Information on the following diseases can be found in the Related Disorders section of this report:

• congenital myopathy
• congenital myasthenia gravis
• Moebius syndrome
• infantile sleep apnea
• obstructive lung disease (general)
• Hirschsprung's disease
• epilepsy

The first signs of congenital central hypoventilation syndrome include a bluish discoloration of the skin and mucous membranes (cyanosis), very shallow breathing, and a general decrease in respiratory function (hypoventilation) during the night (nocturnal). This causes low levels of oxygen in the blood (hypoxemia).

CCHS can affect multiple organ systems. Approximately 16-20% of individuals with CCHS have Hirschsprung’s disease. Other conditions that affect at least 15% of those affected include premature birth, the need for tube feeding during infancy, constipation, diarrhea, fainting episodes, seizures in infancy, backflow from the stomach to the esophagus (gastroesophageal reflux), abnormal heart rhythm, leg pain and excessive yawning during exercise, excessive sweating, infections without fevers, asthma, recurrent pneumonia, low muscle tone and eye and teeth abnormalities. Developmental delays in motor and speech occur in approximately 25% of individuals with CCHS.

The abnormal neural crest development can also lead to specific tumors including neuroblastoma, ganglioneuroma and ganglioneuroblastoma.

Most individuals with CCHS have an abnormal PHOX2B gene located on chromosome 4 at 4p12. The abnormality in the PHOX2B gene is usually a new mutation in which short DNA sequences are repeated a number of times in a row. The repeated DNA sequences cause the protein resulting from this gene to function improperly. Some individuals affected with CCHS have been found to have mutations in other genes, but it has not yet been determined if these mutations can cause the disorder. CCHS can be inherited as an autosomal dominant genetic disorder.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 4p12" refers to band 12 on the short arm of chromosome 4. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Congenital central hypoventilation syndrome is a rare disorder that affects males and females in equal numbers. It is thought to be present at birth but may be overlooked in mild cases. In some rare cases, surgical or accidental trauma may bring on the symptoms of central hypoventilation syndrome in adolescents and adults. Approximately 300 cases are known worldwide. The birth prevalence of CCHS is approximately 1 in 50,000 livebirths.

Symptoms of the following disorders can be similar to those of congenital central hypoventilation syndrome. Comparisons may be useful for a differential diagnosis.

Congenital myopathy is a term for any muscle disorder present at birth. By this definition the congenital myopathies could include hundreds of distinct neuromuscular syndromes and disorders. In general, congenital myopathies cause loss of muscle tone and muscle weakness in infancy and delayed motor milestones, such as walking, later in childhood. Three distinct disorders are definitively classified as congenital myopathies: central core disease, nemaline rod myopathy, and centronuclear (myotubular) myopathy.

Congenital myasthenia usually occurs in infants but may become evident in adulthood. Associated features may vary in severity from case to case. Such abnormalities may include feeding difficulties, sudden episodes in which there is absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and/or other abnormalities.

Moebius syndrome is a rare developmental disorder that may have a number of different causes and is characterized by facial paralysis present at birth (congenital). Facial nerve development is absent or diminished causing abnormalities of the facial muscles and jaw. Additional symptoms may include numerous abnormalities of the mouth and face (orofacial region) and malformations of limbs. Mental retardation occurs in approximately 10 percent of cases. (For more information on this disorder, choose "Moebius" as your search term in the Rare Disease Database.)

Infantile apnea is a sleep disorder of infancy characterized by temporary, recurrent interruptions of breathing (respiration) during sleep. Symptoms of this disorder include periodic wakefulness during the night, excessive sleepiness during the day, abnormally slow heartbeat (bradycardia) and a bluish discoloration of the skin and mucous membranes (cyanosis). There may be no chest movements and no air passes through the mouth or nostrils during episodes of interrupted breathing. The exact cause of infantile apnea is not known. (For more information on this disorder, choose "infantile apnea" as your search term in the Rare Disease Database.)

When central hypoventilation syndrome occurs in adults it may be confused with other more common respiratory diseases such as chronic obstructive lung disease which is characterized by difficulty breathing (dyspnea), coughing and bronchitis.

The following disorders may be associated with congenital central hypoventilation syndrome as secondary characteristics. They are not necessary to confirm a diagnosis of CCHS.

Hirschsprung's disease is a rare gastrointestinal disorder characterized by absence at birth of certain cells (autonomic ganglia) in the lower segment of the large bowel. The ability of the colon to push intestinal contents along the length of the bowel (peristalsis) is absent or impaired. The lower bowel is typically in continuous spasm and is abnormally large (megacolon). The symptoms of Hirschsprung's disease appear soon after birth and may include constipation, abdominal distention and vomiting. Older infants may have a profound loss of appetite (anorexia) and failure to thrive. (For more information about this disease, choose "Hirschsprung" as your search term in the Rare Disease Database.)

Epilepsy is a group of disorders of the central nervous system characterized by repeated convulsive electrical disturbances in the brain. The major symptoms may include loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the nerves that control involuntary body functions (autonomic nervous system). Episodes of these symptoms are frequently preceded by an "aura". The symptoms of a grand mal seizure may include loss of consciousness, violent muscle spasms, gnashing of teeth, loss of bladder and/or bowel control, confusion, and/or drowsiness. (For more information on these disorders, choose "epilepsy" as your search term in the Rare Disease Database.)

Diagnosis
The diagnosis of CCHS is based on physical findings, chest X-ray, specialized imaging techniques and sometimes muscle biopsy. Evaluation of spontaneous breathing during sleep and wakefulness should be conducted in a respiratory physiology laboratory. Neuromuscular, lung, heart and brain stem abnormalities must be ruled out before a diagnosis can be made. Clinical molecular genetic testing is available to identify the PHOX2B repeat expansion mutation. Molecular genetic analysis of the entire PHOX2B gene is available on a research basis only.

Treatment
Infants with CCHS are usually treated by surgically creating a temporary opening in the throat (tracheostomy) into which a small tube (cannula) is inserted, and the baby is then put onto a mechanical ventilator. The baby requires a mechanical ventilator at home (with back-up) as well as experienced nursing care.

Other assistive breathing apparatus and/or techniques may be used. The goal is to lower the pressure in the artery that leads from the lungs, and improve the levels of oxygen delivered to the lung tissue (alveolar ventilation). The periodic administration of low levels of oxygen and the assistance of a respirator during sleep may also help to improve oxygen levels in the blood. Most children with CCHS require a mechanical ventilator while sleeping and approximately 17% also require ventilation when awake.

Some individuals with heart arrhythmias require a pacemaker to correct the rhythm. Treatment of Hirschsprung's disease usually consists of surgery to relieve the obstruction. A temporary bowel opening of the colon in the abdominal wall (colostomy) is usually performed. The second operation consists of removing the diseased parts of the colon and rectum and connecting the normal bowel to the anus. Neuroblastomas are removed surgically followed by chemotherapy in some cases. Treatment for other tumors originating from the neural crest depends on the type and location of the tumor.

Multidisciplinary care from a team of professionals is necessary to optimize the quality of life for individuals with CCHS. This team should consist of pediatricians, pulmonologists, cardiologists, surgeons, gastroenterologists, neurologists, opthalmologists, psychiatrists, social workers, nurses, speech and language therapists and special education teachers.

Early detection and treatment are extremely important, since the disorder, if left untreated, may lead to serious and even life-threatening consequences. It is possible for individuals with CCHS to have a good quality of life and normal life span if appropriate medical treatment and support are provided.

Some individuals with CCHS have been successfully transitioned to noninvasive types of ventilation. Further study is needed to determine the risks and benefits of this approach.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

REVIEWS
Weese-Mayer DE and Silvestri JM. Idiopathic Congenital Central Hypoventilation Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:673.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 209880; Last Update:6/14/04.

Marazita ML, Berry-Kravis EM, Silvestri JM and Weese-Mayer DE. (Updated 1/28/04). Congenital Central Hypoventilation Syndrome. In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2004. Avaailable at http://genetests.org. Accessed 11/04.

JOURNAL ARTICLES
Amiel J, Laudier B, Attie-Bitach, T et al. Polyalanine expansion and frameshift mutations of the paired-like homobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003; 33:459-61.

Goldberg DS, Ludwig IH. Congenital central hypoventilation syndrome:ocular finds in 37 children. J Pediatr Opthalmol Strabismus. 1996;33-176-181.

Rohrer T, Trachsel D, Engelcke G, et al. Congenital central hypoventilation syndrome associated with Hirschsprung’s disease and neuroblastoma: case of multiple neurocristopathies. Pediatr Pulmonol. 2002;33:71-76.

Schafer T Schafer C, Schlafke ME. From tracheostomy to non-invasive mask ventilation: a study in children with congenital central hypoventilation syndrome. Med Klin 1999;94:66-69.

Silverstri JM, Hanna BD, Volgman AS, et al. Cardiac rhythm disturbances among children with idiopathic congenital central hypoventilation syndrome. Pediatr Pulmonol 2000:29-351-368.

Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to autonomic nervous system embryonic development and identification of mutations in PHOX2B. Am J Med Genet. 2003:123A:267-78.

Weese-Mayer DE, Shannon DC, Keens, TG, et al. American Thoracic Society statement on the diagnosis and management of idiopathic congenital central hypoventilation syndrome. Am J Respir Crit Care Med 1999;160:368-373.

Vanderlaan M, Holbrook CR, Wang M, et al. Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome. Pediatr Pulmonol. 2004;37:217-229