Bronchiectasis in a Marfanoid: Diagnosis Beyond Marfans

Unnati Desai, Shailesh Kalamkar and J.M. Joshi

Department of Pulmonary Medicine, T.N. Medical College and B.Y.L. Nair Hospital, Mumbai, India

[Indian J Chest Dis Allied Sci 2014;56:105-107]

IntroductionHomocystinuria is an autosomal recessive inheriteddisorder usually diagnosed in childhood. It is anunusual cause of bronchiectasis in adults. We report acase presenting with bilateral cystic bronchiectasis andMarfanoid features. Associated deep vein thrombosis(DVT), mental retardation and history of childhoodcataract surgeries aroused suspicion of homo-cystinuria. The diagnosis was confirmed by a positiveurine examination for homocystinuria and elevatedserum homocysteine levels.

Clinical SummaryA 35-year-old man, presented with cough with copiousexpectoration with postural variation and exertionaldyspnoea since childhood. He had a past history ofchildhood surgery for cataract in both eyes and a previoussurgery for a right-sided inguinal hernia. He had noaddictions. There was a history of poor scholasticperformance. He also gave a history of sibling deathand recurrent abortions in mother. The family-tree isillustrated in figure 1. On clinical examination, thepatient had Marfanoid features, i.e. tall, thin stature(dolichostenomelia), arm span more than height,arachnodactyly, positive wrist (Walker’s sign) and thumbsign (Steinberg sign). In addition, he had a left-sidedfemoral hernia and bilateral varicose veins with bilaterallower limb ulceration. Respiratory system examination onauscultation revealed bilateral coarse crackles.

[Received: June 20, 2013; accepted after revision: November 11, 2013]

Correspondence and reprint requests: Dr J.M. Joshi, Professor and Head, Department of Pulmonary Medicine, T.N.Medical College and B.Y.L. Nair Hospital, Mumbai-400 008, India; Phone/Fax: 91-022-23003095; E-mail drjoshijm@gmail.com

Radiology Forum

InvestigationsThe haemogram, liver function test and renal functiontests were normal. Chest radiograph (Figure 2)showed cystic lesions in the right lung, which wereconfirmed to be due to bilateral cystic bronchiectasison high resolution computed tomography (HRCT) ofthorax (axial and saggital sections; Figure 3A and B).Spirometry was suggestive of an obstructiveabnormality. Two-dimensional echocardiography(2D ECHO) showed aortic root dilatation. Dualenergy x-ray absorption (DEXA) scan documentedosteopaenia. Lower limb venous Doppler showed aDVT in the right saphenous vein. Intelligent quotient (IQ)

Figure 1. Family-tree showing normal, carriers andaffected members.

Figure 2. Chest radiograph (postero-anterior view)showing cystic bronchiectasis in the right lung.

study revealed a moderate mental retardation. As theGhent criteria for the diagnosis of Marfans syndromewere not fulfilled, the patient was considered to haveMarfanoid features. Homocystinuria was suspectedin view of DVT, mental retardation, history ofchildhood cataract surgeries in the presence ofMarfanoid features. Serum homocysteine levels wereobtained and found to be elevated at 57.64 µg/mL(normal range- 0.73-2.19). Urine examinationdetected homocysteine. Serum vitamin B12 level wasnormal.

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Thus, a diagnosis of classical form ofhomocystinuria was confirmed due to cystathioninebeta synthase (CBS) enzyme deficiency. The patient wastreated with pyridoxine and folic acid supplementationand diet modifications for homocystinuria;anticoagulants for deep vein thrombosis andbronchodilators, postural drainage and rehabilitationmeasures for bronchiectasis and associated chronicobstructive airway disease.

Diagnosis: Bronchiectasis due to homocystinuria

DiscussionHomocystinuria is an autosomal recessive inheriteddisorder of methionine metabolism.1 Neonatalscreening is carried out for homocystinuria indeveloped countries. Deficiencies of CBS enzyme ormethylene tetrahydrofolate reductase (MTHFR) enzymecause homocystinuria. Mutations in CBS, MTHFR,MTR (5-methyl tetrahydrofolate-homocysteinemethyltransferase), MTRR (methionine synthasereductase), and MMADHC (methylmalonic aciduria(cobalamin deficiency) cblD type, with homocystinuria)genes are cited. The classical form of homocystinuria iscaused by the deficiency of CBS enzyme.

Clinical manifestations of homocystinuria arevariable1 and depend on the age at presentation.Usually if missed at newborn screening, these patientspresent in early childhood to an ophthalmologist.Ectopia lentis inferiorly with high myopia is theclassical finding. Later these patients present at varioustimelines with central nervous system, skeletal andvascular system abnormalities.2 Homocystinuria hasseveral features in common with Marfans syndromeincluding dislocation of the lens; a tall, thin-build withlong limbs; arachnodactyly; and a pectus deformity ofthe chest.3 Marfanoid features, subluxated lenses,

Radiology Forum Unnati Desai et al

bronchiectasis, hernia and varicose veins representmanifestations of fibrillin deficiency. The thromboticepisodes are due to increased procoagulants,thromboxane A2 and cofactors. Central nervous systeminvolvement is secondary to thrombotic events andhomocysteine toxicity. Osteopaenia occurs becausehomocysteine interferes with the correct formation ofintra-chain and inter-chain bonds in the early post-translational modification of collagen.

Respiratory system involvement in homocystinuriahas been reported in the form of primary spontaneouspneumothorax, unilateral hyperlucent lung,pulmonary thromboembolism, and restrictiveabnormalities due to scoliosis. Bronchiectasissecondary to homocystinuria is a rare and unusualfinding reported at few countable instances. In a caseseries of 24 homocystinuria patients studied in SaudiArabia only one had bronchiectasis.4 Center for ArabGenomic Studies has reported cases of two Qatarisiblings presenting at 12 and 16 years of age withbronchiectasis as an unusual manifestation ofhomocystinuria.5

A Textbook of Clinical Pediatrics describes a nine-year-old girl who was diagnosed as a case ofhomocystinuria found to have bronchiectasis.6 This isthe first case of homocystinuria presenting asbronchiectasis in India. Bronchiectasis develops due tofibrillin degeneration. Fibrillin is rich in cystine, an endproduct of homocysteine. Hence, cystine formed inhomocystinuria is of poor quality which leads todegenerated fibrillin. Repeated sino-pulmonaryinfections with the ill-formed fibrillin lead to thestructural damage causing bronchiectasis over time.Therefore, bronchiectasis is an unusual anduncommon presenting feature as it is not present atbirth and many patients die early due to vascularcomplications before it develops.

Figure 3 (A and B). High resolution computed tomography of thorax showing bilateral cystic bronchiectasis.

A B

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Diagnostic tests include a panel of investigations.The biochemical tests include urine cyanide-nitroprusside to detect increased excretion ofsulfhydryl-containing compounds in urine; presence ofhomocysteine in urine is pathological. Elevated plasmalevels of free methionine and homocysteine confirm thediagnosis. Measurement of CBS activity in tissues, e.g.liver biopsy, skin biopsy may be done for researchpurposes. Contributory diagnostic tests includeophthalmology tests to detect myopia and dislocatedlens, and imaging, e.g. radiograph or DEXA scan todetect osteoporosis. Treatment depends on the age atpresentation. In a newborn infant, the aim is to preventaffection of various systems and development ofnormal intelligence by diet modifications andsupplementation with pyridoxine and folic acid. Oncethe complications have occurred management revolvesaround preventing further escalation and life-threatening complications.7

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Homocystinuria: an enzymatic defect. Science 1964;143:1443-5.2. Cruysberg JRM, Boers GHJ, Trijbels JMF, Deutman AF.

Delay in diagnosis of homocystinuria: retrospective study ofconsecutive patients. BMJ 1996;313:1037-40.

3. Brenton DP, Dow CJ, James JI, Hay RL, Wynne-Davies R.Homocystinuria and Marfan’s syndrome: a comparison.J Bone Joint Surg Br 1972;54:277-98.

4. Al-Essa M, Rashed M, Ozand PT. Saudi experience withclassic homocystinuria. Ann Saudi Med 1998;18:230-3.

5. Abdul Wahab A, Dawod T, Abdul Satar H, Zyoud M,Al-Ali M. Pyridoxine-nonresponsive homocystinuria withunusual lung manifestation in qatari siblings. Emirates Med J2001;19:51-3.

6. Ozand PT, Al-Essa M. Disorders of organic acid and aminoacid metabolism. In: Abdalaziz Y, editor Textbook of ClinicalPediatrics. Saudi Arabia: Springer-Verlag Berlin Heidelberg;2012:p.498.

7. Mudd SH, Edwards WA, Loeb PM, Brown MS, Laster L.Homocystinuria due to cystathionine synthase deficiency:the effect of pyridoxine. J Clin Invest 1970;49:1762-73.