and coagulation profile. If any of these tests yield abnormal results, it is warranted to consider a hematology consultation for a more extensive evaluation. A hematology evaluation may include individual factor levels, tests of platelet function, and perhaps a bone marrow biopsy. Specific recommendations from a hematologist regarding aspirin use is advisable in NS patients given the risk of baseline platelet abnormalities.
Answer C is correct because patients with NS have a high incidence of hemostatic abnormalities including thrombocytopenia. Answers A,B, and D are not correct because these are not typical findings in NS.
REFERENCES
1. Noonan J.A., Ehmke D.A.: Associated noncardiac malformations in children with congenital heart disease. J Pediatr. 1963; 63: pp. 468-470.
2. Noonan JA. Hypertelorism With Turner Phenotype: A New Syndrome With Associated Congenital Heart Disease. American journal of diseases of children (1960). 1968;116(4):373-380. doi:10.1001/archpedi.1968.02100020377005
3. Allanson JE, Bohring A, Dörr HG, et al. The face of Noonan syndrome: Does phenotype predict genotype. Am J Med Genet A. 2010;152A(8):1960-1966. doi:10.1002/ajmg.a.33518
4. Derbent M, Öncel Y, Tokel K, et al. Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations. Am J Med Genet A. 2010;152A(11):2768-2774. doi:10.1002/ajmg.a.33713
5. Singer ST, Hurst D, Addiego JE. Bleeding disorders in Noonan syndrome: Three case reports and review of the literature. Journal of pediatric hematology/oncology. 1997;19(2):130-134. doi:10.1097/00043426-199703000-00006
6. Morice A, Harroche A, Cairet P, Khonsari RH. Preoperative Detailed Coagulation Tests Are Required in Patients With Noonan Syndrome. J Oral Maxillofac Surg. 2018;76(7):1553-1558. doi:10.1016/j.joms.2017.12.012
7. Witt DR, McGillivray BC, Allanson JE, et al. Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet. 1988;31(2):305-317. doi:10.1002/ajmg.1320310208.
8. Wiegand G, Hofbeck M, Zenker M, Budde U, Rauch R. Bleeding diathesis in Noonan syndrome: is acquired von Willebrand syndrome the clue?. Thromb Res. 2012;130(5):e251-e254. doi:10.1016/j.thromres.2012.08.314
Bleeding disorders are common in patients with NS and represent a serious, yet poorly defined, complication of NS. In her first report, Dr. Noonan described a NS patient with persistent thrombocytopenia. The estimated frequency of bleeding diatheses in NS is between 20-65%. There are reports in the literature of cases of decreased coagulation factor levels (factors II and XI), von Willebrand disease (vWD), thrombocytopenia, and abnormal platelet function. A study published in 1997 by Singer et al. described findings of a literature review of bleeding disorders in NS citing multiple types of hemostatic abnormalities with a wide range of clinical presentations. The most frequently described hemostatic abnormality was low Factor XI levels but thrombocytopenia and abnormal platelet function were also common. NS patients with hemostatic abnormalities may present with easy bruising and prolonged bleeding. Since there is no consistent pattern of hemostatic defects in this patient population, a definitive coagulation abnormality may not be identified in some NS patients. One potential factor leading to increased bleeding tendency may be shear stress due to pulmonary valve stenosis, resulting in reduced quality of functional von Willebrand factor.
The increased likelihood of hemostatic abnormalities in NS patients has important clinical implications. Anesthesiologists need to be aware of the increased risk of bleeding since NS patients often present for cardiac catheterization, open heart surgery, and noncardiac surgical procedures. Given the increased risk of perioperative bleeding, it may be advisable that NS patients have a full hematology workup and screening prior to invasive procedures. Evaluation should include a careful history of bleeding tendencies (i.e. bruising, epistaxis), a complete blood count, and coagulation profile. If any of these tests yield abnormal results, it is warranted to consider a hematology consultation for a more extensive evaluation. A hematology evaluation may include individual factor levels, tests of platelet function, and perhaps a bone marrow biopsy. Specific recommendations from a hematologist regarding aspirin use is advisable in NS patients given the risk of baseline platelet abnormalities.
Answer C is correct because patients with NS have a high incidence of hemostatic abnormalities including thrombocytopenia. Answers A,B, and D are not correct because these are not typical findings in NS.
REFERENCES
1. Noonan J.A., Ehmke D.A.: Associated noncardiac malformations in children with congenital heart disease. J Pediatr. 1963; 63: pp. 468-470.
2. Noonan JA. Hypertelorism With Turner Phenotype: A New Syndrome With Associated Congenital Heart Disease. American journal of diseases of children (1960). 1968;116(4):373-380. doi:10.1001/archpedi.1968.02100020377005
3. Allanson JE, Bohring A, Dörr HG, et al. The face of Noonan syndrome: Does phenotype predict genotype. Am J Med Genet A. 2010;152A(8):1960-1966. doi:10.1002/ajmg.a.33518
4. Derbent M, Öncel Y, Tokel K, et al. Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations. Am J Med Genet A. 2010;152A(11):2768-2774. doi:10.1002/ajmg.a.33713
5. Singer ST, Hurst D, Addiego JE. Bleeding disorders in Noonan syndrome: Three case reports and review of the literature. Journal of pediatric hematology/oncology. 1997;19(2):130-134. doi:10.1097/00043426-199703000-00006
6. Morice A, Harroche A, Cairet P, Khonsari RH. Preoperative Detailed Coagulation Tests Are Required in Patients With Noonan Syndrome. J Oral Maxillofac Surg. 2018;76(7):1553-1558. doi:10.1016/j.joms.2017.12.012
7. Witt DR, McGillivray BC, Allanson JE, et al. Bleeding diathesis in Noonan syndrome: a common association. Am J Med Genet. 1988;31(2):305-317. doi:10.1002/ajmg.1320310208.
8. Wiegand G, Hofbeck M, Zenker M, Budde U, Rauch R. Bleeding diathesis in Noonan syndrome: is acquired von Willebrand syndrome the clue?. Thromb Res. 2012;130(5):e251-e254. doi:10.1016/j.thromres.2012.08.314
