Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2013; 17: 1978-1981 Respiratory failure and pharyngeal hematoma as presenting signs of Moschcowitz’s syndrome: a case report and literature review

S. COCUZZA, P. PAVONE*, M. BONFIGLIO, R. CHIARAMONTE, C. IURATO*, R. FALSAPERLA*, M. VELARDITA**, A. SERRA

Otolaryngology Section, Department of Medicine and Surgery, University of Catania, Catania, Italy *Department of Pediatrics, AOU Vittorio Emanuele-Policlinico, University of Catania, Catania, Italy **Department of Pediatrics, PO Gravina, Caltagirone, Italy

Abstract. – Moschcowitz’s syndrome or consequence of the binding of the platelets from thrombotic thrombocytopenic purpura is a quite ULVWF remaining in the circulation 4, 5. Im - rare pathology in childhood, being, as a matter of munoglobulin G (IgG) autoantibodies that block fact, more frequent among adult people. Often it is hard to distinguish from other pathologies in the activity of ADAMTS13 have been detected in children both for its rare incidence and for the patients suffering from TTP; this may account for presence of clinical forms that are very heteroge - the impairment of ADMATS13 characteristically neous and difficult to be classified. We report on observed in cases of TTP 6, 7. a 13 year-old girl suffering from Moschcowitz’s In children it is often hardly distinguished from syndrome, in whom respiratory failure and pha - ryngeal hematoma were the first sign of the dis - other pathologies with which it can be mistaken, ease follone by jaundice, hematoma of the arm like hemolytic-uremic syndrome, and this difficul - and limbs. The girl was treated with plasmaphere - ty is due to two main factors: scarce incidence of sis with an improvement of her general condition. Moschcowitz’s syndrome, which makes it little Since then we have followed up the girl for two known, and the presence of clinical forms that are years without any reappearance of the sympto - very heterogeneous and not easy classified 1,2 . matology. To our knowledge this is the first re - port of this peculiar presentation in children. Moschcowitz’s syndrome, which takes its name from the discoverer who described it for the first Key Words: time in 1924, is characterized by multifocal stroke Thrombotic thrombocytopenic purpura, Pharyn - geal hematoma, Respiratory failure, childhood. episodes caused by occlusions at microcirculatory level, thrombocytopenia from consumption and hemolytic anemia from mechanical damage with Introduction presence of schistocytes (negative Coombs) 3,4 . It is classified as primary or secondary and can mani - Thrombotic thrombocytopenic purpura (TTP) fest itself both under oligosymptomatic forms and is a condition characterized by thrombocytope - under very perilous forms that can take the subject nia, microangiopathic haemolytic anemia, and to coma and death 1,2 . less frequently with neurological deficits, renal Here we report on a 13 year-old girl who come failure, and fever. TTP is a rare disease, and has recently to our observation. been reported to affect only 3.7 persons per one million annually in the United States 1. It fre - Case Report quently follows a fatal course; 95% of patients A.C., 13-year-old girl, was admitted to Emer - die within three months if not treated 2. gency Department for the presence of dyspnea TTP pathogenesis has been associated with de - with tirage. At the admission she was agitated ficiencies in the metalloproteinase, ADAMTS13 and diaphoretic. At the physical examination, in (A Desintegrin And Metalloprotease with a both lungs, no wheezes were found but tirage ThromboSpondin like domain 13) 3. The principal and muscular accessory respiration was noticed. function of ADAMTS13 involves the cleavage of SAO 2 was 94-95%. Thorax RX was normal. unusually large forms of von Willebrand factor For the respiratory distress associated with a (ULVWF), thereby, preventing ULVWF multi - normal lungs function, suspecting an upper-air - mers from accumulating in the circulation; ways problem, a ENT consultation was request - platelet aggregation in TTP is thought to be the ed. Rhinoscopy showed several varices of locus

1978 Corresponding Author: Piero Pavone , MD; e-mail: [email protected] Pharyngeal hematoma in Moschcowitz’s syndrome valsalvae. Fiber optic laryngoscopic exam re - following a normal pregnancy. Birth weight was vealed the presence of a bulky hematoma in the 3100 grams. History was negative for jaundice at left side of hypopharynx that largely obstructed the birth. The first milestones were normal. the glottis (Figure 1). Vocal cords, partially visi - Thorough anamnesis collection showed that ble, were normal as regards motility and mor - about three weeks before her admission, the girl phology. The otolaryngologist suggested to refer began to show lower limb hematoma and epis - the patient to imaging in order to better assess taxis; for this reason she was taken to the family the extension and the origin of the hematoma. doctor who suggests to made a hematological Laboratory exams showed: platelets 13 × 10^3, test, but the parents refused. The day after we red blood cells 3.2 × 10^6, haemoglobin 10.2 g/dl, found the presence of marked skin and scleral the percentage of reticulocytes were 0.11%; hepat - jaundice with arm and limb hematoma. At this ic functionality tests were within normal range time the blood tests showed: platelets 26 × 10^3, (GOT 27 UI/1; GPT 11 UI/1; gamma-GT 11 red blood cells 2.90 × 10^6 with presence of UI/1); LHD values were very high (1,413 UI/1; schistocytes at the peripheral smear, haemoglo - Reference values 240-480 UI/1); kidney function, bin 9.6 g/dl, the percentage of reticulocytes were according to lab data results, was within the norm 0.21%. Total and unconjugated bilirubin agreed (urea 28 mg/dl, creatinin 0.60 mg/dl). PT, PTT with the presence of haemolytic prehepatic and fibrinogen were normal. icterus (total bilirubin 11.4 mg/dl; unconjugated CT exam was done without and with intra - bilirubin 10.65 mg/dl); hepatic functionality tests venous contrast medium and allowed to identify were within normal range (GOT 32 UI/1; GPT an hypodense formation (about 70 H.U.) in hy - 23 UI/1; gamma-GT 18 UI/1); LHD values were popharyngeal and paralaryngeal spaces on the very high (1,624 UI/1; Reference values 240 -480 left side, with a secondary pharyngolaryngeal UI/1); haptoglobin results were significantly be - dislocation to the right side and a rotation of hy - low the reference limits (1 mg/dl; reference val - oid bone towards the same side. Such formation ues 30 -200 mg/dl). Kidney function, was within extended caudally towards a plane at the level of the norm (urea 23 mg/dl, creatinin 0.70 mg/dl), left upper lobe of thyroid. After injection of con - as well as the FR values and antibodies against trast agent there was not enhancement. TORCH agents and other virus (Toxoplasma Because of the severe respiratory symptomatol - Gondi; German measles; CMV; Herpes Simplex, ogy the patient, after transfusion of three platelets Epstein Barr virus (VCA and EBNA. Native an - units, underwent tracheostomy in order to obtain a ti-DNA antibodies and AMA were absent; within recovery of ventilation function and to protect lower the norm the anticardiolipin and antiphospholipid airways from potential hemorrhage. One hour be - antibodies, while the ANA were present (1/80), fore surgery three platelets unit were transfused. Af - and the ASMA too (1/160). ter the surgery the girl was moved to Pediatric Unit PT, PTT, were normal; fibrinogen 410 mg (nv where further clinical investigation was carried out. 200-400 mg/dl) Thyroid function was within the The girl was second-born to non-consan - norm with hormonal values within limits and ab - guineous parents (the mother suffering from he - sence of anti-thyroglobulin antibodies. The ab - patitis B), by a spontaneous full term delivery dominal ultrasound exam and the abdominal CT, carried out with contrast, showed a normal liver, biliary ducts and gallbladder not swollen, kidneys in the right position, of normal size for the age. On the base of the clinical picture and the tests we made a diagnosis of thrombotic thrombocy - topenic purpura or autoimmune genesis Moschcowitz’s syndrome. Daily therapy with plasma exchange was started, Urbason (40 mg bid intravenously), Persantin and Eparmefolin (1 fl/dl intravenously). The above therapy was con - tinued through which an improvement of the clin - ical picture had been obtained and a negative con - version of ANA and ASMA. The study of ADAMST 13 activity showed a severe deficiency Figure 1. value (< 10%) with positive anti ADAMTS 13

1979 S. Cocuzza, P. Pavone, M. Bonfiglio, R. Chiaramonte, C. Iurato, R. Falsaperla, M. Velardita, A. Serra

IgG and inhibitor. The patient underwent 32 ses - coprotein of a membrane called GPI. This process sions of plasma exchange. Following this sessions needs a precise modulation and this role is carried some nettle-rash manifestations appeared, which out by metalloprotease ADAMST13 that eliminates disappeared without further complications. the Von Willebrand factor in excess limiting the The patient was dismissed with improvement uncontrolled growth of the platelet thrombus. Its of clinical conditions and normalization of hema - deficiency, as it happens when in presence of au - tochemical tests. Symptomatology improvement toinhibitor antibodies, or its malfunction, in the was followed clinically and by means of CT even rarer case of genetic changes causes the un - imaging, which showed progressive reduction controlled growth of thrombuses at peripheral level. and the definitive disappearance of the pharyn - This process is at the base of thrombocytopenia geal hematoma within three months since diag - from consumption and of hemolytic anemia from nosis was established. Such condition allowed us mechanical damage and can cause vasal occlusions to carry out a closure of the tracheostomy, after followed by ischemia at different organs level. the normal respiratory function was assessed. We In Moschcowitz’s syndrome, the most vulnera - have followed up the girl for two years and no ble organ is the central nervous system, so much other episodes were seen. that the neurological damage is considered a funda - mental characteristic in defining this syndrome. An - other part which is exposed to ischemic damage Discussion with a resulting functional damage, even severe, is the kidney, which is for the most part typically hit Thrombotic thrombocytopenic purpura or in the hemolytic-uremic syndrome 4-5 . However, in Moschcowitz’s syndrome is quite rare and it is the case previously shown, neurological or kidney even rarer in childhood. It is a very heteroge - functionality deficit have not been noticed during neous syndrome, with different variants de - all the stay in hospital. In fact, the patient’s neuro - scribed that should be properly distinguished in logical test has always been within the norm for the order to follow a correct therapy. Moschcowitz’s age. Kidney functionality, monitored through syndrome is characterized by scattered thrombo - hematochemical tests, was within the norm too and sis at micro circulatory level, thrombocytopenia this was further confirmed by the reports from ab - and consumption anemia caused by mechanical domen ultrasound and CT. damage (negative Coombs). We can distinguish A very important aspect to evaluate when ap - four very similar forms of thrombotic thrombo - proaching a patient affected by thrombotic cytopenic purpura: the primary form, the sec - thrombocytopenic purpura is the hepatic func - ondary, the hemolytic-uremic syndrome associat - tionality. In fact, as already stated, metallopro - ed to diarrhea and the atypical form 3-4 . tease13 is mostly synthetized in the liver and so The idiopathic form has been studied for a long any hepatic pathology could caused by its not time in order to find out its pathogenesis and in the sufficient synthesis 3-6 . In the reported clinical recet years a lot of progresses have been made in case hepatic functionality has been studied and it this field. It ha been in fact noted that the patho - was within the norm, as the physiological values genetic heart of this anomaly lies in the presence of of the indexes of hepatic functionality and the re - antibodies that inhibit the activity of metallopro - port from image diagnostics through abdomen tease ADAMST13 3-5 . There are even rarer forms in ultrasound and CT show. This case appears par - which changes at ADAMST13 level are present, ticularly interesting since the peculiar presenta - that cause a deficit of its functionality 1. In the above tion, characterized by the unusual finding of a clinical case the normal functionality of bulky haematoma that obstructed upper airways. ADAMST13 has been established, but its quantity From literature review it is shown the absolute was inferior to normal, which has confirmed the au - uniqueness of the presented case, as it is seen that toimmune genesis of the pathology. ADAMST13 is the few reports of occl uding haematomas at the a metalloprotease, synthesized at hepatic level, upper airways level are mainly related to trauma whose substrate is represented by Von Wille - and haemophilia 9,10 . Furthermore the tracheosto - brand’s factor, a multimero that is essential in form - my procedure made in order to protect the air - ing the platelet thrombus because it adheres to the ways and to recover normal respiratory function endothelial cells and to the connective tissue ex - is itself atypical if compared with the diffused in - pounded in the damage place of the vasal wall and dications within pediatric patients, that are main - the circulating platelets adhere to it through a gly - ly represented by prolonged mechanical ventila -

1980 Pharyngeal hematoma in Moschcowitz’s syndrome tion, craniofacial and neurological syndromes, References congenital malformations and trauma. Among airways obstructions the predominant causes are 1) MOSCHCOWITZ E. Hyaline thrombosis of the terminal subglottic stenosis, tracheomalacia and vocal arterioles and capillaries: A hitherto undescribed dis - 11 -16 ease. Proc N Y Pathol Soc 1924; 24: 21-24. cord paralysis . 2) FURLAN M, R OBLES R, G ALBUSERA M, R EMUZZI G, K YRLE The primary forms of Moschcowitz’s syn - PA, B RENNER B, K RAUSE M, S CHARRER I, A UMANN V, drome respond to the plasma exchange therapy MITTLER U, S OLENTHALER M, L ÄMMLE B. Von Wille - to which immunosuppressant medication is often brand factorcleaving protease in thrombotic associated. Plasma exchange therapy allows the thrombocytopenic purpura and hemolytic-uremic syndrome. N Engl J Med 1998; 339: 1578-1584. removal of the autoantibodies and the reactiva - 3) CATALAND SR, J IN M, F ERKETICH AK, K ENNEDY MS, tion of the quantity of ADAMST13. Immunosup - KRAUT EH, G EORGE JN, W U HM . An evaluation of pressant medication is necessary for the modula - cyclosporin and corticosteroids individually as ad - tion of antibody activity, reducing also the pro - juncts to plasma exchange in the treatment of duction of antibodies against ADAMST13. Sec - thrombotic thrombocytopenic purpura. Br J Haematol 2007; 136: 146-149. ondary forms of thrombotic thrombocytopenic 4) CATALAND SR, J IN M, L IN S, K ENNEDY MS, K RAUT EH, purpura are treated differently depending on the GEORGE JN, W U HM . Cyclosporin and plasma ex - primitive underlying pathology. Hemolytic- ure - change in thrombotic thrombocytopenic purpura: mic syndrome does not benefit anyhow from Long-term follow-up with serial analysis of plasma exchange therapy, except in its atypical ADATMS13 activity. Br J Haematol 2007; 139: form for H factor deficiency. 486-493. 5) CURTILLET C, P OULLIN P, D ORE ´ E, F OSSAT C, L EFEVRE P, In conclusion, when approaching a thrombocy - MICHEL G. Paediatric case report of an acquired topenic patient who is also affected by hemolytic autoimmune thrombotic thrombocytopenic purpu - anemia, it is important to pay a particular attention ra. Arch Pediatr 2006; 13: 1521-1524. to the clinical-researcher characteristics that allow 6) JIN M, C ASPER TC, C ATALAND SR, K ENNEDY MS, L IN S, to state the pathogenesis and then to make a correct LI YJ, W U HM . Relationship between ADAMTS13 diagnosis, to give an effective therapy and make activity in clinical remission and the risk of TTP 3-9 relapse. Br J Haematol 2008; 141: 651-658. short and long term prognosis . As for autoim - 7) BREDLAU AL, S EMPLE JW, S EGEL GB . Paediatr Drugs. mune genesis Moschcowitz’s syndrome, it is im - Management of immune thrombocytopenic pur - portant to keep in mind that the solution of the pura in children: potential role of novel agents acute break does not mean complete recovery be - 2011; 13: 213-223. cause the patients affected by this pathology can 8) POS W, L UKEN BM, S ORVILLO N, H OVINGA JA, V OOR - BERG J. Humoral immune response to ADAMTS13 show a recurring in the short or long term, even af - in acquired thrombotic thrombocytopenic purpura. ter many years, besides, being the pathogenesis im - J Thromb Haemost 2011; 9: 1285-1291. mune, it is necessary to keep in mind the possibility 9) COX RG . Retropharyngeal haematoma leading to that these subjects can in the future show other im - airway obstruction in a child with closed head mune diseases, for example herythematous sys - trauma. Paediatr Anaesth 1998; 8: 353-356. temic lupus that, in pediatric age, is more frequently 10) BRAY G, N UGENT D. Hemorrhage involving the up - per airway in hemophilia. Clin Pediatr (Phila) associated with Moschcowitz’s syndrome. 1986; 25: 436-439. 11) SERRA A, C OCUZZA S, L ONGO MR, G RILLO C., B ON - Conclusions FIGLIO M., P AVONE P. Tracheostomy in childhood: new causes for an old strategy Eur Rev Med We think to report this children because to our Pharmacol Sci Ahead of print ID: ERMPS-1100 knowledge this is the first report in the literature 12) MAHADEVAN M, B ARBER C, S ALKELD L, D OUGLAS G, M ILLS N. Pediatric tracheotomy: 17 year review. Int J Pedi - of a thrombotic thrombocytopenic purpura, atr Otorhinolaryngol 2007; 71: 1829-1835. showing as a first sign of the disease a respirato - 13) DAVIS MG. Tracheostomy in children. Paediatr ry failure associated to bulky hematoma of the Respir Rev 2006; 7: S206-S209. pharynx; however in our case, the children re - 14) PARRILLA C, S CARANO E, G UIDI ML, G ALLI J, P ALUDETTI . spond well to the plasmaphereis therapy with an Current trends in paediatric tracheostomies. Int J improvement of her general condition and with - Pediatr Otorhinolaryngol 2007; 71: 1563-1567. out any worsening in the following two years. 15) CARRON JD, D ERKAY CS, S TROPE GL, N OSONCHUK JE, DARROW DH . Pediatric tracheotomies: changing indications and outcomes. Laryngoscope 2000; ––––––––––––– –– ––– –– Conflict of Interest 110: 1099-1104. 16) DEUTSCH ES. Tracheostomy: pediatric considera - None. tions. Respir Care 2010; 55: 1082-1090.

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