Published ahead of print on June 8, 2006, doi:10.1164/rccm.200602-266CR
© 2006 American Thoracic Society doi: 10.1164/rccm.200602-266CR
Brainstem Anomalies in Two Patients Affected by Congenital Central Hypoventilation SyndromeLaboratory of Molecular Genetics, and Departments of Neurosurgery, Neuropsychiatry, Neuroradiology, and Anesthesia and Resuscitation, Giannina Gaslini Institute, Genoa, Italy Correspondence and requests for reprints should be addressed to Giancarlo Ottonello, M.D., U.O. Anestesia e Rianimazione, Istituto Giannina Gaslini, L.go Gerolamo Gaslini, 5, 16148 Genova, Italy. E-mail: giancarloottonello{at}ospedale-gaslini.ge.it
Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy characterized by absence of automatic control of respiration; decreased sensibility to hypoxia and hypercapnia, mainly during sleep; and autosomal dominant inheritance due to heterozygous polyalanine expansions and frameshift mutations in the PHOX2B gene. Because the CCHS phenotype could hide other neurologic diseases, the American Thoracic Society established that the initial evaluation of suspected CCHS should exclude neuroanatomic impairments as the structural basis of the reduced autonomic system function. In this work, we describe the clinical history of two unrelated patients with hypoventilation during sleep and harboring hypoplasia of the pons and a Chiari I malformation, respectively. In both patients, CCHS was diagnosed by detection of PHOX2B polyalanine expansion, suggesting that the American Thoracic Society diagnostic criteria may be too restrictive. Moreover, to exclude a putative role of PHOX2B in non-CCHS neurologic diseases, we have performed PHOX2B mutation screening in a group of individuals with Chiari I malformation, confirming the exclusive role of PHOX2B in the pathogenesis of CCHS.
Key Words: Chiari I malformation • PHOX2B • sleep disorders Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy characterized by absence of adequate control of respiration with decreased sensitivity to hypoxia and hypercapnia (1, 2). CCHS is often associated with other autonomic nervous system dysfunctions or neural crest cell–derived disorders, such as HSCR, ganglioneuroma, and neuroblastoma (2–7). According to an official statement of the American Thoracic Society (ATS), CCHS can be diagnosed in the absence of primary neuromuscular, lung, or cardiac disease or an identifiable brainstem lesion (6). Because CCHS could mimic many treatable diseases, the possibility of discrete congenital myopathy, myasthenia gravis, altered airway or intrathoracic anatomy, diaphragmatic dysfunction, congenital cardiac disease, structural hindbrain or brainstem abnormality, or Moebius syndrome should be considered. Moreover, other pathologic events including asphyxia, infection, trauma, tumor, and infarction should be ruled out. The initial evaluation should include a detailed neurologic analysis that may require muscle biopsy, chest X-rays, fluoroscopy of the diaphragm, bronchoscopy, electrocardiogram, Holter recording, and echocardiogram (6). Furthermore, magnetic resonance imaging (MRI) including T1- and T2-weighted images is the currently recommended imaging approach for anatomic evaluation of the central nervous system and has been widely used to rule out possible medullary lesions, which may be undetected by computerized tomography (8). Heterozygous frameshift mutations and polyalanine expansions in the PHOX2B gene, encoding a tissue-specific transcription factor expressed during autonomic nervous system development, have been identified in the vast majority of individuals with CCHS (9–12), thus providing a means for quick and reliable molecular diagnosis of the disease. A correlation between the length of polyalanine expanded tracts and phenotype severity of patients with CCHS was observed, suggesting that, for these mutations, the onset and severity of the breathing defect can be predicted with good approximation (7, 11, 12). According to a partial dominant negative effect, expansions in the polyalanine tract have resulted in a length-dependent cytoplasmic retention and formation of PHOX2B aggregates including the wild-type protein (13). However, in vivo experiments have shown that PHOX2B haploinsufficiency could also explain, to a lesser extent, the CCHS respiratory phenotype (14). Molecular analysis also disclosed a strict association between the rare frameshift mutations and the development of neuroblastoma (15). On the other hand, whether severe additional symptoms, such as Hirschsprung's disease (HSCR), are more frequently associated with the largest alanine expansions is still debated (11, 15), while an effect of HSCR on mortality in patients with CCHS has been excluded (16). In addition, observations have shown that the frequency of the nonsyndromic HSCR-predisposing allele at the RET locus (17) was higher in a group of patients with Haddad syndrome (CCHS plus HSCR) than within a group characterized by CCHS alone, suggesting that RET acts as a modifier gene for the enteric phenotype in patients with a PHOX2B mutation (18). Finally, a report on a 35-yr-old patient just diagnosed with CCHS suggests that one or more regulatory genes might influence the severity of the autonomic dysregulation in late-onset patients, by modifying the expression or the activity of PHOX2B (19). So far, the reported cases of patients with CCHS carrying a PHOX2B mutation have complied with the diagnostic criteria for CCHS, including absence of structural hindbrain or brainstem abnormalities. In this work, we describe two unrelated patients with a diagnosis of CCHS confirmed by identification of PHOX2B polyalanine expansions, showing pontine hypoplasia and a Chiari I malformation, respectively. Such observations are in contrast with the clinical criteria proposed by the official statement of the ATS to establish a CCHS diagnosis, which should therefore be revised.
Clinical Evaluation of Patients Our diagnostic approach to patients affected with central hypoventilation is directed to identify any possible cause of impairment of respiratory control, and includes the following:
Polysomnographic studies were performed with a Pamela sleep recorder (Medatec, Brussels, Belgium). Recording of blood gas was performed with an ABL 700 (Radiometer, Brønshøj, Denmark) and CO2 transcutaneous monitoring was obtained with a MicroGas 7650 and Tosca 500 (Linde Medical Sensors/Radiometer, Basel, Switzerland).
PHOX2B Mutation Screening
The clinical phenotypes of the two patients were not compatible with a strict CCHS diagnosis according to the ATS guidelines. Nevertheless, mutational analysis of the PHOX2B gene revealed polyalanine expansions, thus allowing us to establish the diagnosis.
Patient 1 The girl presented a few additional anomalies of the autonomic nervous system, including profuse swelling, acrocyanosis, stipsis, reduced perception of pain, headaches, and breath-holding spells. Brain MRI revealed normal supratentorial structures and showed a Chiari I malformation, with downward ectopia of the cerebellar tonsils into the foramen magnum (Figure 1). However, there were no signs of brainstem compression, and the herniated structures extended caudally only a few millimeters below the plane of the foramen magnum, without reaching the C1 arch and with preservation of the surrounding subarachnoid space. Neither myelomeningocele nor hydrosyringomyelia was present. At that time, because such a picture did not seem compatible with severe clinical hypoventilation, a diagnosis of Ondine's curse was advanced as the most likely.
The child was tracheostomized and discharged in 1987, after a long period of hospitalization on mechanical ventilation. In 1990, when she was 4 yr old, she suffered cardiac arrest at home, a consequence of pneumonia. She was transferred to the local hospital and then to our intensive care unit. She recovered from this life-threatening event with signs of cerebral hypoxia and ischemia. At present, she lives most of the time in a rehabilitative institution, and suffers from a moderate neurologic involvement and generalized seizures, treated with barbiturates. She walks autonomously but shows psychomotor delay. During follow-up examinations, no additional clinical signs attributable to the Chiari I malformation have arisen, indicating an absence of clinical deterioration resulting from the disease. Although surgical decompression of the craniocervical junction was contemplated, we decided to refrain from surgery, in agreement with the parents, for several reasons: (1) it was believed that her psychologic situation could not afford this sort of experience; (2) surgery could not be expected to improve sleep ventilation; and (3) the Chiari I malformation was not severe, with no signs of compression of the medulla oblongata on MRI, absence of syringobulbia and hydrosyringomyelia, and absence of clinical signs including dysphagia, hoarseness, headache, vocal cord paralysis, and loss of the gag reflex. In retrospect, this decision was supported by the result of the molecular analysis of PHOX2B, which showed a de novo heterozygous in-frame duplication of 15 nucleotides, leading to five extra alanine residues in the polyalanine stretch of PHOX2B exon 3.
Patient 2 At that time, his psychomotor development was normal; he could speak fluently with a speaking valve and neither motor limitation nor awake hypoventilation were present. Severe stipsis was present and rectal biopsy and X-ray examinations revealed a short form of HSCR, which was surgically corrected later on. No other sign of autonomic dysfunction or ocular anomaly could be detected. A polysomnographic study was performed during mechanical ventilation. When stage 4 non-REM sleep was reached and mechanical ventilation was gradually reduced and stopped, a rapid decrease in SpO2 level (down to 65%) with no increase in spontaneous ventilation was observed. After O2 administration, CO2 reached 80 mm Hg within a few minutes, as recorded by both blood samples and transcutaneous electrode. Even at these CO2 values, the child did not increase his respiratory efforts. Brain MRI showed normal supratentorial structures and vascularization; however, hypoplasia of the pons was identified (Figure 2).
Molecular analysis of PHOX2B revealed a de novo heterozygous in-frame duplication of 18 nucleotides, leading to six extra alanine residues in the polyalanine tract of PHOX2B exon 3.
PHOX2B Analysis of Chiari I Malformation
Patients with CCHS show impaired breathing during sleep because of diminished ventilatory response to hypoxia and hypercapnia (1, 2). The ATS established that CCHS may be diagnosed in the absence of primary neuromuscular, lung, or cardiac disease or an identifiable brainstem lesion (6). In this case report, we describe two patients with CCHS diagnosed on the basis of the presence of typical PHOX2B polyalanine expansions who, in contrast with the clinical diagnostic criteria established by the ATS, showed associated structural neurologic anomalies. In particular, the first patient had a Chiari I malformation, with caudal displacement of the brainstem and herniation of the cerebellar tonsils into the foramen magnum extending to the upper cervical spinal canal at the level of the atlas and lying in close contact with the medulla. The second patient harbored hypoplasia of the pons. At first, by applying the ATS criteria we excluded CCHS, assuming that compromised breathing during sleep could have been due to the observed structural defects. However, the subsequent detection of PHOX2B polyalanine expansions in both patients validated the diagnosis of CCHS and also led us to consider that the ATS criteria for CCHS evaluation may be too restrictive in some cases. This observation is in agreement with the detection of neuroanatomic defects of the limbic structures and cerebellum in a panel of 12 patients with CCHS. These lesions, not identified by conventional MRI, were revealed by using a T2 relaxometry procedure that can detect reduced cell or fiber density or diminished myelination, not found by routine evaluation (23). Expression studies have detected the PHOX2B transcript in several different districts of the autonomic nervous system, in particular in the developing hindbrain and peripheral nervous system as well as in all noradrenergic centers and in specific neuronal groups, such as those involved in the medullary control reflexes of autonomic functions (24). Therefore, the identification of mutations in the neurospecific transcription factor PHOX2B in the vast majority of patients with CCHS (9–12), and the disclosure of the pathogenetic mechanisms mediating the effects of polyalanine expansions and frameshift mutations (13, 25), suggest that a different and variable degree of neuroanatomic impairment could be an additional and unexpected outcome of a defective PHOX2B gene. Such an observation prompted us to hypothesize a possible involvement of PHOX2B mutations in non-CCHS neurologic syndromes. However, analysis of a panel of patients with Chiari I malformation did not reveal any PHOX2B mutations, thus confirming the central role and strict association of PHOX2B with CCHS. In conclusion, we suggest that a less restrictive application of CCHS diagnostic criteria than that previously suggested by the ATS should be encouraged. The present report also confirms the usefulness of the molecular analysis of the PHOX2B gene to ultimately establish the diagnosis.
Supported by a fellowship awarded to T.B. by the Gruppo Giovani Industriali-Assindustria, and by the Italian Telethon (grant GGP04257). Current affiliation for Ivana Matera: Mouse Embryology Section, Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD. Originally Published in Press as DOI: 10.1164/rccm.200602-266CR on June 8, 2006 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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