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Congenital central hypoventilation syndrome

This is part of Rare diseases.

Diagnosis: Congenital central hypoventilation syndrome

Synonyms: CCHS

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Date of publication: 2012-02-08
Version: 2.2

ICD 10 code

G47.3

The disease

Congenital central hypoventilation syndrome (hypo =low, ventilation = breathing) is a neurological disorder characterized by an inability to breathe spontaneously, especially during sleep. The cause is a disorder of brain development. The syndrome was first described in the 1970s, by the American physician Robert B Mellins and co-workers.

“Ondine’s curse” is a name for the disease that refers to a mediaeval myth, and the preferred term today is congenital central hypoventilation syndrome, or the abbreviated form CCHS.

Occurrence

The syndrome is found in less than one per 100,000 newborns. In Sweden there are 15-20 children with the syndrome, but there may be additional cases in which the infant died before the diagnosis could be established. It is also likely that there are cases which have not been accurately diagnosed.

Approximately 1,000 children with congenital central hypoventilation syndrome have been described in the international medical literature. The condition is equally common in boys and girls.

Cause

The cause of congenital central hypoventilation syndrome is a mutation in one of the genes involved in the development of the nerve cells that control breathing. The gene most frequently associated with the syndrome is located on chromosome 4 (4p12) and is known as PHOX2B. This gene controls the formation of (codes for) PHOX2B protein (paired mesoderm homeobox protein 2B). PHOX2B controls the development of nerve cells that are part of the involuntary (autonomic) nervous system. The mutation affects the mechanism that sustains breathing during sleep and adapts respiration to various metabolic conditions. As a result, the child’s automatic breathing control is seriously impaired. It is still possible to breathe voluntarily, as this function is controlled by higher centres of the brain that remain unaffected.

The most common mutation in the PHOX2B gene (approximately 90 per cent) involves an expansion of the DNA sequence of an amino acid known as alanine. Normally the DNA sequence of alanine is repeated 20 times, but in a person with the mutation the number of copies is extended to between 25 and 33. The severity of the disease appears to be related to the size of the expansion. A person with 25 repetitions may need respiratory support at night, while those with more repetitions are dependent on breathing assistance throughout the day and night. In approximately ten per cent of cases no alanine expansion is detected, but by performing a detailed examination of the gene structure (sequencing), it is possible to identify abnormalities in single bases in the DNA sequence (point mutations).

The same gene appears to control several other important functions related to the autonomic nervous system, such as regulation of bowel function, heart rate, sweat function and body temperature. Some people with the syndrome have no nerve cells in the colon (Hirschsprung disease). There is also an association between this mutation and a particular type of tumour called neuroblastoma, which develops in some people with the syndrome.

Heredity

Congenital central hypoventilation syndrome is usually caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children. The inheritance pattern will be autosomal dominant.

Figure: Autosomal dominant inheritance

This means that if one of the parents has the disorder, and so has one normal gene and one mutated gene, sons and daughters of this parent have a 50 per cent risk of inheriting the disorder. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

There are descriptions of isolated families in which several children have the disorder. In these cases it is possible that one of the parents has the mutation in some cells (mosaicism). This condition increases the risk of having children with congenital central hypoventilation syndrome.

Symptoms

The disease is usually recognized in newborns, generally following a normal, full-term pregnancy.

In congenital central hypoventilation syndrome children retain some degree of spontaneous breathing, but during sleep they ventilate poorly and, in the worst cases, they may even stop breathing. Even when awake their skin, lips and nails may have a bluish tint (cyanosis). Most children with the syndrome breathe normally when they are awake. This means that they retain sufficient oxygen, although the level of carbon dioxide in the bloodstream may be slightly elevated. During sleep, however, breathing is severely impaired. As a consequence, the carbon dioxide concentration will rise rapidly, and it becomes impossible to wake the child.

When awake, a child’s breathing is to a great extent regulated by impressions and responses to the surroundings. During dream sleep (REM sleep), brain activity is also high and respiration is maintained. In the deep, dreamless stages of sleep, however, certain reflexes need to take control of respiration. In congenital central hypoventilation syndrome these reflexes are not activated, and respiratory control fails.

The onset of the disorder sometimes occurs late in childhood with less dramatic symptoms, and may be mistaken for a congenital heart defect. When skin and mucous membranes are not sufficiently oxygenated they become bluish, and the tissues become swollen owing to accumulation of fluids (oedema).

Heart rhythm disturbances, impaired sweat function and low body temperature are common disorders of the autonomic nervous system. Children with the syndrome do not always develop a fever during an infection. In less severe cases, symptoms may be a fast heartbeat (tachycardia), sweating and/or becoming cyanotic (bluish) during sleep. Some children with the disorder have recurrent pneumonia. Impaired sweating mechanisms cause increased sweating, and as a result these children drink a lot and therefore need to urinate frequently. This can be a problem, since the dysfunction of the autonomic nervous function makes it difficult to recognise the need to urinate. Impaired bowel movements are sometimes a problem, resulting in constipation. Swallowing problems may occur.

Approximately 20 per cent also have Hirschsprung disease, another congenital disorder with a slightly higher prevalence. People with this disease lack nerves in a section of the colon, so the parts of the colon walls that are innervated become slack and distended (megacolon), with severe constipation as a result. Severe cases of Hirschsprung disease may result in malnutrition and colon inflammation. Sometimes large areas of both the large and small intestines are affected, and in a few cases nerve cells may be absent throughout the gastrointestinal tract.

Eye abnormalities, such as iris defects or asymmetric pupils, are sometimes present. Children with the syndrome may squint (strabismus), and they may also lack tear fluid.

There is also a slightly increased risk of neuroblastoma, a type of tumour that affects the autonomic nervous system and develops in the abdomen.

Diagnosis

The diagnosis is suspected on the basis of observations of poor or absent breathing during sleep. Initial evaluation should include registration of breathing movements, analysis of oxygen and carbon dioxide levels through the skin (transcutaneous PO2 and PCO2), or through blood, and the level of oxygen saturation. It is usually possible to establish the diagnosis by testing the child’s reaction to higher concentration of carbon dioxide. In healthy children the respiratory frequency should multiply, but this reaction fails to present in children with congenital central hypoventilation syndrome.

The examination can be combined with registrations of eye movements and brain activity (EEG).

It may also be valuable to determine the level of carbon dioxide (the PCO2 level) at which breathing stops (the apnoea point or arousal threshold). This test can be carried out if the child is breathing through a ventilator.

Screening to rule out a metabolic disorder should be performed, as well as an MRI of the brain, especially the brain stem.

Medical imaging of the lungs, including a chest X-ray, should be performed in order to assess the movement of the diaphragm and exclude paralysis (diaphragmatic paresis).

Ultrasound of the heart and ECG should be carried out. The ECG examination should include 24-hour measurement of changes in heart rate during wakefulness and sleep.

If the child has symptoms of Hirschsprung disease, a rectal biopsy may also be carried out.

To confirm the diagnosis it is necessary to perform a DNA-based analysis. Foetal diagnosis or embryo diagnosis is possible if the mutation in the family has been identified.

Treatment/interventions

Immediately after birth, babies with the syndrome are usually treated for respiratory failure in a neonatal department. As there are many causes of respiratory failure in newborns it generally takes a few days before the diagnosis is suspected. If the syndrome is suspected, the respiratory clinic at Astrid Lindgren Children’s Hospital should be contacted (see under “Resources at the national and regional level”).

Most children with the syndrome require respiratory support when sleeping. In the past, respiratory support was usually administered via tracheotomy (a surgically created opening through the neck into the windpipe), but in the last few years the non-invasive technique of supplying air to the patient via the nose, or through the nose and mouth, is increasingly used.

Since the lungs are healthy, normal air can be used. Only rarely is pure oxygen administered. The respiratory equipment used weighs 2-4 kilogrammes, making it convenient for use inside and outside the home. The equipment can be powered by batteries, so that respiratory support treatment can be continued when the child sleeps in the stroller or for example, during a car ride.

Regardless of whether the child has a tracheotomy or a nasal mask, vigilant monitoring around the clock is necessary to ensure that breathing support is provided each time the child falls asleep. As the nasal mask should always fit properly over the nose, carers must monitor the child and manage the ventilator day and night. The presence of a relatively large number of healthcare professionals in the home may take a toll on the family.

Medical drug trials are ongoing with the aim of improving breathing, but so far no medication has proven effective enough to replace mechanical respiratory support.

In children over five, a diaphragm pacemaker can be inserted surgically. This intervention is performed at the Uppsala University Children’s Hospital, where there is a national centre for this procedure. The pacemaker stimulates a specific nerve (the phrenic nerve), causing a contraction of the diaphragm muscle between the abdomen and chest and thus breathing movements.

Children with the syndrome who also have Hirschsprung disease are treated surgically, by removing the affected part of the colon. The intervention can be carried out directly, but sometimes it is necessary to perform the surgery in several stages and a temporary stoma (a surgically created bowel opening) may be required.

The treatment for neuroblastoma is a combination of chemotherapy and surgery.

Congenital central hypoventilation syndrome is a lifelong condition. With vigilant monitoring these children can grow up to live active and relatively independent lives. With early diagnosis and treatment, proper care, vigilant monitoring of breathing and improved technical equipment, life expectancy is expected to increase. Adults with the syndrome require continued monitoring of respiration, as well as frequent check-ups at a pulmonary clinic or other department with expertise in respiratory therapy.

Congenital central hypoventilation syndrome is a challenging disorder to live with, both for the affected child/adult and the family. Social and psychological support is required for managing daily life. Parents, siblings and other relatives are also eligible for support. The municipality can provide support in different forms to help the family cope with daily life. The home and work environment needs to be adjusted to compensate for functional limitations.

Practical advice

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National and regional resources in Sweden

There is an assessment and treatment team at the Respiratory Clinic, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.

At the Astrid Lindgren Children’s Hospital in Stockholm there is also LIVA (a long-term intensive care unit), a national resource centre for children in need of respiratory support.

Resource personnel

Evaluation and determination of diagnosis, respiratory registrations:

Coordinator: nurse Kerstin Sundell, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 70 00, fax: +46 8 517 741 54, email: kerstin.e.sundell@karolinska.se.

Professor Hugo Lagercrantz, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, fax: +46 8 517 751 21, email: hugo.lagercrantz@ki.se.

Individual tailoring of ventilators for home use, set-up and maintenance, facial masks or tracheal cannulae:

Associate Professor Agneta Markström, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 741 54, fax: +46 8 517 751 21, email: agneta.markstrom@.ki.se.

DNA analysis:

Professor Agneta Nordenskjöld, Research Group for Malformation Genetics, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 777 05, e-mail: agneta.nordenskjold@karolinska.se.

Diaphragmatic pacemaker:

Senior physician Anders Jonzon, Paediatric Cardiology Clinic, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 59 28, email: anders.jonzon@akademiska.se.

Dr Richard Sindelar, Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 96 27, e-mail: richard.sindelar@kbh.uu.se.

Senior physician Pelle Nilsson, Department of Neuroscience, Uppsala University Hospital. SE-751 85 Uppsala, Sweden. Tel: +46 18 611 49 89, email: pelle.nilsson@neuro.uu.se.

Specialist nurse Eva Lundberg, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 24 96, email: eva.lundberg@akademiska.se.

Parent and personnel education in nasal mask treatment:

Nurse Kerstin Sundell, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, fax: +46 8 517 741 54, email: kerstin.e.sundell@karolinska.se.

Parent and personnel education:

Nurse Alette Bagge, LIVA R12, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 726 24, e-mail: alette.bagge@karolinska.se.

Courses, exchanges of experience, recreation

Parental training is offered at LIVA, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Contact Alette Bagge or Kerstin Sundell (see under “Resource Personnel”).

Organizations for the disabled/patient associations

There is currently no Swedish CCHS Association. In the U.S. there is a CCHS network: www.cchsnetwork.org, which also provides a link to a French website.

Courses, exchanges of experience for personnel

Training for carers/personal assistants is offered at LIVA, The Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Contact Alette Bagge or Kerstin Sundell (see under “Resource Personnel”).

Research and development (R&D)

Intensive research on the mechanisms of respiratory control is ongoing at the Astrid Lindgren Children’s Hospital in Stockholm. This research is of interest for learning more about how respiratory rhythm is generated, which is very valuable, not least in order to understand the cause of Sudden infant death syndrome (SIDS).

Associate Professor Agneta Markström, The Astrid Lindgren Children’s Hospital Respiratory Clinic, is a member of the European management team for CCHS. An important objective of this group’s work is to create a European CCHS register. The aim of the group is to provide medical staff with information about the disease, improving diagnosis and clinical care, to train staff/assistants, and to inform relevant authorities about the special needs of people with the syndrome. The goal is to ensure optimal care and a high quality of life for people with the syndrome.

Information material

An information leaflet on congenital central hypoventilation syndrome (article number 2010-10-22), summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare. Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The LIVA handbook provides instructions on how to care for children in need of respiratory support. The handbook is produced by Alette Bagge at LIVA, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm (see under “Resource Personnel”).

Literature

Marcus LC, Jansen MT, Poulsen MK, Keens SE, Nield TA, Lipsk LE et al. Medical and psychosocial outcome of children with congenital central hypoventilation syndrome. J Pediatr 1991; 119: 888-895.

Ramesh P, Boite P, Samuels M. Mask ventilation in the early management of congenital hypoventilation syndrome. Arch Dis Child 2008; 93: 400-403.

Repetto GM, Corrales RJ, Abarat SG, Zhou L, Berry-Kravis EM, Rand CM et al. Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-alanine repeat expansion in the PHOX2B gene. Acta Paediatr 2009; 98: 192-195.

Trang H, Dehan M, Beufils F, Zaccaria I, Amiel J, Gaultier C. The French congenital central hypoventilation syndrome registry. Chest 2005; 127: 72-79.

Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H et al. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis and management. Am J Resp Crit Care 2010; 181: 626-644.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: autonomic control, congenital failure of

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: Congenital central hypoventilation syndrome

eMedicine: http://emedicine.medscape.com/article/1002927-overview 

European CHS Network: www.ichsnetwork.eu

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Hugo Lagercrantz, Astrid Lindgren Children’s Hospital, Sweden. Associate Professor Miriam Katz-Salamon and Associate Professor Agneta Markstrom contributed to the revised version.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2012-02-08
Version: 2.2
Publication date of the Swedish version: 2011-03-17

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: + 46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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