C l i n i c a l B r i e f I

Management of Wiskott-Aldrich Syndrome

A n a n d S r i v a s t a v a , H a n i A. S w a i d , M a d h u l i k a Kabra a n d I.C. Verma

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi.

Indian J Pediatr 1996; 63:709-712 I

Abstract. A five-month-old boy presented with lower gastrointestinal bleed, recurrent infections and eczema. Blood picture revealed small platelets, high IgA, and IgM levels. A diagnosis of Wiskott-Aldrich Syndrome was made. The recent concepts in molecular pathology of the disease and treatment are discussed.

Key words: Wiskott-Aldrich Syndrome; Diagnosis

Wiskott-Aldrich syndrome is and X-linked recess ive d i s o r d e r cha rac te r i zed by thrombocytopenia, eczema and recurrent infections2 Immunologically, there is poor an t ibody re sponse to po lysacchar ide antigens, progressive decrease in T cell number and function, and a characteristic immunoglobulin profile reflected in low IgM, elevated IgA and IgE and normal IgG levels.2 We present a case of the syndrome from India and highlight important new developments.

CASE REPORT

A 5-month-old boy, born by spontaneous vaginal delivery of a non-consanguineous marriage developed eczematoid skin rash over the scalp on fifth day of life, followed (two days later) by bleeding per rectum. The rash p r o g r e s s i v e l y involved the extremities and the groin. The bleeding per rectum continued, and also occurred from

Reprint requests : Dr. I.C. Verma, Professor of Pediatrics, Genetics Unit, Old Operation Theatre Building, All India Institute of Medical Sciences, New Delhi-l10029.

the nose. The boy developed fever as well. For these symptoms he required recurrent hospi ta l i sa t ion four t imes in four consecutive months. At another hospital, a provisional diagnosis of he red i t a ry hemorrhagic telengiectasia was made on the basis of a rectal biopsy and the patient was referred to this hospital for further evaluation.

On admission he was afebrile, alert and active. He had mild pallor, pulse rate of 90 per minute, respiratory rate of 26 per minute, weight 4.0 kg (grade II protein energy malnutrit ion), sparse hair and eczematoid rash over the scalp, neck, skin folds of upper and lower limbs. His head c i rcumference was 38 cm and chest c i rcumference 35 cm. There were no congenital malformat ions or b leeding manifestations, except small amount of b l eed ing in the stools. Chest , cardiovascular and central nervous system were within normal limits while the liver was enlarged upto 3 cm below the costal margin.

Three brothers had died at age of 4, 6 and 5.5 months respectively. The first brother died due to skin infection and

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generalised sepsis, the second brother died due to gastroenteritis and septicemia whiIe the third one died of pneumonia. Based on the above features a provisional diagnosis of Wiskott-Aldrich syndrome was made. Other possibilities considered were of a defect of platelet function and hereditary hemorrhagic telengiectasia (Osler-Weber- Rendu disease).

Labora tory inves t iga t ions revealed hemoglobin (Hb) of 11.3 gm/d l , total leukocyte count 6000/cumm and platelet count 75,000/cumm. Bleeding time was 3 minutes 5 seconds and clotting time 2 minutes. General blood picture revealed small platelets about one-fourth to one- third of the size of normal platelets. After three days h e m o g l o b i n d r o p p e d to 10.5 gm/d l and platelet count fell to 20,000 requi r ing t r ans fus ion of platelet rich plasma. Urine was normal on routine e x a m i n a t i o n and microscopy. Stool showed red blood cells and pus cells. Cultures of urine, stool and blood (for bacterial and fungal pathogens) were sterile on the first occasion. The second culture of stool, taken eight days after admission, grew Salmonella typhimurium. Immunoglobulin profile showed high IgA levels (315 m g / d l , normal 14.4-81 mg/d l at age 5 to 9 months), but normal IgM and IgG levels.

Review of rectal biopsy obtained at another hospital was not suggestive of any angiomatous malformation. Colonoscopy was normal and colonoscopic biopsy revea led focal in f i l t ra t ion of lamina propria by acute and chronic inflam- ma to ry cells. Other inves t iga t ions included a negative VDRI, and HIV test. Bone marrow picture was normal with adequate number of megakaryocytes.

Initially the child was treated with oral antibiotics but later he received injectable aminoglycosides for one week, to which he responded well. He also received blood and platelet rich plasma on two occasions. After one week of hospi ta l s tay his bleeding per rectum was minimal, but skin rash persisted despite therapy with local steroids and antibiotics. The child was active and was feeding well and at this time he was discharged.

At the second admission he was very sick with fresh bleeding per rectum, cough, fever and lethargy. Examination revealed temperature of 10113F tachypnoea, severe pallor, bi lateral c rep i ta t ions and hepatomegaly (5 cm below the costal margin) and skin rash in the same areas as observed earlier. A d iagnos is of generalised sepsis with severe anemia and chest infection was reached. He was admitted in Intensive Care Unit and third g e n e r a t i o n cepha lospor ins and aminoglycosides were administered. After two days of therapy amphotericin B was a d d e d emperical ly . Labora to ry investigations revealed Hb of 8.9 gm/dl , total leukocyte count 22,000, polymorphs 70% and lymphocytes 30%, and platelets 20,000. Radiograph of the chest showed florid infection and blood culture drawn on day of admission grew Klebsiella species sensit ive to third genera t ion caphalosporins and gentamicin. Repeat sample of blood for immunoglobulins revealed IgA 307 mg/dl , IgM 196 mg/d l (normal 33 to 126 mg/dl) IgG 1572 mg/dl (normal 172 to 1069 mg/dl) and IgE 380 IU per ml (normal 0-230 IU per ml). Tests for platetet functions and lymphocytes markers could not be performed owing to the condi t ion of the child requ i r ing

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t r a n s f u s i o n s of b l o o d and b l o o d components . He required venti-lation for five days, and succumbed on eighth day of admission.

DIscussION

The presen t case demons t ra ted charac- teristic clinical triad of Wiskott-Aldrich syndrome- in termi t ten t bleeding because of thrombocytopenia , progressive eczema during the first month of life and recurrent s i nopu lmonary bacterial infections. The a n t i b o d y prof i l e on the first occas ion showed increased IgA levels but normal IgG & IgM levels. On the second occasion, the i m m u n o g l o b u l i n levels were more s u g g e s t i v e as bo th IgA and IgE were raised. IgG and IgM levels showed a slight increase p robab ly because of infection. Small platelets size ranging from half to one-third of normal clinched the diagnosis in favour of Wiskott-Aldrich syndrome?

At a later age when T ceil functions are affected, infections with fungi, viruses and Pneumocystis carinii occur. Children who survive the first 8-10 years are at risk for the d e v e l o p m e n t of l y m p h o i d mal ignanc ies . 4 In a large re t rospec t ive review the median survival of boys with WAS was less than 6 years, s infection being the leading cause of death.

The d i a g n o s i s of Wisco t t A l d r i c h Syndrome is based on the demonstrat ion of i n c r e a s e d s e r u m IgA and IgE and d e c r e a s e d serum IgM levels, absence of i sohemagglut inins , 2 and poor ant i -body response to po lysacchar ide antigens in males with characteristic constellation of c l in ica l f e a t u r e s . A recen t m u l t i - institutional survey found the classic triad in only 27% of the patients and suggested

that the syndrome m a y at t imes have an atypical presentation. 6 Diagnosis in such a situation is made by lack of proliferation of T lymphocytes in response to periodate.7

The gene for Wiscott Aldrich Syndrome maps to Xp 11.22-11.23, which codes for a 501 amino acid proline rich cytoplasmic p r o t e i n k n o w n as W i s k o t t A l d r i ch syndrome protein (WASP).8 The protein is e x p r e s s e d e x c l u s i v e l y in cel ls of l y m p h o c y t i c and m e g o k a r y o - c y t i c l ineages. The p la te le t m e m b r a n e s are d e f i c i e n t in g l y c o p r o t e i n I6 and l y m p h o c y t e s in CD-43. 9 A n u m b e r of m u t a t i o n s in this gene h a v e b e e n described. I~ Pre-natal diagnosis is possible using DNA technology, ei ther by direct identification of mutat ion or by linkage.

Treatment is directed mainly at control of bleeding through transfusions of blood and platelets, and control of infections with antibiotics. Sp lenec tomy improves the platelet number but makes the patient susceptible to sepsis, requir ing life long prophylaxis with antibiotics. 1~ Immuno- g lobu l in s g iven i n t r a v n o u s l y m a y be helpful in prophylaxis of both viral and bacterial infections, bu t do not improve thrombocytopenia. Eczema is difficult to manage and may persist even after long term use of local steroids. Bone marrow t r ansp lan ta t ion us ing h i s t o c o m p a t i b l e s ib l ing m a r r o w res to res i m m u n o l o g i c c o m p e t e n c e and a l so c o r r e c t s b o t h thrombocytopenia and eczema of Wiscott Aldrich Syndrome. 12

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9. Parkman R, Remold O 'Donne l E, Kenney DM, Perrine S, Rosen FS. Surface p ro te in abnormali t ies in lymphocytes and platelets f rom p a t i e n t s w i t h W i s k o t t - A l d r i c h syndrome. Lancet 1981; 2 - 1387-1389.

10. Ko l lu r i R, S h e h a b e l d i n A, Peacocke M, L a m b r o n w a h AM, W e i s s m a n MS, Siminovitch KA et al. Identif icat ion of Wasp mutat ions in pat ients wi th Wiskot t -Aldr ich syndrome and i so la ted th rombocy topen ia reveals al le l ic h e t e r o g e n e i t y at the WAS locus. Hum Mol Genet 1995; 4 - 1119-1126.

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12. Parkman R, R a p p a p o r t J, Geha R, Belli J, C a s s a d y R, L e v e y R et al. C o m p l e t e correction of the Wiskot t -Aldr ich syndrome by allogenic bone mar row transplantat ion. N Engl J Med 1978; 298 : 921-927.