Marfan syndrome

Marfan syndrome (MFS) is a genetic disorder of the connective tissue

1. Marfan Syndrome By: Zakariya Al- nuaimi

2. INTRODUCTION Antoine Bernard-Jean Marfan (June 23, 1858 – February 11, 1942), a French pediatrician . In 1896, Marfan described a hereditary disorder of connective tissue in a 5 yr old girl with disproportionately long limbs that later became to be known as Marfan syndrome

3. INTRODUCTION Marfan syndrome (MFS) is an inherited, systemic, connective tissue disorder caused by autosomal dominant mutations in the gene encoding the extracellular matrix (ECM) protein fbrillin-1. It is primarily associated with skeletal, cardiovascular, and ocular pathology

4. EPIDEMIOLOGY incidence is reported to be 1 in 10,000 live births approximately one-fourth of cases are sporadic The disorder shows autosomal dominant inheritance with high penetrance, but variable expression both interfamilial and intrafamilial clinical variation is common. There is no racial or gender preference

5. PATHOGENESIS MFS is associated with abnormal production, matrix deposition and/or stability of fbrillin-1 fibrillin-1, a glycoprotein component of the extracellular matrix protein that is the major constituent of microfbrils The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors MFS was traditionally considered to result from a structural defciency of connective tissues. The fbrillin-1 (FBN1) locus resides on the long arm of chromosome 15 (15q21), the involvement of FBN1 has been demonstrated in >90% of cases

6. PATHOGENESIS Elastic fibers are found throughout the body, but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye Transforming growth factor beta (TGF-β) plays an important role in Marfan syndrome The simplest model of Marfan syndrome suggests reduced levels of fibrillin-1 allow TGF-β levels to rise due to inadequate sequestration (TGF-β) family of cytokines influences a diverse repertoire of cellular processes, including cell proliferation, migration,differentiation , (TGF-β) in MFS is high which mean more growth

7. CLINICAL MANIFESTATIONS MFS is a multisystem disorder with cardinal manifestations in the skeletal cardiovascular ocular systems

8. Skeletal System Long and slender fingers (arachnodactyly) the Walker-Murdoch or (wrist sign) the Steinberg or (thumb sign) Anterior chest deformity outward ( pectus carinatum ) or inward ( pectus excavatum ). flatfeet (pes planus ) ( protrusio acetabuli ) Abnormal curvatures of the spine (scoliosis) joint hypermobility Contracture of the fingers ( camptodactyly ) and elbows is commonly observed long narrow skull ( dolichocephaly ) recessed lower mandible ( retrognathia ) or small chin ( micrognathia ), flattening of the midface (malar hypoplasia) Overgrowth of the long bones (dolichostenomelia)

9. Cardiovascular System Aortic aneurysm, dissection and rupture principally at the level of the sinuses of Valsalva ( aortic root ) the most life-threatening manifestations of MFS thickening of the atrioventricular valves is common and often associated with valvular prolapse In children with early onset and severe MFS insufficiency of the mitral valve can lead to congestive heart failure , pulmonary hypertension and death in infancy Dilated cardiomyopathy Aortic valve dysfunction Dilation of the main pulmonary artery is common Enlargement of the descending thoracic or abdominal aorta can also occur, although relatively rarely.

10. Ocular System Dislocation of the ocular lens ( Ectopia lentis ) occurs in approximately 60-70% of patients early and severe myopia flat cornea increased axial length of the globe, hypoplastic iris ciliary muscle hypoplasia, causing decreased miosis . Patients are also predisposed to retinal detachment and early cataracts or glaucoma .

11. Other Systems Widening of the Dural sac or root sleeves ( Dural ectasia ) is present in 63-92% of MFS patients Another common manifestation is congenital or acquired inguinal hernia pulmonary disease in MFS .widening of the distal airspaces predisposes patients to spontaneous pneumothorax ,which occurs in up to 15% of patients. most common skin finding is stretch marks —pinkish, scar-like lesions that later become white ( striae atrophicae )

12. DIAGNOSIS

13. DIAGNOSIS

14. DIFFERENTIAL DIAGNOSIS Aortic Aneurysm Syndromes Loeys -Dietz syndrome (LDS)… TGFBR1 or the TGFBR2 gene familial thoracic aortic aneurysm Shprintzen -Goldberg syndrome…SKI gene..FBN1 gene Ectopia Lentis Syndromes Weill- Marchesani syndrome..FBN1 gene Homocystinuria Familial ectopia lentis .. FBN1 gene SYNDROMES WITH SYSTEMIC MANIFESTATIONS OF  MFS Congenital contractural arachnodactyly .. fbrillin-2(FBN2 ) MASS (mitral valve prolapse, aortic enlargement, skin and skeletal findings) syndrome.. FBN1 gene

15. LABORATORY FINDINGS Most, if not all, people with classic MFS have an FBN1 mutation, the large size of this gene and the extreme allelic heterogeneity in MFS have frustrated efficient molecular diagnosis. The yield of mutation screening varies based on technique and clinical presentation

16. MANAGEMENT Management focuses on preventing complications and genetic counseling . Yearly evaluations for cardiovascular disease, scoliosis, or ophthalmologic problems are imperative .

17. CURRENT THERAPIES ACTIVITY RESTRICTIONS Physical therapy can improve cardiovascular performance, neuromuscular tone, and psychosocial health AORTIC SURGERY aortic surgery should be recommended for adult patients when their aortic root diameter approaches 50 mm

18. PREGNANCY Prophylactic aortic root replacement can minimize the risk of aortic dissection and death in women with MFS who wish to become pregnant ENDOCARDITIS PROPHYLAXIS the National Marfan Foundation believes that patients with MFS should continue to receive prophylaxis for bacterial endocarditis, in part because it remains unknown

19. Current Pharmacologic Approaches β- Blockers β-Blockers have traditionally been considered the standard of care in MFS multiple small observational studies suggest there is a protective effect on aortic root growth

20. EMERGING THERAPEUTIC STRATEGIES Angiotensin II Receptor Type 1 Blockers {losartan} There is extensive evidence linking angiotensin II signaling to TGF-β activation and signaling A retrospective study assessing the effect of angiotensin II receptor type 1 blockers in a small cohort of pediatric patients with MFS who had severe aortic root enlargement despite previous alternate medical therapy, showed that angiotensin II receptor type 1 blockers significantly slowed the rate of aortic root and sinotubular junction dilation (both of which occur in MFS)

21. PROGNOSIS early diagnosis and refined medical and surgical management has greatly improved the prognosis for patients with the condition. In the more classic form of MFS, it is estimated that more than 90% of individuals will have a cardiovascular event during their lifetime In a review of 54 patients diagnosed during infancy , 89% had serious cardiac pathology; cardiac disease was progressive despite standard care (22% died during childhood, 16% before age 1 yr ).

22. REFERENCE Nelson…TEXTBOOK of PEDIATRICS….EDITION 20 Chapter 702.Marfan Syndrome.Alexander Doyle, Jefferson J. Doyle,and Harry C. Dietz III. Page 3384  PartXXXII   ◆  Bone and Joint Disorders