phox2b gene mutation in a patient with late-onset central hypoventilation
TRANSCRIPT
Pediatric Pulmonology 38:349–351 (2004)
PHOX2B Gene Mutation in a Patient With Late-OnsetCentral Hypoventilation
Ha Trang, MD, PhD,1* Beatrice Laudier, MD,2 Delphine Trochet, MD,2 Arnold Munnich, MD,2
Stanislas Lyonnet, MD, PhD,2 Claude Gaultier, MD,1 and Jeanne Amiel, MD2
Summary. Congenital central hypoventilation syndrome, which is related to abnormal autonomic
control of breathing and typically manifests at birth, was recently associated with PHOX2B gene
mutations. In contrast, central hypoventilationwith later onset constitutes a poorly defined group of
unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B
mutation in a patient with central hypoventilation manifesting in childhood. This finding suggests
that some of these cases may be genetically determined and allelic to congenital central
hypoventilation syndrome. Pediatr Pulmonol. 2004; 38:349–351. � 2004 Wiley-Liss, Inc.
Key words: central hypoventilation; late-onset; PHOX2B.
INTRODUCTION
Congenital central hypoventilation syndrome (CCHS)is characterized by abnormal autonomic control ofbreathing that results in severe hypoventilation duringsleep. Typically, CCHS manifests as a life-threateningcondition at birth.Nearly 20%of patientswithCCHShaveHirschsprung disease, in addition to CCHS.1 Recently, anassociation between heterozygous mutations of the paired-like homeobox gene (PHOX2B) and CCHS was foundby our group,2 and confirmed by other studies.3,4 ThePHOX2B gene, which maps to chromosome 4p12, isincluded in signalling pathways known to be essential forearly noradrenergic differentiation of the central andperipheral autonomic nervous system.5
Rarely, patients may present later during childhood,either with pulmonary hypertension or with clinicallysignificant persisting alveolar hypoventilation followingan acute respiratory illness. Investigations found no causefor the central hypoventilation. As opposed to CCHSdiagnosed at birth, these cases of late-onset centralhypoventilation constitute a poorly defined and hetero-geneous group. The need for better understanding anddefinition is evident. Whether central hypoventilation haslater onset or later recognition, or whether all idiopathiccentral hypoventilation syndromes share similar physio-pathological bases, have yet to be determined.
Here we report on the identification of a PHOX2Bgene mutation in a patient with central hypoventilationmanifesting in childhood.
CASE REPORT
Themale patient was born of unrelated healthy parents.Polyhydramnios was noted during gestation. He was
healthy until age 2 years and 3 months, experiencingseveral episodes of upper airway infection or bronchitiswithout noticeable cyanosis, sweating, or headache. Hethen went into cardiorespiratory arrest and coma during abronchitis episode. Echocardiography showed pulmonaryhypertensionwithout heart disease. After resolution of thebronchitis, he remained ventilator-dependent during sleep.He was referred to the Department of Physiology,
Robert Debre Hospital (Paris, France), 1 year after thisepisode. Full overnight polysomnography attended by oneof us and a technician was performed. The child wasallowed to go to sleep while spontaneously breathingroom air. He slept in such a condition for 3 consecutivehours during which tidal volume, respiratory rate, oxygensaturation (SpO2), and end-tidal PCO2 (PETCO2) weremeasured and minute-ventilation was calculated breath-by-breath. SpO2 was 94–95%, and PETCO2 was 38–
1Service de Physiologie, INSERM E-9935, Hopital Robert Debre,
Universite Paris 7, Paris, France.
2Departement de Genetique, INSERM U-393, Hopital Necker Enfants
Malades, Paris, France.
Grant sponsor: INSERM 4M309D; Grant sponsor: GIS-Institut des
Maladies Rares.
*Correspondence to: Ha Trang, Service de Physiologie, Hopital Robert
Debre, 48 Boulevard Serurier, 75019 Paris, France.
E-mail: [email protected]
Received 20 November 2003; Revised 12 January 2004; Accepted 12
January 2004.
DOI 10.1002/ppul.20074
Published online 15 June 2004 in Wiley InterScience
(www.interscience.wiley.com).
� 2004 Wiley-Liss, Inc.
43 mmHg during wakefulness. Alveolar hypoventilationwasmost severe during nonrapid-eye-movement (NREM)sleep: his nadir SpO2 was 70%, with SpO2 below 90%during 74% of NREM time (and 21% of rapid-eye-movement (REM) time); peak PETCO2 was 65 mmHg,with PETCO2greater than 50mmHgduring 59%ofNREMtime (and 40% of REM time). Minute ventilation waslowest in NREM sleep (P< 0.001 vs. wakefulness orREM, Fig. 1), and not significantly different betweenREM and wakefulness (P¼ 0.204, Wilcoxon test). Therewere no sleep apneas. By midnight, the child was placedunder mechanical ventilation for the rest of the night. Thenextmorning, ventilatory and cardiac responses to inhaledCO2 were measured during wakefulness, using the rebre-athing method,6 and were found to be absent (Fig. 2).Diaphragm latencies and action potentials elicited byelectrical stimulation were normal. Thus, our investi-gations established that the hypoventilation was centralin nature.The boy had normal growth, psychomotor, and beha-
vioral development. His body mass index was 18 kg/m2.Body temperature occasionally dropped to between3385–358C, suggesting possible thermal dysregulation.Cerebral MRI and endocrine studies were normal, as wellas histological examination of a rectal biopsy, ocularmotility, and heart rate variability. However, there was nodifference between blood pressure measured noninva-sively during daytime and nighttime, suggesting abnormalbaroreflex control.7
DNA molecular testing was performed as previouslydescribed, with the consent of both parents.2 We screenedthe coding sequence of the PHOX2B gene by direct DNAsequencing, using the fluometric method on both strands.A heterozygous triplet expansion of 15 nucleotides (dup766–780), adding 5 alanines to the 20-residue polyalaninetract of the PHOX2B protein, was identified in the child(Fig. 3), and was shown to have occurred de novo asneither of the parents carried the mutation. No alaninetriplet expansions were found in 250 control chromo-somes. There was no other gene mutations (RET, GDNF,HASH-1, PHOX2A, RNX, endothelin-3, or endothelin Breceptor) identified in the patient.
Fig. 1. Spontaneous minute ventilation in different states of
alertness. VE, minute ventilation (ml/kg/min); NREM, nonrapid-
eye-movement sleep; REM, rapid-eye-movement sleep. Boxes
show median values (bold bars) with interquartile ranges.
Error bars represent 5–95% values. *P<0.001, Wilcoxon test.
Fig. 2. Cardiac and ventilatory responses to inhaled CO2 during
wakefulness: VE (minute ventilation; ml/kg/min), PETCO2 (end-
tidal PCO2 mmHg).
Fig. 3. A: Genomic organization of PHOX2B protein. Homeobox domain and 9- and 20-residue
polyalanine tracts are indicated (dark boxes). B: Wild-type and mutant PHOX2B proteins.
350 Trang et al.
DISCUSSION
Our patient had central hypoventilation manifesting inchildhood with minimal autonomic symptoms. A hetero-zygous, de novo PHOX2B mutation, identical to thosepreviously reported in CCHS,2 was identified. This casestudy is the first to demonstrate this gene mutation in apatient with late-onset central hypoventilation. CCHS hasa broad range of phenotypic variability according to theseverity of hypoventilation and associated autonomicnervous dysfunction. A recent study showed the associa-tion between PHOX2B mutation length and severity ofCCHS.4 Since only 5-alanine expansion was found in ourpatient, this could correlate with a mild degree ofrespiratory deficit, and could account for the later clinicalmanifestation of the condition. Thus, onemay suggest thatlate-onset CCHS may have less of a mutation lengthcompared to typical CCHS.
Our patient showed no evidence of hypothalamicdysfunction. However, a subset of patients with late-onsetcentral hypoventilation syndrome presented with severeobesity and endocrine and behavioral problems suggestiveof hypothalamic dysfunction.8 As studies in bothmice andhumans showed that PHOX2B is not expressed inhypothalamic nuclei,5 it is likely that hypothalamicdysfunction cannot be ascribed to PHOX2B mutationsper se. Therefore, onemay further speculate that late-onsetcentral hypoventilation with hypothalamic dysfunctionconstitutes a group distinct from late-onset CCHS, notonly clinically but also genetically.
This study is a single case report, which limits ourpresent conclusions. Therefore, it is essential to report allcases of idiopathic late-onset central hypoventilation,owing to both the rarity and poor delineation of thecondition. We suggest that PHOX2B gene testing beincluded in the investigative protocol of such patients, as
the present report shows that at least some of these casesmay be genetically determined and allelic to CCHS.
ACKNOWLEDGMENTS
We thank Dr. M. Cori for referring the patient, and theCentre d’Investigation Clinique (Hopital Robert Debre).
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