Ondine's curse

Soumya Swaminathan, M.D.; Vincente Gilsanz, M.D.; James Atkinson, M.D.; and Thomas G. Keens, M.D., F.C.C.P.

A five-year-old girl had congenital central hypoventilation syndrome and mediastinal and adrenal tumors. The mediastinal mass was thought to be present, retrospectively, for at least four years prior to surgery. Pathology of the excised tumors revealed benign ganglioneuromas. This is the first case reported of an association between CCHS and multiple ganglioneuromas. This suggests that CCHS, like neural crest tumors, may result from maldevelopment of the embryonic neural crest.

Congenital central hypoventilation syndrome (CCHS) is a rare disorder involving abnormal neurologic control of ventilation. Diminished output from the central respiratory pattern generator to respiratory muscles results in hypoventilation, hypoxemia, hypercarbia, and acidosis. Other congenital anomalies that have been described in association with CCHS include neuroblastoma,[1,2] Hirsch-sprung's disease,[1,3,4] ganglioneuroblastoma,[2] and abnormalities in the control of heart rate.[3] It has been postulated that all these abnormalities may be related to abnormal development or abnormal migration of neural crest cells in fetal life.[1] We report a five-year-old girl with CCHS whose multiple ganglioneuromas were discovered at the age of 4.5 years.

CASE REPORT

The patient was the product of a full term pregnancy and normal delivery with Apgar score 9,9; she weighed 7 lbs 9 oz. She became dusky two hours after birth and continued to have several apneic spells thereafter. She was admitted to CHLA at the age of one month. She was diagnosed as having CCHS and received a tracheostomy and mechanical assisted ventilation while asleep. Her initial EEG, cranial ultrasound, and CT scan were normal. Cardiac echo done at the age of four months revealed mild right ventricular dilatation and hypertrophy, which later resolved. The EMG and nerve conduction studies were normal. She had a polysomnogram at the age of four months which showed hypoventilation during sleep (PET[CO.sub.2] 55 to 60 mm Hg and oxygen saturation 78 to 83 percent) without central or obstructive apneas. She was discharged home at the age of seven months on an LP-4 ventilator and has continued to do well since then. In October 1987, at the age of 4.5 years, she was seen at the Pulmonary Clinic for an episode of pneumonia. A chest x-ray film revealed a left upper thoracic mediastinal mass with abnormal splitting of ribs (Fig 1). On close examination of her previous chest x-ray films, the mass was noted as early as eight months of age. A CT scan of the chest revealed a left paravertebral mass (Fig 2). A CT scan of the skull and a myelogram done at the same time were normal. An abdominal CT scan revealed a 5 x 5 cm right adrenal mass. Routine hematologic studies, bone marrow examination, urinary catecholamines, and a bone scan were all within normal limits.

In November 1987, an exploratory laparotomy and excision of the right adrenal mass was performed. Histopathology of the tumor revealed multiple rests of mature ganglion cells scattered throughout a fibrillary and neuromatous background, suggestive of a ganglioneuroma. In January 1988, she underwent a thoracotomy and resection of the left paravertebral mass which was 5 x 5 cm and extended from T1 to T4. Some residual tumor had to be left in the T2 intervertebral space. Histopathologic findings of this tumor also revealed a ganglioneuroma. There has been no recurrence or regrowth of the tumors since their removal.

DISCUSSION

The CCHS, synonymous with Ondine's curse, is a rare disorder of respiratory control. In the classic form, affected children have adequate minute ventilation during wakefulness but develop progressive hypoxia and hypercapnia during quiet sleep. The primary derangement is believed to result from failure of central chemoreceptors located in the ventrolateral area of the medulla.

The CCH syndrome has been associated with Hirsch-sprung's disease,[1,3,4,5] neuroblastoma,[1,2] ganglioneuroblastoma,[2] and lack of heart rate variability,[3] and also with hypothalamic dysfunction.[6] This suggests a primary defect of the stem serotonergic nerve cell[3] or a neural crest migrational abnormality.[1] Bolande[7] first coined the term "neurocristopathy" to describe lesions resulting from aberrations in the early migration, growth and differentation of neural crest cells. Neuroblasts from the neural crest migrate along each side of the developing spinal cord to give rise to the sympathetic ganglia. They also migrate ventrally to form the visceral autonomic ganglia, the chromaffin system, the Schwann cells investing all peripheral nerves, the leptomeninges and some of the central nervous system may also arise from the neural crest. Neuroblastoma, pheochromocytoma, ganglioneuroma, carcinoid tumors and Hirschsprung's disease may be related to the maldevelopment of these neural crest cells.[8]

We have described a five-year-old girl with CCHS and mediastinal and adrenal ganglioneuromas. This is the first case report of an association between CCHS and a benign tumor of neural crest origin that we are aware of. Hunt et al,[2] reporting three cases of CCHS, described one patient with multiple abdominal and thoracic ganglioneuroblastomas. Haddad et al[3] also described three cases of CCHS and Hirschsprung's disease, recurrent diarrhea, and multiple abdominal and thoracic neuroblastomas and ganglioneuroblastomas.

The reason for the reported association between CCHS and neural crest tumors is unclear. It is conceivable that as a result of early maldevelopment of the neural crest, there is an abnormality in the respiratory control pathway either in the chromaffin tissue of the carotid body chemoreceptors or in the afferent pathway (IX, X) nerves. It is possible that abnormally functioning chemoreceptors or their neural innervations could lead to sleep apnea or hypoventilation. Up to this time, MRI and CT scans have not revealed a specific brainstem lesion in primary CCHS.[9]

REFERENCES

1 Bower RJ, Adkins JC. Ondine's curse and neurocristopathy. Clin Pediatr 1980; 19:665-68

2 Hunt CE, Matalon SV, Thompson TR, Demuth S, Loew JM, Liu HM, et al. Central hypoventilation syndrome--experience with bilateral phrenic pacing in 3 neonates. Am Rev Respir Dis 1978; 118:23-28

3 Haddad GG, Mazza NM, Defendini R, Blanc WA, Driscoll JM, Epstein MF, et al. Congenital failure of automatic control of ventilation, gastrointestinal motility and heart rate. Medicine 1978; 57:517-26

4 Guilleminault C, McQuitty J, Ariagno RL, Challamel MJ, Korobkin R, McLead RE. Congenital central alveolar hypoventilation in six infants. Pediatrics 1982; 70:684-94

5 Stern M, Erttmann R, Hellwege HH, Kuhn N. Total aganglionosis of the colon and Ondine's curse. Lancet 1980; 1:877-78

6 Du Rivage SK, Winter RJ, Brouillette RT, Hunt CE, Noah Z. Idiopathic hypothalamic dysfunction and impaired control of breathing. Pediatrics 1985; 75:896-98

7 Bolande RP. The neurocristopathies. Hum Pathol 1974; 5:409-29

8 Langman JL. Medical embryology. Baltimore: Williams and Wilkins, 1969:329-32

9 Weese-Mayer DE, Brouillette RT, Naidich TP, Mclone DG, Hunt CE. Magnetic resonance imaging and computerised tomography in central hypoventilation. Am Rev Respir Dis 1988; 137:393-98

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