In some patients, a secondary prophylaxis regimen is prescribed for short peri- ods to redu ce the frequency of bleeds in target joints. Published evidence on the 53 CASE 8 benefits of long-term secondary prophylaxis in young adult hemophiliacs has been from small retrospective studies. They show that severe hemophiliac adults switching from on-demand t o secondary prophylaxis used more concentrate but had fewer joint bleeds. Secondary prophyl axis has not yet been shown to slow the progression of HA in patients with established join t damage. Various radiologi- cal scoring systems have been developed to monitor disease pro gression by MRI and are important in measuring response to prophylactic factor VIII treatme nt. Further reading Coppola A , Di Capua M, Simone CD ( 2008 ). Primary prophylaxis in children with hemophilia . Blood Transfus ; 6 (Suppl 2 ): s4 \200\223 11. Jelbert A , Vaidya S , Fotiadis N ( 2009 ). Imaging and staging of haemophilic arthropathy . Clin Radiol ; 64 : 1119 \200\223 28. Tagliaferri A , De Perna C , Rivolta GF ( 2008 ). Secondary prophylaxis in adolescents and adult hemophiliacs . Blood Transfus ; 6 (Suppl 2 ): s17 \200\223 20. Vassilopoulos D , Calabrese LH ( 2008 ). Virally associated arthritis 2008 : clinical, epid emiologic, and pathophysiologic considerations . Arthritis Res Ther ; 10 : 215. 54 CASE HISTORIES IN RHEUMATOLOGY Case 9 A 30-year-old female with a 10-year history of systemic lupus erythematosus (SLE) was revie wed in clinic. She had recently married and was keen to start a family. At diagnosis she ha d presented with a photosensitive rash, fleeting arthralgia, migraine, depression, and prot einuria. A renal biopsy had confirmed membranous glomeru- lonephritis, consistent with clas s V lupus nephritis. She was initially treated with prednisolone and azathioprine, but ongo ing active renal disease necessitated escalation to cyclophosphamide and subsequent mainten ance therapy with mycophenolate mofetil 1g twice daily. Examination was normal, including a blood pressure of 120/80 mmHg. Dipstick urinalysis was normal. 55 CASE 9 Questions \200\224Part 1 1. How would you assess her disease activity? What other tests would you consider in preparation for pregnancy? 2. What pre-conception counseling would you provide with regard to the following? i. Medication and contraception. ii. Renal disease. iii. Pregnancy-related risks? What additional monitoring may be required during pregnancy? 56 CASE HISTORIES IN RHEUMATOLOGY Answers 1. How would you assess her disease activity? What other tests would you consider in prepar ation for pregnancy? Pregnancy outcome is better if conception occurs during a period of remission, or 6 months after control of a flare or a change in maintenance therapy. Disease activity in SLE can be assessed using the SLE Disease Activity Index, a global dise ase activity score (DAS) validated against experienced clinical judge- ment used to quantif y organ involvement and guide therapeutic management. Pre-conception all patients with SLE should be screened for a lupus anticoagu- lant, antiph ospholipid, and anti-Ro and anti-La antibodies. Anticoagulants includ- ing aspirin and hepa rin have been shown to improve pregnancy outcome in women with antiphospholipid syndrome (A PS) (see p. 75). Ds DNA, anti-Ro antibodies, and anti-La antibodies may result in neonatal lupus which requires further moni- toring (see Answer 2). 2. What pre-conception counseling would you provide with regard to the following? i. Medication and contraception. ii. Renal disease. iii. Pregnancy-related risks. What additional monitoring may be required during pregnancy? i. Patients taking teratogenic medications should be advised regarding contracep- tion, avo iding estrogen-containing preparations due to the risk of flare. Animal studies suggest tha t mycophenolate mofetil is associated with an increase in congenital malformations and shou ld be avoided in pregnancy. It is standard practice to switch to azathioprine and hydroxych loroquine, as was done in this case, which are considered safe in pregnancy. ii. There is a risk of deterioration in renal function due to the change in medication or a s a result of pregnancy. The risk is higher with pre-existing hypertension, proteinuria ( > 1 g/24 h), or high baseline serum creatinine ( > 125 mol/L). iii. Lupus itself does not usually affect fertility, but NSAIDs, previous cyclophospha- mid e treatment, and ongoing disease activity may prevent conception. There are increased risks of early miscarriage, intra-uterine fetal death, pre-eclampsia, intra-uterine growth retar dation, and pre-term delivery. Pregnancy may increase the risk of flare both antenatally an d in the puerperium. Patients with active lupus, particularly if nephrotic, are at increase d risk of venous thromboembo- lism (VTE) in pregnancy. Therefore it is imperative that a de tailed history is taken of previous history of clots or other risk factors, and thromboprop hylaxis should be considered. Women with APS are at increased risk of VTE and fetal loss, a nd low-dose aspirin and low molecular weight heparin are recommended throughout pregnancy a nd 6 weeks post-natally. Such patients should be man- aged under collaborative care of obst etrics and hematology. 57 CASE 9 Increased maternal and fetal surveillance is required during pregnancy, particularly in wom en with hypertension, renal disease, APS, and Ro antibodies. Ro antibodies are associated w ith congenital heart block in 1 \200\2232 % of cases; early cardiac fetal monitoring is imp ortant in detecting this as it can result in intra-uterine death. Ro and La antibodies can cross the placenta and 5 % of babies may suffer a neonatal lupus syndrome which is transien t. She conceived 8 months later and was initially well, but at 21 weeks \200\231 gestation was noted to have deteriorating renal function and hypertension (BP 170/110 mmHg). Investigati ons showed: \227\206 urea 18 mmol/L \227\206 creatinine 171 mol/L \227\206 albumin 16 g/dL \227\206 urinary protein 10 g/24 h. Questions \200\224Part 2 3. There are two main causes of this presentation, what further investigations would you request in order to differentiate between the two? 58 CASE HISTORIES IN RHEUMATOLOGY Answer 3. There are two main causes of this presentation. What further investigations would you re quest in order to differentiate between the two? Deteriorating renal function, hypertension, and proteinuria suggest a flare of her lupus ne phritis, pre-eclampsia, or both. These conditions are potentially life- threatening to both mother and baby. The features distinguishing a lupus flare and pre-eclampsia are shown in Table 9.1 . Steroids are first-line therapy for lupus flare during pregnancy. Prednisolone is inactivat ed by placental 11 -hydroxysteroid dehydrogenase 2 so that only 10 % of the active drug reaches the fetus. High-dose steroids increase the risk of maternal gestational diabetes, h ypertension, infection, and osteoporosis. Other immuno- suppressive agents that are conside red to be safe in pregnancy include azathioprine, hydroxychloroquine, ciclosporin, tacrolim us, and intravenous immunoglobulin. There are few data for the use of biological agents suc h as anti-TNF therapy, but so far there is no suggestion of adverse maternal or fetal outco me. In rare severe cases, cyclophosphamide has been used in pregnancy. Table 9.1 Features distinguishing a lupus flare from pre-eclampsia Lupus flare Pre-eclampsia Hypertension Yes Yes Urine analysis Proteinuria Red cell casts and proteinuria Platelet count Low Low Abnormal LFTs Unusual Common Creatinine Raised Raised Serology Raised dsDNA and low C3/C4 Normal Uric acid Normal High Further reading Bombardier C , Gladman DD , Urowitz MB , Caron D , Chang CH ( 1992 ). Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE . Arthritis Rheum ; 35 : 630 \200\223 40 . Mackillop LH , Germain SJ , Nelson-Piercy C ( 2007 ). Systemic lupus erythematosus . BMJ ; 335 : 933 \200\223 6 . 59 CASE 10 Case 10 A 73-year-old woman was admitted to the trauma ward with a fractured neck of femur after fa lling from her chair. Despite fixation surgery with a good technical result, her rehabilita tion was slow and she complained of generalized muscle aches. Her past medical history was unremarkable apart from anemia, treated with three-monthly B 12 injections. Twelve months prior to her fall, she had developed severe pain and stiffness affecting both shoulders, unresponsive to steroid, with limited movement preventing her from playing lawn bowls. The shoulder pain did not resolve after steroid injections into her shoulders. Furt hermore, she was not able to return to her bowls as she developed reduced grip strength and numbness of her right thumb and index finger. She had difficulty getting out of bed in the morning and would tend to sit in her chair, by her heater, for most of the day as she found it difficult to stand up because of weakness in her thighs. Her daughter was worried as her mother was becoming increasingly withdrawn a nd sedentary. Questions 1. Based on the history, which aspects of the musculoskeletal and neurological systems have been affected? 2. What is the most likely unifying diagnosis? 3. Which rheumatological and other conditions have been associated with an autoimmune cause for this underlying diagnosis? 4. What factors may have contributed to her risk of fracture? 60 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Based on the history, which aspects of the musculoskeletal and neurological systems have been affected? The clinical features of this case suggest: \227\206 proximal myopathy \227\206 carpal tunnel syndrome \227\206 bilateral shoulder adhesive capsulitis \227\206 fragility fracture. 2. What is the most likely unifying diagnosis? The most likely unifying diagnosis is hypothyroidism, which can affect up to 14 % of the el derly population. Patients often present with myalgia, proximal muscle weakness, which may be associated with a mild elevation in CK, and arthralgia. This patient had symptoms of a p roximal myopathy with quadriceps weakness. Nerve-entrapment syndromes are common, with carp al tunnel syndrome occur- ring in 30 % of patients with hypothyroidism in one series. Adhes ive capsulitis was reported in 11 % of patients with thyroid disease, including those with hyperthyroid, hypothyroid, and euthyroid states. This is higher than the reported prevalenc e of primary idiopathic adhesive capsulitis in the general population of 2 \200\2233 % . Lethargy, weight gain, cold intolerance, depression, poor memory, change in appearance, dry hair, and dry skin are other features which should be sought in the history. Mild haemolys is can also occur with hypothyroidism, which would contribute further to this woman \200 \231s anemia and lethargy. 3. Which rheumatological and other conditions have been associated with an autoimmune cause for this underlying diagnosis? Chronic autoimmune thyroiditis, characterized by diffuse lymphocytic infiltration of the th yroid gland, presence of antithyroid antibodies in the serum and frequently thyroid dysfunc tion, has been associated with a variety of rheumatic manifesta- tions. In addition to the features attributed to hypothyroidism, described above, there are a collection of autoimmun e rheumatic diseases which may overlap with autoimmune thyroid disease per se . Autoimmune thyroid disease occurs in more than one-third of patients with primary Sj gren \200\231s syndrome, and Sj gren \200\231s syndrome is present with similar fre- quency in autoimmune thyroid disease. Therefore screening should be conducted in these groups of pati ents. Recent studies have also demonstrated a high frequency of autoimmune thyroid disease in patients with rheumatoid arthritis (RA), as well as in their families. The overlap in sy mptoms, including lethargy and muscle and joint pains, highlights the need to screen RA pat ients. Other rheumatological conditions with a less clear link include SLE, scleroderma, and polym yalgia rheumatica (PMR). Muscle symptoms including pain, weakness, 61 CASE 10 and cramps, sometimes associated with raised creatine kinase (CK) may be seen with hypothyr oidism. However, clinical and biochemical features of muscle dysfunction can also occur in the context of subclinical hypothyroidism. Patients with euthyroid autoimmune thyroid disea se have also been found to demonstrate electron microscopic capillary abnormalities and mac rophage, lymphocytic, and mast cell infiltration of skeletal muscle. 4. What factors may have contributed to her risk of fracture? Fracture risk is multifactorial in patients with hypothyroidism. Risk of falling is increas ed by proximal muscle weakness, arthralgia, peripheral sensorimotor neu- ropathy, bradycard ia, heart failure, slowness of thought, and poor attention. Fragility fractures are seen in both hypothyroidism and hyperthyroidism. Hyperthyroidism is associated with increased bone resorption, reduced bone mineral density (BMD), and so incr eased fracture. Hypothyroidism results in a reduction in osteoblastic and osteoclastic acti vity, leading to prolongation of the remodeling cycle with reduced bone turnover. Although BMD subsequently tends to be higher than normal in patients with hypothyroidism, fracture r isk remains increased. Reduced bone quality, rather than dual-energy X-ray absorptiometry ( DEXA) score, may explain this link. It is still unclear whether thyroxine therapy itself al so has a deleterious effect on bone. Further reading McLean RM , Podell DN ( 1995 ). Bone and joint manifestations of hypothyroidism . Semin Arthritis Rheum ; 24 : 282 \200\223 90 . Punzi L , Betterle C ( 2004 ). Chronic autoimmune thyroiditis and rheumatic manifestations . Joint Bone Spine ; 71 : 275 \200\223 83 . 62 CASE HISTORIES IN RHEUMATOLOGY Case 11 A 26-year-old female graduate student was admitted to the acute admissions unit with a 12-h our history of rapid-onset fever, left-sided pleuritic chest pain, and a swollen left knee. There was no shortness of breath or haemoptysis. Her knee was hot, red, and swollen, and s he was unable to weight bear. She had small tender red swellings over the dorsum of her rig ht foot. She had recently returned from a holiday in Gibraltar where she had visited her grandparent s. She had no history of insect bite, infection, or excessive sun exposure. She was previou sly healthy, apart from a recurrent febrile tonsillitis throughout child- hood, severe dysm enorrhoea, and appendectomy aged 17. She was married and was under investigation for primar y infertility. She has no past or family history of arthritis, enthesitis, iritis, arthriti s, photosensitive rash, mouth ulcers, or Raynaud \200\231s phenomenon. On examination her temperature was 40 C, pulse 100 beats/min, BP 130/80 mmHg, respirator y rate 15 breaths/min, chest clear to auscultation. She had a tense effusion around her lef t knee and a skin rash with three red, raised, tender, well-demarcated flat lesions 2 cm in diameter over the dorsum of her right foot. She had no other joint swelling, and her skin and nails were otherwise normal. She was admitted and 30 mL of murky fluid was aspirated from her knee. She was started on i ntravenous flucloxacillin. Six hours after the infusion had started the chest pain resolved completely. The intravenous antibiotics were continued for 48 hours. The knee remained swo llen and red for a further 3 days. The swelling gradually resolved over the course of the n ext 3 weeks. Investigations showed the following: \227\206 Hb 12.6 g/dL; WCC 11.5 \227 109/L; neutrophils 4.3 \227 109/L; platelets 448 \227 109/L \227\206 Blood movie normal \227\206 Blood cultures: no growth on prolonged culture \227\206 Throat swab: no growth \227\206 LFTs normal \227\206 GFR normal \227\206 CXR clear \227\206 ECG normal \227\206 ANA negative; RF negative; ANCA negative; complement levels normal \227\206 ASOT <200 units/mL \227\206 CRP 70 mg/L \227\206 Dipstick urinalysis: + protein; MSU no growth \227\206 Joint aspirate: > 100 WCC/hpf. No other cells, organisms, or crystals. No growth on prolonged culture. 63 CASE 11 Questions 1. What is the differential diagnosis? 2. What is the likely diagnosis? 3. How is the diagnosis is usually made? 4. What is the treatment and prognosis? 64 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis There is a wide differential diagnosis in this woman: \227\206 septic arthritis \227\206 SLE \227\206 acute rheumatic fever \227\206 reactive arthritis \227\206 adult Still \200\231s disease \227\206 acute sarcoidosis \227\206 periodic fever syndrome. Septic arthritis is the most important diagnosis to exclude, and giving parenteral flucloxa cillin (plus penicillin depending on local antibiotic policy) until cultures are negative i s standard practice. The negative auto-antibody screen excludes SLE and makes other connective tissue diseases unlikely. Patients with acute sarcoidosis usually present with periarthritis rather than arthritis, e rythema nodosum and have hilar lymphadenopathy on CXR, and erythema nodosum skin lesions. I n this patient the CXR, arthritis rather than periarthritis, and flat skin lesions were all against the diagnosis of acute sarcoid. Reactive arthritis rarely presents with pleuritic chest pain. Associated rashes are palmo-p lantar pustulosis or keratoderma blennorrhagica on the soles and palms rather than on the d orsum of the feet. Acute rheumatic fever is an important diagnosis to exclude, particularly with a past histor y of recurrent childhood tonsillitis. The rash of acute rheumatic fever, erythema marginatu m, classically affects the trunk and upper limbs and not the feet. The lack of laboratory e vidence for streptococcal infection makes the diagnosis unlikely. It is important to re-evaluate the previous childhood febrile episodes. Her mother and mate rnal grandparents were from Gibraltar and of Jewish descent. Her father was Turkish and she had been raised in the UK. Her childhood febrile tonsillitis episodes usually started dramatically, with high fevers d eveloping during the course of a few hours. The episodes lasted up to 3 days and were somet imes associated with abdominal pain and aching wrists. She was well between attacks. Her appendectomy occurred during one of these episodes, when the abdominal pain worsened ra ther than improved overnight. She was told that the appendix was normal. She was used to having attacks of lesser fevers before her periods, which were always painful and associated initially with constipation, and then diarrhea. She and her husband had been trying to conceive for a year and were just considering referral for fertility investigations. 65 CASE 11 2. What is the likely diagnosis? A likely diagnosis is familial Mediterranean fever (FMF) which is one of the auto- inflamma tory syndromes. The recurrent febrile episodes in childhood can be misdiagnosed as tonsillitis. The severe dysmenorrhoea and appendectomy probably represented mild episodes of abdominal serositis. The presenting episode was more severe, with symptoms of fever, pleurisy, cuta- neous lesio ns, and monoarthritis. The classical skin lesions are sharply bordered, hot, tender erysipe las-like plaques 10 \200\22335 mm in diameter occurring on the exten- sor surface of the an kle or the dorsum of the foot, appearing with the rapidly rising fever. The dipstick protei nuria is important to follow as it may suggest early amyloidosis. 3. How is the diagnosis usually made? The diagnosis can be made clinically on the basis of typical attacks in an individual from the appropriate ethnic population. FMF characteristically affects people descended from Sephardic (Spanish from North Africa) Jews, and is less common amongst East European Jews, Anatolian Turks, Arabs, Armenians, and other Mediterranean groups. Intermarriage and migration means that the condition can occur sporadically in most populations. Tel Hashomer criteria for the diagnosis of familial Mediterranean fever \227\206 Major: recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis amyloidosis of amyloid A type without predisposing disease favorable response to colchicine. \227\206 Minor: recurrent febrile episodes erysipelas-like erythema FMF in a first-degree relative. \227\206 Definitive diagnosis \200\224 two major or one major and two minor. \227\206 Probable diagnosis \200\223one major and one minor. Specificity in a Jewish population is > 95 %. Gene testing This is an autosomal recessive condition. Genetic screening is now possible fo r com- mon mutations in the FMF gene. The MEFV gene is located on the short arm of chro- mo some 16p13.3. It is a 10-exon gene encoding pyrin (a 781 amino acid protein). Pyrin is expr essed in myeloid cells and is believed to regulate inflammation via apop- tosis.There are f our common missense or nonsense mutations which produce differ- ent clinical patterns. 66 CASE HISTORIES IN RHEUMATOLOGY Testing for amyloid In this patient, the presence of proteinuria, if persistent, suggests A A amyloidosis. The gold standard for diagnosis is the presence of biopsy-proven amyloid dep osits. The biopsy sites used are abdominal fat aspiration (safe outpatient test, 55 \200 \22375 % sensitive), rectal biopsy (uncomfortable, risk of rectal bleeding, 75 \200\22385 % sensitive), and liver or kidney biopsy (risk of life-threatening bleed from vascular amylo id deposits, 99 % sensitive). Biopsy is becoming superseded by total body scintigraphy using radiolabelled serum amyloid protein (SAP). This is a sensitive non-invasive technique that locates and quantifies amylo id deposits throughout the body. Affected organs are highlighted and the test can be repeat ed to follow the effects of treatment and progress. 4. What is the treatment and prognosis? Acute attacks are self-limiting and require simple analgesia and NSAIDs. Attacks occur at i rregular intervals with no clear precipitating cause. Severe abdominal pain is the first presentation in 70 % of cases and is the most frequent m anifestation, occurring in 90 % of patients. Symptoms and signs can resemble an acute abdom en and appendectomy is often undertaken (with normal histology). Attacks reach a peak withi n a few hours and start to abate after 6 \200\22312 hours. Most patients return to normal w ithin 24 \200\22348 hours. Fertility is sometimes impaired in women because pelvic adhesions can develop after frequen t abdominal attacks. Treatment with colchicine lessens the frequency of attacks, the develo pment of adhesions, and the rate of early miscarriage. Arthritis affects 75 % of patients, and is the second most common presentation. Classically , patients present with painful sterile monoarthritis of a hip or knee. Most resolve over 4 8 \200\22372 hours and NSAIDs plus colchicine are usually sufficient to control symptoms wh ilst attacks settle. Five per cent develop a chronic destructive arthritis which can lead t o aseptic necrosis and require joint arthroplasty. Acute febrile pleurisy occurs in 45 % of patients. Although painful, it is benign and resolves within 48 hours with no significant sequelae. The most serious long-term complication is AA amyloidosis with renal failure. The risk of d eveloping AA amyloidosis increases if there is a family history of amy- loidosis and varies between genetic mutations, with the M694V mutation having the highest risk. Treatment is with colchicine (1 \200\2232 mg/day) which reduces the duration of acute attac ks, prevents further acute inflammatory attacks, and prevents the long-term development of amyloidosis. Colchicine also decreases the rate of progression of established amyloid. Colchicine is usually well tolerated; the most common side effects are diarrhea and nausea which patients adjust to. Compliance can be difficult, particularly with teenagers. However , even short breaks from treatment can result in flare of disease and development of AA amy loid. Pregnancy is usually associated with remission of symptoms. However, it is usually re commended that colchicine treatment is continued during pregnancy, as the flares of disease can lead to miscarriage. Long-term follow-up is needed with regular urinalysis and renal function testing to detect early amyloid. 67 CASE 11 Patients with amyloidosis need careful hypertensive control and usually progress to renal failure and transplantation in their fifties. Prior to colchicine therapy, amyloidosis caused by FMF was universally fatal by the early forties. Corticosteroids are generally ineffective during acute attacks and in preventing development of amyloidosis. Approximately 10 % of FMF patients are resistant or non-responsive to colchicine treatment. There are early reports that the IL-1 receptor antagonist anakinra is effective in treatin g colchicine-resistant cases. Further reading Diav-Citrin O , Shechtman S , Schwartz V , et al . ( 2010 ). Pregnancy outcome after in ute ro exposure to colchicine. Am J Obstet Gynecol ; 203 : 144. Livneh A , Langevitz P , Zemer D, et al . ( 1997 ). Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum ; 40 : 1879 \200\223 85. Yao Q , Furst D ( 2008 ). Autoinflammatory diseases: an update of clinical and genetic aspe cts. Rheumatology ; 47 : 946 \200\223 51. Zemer D , Pras M , Sohar E , Modan B , Cabili S , Gafni J ( 1986 ). Colchicine in the preve ntion and treatment of amyloidosis of familial Mediterranean fever. N Engl J Med ; 314 : 1001 \200\223 5. 68 CASE HISTORIES IN RHEUMATOLOGY Case 12 A teenager presented to her GP concerned about her appearance as she was teased at school. She was the tallest in her class and thinner than her peer group. She had disproportionatel y long limbs and a concave chest wall. Clinical examination revealed a systolic murmur. 69 CASE 12 Questions 1. What is the differential diagnosis? 2. What is Marfan \200\231s syndrome? 3. Which gene is involved and what is the recommended genetic screening? 4. What are the long-term complications of Marfan \200\231s syndrome? 5. What advice regarding sport should be given to a patient with Marfan \200\231s syndrome? 70 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis? The differential diagnosis is: \227\206 constitutional tall stature \227\206 Marfanoid habitus \227\206 Marfan \200\231s syndrome \227\206 pituitary hypersecretion of growth hormone (GH) (gigantism) \227\206 Ehlers \200\223Danlos syndrome \227\206 homocystinuria \227\206 congenital contractural arachnodactyly. If the patient \200\231s height is greater than the 95th percentile, it should be compared with her expected height which can be calculated from parental height and may be normal. Sh e may have a Marfanoid habitus which might be associated with hyper- mobility but not with disease manifestations. Congenital contractural arachnodactyly is an autosomal dominant condition caused by mutatio ns in the FBN2 gene and results in a tall slender habitus with long fingers, crumpled ears, and arm span exceeding height, but with normal eyes and aorta. Homocystinuria may present with skeletal features similar to Marfan \200\231s syndrome and a downward lens dislocation . This is a recessively inherited inborn error of amino acid metabolism due to a deficiency of cystathionine -synthetase. Patients have a positive urine cyanide \200\223nitropruss ide test to detect homocysteine. 2. What is Marfan \200\231s syndrome? Marfan \200\231s syndrome is a multisystem disorder of connective tissue which is generally inherited as an autosomal dominant condition but occurs after sporadic mutation in 25 % of cases. It is one of the most common single-gene malformation syndromes with a prevalence o f 1 in 5000 \200\22310 000. Isolated clinical features are common; many clinicians will enc ounter potential cases, and diagnostic accuracy is relevant not only for the patient but al so for family members. It is characterized by arachnodactyly, tall stature, pectus deformities of the chest, facia l and eye abnormalities, and mandibular hypoplasia. There are no unique characteristics but more than 35 clinical features may be variably associated. The diagnosis is based on the Ghent criteria which include clinical features from the skele tal, ocular, cardiovascular, and pulmonary systems, the dura, and the skin, and family or g enetic history. A diagnosis of Marfan \200\231s syndrome requires the presence of a major c riterion in two systems and involvement of a third. Major criteria \227\206 Skeletal: pectus carinatum or pectus excavatum requiring surgery upper to lower segment ratio <0.86, or span to height ratio > 1.05 wrist and thumb signs 71 CASE 12 scoliosis > 20 reduced elbow extension <170 pes planus protrusio acetabulae. \227\206 Dura: lumbosacral dural ectasia. \227\206 Cardiovascular: dilatation of the aortic root dissection of the ascending aorta. \227\206 Ocular: ectopia lentis. \227\206 Genetic: first-degree relative meets criteria independently presence of FBN-1 mutation. Minor criteria The minor criteria define involvement of a particular organ system and can b e included in the diagnosis of Marfan \200\231s syndrome if major criteria are also present . They include pectus excavatum of moderate severity, joint hypermobility, high arched pala te, dental crowding, characteristic facies, flat cornea, hypoplastic iris, mitral valve pro lapse, calcified mitral annulus, dilatation of the pulmonary artery, spontaneous pneumothor ax, apical blebs, striae atrophicae, and recurrent or incisional hernia. 3. Which gene is involved and what is the recommended genetic screening? Marfan \200\231s syndrome is caused by mutations in a single fibrillin gene (FBN1) on chrom osome 15. Fibrillin is a glycoprotein produced by fibroblasts and aggregates in the extrace llular matrix, forming the meshwork on which elastin is deposited. Elastin fibers are abund ant in the aorta, ligaments, and the ciliary zonules of the lens, and these areas are chara cteristically affected in the condition. A transgenic mouse has been created to carry a sin gle copy of a mutant fibrillin-1 gene, and demonstrates many features of Marfan \200\231s s yndrome. Fibrillin-1 indirectly binds an inactive form of transforming growth factor- (TGF- ). A mechanism of disease has been suggested whereby reduced levels of fibrillin-1 result in a rise in TGF- resulting in an inflammatory reaction and release of elastin degrading pr oteases. Genetic screening may be useful in defining new mutations. The risks to other family member s are different depending on whether the mutation is inherited or spontaneous, and family m embers sharing an identical mutation may show great clinical variety. It is important to ma ke a clear diagnosis of Marfan \200\231s syndrome as it is a cause of preventable sudden de ath in young adults. Patients should be included in a screening program for cardiovascular, ophthalmological, and musculoskeletal complications. 72 CASE HISTORIES IN RHEUMATOLOGY 4. What are the long-term complications of Marfan \200\231s syndrome? The main cardiovascular complications are aortic root enlargement, mitral valve prolapse, a nd arrhythmias. Routine care includes annual echocardiography and an electrocardiogram. Ris k factors for aortic dissection include an aortic diameter > 5 cm, aortic dilatation extend ing beyond the sinus of Valsalva, a rapid rate of aor- tic root dilatation, or a family his tory of aortic dissection. Aggressive management of aortic root dilatation with -blocker s reduces the risk of dissection. Patients are referred for prophylactic aortic root surger y when the diameter at the sinus of Valsalva exceeds 5.5 cm in an adult or 5 cm in a child. Pregnant women with Marfan \200\231s syndrome are at increased risk of aortic dissection w hen the aortic root diameter is \211 4 cm in the presence of aortic dilatation. A number of ophthalmological complications are associated with Marfan \200\231s syndrome. A pproximately 60 % have ectopia lentis which is managed with miotic drugs to constrict the p upil and refractive lenses. Patients frequently have strabismus, requiring treatment to pre vent amblyopia. There is an increased risk of retinal detachment as the globe is elongated. Kyphosis and scoliosis may develop during childhood. A scoliosis beyond 40 may contribut e to restrictive lung disease, resulting in cor pulmonale, and require corrective surgery. Pectus excavatum may require surgery in early adulthood as the reduced spinal \200\223stern um diameter may lead to cardiac complications. Pectus cari- natum rarely causes medical com plications but may be repaired for cosmetic reasons. Figure 12.1 shows an MRI of a marked thoracolumbar scoliosis in Marfan \200\231s syndrome, convex to the right. Dural ectasia is a dilation of the dural sac, usually at the L5 \200\223S1 level of the spi ne (Fig. 12.2 ) and can occur in two-thirds of adults with Marfan \200\231s syndrome. It ty pi- cally presents with unremitting headache or spinal pain and may cause peripheral neurol ogical symptoms due to nerve root pressure, such as referred pain, weak- ness, or loss of b ladder control. It may be treated conservatively with gabapentin, physiotherapy, and hydro- therapy, but ma y require neurosurgical repair of the dura for symptomatic relief. 5. What advice regarding sport should be given to a patient with Marfan \200\231s syndrome? Low to moderate degrees of activity are advised for patients with Marfan \200\231s syn- dro me depending on the presence of risk factors, and a reduction of physical and haemodynamic stress may be advised for those with cardiopulmonary or ophthal- mological disease. Patient s are advised about the dangers associated with some sports and to avoid those that involve blows to the head and eye such as boxing and some racquet sports. Contact sports and high diving should be avoided because of the risks of aortic dissection and lens dislocation. Pa tients who have undergone aortic root or valve replacements may need further caution, parti cularly if receiv- ing anticoagulation. Diving should be avoided because of the risk of spo ntaneous pneumothorax. 73 CASE 12 Fig. 12.1 T 1 -weighted MRI scan of the spine in a patient with Marfan \200\231s syndrome. Fig. 12.2 Dural ectasia with a large cystic cerebrospinal fluid (CSF) out-pouching extendin g through the left S2 exit foramen. (Note: this is not the same patient as in Fig. 12.1 ). 74 CASE HISTORIES IN RHEUMATOLOGY Follow-up This patient developed dyspnoea and bilateral pedal oedema due to mitral valve prolapse whe n she was 25 years old and underwent a 33 mm Bjork \200\223Shiley tilting mitral valve repl acement. Regular echocardiograms demonstrated aortic root dilatation of 6 cm at the age of 30 years and she underwent an aortic root replacement. Further reading de Paepe A , Devereux RB , Dietz HC , Hennekam RC , Pyeritz RE ( 1996 ). R evised diagnosti c criteria for the Marfan syndrome. Am J Med Genet ; 62 : 417 \200\223 26. Ho NCY , Tran JR , Bektas A ( 2005 ). Marfan \200\231s syndrome. Lancet ; 366 : 1978 \200 \223 81. Summers KM , Wes JA , Peterson MM , Stark D , McGill JJ , West MJ ( 2006 ). Challe nges in the diagnosis of Marfan syndrome . Med J Aust ; 184 : 627 \200\223 31. 75 CASE 13 Case 13 A 12-year-old girl presented with a 4-week history of involuntary choreiform movements when walking, initially affecting her right arm, progressing to involve her left arm, legs, and subsequently her face, head, and trunk. It interfered with dressing and feeding herself. S he had dysphasia and was noted to have easy bruising. There was no past medical history, bu t her paternal grandmother had Sydenham \200\231s chorea as a child. She had normal cardiov ascular, respiratory, and abdominal examinations, and normal eye movements and fundoscopy. She had small widespread bruises and a mottled rash on her legs (Fig. 13.1 ). A full blood count showed her to have a throm- bocytopenia with platelets of 58 \227 10 9 /L. 76 CASE HISTORIES IN RHEUMATOLOGY Fig. 13.1 (See also Plate 9) Rash on patient \200\231s legs. 77 CASE 13 Questions 1. What is the differential diagnosis of choreiform movements? 2. What investigations would narrow the differential and elucidate the diagnosis? 3. What is the most likely diagnosis? 4. What is the significance of the rash (Fig. 13.1 ), the chorea, and the thrombo- cytopenia? 5. How would you treat her at this stage? How may this change in the future? 78 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis of choreiform movements? Choreiform movements are likely to result from basal ganglia pathology. The differential di agnosis includes the following: \227\206 Infection-related: viral \200\224 varicella, HIV, measles, mumps, herpes simplex, Epstein \200\223Barr, cyto megalovirus pertussis, diphtheria Sydenham \200\231s chorea bacterial endocarditis Lyme disease mycoplasma. \227\206 Autoimmune/vasculitis: SLE APS BD sarcoid. \227\206 Vascular: arteriovenous malformation basal ganglia infarction or hemorrhage. \227\206 Endocrine: hyperthyroidism hypoparathyroidism, pseudo-hypoparathyroidism. \227\206 Metabolic: hypocalcaemia hypoglycaemia renal failure hypomagnesaemia hypo- or hypernatraemia. \227\206 Neoplastic: primary and metastatic brain tumor primary CNS lymphoma paraneoplastic syndrome. \227\206 Drug-related: anticholinergics anticonvulsants 79 CASE 13 antidopaminergics antihistamines CNS stimulants dopamine agonists lithium. \227\206 Epilepsy \227\206 Inherited conditions e.g. Wilson \200\231s disease. 2. What investigations would narrow the differential and elucidate the diagnosis? \227\206 Infection screen including viral studies, blood cultures, throat swab, antistrep- tolysin-O titre (ASOT), and an echocardiogram. \227\206 Autoantibodies to include antinuclear antibody (ANA), extractable nuclear antigen (ENA), complement, immunoglobulins, anticardiolipin antibody(aCL), and anti- 2 -glycopr otein-I antibody \227\206 Clotting studies, lupus anticoagulant (LA) \227\206 Urine dipstick for protein and blood, microscopy for casts \227\206 MRI brain \227\206 Lumbar puncture Investigations showed the following: \227\206 Hb 10.6 g/dL; MCV 79 fL; platelets 58 \227 109/L; WCC 6.8 \227 109/L with lymphocytes 2.2 \227 109/L; ESR 4 mm/h \227\206 Prolonged clotting: PT 15.4 s; activated partial thromboplastin time (APTT) 66.7 s \227\206 Positive LA; aCL 27 IU/ml \227\206 Positive ANA and negative ENA; C3 88 mg/dL (65 \200\223190); C4 11.8 mg/dL (14 \200\22340) \227\206 CRP <8 mg/L \227\206 Renal and liver function were normal \227\206 Viral studies and ASOT were negative \227\206 Echocardiogram showed mild mitral regurgitation with minor thickening of atrium m itral leaflet and absence of left ventricular or left atrial enlargement. \227\206 MRI excluded focal lesions in the basal ganglia. 3. What is the most likely diagnosis? What is the significance of the rash (Figure 13.1 ), the chorea, and the thrombocytopenia? This patient had positive LA and antiphospholipid, with clinical manifestations of anti-pho spholipid syndrome (APS), but did not satisfy the classification criteria for the syndrome since she did not have a history of arterial or venous thrombosis.