Undine Syndrome

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Classification according to ICD-10
G47.3 (central) sleep apnea
ICD-10 online (WHO version 2019)

The Ondine's curse or congenital central hypoventilation syndrome (formerly also Undine Bane syndrome ) is a rare inherited disease of the central nervous system , whose main symptom is a disorder of respiratory control. Translated from English, the abbreviation CCHS ( Congenital Central hypoventilation syndrome ) is also used in the German-speaking area.

In addition to respiratory disorders, the syndrome also includes other dysregulations of autonomic functions such as over- or under-temperature, cardiac arrhythmias , swallowing disorders or, rarely, tumors. The simultaneous presence of CCHS and Hirschsprung's disease is also known as Haddad syndrome .

In sleep medicine , the “congenital central alveolar hypoventilation syndrome” as a sleep disorder belongs to the “sleep-related breathing disorders” and is coded as “congenital central alveolar hypoventilation syndrome” with G47.35 according to ICD-10-GM. In the International Classification of Sleep Disorders International Classification of Sleep Disorders ICDS-3 diagnostic criteria are established. These are the presence of sleep-related hypoventilation and the presence of a mutation in the PHOX2B gene.

Distribution / Incidence

About one in 180,000 live births is affected.

root cause

The PHOX2B gene

The gene defining the disease is the PHOX2B gene, which is located on the short arm of chromosome number 4 . It consists of 3 exons, which encode information for the structure of the PHOX2B protein (egg white) in the DNA . In exon 3 there is a region that codes for a repetition of an incorporation of the amino acid alanine into the protein. Normally, 20 alanines are encoded one after the other in this gene region. Therefore, the site in the gene is P oly a lanin r epeat, (literally Vielfachalaninwiederholung) or short PAR called.

Mutations in the PHOX2B gene

The autosomal dominant inheritance

In about 80% of CCHS patients, there is a prolongation of the PAR. The disease occurs from an extension of 4 alanines. The longest extension of the PAR is 33 alanines. This type of gene change is known as a polyalanine repeat mutation and is abbreviated as PARM . The allele combination occurring in the normal population is described as 20/20 with regard to the PAR. Both PHOX2B genes contain a PAR of 20 alanines. For PARMs that can cause CCHS, these are 20/24, 20/25, 20/26 ... to 20/33. Very rarely, a shortening of the PAR can also cause CCHS.

In addition to the PARMs, there are also frameshift , dot or missense mutations. These genetic changes occur in around 20% of patients.

Mostly it is a matter of new mutations, which are found in people with CCHS. In this case, the parents are neither sick nor do they carry the changed gene. However, the disease can be passed on to children if one of the parents has CCHS themselves or carries a mutation for the gene in question in the gonads. The latter can occur without any symptom and is known as the genetic mosaic.

The inheritance of the disease is autosomal dominant. This means that there is a statistical probability of 50% that the disease is transmitted to the children if one of the parents is affected themselves.

Symptoms

Hypoventilation

This is a disorder of the central CO 2 chemoreceptor sensitivity (reduced CO 2 response). The respiratory response of a person with CCHS to hypercapnia (increase in carbon dioxide) in the blood or hypoxia (low oxygen saturation ) is typically restricted during sleep, but also for many while awake. In newborns, the lack of spontaneous breathing or insufficient, superficial breathing is noticeable. This is more pronounced during sleep than when awake and can be interrupted by episodes of normal breathing. During the hypoventilation phases and especially in deep sleep, life-threatening conditions can arise.

Hirschsprung's disease

Around 25% of Undine children also suffer from Hirschsprung's disease , a congenital malformation of the intestine , the main symptom of which is constipation or chronic stool retention. A constriction of the intestine and possibly an expansion of the intestine in front of it is responsible for the symptoms. Incorrect sprouting of neurons can occur throughout the digestive tract and thereby also trigger swallowing disorders.

Cardiac arrhythmias

Sin pauses (pauses between two heartbeats) can occur in CCHS. Even if there is no direct evidence so far, sinus pauses have been linked to deaths. In at least one scientific publication, pauses of 3 seconds or more are considered pathological. In some patients, signs of long QT syndrome were found on the ECG . This rarely appears to be of clinical significance.

Tumors

CCHS patients can develop neuroectodermal tumors. These are new formations that originate from nerve cells or cells similar to nerve cells. These cells have their origin in the neural crest of the embryo. They are neuroblastomas and ganglioneuroblastomas .

Temperature regulation disorders

Patients with CCHS can live with hyper - or hypothermia have. In addition, infections occur without a fever.

treatment

Diaphragmatic pacemaker in Undine syndrome.

Around 17% of Undine children do not breathe adequately even when they are awake, so they have to be ventilated 24 hours a day. Many of these children are provided with a diaphragmatic pacemaker and are therefore mobile. If Undine patients breathe spontaneously during the day, night ventilation with a nasal mask is recommended. Some children are initially ventilated with a tracheostomy after birth and then switched to a mask when they are in kindergarten or primary school.

Healing prospects

Thanks to the modern ventilation and monitoring options in the home, Undine children can lead a full and productive life today. A recent study of 94 Undine children in North America showed that 77.5% of all children achieved normal school performance. The prerequisite for this is the earliest possible diagnosis of the disease and the provision and training of parents and caregivers with the latest equipment and information. Since the diagnosis and treatment options for this clinical picture are only known and available for a relatively short period of time, the oldest Undine patients are in their early twenties, but occasionally also in their mid-thirties. They can work and have children themselves.

Origin of the designation

The syndrome was first described in 1962 by Severinghaus and Mitchell. Undine is the name of some aquatic beings that appear in legends . Inspired by this, Friedrich de la Motte Fouqué published a fairytale-like story in 1811 in which the mermaid Undine kills a knight who has become unfaithful to her with a kiss. From this material Jean Giraudoux developed his play of the same name in 1939 , to which he added the theme of failing physiological automatisms. Another modification tells that Undine cursed her unfaithful husband for not being able to breathe in his sleep. This version led to the English name Ondine's curse , "Undine's curse".

Occurrence in art and literature

  • In the film The Black Widow (1987), Undine Syndrome is given as the cause of death of a Mafioso.
  • At the beginning of the thriller Der Augensammler by Sebastian Fitzek (2010) the syndrome is mentioned by name, explained and its name is explained based on the play by Giraudoux; however, the subject is deliberately wrongly attributed to Germanic mythology.
  • The Polish short film Nasza Klątwa (Our Curse) tells the autobiographical story of a young family whose child is diagnosed with Undine's syndrome.

Web links

  • Undine Syndrome. In: Orphanet (Rare Disease Database).
  • Undine self-help group : This group of affected and affected parents of children with CCHS has around 83 members between the ages of zero and 35 in Germany and in the neighboring countries of Switzerland and Austria.
  • EU CHS Network : The international CHS network is an association of European doctors who want to provide information about central hypoventilation syndromes. Funded by the EU, it compiles guidelines on the diagnosis and treatment of CCHS, which have not yet been published. An international epidemiological study on the CCHS disease is also part of the joint work.
  • CCHS Network: The CCHS Network is the self-help group in the USA. The group is open to members from all over the world.

Videos

Individual evidence

  1. ↑ Orphanet: Haddad Syndrome. Retrieved November 2, 2018 .
  2. ↑ GG Haddad et al: CONGENITAL FAILURE OF AUTOMATIC CONTROL OF VENTILATION, GASTROINTESTINAL MOTILITY AND HEART RATE . Ed .: Medicine. Volume 57, Issue 6, November 1978, pp. 517-526 .
  3. ↑ a b S3 guideline for non-restful sleep / sleep disorders of the German Society for Sleep Research and Sleep Medicine (DGSM). In: AWMF online (as of 2009)
  4. ↑ German Institute for Medical Documentation and Information: ICD-10-GM Version 2019. Retrieved on November 1, 2018 .
  5. ↑ G. Mayer, Andrea Rodenbeck, Peter Geisler, Hartmut Schulz: International Classification of Sleep Disorders: Overview of the changes in the ICSD-3 . In: Somnology - sleep research and sleep medicine . tape 19 , no. 2 , 2015, ISSN  1432-9123 , p. 116–125 , doi : 10.1007 / s11818-015-0006-8 ( PDF download from Research Gate ).
  6. ^ JG Schöber, S. Neumayer, H. Meisner, R. von Kries: Prevalence and incidence of Undine syndrome in Germany. In: Monthly Children's Health . tape 142 , 1994, pp. S32 .
  7. ↑ PAIRED-LIKE HOMEOBOX 2B; PHOX2B.  In: Online Mendelian Inheritance in Man . (English)
  8. ↑ Jeanne Amiel, Béatrice Laudier, Tania Attié-Bitach, Ha Trang, Loïc de Pontual: Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome . In: Nature Genetics . tape 33 , no. 4 , March 17, 2003, ISSN  1061-4036 , p. 459-461 , doi : 10.1038 / ng1130 ( nature.com [accessed November 1, 2018]).
  9. ↑ a b Jerome O. Gronli, Barbara A. Santucci, Sue E. Leurgans, Elizabeth M. Berry-Kravis, Debra E. Weese-Mayer: Congenital central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death . In: Pediatric Pulmonology . tape 43 , no. 1 , 2007, ISSN  8755-6863 , p. 77-86 , doi : 10.1002 / ppul.20744 ( wiley.com [accessed November 20, 2018]).
  10. ↑ Delphine Trochet, Louise M. O'Brien, David Gozal, Ha Trang, Agneta Nordenskjöld: PHOX2B Genotype Allows for Prediction of Tumor Risk in Congenital Central Hypoventilation Syndrome . In: The American Journal of Human Genetics . tape 76 , no. 3 , March 2005, ISSN  0002-9297 , p. 421-426 , doi : 10.1086 / 428366 , PMID 15657873 , PMC 1196394 (free full text) - ( elsevier.com [accessed November 20, 2018]).
  11. ^ JW Severinghaus, RA Mitchell: Undine's curse - failure of respiratory center automaticity while awake. In: Clin Res. 10, 1962, p. 122.
  12. ↑ R. Nannapaneni, S. Behari. NV Todd, AD Mendelow: Retracing "Undine's curse" . In: Neurosurgery . tape 57 , no. 2 , 2005, p. 354-363; discussion 354–363 , doi : 10.1227 / 01.NEW.0000166684.69422.49 , PMID 16094167 .