© 2002 American Thoracic Society
Mother–Daughter Transmission of Congenital Central Hypoventilation SyndromeDivision of Pediatric Pulmonology, Childrens Hospital Los Angeles, and Keck School of Medicine of the University of Southern California, Los Angeles, California Correspondence and requests for reprints should be addressed to Thomas G. Keens, M.D., Division of Pediatric Pulmonology, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Mailstop #83, Los Angeles, California 90027–6062. E-mail: tkeens{at}chla.usc.edu ABSTRACT The cause of congenital central hypoventilation syndrome (CCHS) is unknown, but a genetic etiology is strongly suspected. We report a 25-year-old woman with CCHS (no Hirschsprung's disease) who gave birth to a daughter who also has CCHS. This suggests a dominant mode of inheritance for CCHS in this family. Pregnancy can be associated with physiologic challenges in CCHS. The increase in endogenous progesterone may stimulate breathing and may possibly improve symptoms of hypoventilation. Although this patient did not have any worsening in symptoms, her hyperoxic hypercapnic rebreathing ventilatory response was not different when pregnant versus when not pregnant. Ventilatory support for the patient was successfully managed with diaphragm pacing throughout the pregnancy without the need to adjust settings, despite the enlarged abdomen during pregnancy. We conclude that CCHS may be an inherited disorder. Increased endogenous progesterone during pregnancy has no effect on the ventilatory response, and diaphragm pacing can successfully provide adequate ventilation throughout pregnancy.
Key Words: diaphragm pacer • pregnancy • hypercapnic ventilatory response • progesterone • inherited disorder Congenital central hypoventilation syndrome (CCHS) is defined as the failure of automatic control of breathing, present from birth, of unknown etiology (1–5). Because breathing during quiet sleep is neurologically controlled almost entirely by the automatic system, ventilation is most severely affected during quiet sleep in this disorder (2, 5, 6). However, breathing is also abnormal during active sleep and wakefulness, although usually to a milder degree (1, 5, 6). CCHS is a rare disorder, and the etiology is unknown (1). There is considerable evidence that CCHS may be genetic (7–12). There have been reports of CCHS in siblings (9–11) and in female twins (12). Several other monozygotic twins have been observed, although not reported in the medical literature (1). We report a CCHS mother who gave birth to a CCHS daughter, suggesting an inherited basis for CCHS. Pregnancy raises many issues in CCHS. Progesterone is a respiratory stimulant, and increased endogenous progesterone during pregnancy might improve ventilation in CCHS. Milerad and coworkers reported two children with alveolar hypoventilation who were successfully weaned off from mechanical ventilatory support after treatment with exogenous medroxyprogesterone (13). However, the effect of pregnancy on ventilatory responses in CCHS has not been measured. Diaphragm pacing provides ventilatory support using the patient's own diaphragmatic contraction (14), which may be hindered by the increasing abdominal contents associated with pregnancy. However, the effect of pregnancy on the efficacy of diaphragm pacing has not been assessed. CASE REPORT A 25-year-old female was diagnosed with CCHS at the age of 14 months, when she presented with cyanosis and cardiorespiratory arrest (PaCO2 was 70 mm Hg) after an upper respiratory tract infection. She had severe pulmonary hypertension and cor pulmonale, without primary heart or lung disease, suggesting that the process had been ongoing for months before diagnosis. In retrospect, the patient's mother observed pallor and sweating during sleep since the first few weeks of life. The patient failed extubation several times because of alveolar hypoventilation without any respiratory distress. She became dusky, sweaty, and had tachycardia when she fell asleep and breathed spontaneously. On awakening, these clinical signs disappeared. There was no evidence of any primary lung, heart, neuromuscular, neurologic, or metabolic disorder to explain the hypoventilation. She had absent ventilatory responses to hypercapnia and hypoxia. Several respiratory stimulants, such as aminophylline, medroxyprogesterone, ephedrine, and imipramine, failed to stimulate breathing adequately. She was diagnosed with CCHS. There was no family history of CCHS or any other autonomic nervous system disorder. She required ventilatory support only during sleep. She had diaphragm pacers implanted bilaterally at the age of 17 months. The original phrenic nerve electrodes and lead wires remain intact. The diaphragm pacer receivers have been changed three times. The most recent change was at 18 years of age. She married at the age of 22 years and became pregnant at the age of 24 years. She continued to use diaphragm pacers for ventilatory support during sleep throughout the pregnancy. She had no apparent problems such as morning headache or other signs of hypoventilation during pregnancy. Polysomnography, performed at 22, 29, and 35 weeks of gestation, showed arterial oxygen saturation of hemoglobin (SpO2) of more than 95% and end-tidal PCO2 of less than 40 mm Hg with diaphragm pacing, and no adjustments in settings were required. Pulmonary function testing performed at these times was also normal. The fetal ultrasounds showed normal growth of the fetus during pregnancy. A hyperoxic hypercapnic rebreathing ventilatory response test (5) showed an absent ventilatory response to hypercapnia at the 35th week of gestation (Figure 1) . At 41 weeks of gestation, the baby was in the breech position, and thus, a Caesarean section was performed under epidural block. A baby girl was delivered. The mother's diaphragm pacers were not used immediately after the Caesarian section because of pain, and thus, she was ventilated with bilevel positive airway pressure by mask for 1 week, after which she returned to diaphragm pacing. Hyperoxic hypercapnic rebreathing ventilatory responses showed absent ventilatory responses 6 weeks after delivery, not different than those during pregnancy (Figure 1).
The newborn daughter of our CCHS mother was noted to have cyanosis in the delivery room. The PaCO2 was 70–80 mm Hg, and pH was less than 7.20, without any evidence of lung disease. She was intubated soon after birth, and mechanical assisted ventilation was begun. She failed extubation several times secondary to hypoventilation. Her ability to breathe spontaneously was measured at 13 days of age. Her transcutaneous PCO2 increased during sleep (61 ± 6 mm Hg) and fell when she awakened (41 ± 6 mm Hg, p < 0.0001; Figure 2) . Several laboratory investigations (including chest X-ray, echocardiogram, magnetic resonance imaging of brain and brainstem, and full metabolic diagnostic evaluation) did not demonstrate other causes for hypoventilation. The diagnosis of CCHS was made. A tracheostomy was performed, and she was discharged home at 7 weeks of age on mechanical-assisted ventilation during sleep using a portable positive pressure ventilator via tracheostomy.
The CCHS mother has two sisters who do not have CCHS, and they each have two children, also not affected. The parents of the CCHS mother do not have CCHS. DISCUSSION Our 25-year-old patient with CCHS gave birth to a daughter who also has CCHS. There is one published report of a CHS mother who gave birth to a CHS daughter (15), and we are aware of a third CCHS mother who gave birth to a CCHS daughter (personal communication). Although the etiology of CCHS is unknown, a genetic cause has been postulated (7–12). These CCHS mother–daughter pairs suggest a dominant mode of inheritance. There have also been reports of CCHS in siblings (9–11) and in female twins (12). Several other monozygotic twins have been observed, although not reported in the medical literature (1). CCHS occurring in siblings or twins also suggests a dominant mode of inheritance. In the two CCHS maternal–infant pairs, the parents of the mothers did not have CCHS. Therefore, if CCHS is inherited by a dominant mode, the CCHS mutation must have been spontaneous in the mothers and transmitted to their daughters, or a spontaneous mutation could have occurred in germ cells of the mothers' mothers, and was thus transmitted to the first daughter and then to the second. We do not know whether there are CCHS parents who have given birth to children without CCHS. In a larger study of several CCHS families, Weese-Mayer and colleagues found a suggestion of multifactorial inheritance in patients with CCHS with Hirschsprung's disease, but this was less strong in CCHS without Hirschsprung's disease (8). She also found an increased familial incidence of sudden infant death syndrome in CCHS families (8), suggesting that there may be an inherited basis to some aspects of cardiorespiratory control. First- and second-degree relatives of patients with CCHS have a higher incidence of symptoms, indicating autonomic nervous system dysfunction than relatives of control subjects (7). Further analysis indicated that the mode of inheritance was most consistent with a Mendelian codominant pattern (7). This would be consistent with our hypothesized mode of inheritance for the CCHS mother–daughter pairs, except that our patients do not have Hirschsprung's disease. Endogenous progesterone increases during pregnancy, and progesterone stimulates breathing by increasing the central chemoreceptor sensitivity in normal subjects. Milerad and coworkers found that medroxyprogesterone improved the ventilatory response to hypercapnia in two children with alveolar hypoventilation (13). However, most patients with CCHS do not benefit from treatment with medroxyprogesterone (1). Our patient demonstrated no improvement in ventilatory response to hypercapnia during pregnancy. In fact, during pregnancy, ventilation was less at each PaCO2 than when she was not pregnant, and the baseline PaCO2 was elevated. We believe that these were due to mechanical loading from the large uterus and not from a change in ventilatory control. The absence of improvement with progesterone is consistent with the clinical experience in most patients with CCHS. The CCHS mother in our report used diaphragm pacing for chronic ventilatory support (14). Because diaphragm pacing depends on contraction of the patient's own diaphragm for ventilation, we were concerned that the technique might prove ineffective as the uterus increased in size during pregnancy. Therefore, we performed polysomnograms every 6 weeks during the last half of pregnancy to assure adequate gas exchange with diaphragm pacing. In our patient, we found that SpO2 remained more than 95% and PETCO2 remained less than 40 mm Hg with diaphragm pacing during sleep and that no adjustments in settings were required. She had no symptoms suggesting hypoventilation, such as morning headaches. Therefore, diaphragm pacing was used successfully in this one CCHS woman during pregnancy without hypoxia or hypercapnia. However, we do recommend that pregnant CCHS women should be monitored frequently during the pregnancy to assure that no changes in pacer settings are necessary. In conclusion, we report a CCHS mother who gave birth to a CCHS daughter. This supports a dominant mode of inheritance for CCHS. Hypercapnic ventilatory responses were not affected by pregnancy. Diaphragm pacing provided adequate gas exchange throughout pregnancy, despite the increasing abdominal load. Received in original form December 27, 2001; accepted in final form May 3, 2002 REFERENCES
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