Case Presentation- Marfan Syndrome Agatha Stanek

Case presentation 13 year old female patient presents to clinic for routine check-up. Patient has myopia but has appropriate prescription Noticeable thin and lean build of patient with arachnodactyly Pes planus Headaches, weakness and occasional pain in the genital area that is relieved in the supine position Myopia- near-sightedness Arachnodactyly- long thin fingers Pes planus: flat feet The most common clinical symptoms are low back pain, headache, weakness, and loss of sensation above and below the affected limb, occasional rectal pain and pain in the genital area.8 The symptoms are aggravated mainly in the supine position and are relieved by lying on the back

Patient hx Medical hx: Broken arm at age 7. All immunizations are current Family hx: Father died of an early heart-related death (26) Aunt has Type 2 Diabetes

Social hx Oldest of 2 children. Patient lives with grandparents, mother and sibling in downtown area close to their high school Mother is a full time teacher at a nearby university. Occupational hx: Patient attending high school; grade 8.

Physical Exam Afebrile Reduced upper-to-lower body segment ratio (0.85 vs 0.93 Positive wrist (Walker) and thumb (Steinberg) signs... HEENT: Notice high arched palate and dental crowding Narrow face observed Patient alert CARDIOVASCULAR: Dysrhythmia- decrescendo diastolic murmur from aortic regurgitation RESPIRATORY: Clear Two simple maneuvers may help demonstrate arachnodactyly. First, the thumb sign is positive if the thumb, when completely opposed within the clenched hand, projects beyond the ulnar border. Second, the wrist sign is positive if the distal phalanges of the first and fifth digits of one hand overlap when wrapped around the opposite wrist

Physical Exam continued SKIN: Noticeable stretch marks near patient’s lower back area Abd: Clear Nervous system: Pain in lower spinal region

Differential Diagnosis Gigantism and acromegaly Hyperpituitarism Hyperthyroidism Fragile X syndrome Homocystinuria Loeys-Dietz syndrome Homocystinuria: A recessively inherited metabolic disorder Characterized by ectopia lentis, long bone overgrowth, mental retardation, and a high predisposition to thromboembolism and coronary artery disease in the absence of aortic root dilation. Diagnosis is based on the presence of elevated concentrations of homocystine in urine or plasma. Loeys-Dietz syndrome (2 types)- have a diagnostic test for it Loeys-Dietz syndrome type I (OMIM 609192)1 Loeys-Dietz syndrome type I is a novel autosomal-dominant aortic aneurysm syndrome. It is characterized by the triad of hypertelorism, bifid uvula/cleft palate, and arterial tortuosity with ascending aortic aneurysm/dissection. It is caused by heterozygous loss-of-function mutations in the TGFβR1 or TGFβR2 gene. The main differences with Marfan syndrome include the absence of significant long bone overgrowth or lens dislocation, and the presence of multiple other findings, including craniosynostosis, Chiari malformation, club feet, patent ductus arteriosus, and aneurysms/dissection throughout the arterial tree. Loeys-Dietz syndrome type II (OMIM 309520)18 In contrast to Loeys-Dietz syndrome type 1, some patients have less craniofacial abnormalities but prominent skin and joint manifestations, more reminiscent of vascular EDS. These subset of patients (Loeys-Dietz syndrome type II) is characterized by a velvety and translucent skin, easy bruising, widened atrophic scars, uterine rupture, severe peripartal bleedings, and arterial aneurysm/dissections throughout the arterial circulation. Importantly, the natural history of patients with TGFβR1/2 mutations is far more aggressive than in Marfan syndrome or even vascular Ehlers-Danlos syndrome, with a mean age at death of 26.1 years. Aortic dissections occur in young childhood and/or at smaller aortic dimensions (<40 mm), and the incidence of pregnancy-related complications is high.

Additional tests Imaging: X-rays of spine detects scoliosis Echocardiogram: presymptomatic aortic root dilation MRI shows: Sagittal width of the dural sac at S1 or below that is greater than the sagittal width of the dural sac above L4

Diagnosis Marfan’s Syndrome- run test to assess genetic cause How many body systems must be affected in a patient with this diagnosis if it does not run in one’s family?  3 Ghent criteria Dural ectasia explains some of her symptoms... Definition: Heritable condition (in most cases) that is autosomal dominant or by a new mutation. Caused by mutation on FBN1 gene on chromosome gene that codes for fibrillin, a large glycoprotein constituent of microfibrils. Connective tissue is thus defective. Wide range of symptoms (mild to severe) and is diagnosed from early age to adulthood. No gender, ethnic or racial predisposition. Recent studies have suggested that abnormalities in the transforming growth factor-beta (TGF β )-signaling pathway may represent a final common pathway for the development of the Marfan phenotype.1 The gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix. The identification of mutations in transforming growth factor-beta receptor 2 (TGF β R2) in patients with Marfan syndrome type II (MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of Marfan syndrome. Abnormalities in TGF β R 2 and TGF β R1 were also reported to cause a new dominant syndrome similar to Marfan syndrome; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz aortic aneurysm syndrome (Online Mendelian Inheritance in Man [OMIM] 609192).1 These results define a new group of Marfan syndrome–related connective-tissue disorders, namely, TGF β signalopathies. A second fibrillin gene, the FBN2 gene, is responsible for the congenital contractural arachnodactyly, known as Beals syndrome.2 From: http://emedicine.medscape.com/article/946315-overview Ghent criteria: http://www.crkirk.com/thumbnail/syndromes/marfan.htm#Ghent Diagnostic Criteria

Treatment There is no known cure. General measures: multi-discpilinary approach to include cardiologist, opthamologist, orthopedic surgeon if necessary Fully activity as tolerated. No specific diet Drugs of choice: Propranolol to decrease force of cardiac contraction and dely aortic root dilatation Calcium channel blockers to retard further aortic growth

Prognosis/ Follow-up Frequent examinations including echocardiograms at least twice a year until age 18. Eye examinations If patient becomes pregnant, she must immediately contact physician

Possible Complications Skeletal: Scoliosis, flat feet Eyes: Retinal detachment, glaucoma, cataracts Cardiovascular: Aortic dissection/ rupture Aortic or mitral valve insuffiency Dilated cardiomyopathy Bacterial endocarditis Nervous System: Dural ectasia Respiratory: Sleep apnea Dural ectasia is a widening or ballooning of the dural sac surrounding the spinal cord usually at the lumbosacral level. It is one of the major manifestations of Marfan syndrome. It may cause low back pain, headaches and neurologic deficits such as weakness and loss of bowel and bladder function, but in many patients it is asymptomatic.