Complications in children and adolescents with Chuvash polycythemia

To the editor:

In the Chuvash form of congenital polycythemia,¹ a homozygous germ-line VHL^R200W mutation leads to impaired degradation of the α subunits of the hypoxia inducible transcription factors (HIF-1α and HIF-2α) and augmented hypoxic responses during normoxia including inappropriately elevated erythropoietin levels.² Mutated VHL^R200W reportedly binds with increased avidity to suppressor of cytokine signaling 1, which hinders Janus kinase (JAK) 2 degradation, leading to erythropoietin-hypersensitive growth of erythroid progenitors.³ JAK2 inhibitors have been shown to correct the Chuvash polycythemia phenotype in a mouse model³ and anecdotally in people. In addition to elevated red cell mass, Chuvash polycythemia is marked by headache, vertigo or dizziness, leg varices, increased systolic pulmonary artery pressure, aberrant iron metabolism, hemorrhage, thrombosis not correlating with hematocrit elevation, and early mortality.^1,4,5 There is no demonstrated effective therapy for reducing symptoms, complications, or mortality.

The complications of Chuvash polycythemia have not been addressed specifically in children and adolescents, but available evidence raises concern for untoward consequences. In the first description of this disorder in the 1970s, 103 patients were diagnosed at a median age range of 10-19 years and followed for a median of 6 years.^1,6 Eleven patients died, 2 of them <20 years of age. In a follow-up of this cohort in 2001, mortality (often attributable to cerebral infarction or hemorrhage) was >25% by age 40 years.⁴

We enrolled 30 subjects with Chuvash polycythemia (VHL^R200W homozygotes) and 16 Chuvash controls (VHL wild type) <21 years of age into a registry in 2005-2006 to prospectively evaluate their clinical course. The health status of these subjects was reevaluated in June 2014. Approval was obtained from the institutional review boards of Cheboksary Children’s Hospital and Chuvash Republic Clinical Hospital 1 for the study, and the subjects or parents gave written informed consent according to the Declaration of Helsinki.

Baseline characteristics of this cohort are summarized in Table 1. The VHL^R200W homozygotes (age range of 6-20 years) tended to be older than the VHL wild-type controls (age range of 3-20 years) but the sex distributions were similar. Eight VHL^R200W homozygotes had had intermittent phlebotomies, 13 were being treated with aspirin, and 13 were being treated with cinnarizine, an antihistamine and calcium channel blocker used to promote cerebral blood flow. Prominent symptoms at study entry in the VHL^R200W homozygotes included headache in 22, lower extremity pain in 15, and dizziness in 13. Frequent physical findings included plethora and a tendency to lower systolic blood pressure. The median hemoglobin concentration was 19.1 g/dL in the VHL^R200W homozygotes vs 14.0 g/dL in the controls, and the erythropoietin concentrations were higher in the VHL^R200W homozygotes despite the higher hemoglobin concentrations. Headache was reported in 13 (100%) of VHL^R200W homozygotes treated with cinnarizine vs 9 (53%) of those not treated (P = .004), and dizziness was a symptom in 6 (46%) of homozygotes treated with cinnarizine vs. 5 (29%) of those not treated (P = .3). Similarly, headache was a symptom in 12 (92%) of VHL^R200W homozygotes treated with aspirin vs 10 (59%) in those not treated (P = .09), and dizziness was a symptom in 5 (38%) of homozygotes treated with aspirin vs 6 (35%) of those not treated (P = .6).

Table 1.

Baseline characteristics and follow-up of children by genotype

	VHLR200W homozygotes (N = 30)	VHL wild type (N = 16)	P
Baseline
Demographics
Age in years, median (IQR)	16 (12-18)	11 (8-13)	.006*
Female, no. (%)	16 (53.3%)	7 (43.8%)	.8*
Treatment
Phlebotomy, no. (%)	8 (26.7%)	1 (6.3%)	.1*
Aspirin, no. (%)	13 (43.3%)	0 (0%)	<.001*
Cinnarizine, no. (%)	13 (43.3%)	0 (0%)	<.001*
Medical history
Headache, no. (%)	22 (73.3%)	5 (31.3%)	.011*
Leg pain, no. (%)	15 (50.0%)	1 (6.3%)	.003*
Vertigo or dizziness, no. (%)	11 (36.7%)	4 (25.0%)	.5*
Chest pain, no. (%)	8 (26.7%)	3 (18.8%)	.7*
Bleeding, no. (%)	2 (6.7%)	0 (0%)	.5*
Physical exam
BMI, median (IQR)	17.0 (15.2-19.8)	15.8 (14.8-18.3)	.3†
Systolic blood pressure, median (IQR)	99 (95-103)	105 (91-110)	.005†
Plethora, no. (%)	26 (86.7%)	1 (6.7%)	<.001*
Systolic murmur, no. (%)	9 (30.0%)	2 (12.5%)	.3*
Splenomegaly	1 (3.3%)	0 (0%)	>.9*
Laboratory data
Hemoglobin (g/dL), median (IQR)	19.1 (16.7-20.2)‡	14.0 (12.8-14.4)	<.001*
Ferritin (ng/mL), median (IQR)	13.3 (11.3-26.7)§	21.0 (15.2-45.8)||	.14*
Erythropoietin (U/L), median (IQR)	15.5 (11.0-31.3)§	4.8 (3.9-7.2)||	.003†
Follow-up
Age in years, median (IQR)	22 (20-24)‡	20 (17-22)	.044*
Complications	9 (31.0%)‡	0 (0%)	.017*
Death	2 (6.9%)	0 (0%)
Organ cysts	2 (6.9%)	0 (0%)
Cardiac complications	2 (6.9%)	0 (0%)
Peptic ulcer	1 (3.4%)	0 (0%)
Headache and tremor of hands	1 (3.4%)	0 (0%)
Chronic myelogenous leukemia	1 (3.4%)	0 (0%)

BMI, body mass index; IQR, interquartile range.

^*From Kruskal-Wallis or Fisher’s exact test.

^†From linear regression or penalized logistic regression adjusted for age.

^‡N = 29.

^§N = 20.

^||N = 8.

We were able to obtain follow-up information for 29 of the VHL^R200W homozygotes and all 16 controls in 2014 at a median of 8 years (range 1-9 years) after entry into the registry (Table 1). Nine subjects (31%), 3 of 15 females and 6 of 14 males, and no controls have had complications. In 7 of these subjects, the complications are plausibly related to Chuvash polycythemia. One male died at the age of 17 years from thromboembolism. Two subjects had cardiac complications at age 19 and 24 years (i.e., chest pain with exertion and paroxysmal atrial tachycardia, respectively). Two subjects were found to have benign cysts: 1 investigated for severe headache at age 21 years had a retro-cerebellar arachnoid cyst, and the other had a cyst of the spleen. A sixth subject was found to have a peptic ulcer at age 22 years. Thromboembolism, cardiac disease, organ cysts, and peptic ulcers are all previously described complications of Chuvash polycythemia.^1,4,6,7 The seventh subject, a 22-year-old male with severe headache and tremor of both hands, is not available for brain imaging; however, we have previously found ischemic lesions as well as Chiari I malformation and a venous angioma in more than half of 33 asymptomatic adults with Chuvash polycythemia who were undergoing brain magnetic resonance imaging.⁴ In 2 of the present subjects, the complication is not obviously related to Chuvash polycythemia: 1 subject died at age 21 years from head trauma sustained in a motor vehicle accident, and another developed chronic myelogenous leukemia at age 19 years. Over half of the subjects continue to suffer from previously reported Chuvash polycythemia symptoms: chronic headache, fatigue, and/or lower extremity pain. Baseline predictors of developing a major complication related to Chuvash polycythemia during the follow-up period include vertigo or dizziness (odds ratio 13.8; P = .001), pulse rate (odds ratio 0.9; P = .08), and treatment with cinnarizine (odds ratio 3.8; P = .13).

This report underscores the life-threatening complications and symptoms impairing quality of life that occur in children and adolescents with Chuvash polycythemia. It is possible that other forms of congenital polycythemia due to disordered hypoxia sensing also have similar adverse effects in children and adolescents, but the sporadic nature of these disorders precludes the assessment of their morbidity and mortality. Further research to identify the mechanisms of these complications and symptoms and to develop effective therapy is needed.

Authorship

Acknowledgments: This research was supported in part by Incyte Corporation.

Contribution: A.I.S. participated in designing and conducting the study, data analysis and interpretation, identifying study subjects, and writing the manuscript; G.Y.M. participated in designing and conducting the study, data analysis and interpretation, and identifying study subjects; L.A.P. participated in study hypothesis and identifying study subjects; M.N. performed the statistical analysis and participated in writing the manuscript; J.T.P. participated in designing the study, genotyping, data analysis and interpretation, and writing the manuscript; and V.R.G. designed and conducted the study, participated in data analysis and interpretation, and wrote the manuscript.

Conflict-of-interest disclosure: A.I.S., G.Y.M., M.N., J.T.P., and V.R.G. have served as consultants for Incyte Corporation. J.T.P. and V.R.G. have received travel support from Incyte Corporation.

Correspondence: Victor R. Gordeuk, Sickle Cell Center (M/C 712), Suite 172, Clinical Sciences Building, 820 South Wood St, Chicago, IL 60612; e-mail: vgordeuk@uic.edu.