Pediatric Pulmonology 46:826–828 (2011)

Case Report

Sinus Vein Thrombosis as Presenting Finding in theCongenital Central Hypoventilation Syndrome:

An Insight on the Pathophysiology of the Association

Leon Joseph, MB, ChB,1 Shmuel Goldberg, MD,1 Sarit Shahroor, MD,2 Moshe Gomori, MD,3

Francis B. Mimouni, MD,4 and Elie Picard, MD1*

Summary. Congenital central hypoventilation syndrome (CCHS) is an increasingly recognized

diagnosis causing central hypoventilation and may be definitively diagnosed by genetic testing.

Previous authors reported the association between CCHS and central sinus venous thrombosis

(CSVT) and hypothesized thatCCHScould be secondary toCSVT.We report a case of CCHSwith

the typical PHOX2B mutation who also suffered from CSVT. We assume that effects, secondary

to CCHS, upon the central venous system may explain the etiological connection between CSVT

and CCHS including dysautoregulation, venous stasis or polycythemia. We believe that CCHS

should be included in the differential diagnosis of patients with CSVTaccompanied by respiratory

abnormalities. Pediatr Pulmonol. 2011; 46:826–828. � 2011 Wiley-Liss, Inc.

Key words: congenital central hypoventilation syndrome; sinus venous; thrombosis.

Funding source: none reported.

INTRODUCTION

Congenital central hypoventilation syndrome (CCHS)is an increasingly recognized diagnosis causing centralhypoventilation.1 It may present in the neonatal period orhave a ‘‘late onset.’’2 The definitive diagnosis of CCHShas beenmade possible by genetic testing of the PHOX2Bgene, showing excess phenylalanine repeats in childrenaffected by this condition.1

Boubred et al.3 reported two cases of central sinus veinthrombosis (CSVT) associated with CCHS. They postu-lated that CSVT may damage the respiratory centers ofthe brain and subsequently cause CCHS. Their hypothesiswas made prior the availability of the genetic test forPHOX2B mutations.We hereby report a case of CSVT found in a child with

CCHS. We confirmed the diagnosis of CCHS by geneticstudies and therefore suggest that CCHSmay be the cause,rather than the consequence, of CSVT.

CASE REPORT

A 35-day-old infant first presented to the emergencyroomof another institution because of recurrent episodes ofapnea. Hewas the product of an uneventful term pregnancy

anddelivery.His birthweightwas3,170 g (25th centile).Hewas admitted after his community pediatrician witnessedan apneic episode causing significant cyanosis and wasventilated via bag and mask until arrival in hospital. Hisweight on admission was 3,600 (10th centile). Complete

1Pediatric Pulmonology Unit, Shaare Zedek Medical Center (affiliated to

The Hebrew University, School of Medicine), Jerusalem, Israel

2Pediatric Intensive Care Unit, Shaare Zedek Medical Center (affiliated to

The Hebrew University, School of Medicine), Jerusalem, Israel

3Department of Radiology, Hadassah Ein Kerem Hebrew University

Medical Center, Jerusalem, Israel

4Pediatric Department, Shaare Zedek Medical Center (affiliated to The

Hebrew University, School of Medicine), Jerusalem, Israel

*Correspondence to: Elie Picard, MD, Pediatric Pulmonology Unit, Shaare

Zedek Medical Center, POB 3235, Jerusalem 91031, Israel.

E-mail: picard@szmc.org.il

Received 18 November 2010; Revised 30 December 2010; Accepted

29 January 2011.

DOI 10.1002/ppul.21450

Published online 4 April 2011 in Wiley Online Library

(wileyonlinelibrary.com).

� 2011 Wiley-Liss, Inc.

blood count and serum biochemistry were normal and hisinitial venous blood gas showed ph 7.31, pCO2 72mmHgandHCO3 29mmol/L. His blood, urine, and cerebro-spinalfluid (CSF) cultures were negative as was a PCR test forherpes simplex virus (HSV). A chest X-ray, echocardiog-raphy examination, brain ultrasound, and computedtomography of the brain were all normal. His electro-encephalogram showed non-specific findings. Neuro-logical assessment showed non-specific hypotonia andmetabolic tests including ammonia, lactate, organic acid,and amino acid levels were normal. Because of increasedfrequency of apneas, he was transferred to the pediatricintensive care unit (PICU) of our institution. On admissionhe continued to have apneic episodes and was treated withmethylxanthines and subsequently continuous positiveairway pressure (CPAP). Because the frequency andseverity of the apneas increased together with a continuingrise in his partial pressure of carbon dioxide (PaCO2), hewas ventilated.

Magnetic resonance imaging (MRI) of the brain wasperformed as part of the neurological investigations andrevealed CSVT with no evidence of edema (Fig. 1A,B).There was no papilledema on retinal examination.Heparin therapy was initiated. The thrombophilia screenwas negative. This screen included: levels of protein C,protein S, factors VIII, IX, XI andXII, genetic analysis forMTHFR, Factor V Leiden and prothrombin mutations,lupus anticoagulant and anticardiolipin antibodies. Arepeat MRI 9 days later showed some improvement andthe child was weaned off ventilation. At discharge atthe age of 69 days he had a normal oxygen saturation inroom air, no clinically evident apneas, and was mildlyhypotonic.

He returned for the first follow-up visit at thehematology clinic at the age of 5 months where hewas found to be cyanotic. His weight was 6,900 g(25th centile), his oxygen saturation was 65% and hewas sent immediately to the ER. Because of hypercarbiaover 100mmHg, he was initially placed on nasal CPAPand treated with methylxanthines. Because of furtherdeterioration, he was intubated and ventilated. Furtherinvestigations showed supra-systemic pulmonary hyper-tension and right ventricular hypertrophy (RVH). Neuro-logical imaging studies including MRI, magneticresonance arteriography and venography (MRA MRV)were performed and did not show evidence of thrombosis.A toxic screen was negative. Trials of extubation wereunsuccessful due to hypoventilation and a tracheostomywas inserted. The possibility of a diagnosis of CCHS wasraised and the diagnostic test of a PHOX2Bmutation cameback positive with a polyalanine stretch of 25 residuesin exon 3. He was discharged from the hospital to therehabilitation unit and is currently ventilated at night viathe tracheostomy. His pulmonary arterial pressures havenormalized and his RVH has disappeared.

DISCUSSION

Boubred et al.3 have reported an association betweenCCHS and CSVT in 2002 at a time when geneticconfirmation of CCHS was not readily available. Theseauthors described two cases with late onset CCHS,diagnosed on clinical grounds. The first child was a3.5-year-old boy who suffered from recurrent syncope.A brain MRI showed an old thrombosis of the lateralvenous sinus. Thrombophillia screen was normal. Afterthe anesthesia for brain MRI, a severe and persistenthypoventilation was observed with carbon dioxideretention which required later tracheostomy for nocturnalassisted ventilation. A diagnosis of CCHS was made.The second case was a 7-year-old boy who was underpsychiatric follow up for behavioral disturbance. He wastreated with neuroleptics. He also suffered from syncope.He was admitted with reduced consciousness and

Pediatric Pulmonology

Fig. 1. A: Oblique projection of 3D MR venogram shows no flow

in the right transverse sinus (arrows). B: Axial Contrast

enhanced MR venogram shows the thrombus in the right

transverse sinus as a filling defect (arrows).

Sinus Vein Thrombosis and CCHS 827

nocturnal cyanosis. The diagnosis of CCHS was madeand a tracheostomy was placed for nocturnal assistedventilation. Brain MRI was performed as part of theroutine investigations and revealed a lateral venous sinusthrombosis with a normal brainstem. Muscle biopsy andthrombophilia screenwere normal. The authors concludedthat in their two cases the thromboses were both oldand there was probably an etiologic link between CCHSand CSVT. They hypothesized that CSVT may causeischemia which affects integration of the information ofthe respiratory receptors. This hypothesis was put forwardin the absence of a genetic diagnosis for CCHS. Theyreported that no previous cases of this associationhave been published. They also noted that both childrenhad behavioral issues which they postulated was due tochronic hypoxia.Our patient was admitted because of hypoventilation

and was found to have CSVT. CSVT is known to causeencephalopathy including impaired level of conscious-ness4 and we thought initially that it was the cause of hishypoventilation. Anticoagulation therapy was started andthe child recovered. The improvement of imaging studiesparalleling clinical improvement supported the diagnosis.A few months later he was noted to have hypoventilationand hypoxia at a routine clinic appointment this timewithout CSVT. The increased severity of the centralapneas and the normal MRI suggested the diagnosis ofCCHS which was later on confirmed by a genetic study.The polyalanine stretch of 25 residues in exon 3 representsonly 5 additional residues which explain the relativelymild phenotype in our patient.Risk factors known to be associated with CSVT include

systemic factors (pro-thrombotic state, severe infectionand dehydration) and local factors causing venous stasis.4

In our case there was no evidence of hypercoagulablestate, infectious process or dehydration. The fact thatCCHS was confirmed by genetic studies makes usspeculate that CCHS preceded CSVT. This hypothesis issupported by the respiratory acidosis with metaboliccompensation at the initial presentation. The fact that twoadditional cases of this association have been reportedmay indicate that the association is not fortuitous. Thereason that this association has been rarely reportedmay be due to the low incidence of CCHS and that manycases are diagnosed as neonates prior the possibility ofdeveloping such a complication.If indeed a pathophysiological link exists between

CCHS and CSVT, it is likely to occur through a localphenomenon of stasis. Theoretically, there are many

mechanisms bywhichCCHSmay cause stasis in the bloodflow though the sagittal sinus. Indeed, in CCHS theremight be decreased cerebral blood flow due to impairedcerebral autoregulation.5 Additionally, excessive headflexion during apneamight play a role.6 Indeed, it has beenshown that prolonged head flexion may cause compres-sion of the superior sagittal sinus by the occiput.6 Infantswith CCHS have hypotonia7 and recurrent apneas, both ofwhich may cause a compression of this nature. Further-more, polycythemia related to persistent hypoxia maycause a hypercoagulable state although this was not foundin our case. Finally, cardiac asystoles and other arrhyth-mias are associated with CCHS and may contribute to thevenous stasis.8

In conclusion, we report here an association betweenCCHS and CSVT and we suggest several possiblemechanisms to explain it. We believe that CCHS shouldbe included in the etiologic work up performed in patientswith respiratory abnormalities and CSVT.

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