Marfan's Syndrome

Classification according to ICD-10
Q87.4	Marfan's Syndrome
ICD-10 online (WHO version 2019)

The Marfan syndrome is a genetic disease in which there in an increased elasticity or laxity of connective tissue comes. You can autosomal - dominant inherited are or as new mutation occur.

Synonyms are: Marfan's syndrome type I; MASS syndrome (mitral valve prolapse - aortic dilation - striae - skeletal involvement).

Frequency of occurrence

The incidence of the disease is around 1: 5,000 to 1: 10,000, with six to seven out of ten cases being familial. The proportion of new mutations is 25 to 40%. Since the definition of “Marfan syndrome” is currently based on auxiliary criteria and there are several confusable “parallel diseases”, it is better to speak of the Marfan phenotype . Overall, the frequency is about 1: 6,000. The group of diseases of the Marfan phenotype has recently been called "fibrillopathies".

Initial description

The autosomal dominant inheritance

The syndrome was first described from a scientific point of view in 1896 by the French pediatrician Antoine Marfan (1858–1942). Before the Société Médicale des Hôpitaux de Paris he presented the case of the five-year-old girl Gabrielle, who had very long and fine limbs, which he called dolichostenomelia (Greek “dolicho” = long, “stenos” = narrow, “melos” = limb ). He coined the term “spider fingering” ( arachnodactyly ) for the long, narrow fingers .

Six years later, the girl was examined by the doctors Méry and Babonneix, who now also had the X-ray diagnostics at their disposal. They described a curvature of the thoracic spine and an asymmetry of the thorax (chest). Also in 1902, Emile Charles Achard described another girl with similar symptoms and also found that her joints were extremely agile (hyperlaxicity).

Changes in the cardiovascular system and the eyes were later assigned to the symptom complex. In the 1930s it was recognized that the peculiarity is not inherited sex-linked (gonosomal), but that changes on chromosome  15 are causal ( autosomal dominant inheritance ). These changes were first described in 1931 by doctors in Utrecht as Marfan's syndrome , when it entered the medical literature.

The French girl from Marfan's first description died of tuberculosis in adolescence, so that the diagnosis could never be confirmed beyond doubt. On the other hand, it has been questioned several times that Gabrielle suffered from Marfan's syndrome, most recently in 1972 by Hecht and Beals, who suspected congenital arachnodactyly.

The assumption that Niccolò Paganini and Abraham Lincoln were affected by Marfan syndrome is controversial.

Cause of illness

The gene for Marfan syndrome is on the long arm of chromosome 15 (15q21.1) and has since been sequenced . A mutation in the fibrillin-1 gene (=  FBN1 gene ) leads to a shortened gene product or a missense mutation.

Mutations in the TGF-β- I or TGF-β-II gene can lead to similar symptoms in the context of Loeys-Dietz syndrome .

features

Marfan's syndrome is a congenital, pathological condition of the connective tissue that can affect bones, muscles, ligaments and the skeleton, among other things. Most of those affected are larger than average, have elongated limbs and narrow hands and feet. If there is a weak connective tissue in the main artery, it can tear unexpectedly.

In terms of tissue, Marfan's syndrome manifests itself in the fine structure of the connective tissue (the microfibrils). The connective tissue is therefore incorrectly built up, which leads to a more or less pronounced instability of all connective tissue in the body.

The following symptoms are common in people with Marfan syndrome, although not all characteristics are equally pronounced in all people:

1. Heart and vascular system
   • Heart valve defects (inability to close the aortic or mitral valve - aneurysm of the aortic root, bicuspid aortic valve)
   • Aortic dissection (splitting or tearing of the aortic wall)
2. eyes
   • Loosening of the holding apparatus of the lenses ( lens dislocation )
   • myopia
   • Glaucoma (glaucoma = high intraocular pressure)
   • Cataract (cataract = lens opacity)
   • Keratoconus (cornea disease)
   • Retinal detachment : This leads to the symptom of light flashes ( differential diagnosis )
   • blue sclera
   • possibly iridodonesis (shivering iris when moving the head)
   • often megalocornea
3. Skeletal system
   • vertical overdevelopment of the head ( dolichocephaly / long skull)
   • Hyperlaxicity ( overstretchability ) of the joints
   • high palate ( Gothic palate )
   • Arachnodactyly ( spider fingering ); narrowed fingers ( Madonna fingers )
   • Funnel or keel chest
   • Tall stature
   • Deformations of the spine ( scoliosis , hyperkyphosis )
   • poorly developed muscles ( muscle hypotrophy )
   • Flat feet
   • velvety skin prone to striae (stretch marks)
   • Tendency to hernia
   • Tendency to atlantoaxial or cervical-occipital instability, resulting in increased susceptibility to Grisel's syndrome
   • too deep acetabulum (coxa profunda), increased risk of pain as a result of impingement and coxarthrosis
   • Meningeal cysts, so-called Tarlov cysts , are found in the spinal cord , and sacral changes, especially sacral ectasia, are more common.
4. Internal organs
   • The weak connective tissue can also attack the lungs , which can lead to a so-called pneumothorax .

Diagnosis and treatment

The diagnosis and treatment should always interdisciplinary (including by pediatric cardiologists / cardiologists , orthopedists , ophthalmologists ) made in accordance with the Ghent nosology (systematic description of diseases). Using an app, it is possible to use a photo analysis to analyze the face for characteristic features of Marfan syndrome.

So far, there is no causal healing therapy .

A causal therapy approach conceivable for the future was shown by the results of a study published in the science magazine Science in April 2006 , which was able to link the cytokine TGF-β with the typical development of aortic aneurysms and dissections in a mouse model of Marfan's syndrome . Treatment with the AT1 antagonist losartan , which is already used in human medicine as a blood pressure lowering agent , effectively protected the mice from the development of these life-threatening changes in the vascular wall, since losartan antagonizes the effect of the overactive TGF-β . Changes in the heart that already existed largely normalized, and changes in other areas of the body at least partially. However, a study of over 600 young patients from 2007 to 2011 shows no significant difference in the effect of losartan compared to the (already weak) effect of beta blockers with regard to the enlargement of the aortic root. In animal experiments, statins were able to reduce the growth rates of aortic aneurysms. Also in animal experiments, a significant reduction in the aortic root diameter was achieved in the Marfan mouse using the active ingredient resveratrol .

Differential diagnosis

To be distinguished are u. a .: Ehlers-Danlos syndrome , Loeys-Dietz syndrome , Stickler syndrome , Weill-Marchesani syndrome type I, acromicric dysplasia , ectopia lentis syndrome .

Congenital contractural arachnodactyly should be considered if contractures and abnormalities of the auricle are present . Together with craniosynostosis, Shprintzen-Goldberg syndrome is an option. There is also the Marfanoid Progeroid Syndrome , Neonatal Marfan Syndrome , Marfanoid Syndrome Type de Silva , Stiff Skin Syndrome and Geleophysical Short Stature , mostly with mutations at the same gene location .

Life expectancy

The greatest importance to a significant increase in life expectancy falls within the area of pediatric / Cardiology . There is some evidence that beta-blockers can reduce the rate at which aortic dilation occurs . To what extent an early and prophylactic intake in childhood prevents aortic dilation is still unclear; First experiences after 14 years of beta-blocker therapy in children (2005), begun in three to four year old affected children, but show that progression of the enlargement of the aortic root does not occur in almost all cases and the enlargement under the medication is then only age-specific he follows.

If the aortic root in adults over 55 mm extended, make an operation , carried out an aortic dissection or prevent -ruptur. This may be done through an aortic root replacement with an artificial heart valve . The postoperative survival rate after ten years is between 70 and 75%. In children, the need for an operation is derived from the deviation of the current aortic diameter from the age-related normal value, which must be checked individually. It is crucial that endocarditis prophylaxis is taken particularly seriously in children and adults (even in the case of dental interventions, small wounds, sore feet, etc.), since colonization / vegetation on the particularly sensitive heart valves and valve edges advance the tissue instability typical of Marfan can trigger.

If the course is severe, ophthalmological interventions may also be necessary to maintain or restore vision. With overstretching and increasing loss (tearing) of the zonular fibers, the so-called "lens slap" occurs. Schlotter lenses do not have to be operated on, only moving the lenses can cause the eye pressure to become so strong that it becomes necessary to remove the lens. In the meantime, new surgical techniques have been developed which, while preserving the capsular bag and implanting a special lens, can preserve the ability to see even in small children.

Straightening operations are likely if the spine is severely bent. New surgical techniques have been developed that enable the spine to be straightened without full stiffening.

In the 1970s, a study found the life expectancy of a person with Marfan syndrome was 30 to 40 years old. Since that time, diagnostics as well as drug and surgical treatment have been optimized so that life expectancy has come close to that of the normal population. Nevertheless, many of those affected still die from a dissection of the thoracic aorta because the diagnosis was not made and therefore no therapy could be initiated.

In the meantime, special consultation hours have emerged where people with Marfan's syndrome are cared for on an interdisciplinary basis. The first Marfan consultation took place in 1997 at the University Medical Center Hamburg-Eppendorf.

literature

• Mine Arslan-Kirchner, Yskert von Kodolitsch, Jörg Schmidtke: Genetic diagnostics in Marfan's syndrome and related diseases: the importance of clinical management. In: Dtsch Arztebl. July 4, 2008; 105 (27), p. 483, doi: 10.3238 / arztebl.2008.0483 (review article).
• Marfanhilfe (Germany) e. V. (Ed.): Marfan Syndrome, a guide for patients, relatives and carers. Steinkopf, Darmstadt, ISBN 3-7985-1565-4 .
• Marfan Foundation Switzerland (Ed.): A matter of the heart. Health literacy and empowerment using the example of Marfan's syndrome. Bern 2008, ISBN 978-3-033-01587-6 .
• R. Witkowski, O. Prokop, E. Ullrich, G. Thiel: Lexicon of the syndromes and malformations. 7th edition. Springer, Berlin 2003, ISBN 3-540-44305-3 .

Web links

• Marfan Initiative Austria Information for people with Marfan Syndrome in Austria
• Marfan Hilfe (Germany) eV Association for people with Marfan syndrome or other microfibrillar diseases
• Marfan Foundation Switzerland Information, documentation and advice for people with Marfan syndrome and related weaknesses in connective tissue
• Genetics Center for Marfan Syndrome in Switzerland Genetic testing and advice for people with Marfan Syndrome and related aortic diseases
• Marfan Syndrome (English) Website of the Cold Spring Harbor Laboratory with lots of animations and videos

Individual evidence

1. ^ MASS syndromes.  In: Online Mendelian Inheritance in Man . (English)
2. ↑ Marfan's syndrome. In: Orphanet (Rare Disease Database).
3. ↑ Chantal Maron: Marfan: une maladie connue, un pédiatre oublié. In: Le Journal du Médecin (Belgique). 2013, No. 2317 of May 10, 2013, p. 17.
4. ↑ marfansyndrom.blogspot: Known people with Marfan syndrome .
5. ^ Loeys-Dietz Syndrome - MeSH - NCBI. Retrieved January 30, 2014 . 
6. ↑ Classification of bicuspid aortic valves. (PDF) Retrieved August 28, 2017 . 
7. ↑ Clinical monthly sheets for ophthalmology. 1986: Keratoconus - the riddle of pathogenesis , p. 365 f.
8. ↑ Megalocornea.  In: Online Mendelian Inheritance in Man . (English)
9. ↑ Deutscher Ärzteverlag GmbH, editorial office of Deutsches Ärzteblatt: App recognizes hereditary diseases by the shape of the face. January 8, 2019, accessed January 13, 2019 . 
10. ↑ J. Habashi et al.: Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome. In: Science. 2006; 312, pp. 117–121 (abstract) (material and methods + very impressive images PDF; 462 kB) ( memento of the original from September 30, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. 
11. ↑ Sonja Böhm: One less hope in Marfan's syndrome: Losartan does not protect the aorta better than a beta blocker . Medscape, November 19, 2014.
12. ↑ Tetsuya Sato, Mamoru Arakawa, Yasushi Tashima, Eitoshi Tsuboi, Grayson Burdon: Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras-Induced ERK (Extracellular Signal-Regulated Kinase) Signaling Pathway . In: Journal of the American Heart Association . November 6, 2018, doi : 10.1161 / jaha.118.008543 ( ahajournals.org [accessed November 6, 2018]).
13. ↑ Stijntje Hibender, Romy Franken, Cindy van Roomen, Anique Ter Braake, Ingeborg van der Made: Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G / + Marfan Mouse Model . In: Arteriosclerosis, Thrombosis, and Vascular Biology . tape 36 , no. 8 , August 2016, ISSN  1524-4636 , p. 1618–1626 , doi : 10.1161 / ATVBAHA.116.307841 , PMID 27283746 , PMC 4961273 (free full text).
14. ↑ Ectopia lentis, isolated. In: Orphanet (Rare Disease Database).
15. ↑ Ectopia lentis, familial.  In: Online Mendelian Inheritance in Man . (English)
16. ↑ Marfan's syndrome with neonatal progeroid syndrome-like lipodystrophy. In: Orphanet (Rare Disease Database).
17. ↑ Marfan syndrome lipodystrophy.  In: Online Mendelian Inheritance in Man . (English)
18. ^ Marfan's syndrome, neonatal. In: Orphanet (Rare Disease Database).
19. ↑ Marfanoides syndrome of the de Silva type. In: Orphanet (Rare Disease Database).
20. ↑ 10 years Marfan consultation hour Hamburg - Marfan Hilfe (Germany) eV Accessed on August 31, 2017 . 
21. ↑ Marfan consultation hours in the UKE according to § 116 b SGB V approved. Retrieved November 15, 2017 . 

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !