Hereditary thrombocytopenia: Relation to Wiskott-Aldrich syndrome with special reference to splenectomy

226

February, 1972 T h e ]ournal of P E D I A T R I C S

Hereditary tbrombocytopenia: Relation to Wiskott-Aldricb syndrome with special reference to splenectomy Report oJ a ]amily and review of the literature Two brothers with eczema and congenital thrombocytopenia, thought to be inherited as a sex-linked recessive defect, are presented. Although both had some of the immunologic deficiencies associated with Wiskott-Aldrich syndrome, they could respond in both the humoraI and cellular immune systems following antigenic challenge. After splenectomy, the older brother had several serious infections and died. The disorder present in this family raises important questions concerning the relationship of inherited thrombocytopenia, eczema, and immunologic deficiency and the role of splenectomy in the treatment of chronic thrombocytopenia in children. Whereas only 2 to 3 per cent of children develop serious infections following splenectomy for idiopathic thrombocytopenia, the risk is significantly higher in boys than in girls and in patients with sex-linked recessive thrombocytopenia. It seems likely that spIenectomy can unmask a latent immunologic deficiency in certain thrombocytopenic males, and hence should be approached with extreme caution in any individual with eczema, a family history of thrombocytopenia, or evidence of immunologic deficiency.

Paul L. Weiden, M,D., and R. Michael Blaese, M.D., Bethesda, M d .

A M o N G the conditions associated with chronic thrombocytopenia in children is the Wiskott-Aldrich syndrome, a sex-linked recessive disease also characterized by eczema and immunologic deficiency in both the cellular and humoral immune systems?, 2 Identification of patients in whom thrombocytopenia is part of the Wiskott-Aldrich synFrom the Immunophysiology Section, Metabolism Branch, National Cancer Institute. Address: Building 10, Room 4Nl17, National lnstltutes of Health, Bethesda, Md. 20014.

Vol. 80, No. 2, pp. 226-234

drome is essential in establishing the prognosis and planning the management of childhood thrombocytopenia. When a boy is encountered with chronic thrombocytopenia associated with minimal eczema and little history of infection, or with a history suggestive of hereditary sex-linked recessive thrombocytopenia, the clinician faces a diagnostic dilemma of considerable therapeutic importance, for ultimately splenectomy will be considered in the management of such a patient.

Volume 80 Number 2

A l t h o u g h considerable controversy has existed r e g a r d i n g the incidence of infection in children following splenectomy, a, 4 f u r t h e r insight has been gained by the separation of patients according to the indication for splenectomy..~, o Children with i m m u n e deficiency diseases including the W i s k o t t - A l d r i c h syndrome, 7-9 malignancy, and o t h e r serious underlying diseases h a v e a high incidence of serious, often fatal infections following splenectomy. N o r m a l children u n d e r g o i n g splenectomy following t r a u m a a n d children w i t h i d i o p a t h i c t h r o m b o c y t o p e n i a are r e p o r t e d to have no increased incidence of infections postoperatively. 5 I n children with sex-linked recessive t h r o m b o c y t o p e n i a , which is considered by some to be distinct a n d clearly separable from the Wiskott-AIdrich syndrolne, splenectomy has been r e p o r t e d to be an effective t h e r a p e u t i c m a n e u v e r ? ~ a* H o w ever, we shall describe here a family which suggests a close relationship between sexlinked h e r e d i t a r y t h r o m b o c y t o p e n i a a n d the W i s k o t t - A l d r i c h syndrome. T h e i m p l i c a t i o n of this relationship, w h i c h is also suggested by several other families ~2-~ a n d by a review of the l i t e r a t u r e concerning serious infectious sequelae in children following splenectorny, is t h a t splenectomy should be a p p r o a c h e d with caution in any child w i t h t h r o m b o cytopenia potentialIy inherited as a sex-linked recessive trait, as well as in any boy with eczema or any evidence of i m m u n e deficiency. CASE REPORTS

Case 1. Patient J. T. was evaluated at the National Institutes of Health when 25 months of age. Eczema had been present since 3 months of age and thrombocytopenia documented since one year of age. Platelet counts of 12 to 75,000 per cubic millimeter had not responded to administration of steroids or fresh-frozen plasma. IIe had otitis media on two occasions but never any serious infectious illnesses requiring hospitalization. The family history of both parents, who are unrelated, did not reveal any members with bleeding disorders, eczema, or increased susceptibility to infections. The parents and an older sister were hematologically normal. PhysicaI examination revealed generalized

Hereditary thrombocytopenia

227

shotty adenopathy, scattered areas of m'ild eczema, and occasional petechiae. Routine urinalysis, blood chemistries, and radiographic examinations were within normal limits. Iron deficiency anemia and thrombocytopenia were present. Platelet counts welJe 16 to 89,000 per cubic millimeter using a Coulter counter and ~ 25,000 per cubic millimeter, often in the range of 4 to 10,000 per cubic millimeter, by phase contrast microscopy. This discrepancy was most likely attributable to microplatelets and cellular fragments which were observed in the patient's plasma by electron microscopy. Bone marrow examination revealed lymphocytosis and many megakaryocytes, some with cytoplasmic budding. A homologous ~lCr platelet survival study as demonstrated a moderately shortened survival of about 3 to 3.5 days without evidence of splenic sequestration. Results of various studies to assess the competency of the patient's immune system were performed by the method of Blaese and associatesl and are outlined in Tables I to IV. Immunoglobulin levels (Table I) were within normal limits. In spite of low naturally occurring antibody levels (Table I I ) , antibody responses to several antigens were normal (Table I I I ) . Although all intradermal skin tests were negative, the patient could be sensitized to dinitrochlorobenzene (DNCB) (Table I V ) . On tee basis of his ability to respond in both the humoral and cellular immune systems, his normal immunoglobulin levels, and the absence of a history of significant infection, the patient was felt not to have the Wiskott-Aldrich syndrome. Splenectomy was therefore recomrnended and performed without difficulty elsewhere at age 2 ~/i2 years. Pathologic sections, subsequently reviewed at the National Institutes of Health, revealed lymphoid atrophy and hyalinization of reaction centers, changes similar to those seen in the WiskottAldrich syndrome and not characteristic of idiopathic thromboeytopenic purpura. Postoperatively the patient's platelet count was generally > 100,000 per cubic millimeter. One year after sptenectomy he developed pneumococcal meningitis which responded to standard therapy. During his fourth year the patient had severe eczema which was intermittently infected; when 5 7A2 years of age he developed an infected epidermoid cyst in the neck which required surgical excision. At age 5 l~ he suddenly developed pneumococcal sepsis complicated by generalized intravascular coagulopathy and died. Case 2. Patient M. T., the only brother of

228

W e i d e n and Blaese

The Journal of Pediatrics February 1972

T a b l e I. I m m u n o g l o b u l i n levels r

. Immunoglobulin

Patients

Normal

Wiskott-Aldrich J. T. I M. T. IgG 9.1 -+ 2.6 10.3 -2-3.5 11.6 8.5 IgA 1.7 +- 1.1 4.8 +- 2.2 2.1 2.85 IgM 1.06--- 0.46 0.55 + 0.25 1.15 0.44 IgD 0.12 +- 0.08 0.24 +- 0.18 0.11 N.D.t IgE 76 (22-266) 3180 (434-23,300) 260 720 *Except for IgE, values are mean milligrams pc: milliliter • S.D. For IgE, values are geometric mean nanograms per miniliter + l S.D. log-normal range. Normal and Wiskott-Aldrlchvalues are from Blaese and assoeiates.-02 "~N.D. = not done.

T a b l e I I . T i t e r s of n a t u r a l l y o c c u r r i n g a n t i b o d i e s

Patients ]. T . t Antibodies

Normal ~

W iskott-Aldric h ~

B.el~

I

Alter

M.T.

E. coli

014 4 (0-16) 1 (0-16) 0 4 06 84 (8-512) 3 (0-32) 4 8 013 123 (8-512) 6 (0-1024) 0 8 050 62 (0-256) 5 (0-64) 0 512 075 21 (0-128) 4 (0-24) 0 8 Sheep ceil hemolysins, Ab H~o 65 (10-233) 20 (0-80) 6 Isohemagglutinin 120 (8-1024) 2 (0-16) 8 *Normal and Wiskott-Aldrich geometric means and ranges are from Blaese and associates.1 tPatient J. T.'s values of E. coli natural antibodies are given before and after typhoid immunization. SN.D. = not done.

9 Patient j. T., had documented thrombocytopenia (platelet count 11,000 per cubic millimeter) immediately following delivery. Although intermittent petechiae were observed and platelet counts remained below 100,000 per cubic millimeter, only occasional mild epistaxis occurred. The patient rarely had eczema about the scalp and intermittent diaper rash; otherwise his skin was clear, There was no increased susceptibility to infections. The patient was admitted to the National Institutes of Health for evaluation following the death of his brother. Physical examination revealed a pale, alert boy with scattered petechiae and small patches of eczema on the head and neck. Routine urinalysis, blood chemistries, and radiologic examinations were within normal limits. Hematologic studies revealed iron deficiency anemia and thromboeytopenia. Platelet count was 35,000 per cubic millimeter on Coulter counter and 18,000 per cubic millimeter by phase contrast microscopy. Bone marrow examination showed adequate megakaryocytes. Unlabeled homologous platelets were infused into the patient on 2 separate oc-

N.D.~ N.D. N.D. N.D. N.D. N.D. 0

casions 21 and had only minimally shortened survival of 4 to 4.5 days. The results of immunologic studies on this patient are shown in Tables I to I V and Fig. 1. Immunoglobulin levels (Table I) demonstrated a slightly high IgA and more significantly" low I g M l e v e l - - a pattern similar to that seen in Wiskott-Aidrich syndrome. Nevertheless, protein turnover studies showed that the survival of IgG and albumin were normal (serum half-life of 19 days and 14.5 days, respectively), whereas significantly accelerated catabolism of these proteins is characteristic of the Wiskott-Aldrich syndrome32 Although the patient's natural isohemagglutinin level (Table I I ) and antibody response to blood group substance (Table I I I ) were low, he had a normal response to other antigens, including purified polysaccharide antigens (Table I I I ) . As with his brother, although multiple skin tests were negative, the patient could be sensitized to D N C B (Table I V ) . In vitro lymphocyte transformation responses (Fig. 1) were normal with nonspecific mitrogens, nmderately suppressed with specific antigens, and

Volume 80 Number 2

Hereditary thrombocytopenia

229

T a b l e I I I . A n t i b o d y response to i m m u n i z a t i o n *

I Immunization

Normal

Blood group substance Pneumococcal polysaccharide type I Pneumococcal polysaceharide type II Brueella organisms Typhoid anti-H anti-O Diphtheria toxold (Schick test)

4.1 8.3 8.0 7.8

Wiskott-Aldrich

-+ 1.6 + 2.4 -+ 2.0 + 1.9

---Negative

J. T.

1.1 + 1.3 0 +0 0 +0 3.3 + 2.5 10.0 + 2.7 -4 negative 4 positive in 8 patients

Patients ] M. T.

6 N.D.t N.D. N.D.

3 11 8 14

13 6 Negative

N.D. N.D. Negative

*Values are change in titers (log2) following immunization as indicated; values of normal and Wiskott-Aldrich are means + S.D., taken from Blaese and associates 1 and unpublished observations. "~N.D. = not done.

T a b l e I V . Cellular i m m u n e function

Function Lymphocyte count/mm, a Skin tests* Dinitrochlorobenzenet

Normal

Wiskott-Aldrich

5,000 One or more positive Positive

2,300 None Positive Negative

]. T. 3,170 6/6 negative Positive

Patients ]

M. T. 1,740 8/8 negative Positive

*All patients received mumps, purified protein derivative, eandida, and trichophyton; others selected from streptokinasestreptodornase, diphtheria toxold, tetanus toxoid, histoplasmin, brucellergin, and keyhole limpet hemocyaniu (following sensitization). "~Response to 100 #g challenge dose administered two weeks following topical sensitization with 2 rag.

more markedly suppressed in mixed leukocyte cultures--a pattern consistent with but not diagnostic of the Wiskott-Aldrich syndromeY REVIEW

OF THE LITERATURE

W e have reviewed 34 reports in the literature in an a t t e m p t t o establish the incidence of serious infections (sepsis or meningitis) following splenectomy for t h r o m b o c y t o p e n i a in childhood. 4-6, 12-14, 24-51 T w e l v e instances of serious infection ( T a b l e V ) are reported in 492 children who u n d e r w e n t splenectomy a n d w h o satisfied the following criteria: 1. Splenectomy was p e r f o r m e d for docum e n t e d t h r o m b o c y t o p e n i a n o t secondary to to any other recognized disease process. 2. Patients were less t h a n 15 years of age. 3. Sex of patients who developed complications was reported. 4. Patients were not seriously ill prior to splenectomy a n d survived the i m m e d i a t e postoperative period.

Several cases of postsplenectomy infection often i n c l u d e d in such compilations 12' 14, 2~, 36, 41, 4~-51 are excluded here because they failed to meet the above criteria, most often because of d o c u m e n t e d serious infections prior to splenectomy or failure to survive the i m m e d i a t e postoperative period. M a n y criticisms m a y justly be m a d e of such a s u m m a r y of reports from authors in widely differing times a n d settings, but several conclusions seem justified. T h e risk of serious infection following splenectomy for t h r o m b o c y t o p e n i a in children is low, i.e., 2 to 3 p e r cent. T w o factors a p p e a r to affect this risk: sex a n d family history. T h e incidence of idiopathic thrombocytopenic p u r p u r a in children is equal between the sexes. ~2-54 However, the literature review revealed 10 boys b u t only 2 girls who suffered serious infectious sequelae following splenectomy. A l t h o u g h the numbers are small, the difference is statistically significant (chi

230

Weiden and Blaese

The Journal of Pediatrics February 1972

T a b l e V. Serious infections following splenectomy for thrombocytopenia: Review of the literature

History prior to splenectomy Age o[ Infeconset Eczema lions 2 ~ yr. Absent None serious

Age at splenectomy 3 yr.

Source Adner and associates, 19702~

Sex M

HaUer and Jones, 196625

F M

Not discussed Not discussed

3 yr. 8 yr.

M

Not discussed

~ 10 yr.

Lowdon and assoeiates, 196626

M

7 yr.

"Small area of None impetiginised seborrhea"

M

6 mo.

None mentioned

Schaar, 1963zr

M

6 too.

Absent

Baldi and Bigardi, 1961es

M

Lucas and Krivit, 1960~9

M

6 wk.

None

Robinson and Sturgeon, 19606

M

t3 mo.

None

Huntley, 1958a0

F

Not None mengiven tioned

Simpkiss and Cathie, 195421

M

None

None mentioned

square = 5.3; p < 0.025). I t is possible that boys with thrombocytopenic p u r p u r a are more likely to come to splenectomy t h a n are girls a n d therefore have a n increased likelihood of developing postsplenectomy infections. I t is impossible to evaluate adequately this possibility from the literature. Nevertheless, if this were true, it would be consistent

23 days 1 yr. ?

Presumed septicemia Pneumococcal septicemia Died with septicemia

10 yr.

3 too.

Pneumoeoccal sepsis and meningitis with shock. Died 2 yr. later with pneumococcal sepsis and adrenal hemorrhage

4 yr.

16 too.

Pneumococcal meningitis; many subsequent infections, including otitis meningitis, pneumonias, bronchitis

3 ~ yr.

3~2 yr.

Died with pneumococcal sepsis and meningitis

3 yr.

6 too.

Died with fulminant iIlness, presumed septicemia

None

10 wk.

5 mo.

Presumed sepsis with adrenal hemorrhage

None

27 too.

3 yr.

Pneumococcat meningitis Died 1 mo. later with pneumococcal sepsis

10 yr.

3~2 yr.

Pneumococcal meningitis

14 too.

2 too.

Died of septicemia

Not mentioned

6 wk.

History /ollowing splenectomy Interval to first serious Course injection Pneumonoeoceal 2 yr. sepsis with disseminated intravascular coagulopathy

with the inclusion a m o n g the boys with thrombocytopenic p u r p u r a , a group having more severe a n d / o r refractory disease. If, on the other hand, equal n u m b e r s of boys and girls with idiopathic thrombocytopenic purp u r a come to spleneetomy, the increased risk of infectious sequelae in the boys is compatible with the inclusion a m o n g the boys of a

Volume 80 Nurnber 2

Hereditary thrombocytopenia

231

Log

Scale

N0niSPue~iicf

_.i /Z: ~o o >-ar flow z O-

.

Antigen,

Atlogenelc

Cells

[5xI0 4

o~ o_Z ~

5X104I 104I

IOxlO4

L0xl04

PatientMZ. I--7 Normal Wiskott-Aldrich

-~ c2_c~

~uJ )-I-

~--_] 5xlO4 I 1 5xi04

v-g

2:(/3 OAZ Wac as ta3 G}> 2:O

0

PHA PWM SF

10a~ I

SLO DIPH TET

PnT

Fig. 1. In vitro lymphocyte transformation was performed as in Oppenheim and associates~8 except that in most experiments 10 per cent autologous serum and 5 x 10s mononuclear cells per milliter were used. Nonspecific stimuli are phytohemagglutinin (PHA), pokeweed mitogen (PWM), and staphylococcal filtrate (SF). Antigens used are streptolysin-O (SLO), diphtheria toxoid (DIPH), tetanus toxoid (TET), and type I pneumococcal organisms (PnI). Values of Patient M. T. represent the geometric mean of the mean of duplicate determinations on 2 different dates; values of several normal subjects and patients with Wiskott-Aldrlch syndrome for nonspecific stimuli and antigens are from Oppenheim and associates.2a Mixed leukocyte reactions (allogenelc cells) represent "one-way" stimulation of experimental cells by irradiated normal cells; values of normal children and patients with Wiskott-Aldrich syndrome were determined under identical conditions.

subpopulation with increased tendency to infection following splenectomy. Sex-linked hereditary thrombocytopenia has been previously reported by several authors. Of the 4 boys in the family reported by Schaar, 2~ all of whom underwent splenectomy, one died of pneumococcal meningitis and sepsis 3 ~ years following splenectomy. The patient with sex-linked thrombocytopenia described by Robinson and Sturgeon ~ died 3 years after splenectomy with pneumococcal sepsis; the one member of the family reported by Canales and Mauer ~a who had a splenectomy sustained no infectious sequelae. Thus including the 3 cases in the family reported by Ata and associates, ~* of 9 boys with familial thrombocytopenia who underwent splenectomy, 2 died of pneumococcal sepsis. Although again the numbers are small, this incidence of infectious sequelae following splenectomy is significantly higher than in the total group of splenectomies performed for thrombocytopenia (chi square with cor-

rection for continuity == 7.8; p - 0.005). Furthermore, one of the 3 patients reported by Ata and associates had a clinical illness consistent with meningitis 1~2 years following splenectomy, and in the family reported by Vestermark and Vestermark, r' one of the 2 members to undergo splenectomy died suddenly one year later of unknown cause, but with bilateral adrenal hemorrhage, a lesio~ suggestive of pneumococcal sepsis. 5n 5G These patients were not included in Tabie V because one had eczema and each had significant infections prior to splenectomy, but many of the affected members of each family did not have eczema, frequent infections, or other stigmata of the Wiskott-Aldrich syndrome. Thus if one includes these cases and that of the current report, 12 boys with sexlinked recessive thrombocytopenia in whom there was not sufficient evidence to establish the diagnosis of Wiskott-Aldrieh syndrome and who underwent splenectomy, 5 sustained serious infectious sequelae. This suggests that

232

Weiden and BIaese

patients with sex-linked hereditary thrombocytopenia are more likely to develop serious infection if subjected to splenectomy than are other children with chronic thrombocytopenia. DISCUSSION The case histories of the 2 brothers presented here accentuate the dilemmas faced in the consideration of chronic thrombocytopenia in male children : 1. What is the relationship of chronic thrombocytopenia in boys to the WiskottAldrich syndrome, and how may the latter diagnosis be excluded in an individual case? 2. What is the risk of splenectomy per~ formed for apparently idiopathic thrombocytopenia, and in particular is there any identi~ fiable group with an increased risk of postoperative infectious sequelae? In spite of the rather extensive evaluation which these brothers underwent, we are unable to categorize them with certainty. It is most likely, however, that their thrombocytopenia was inherited as a sex-linked recessive trait. The absence of maternal antiplatelet antibodies and persistence of the thrombocytopenia for over 2 years in each affected boy excludes "neonatal" thrombocytopenia. The absence of thrombocytopenia in either parent makes a dominant lesion unlikely, and the pattern of one unaffected girl and 2 affected boys is more than 5 times as likely to occur if the defect is inherited as a sex-linked recessive rather than as an autosomal recessive trait. Platelet survival in patients with classical idiopathic thrombocytopenic purpura is usually markedly shortened (1 to 3 days), ~6 whereas patients with thrombocytopenia secondary to the Wiskott-Aldrich syndrome who have not been immunized to platelet antigens by nmltiple transfusions have a longer and nearly normal platelet survival? s-21 Platelet survival studies have only recently been performed in other families with sexlinked thrombocytopenia. ~7 Although survival of homologous normal platelets was somewhat less than normal in both of our patients, it was more prolonged than in classical idio-

The Journal o[ Pediatrics February 1972

pathic thrombocytopenic purpura and appeared to be insufficiently shortened to be the sole basis of the thrombocytopenia observed. 16 Therefore defective platelet production a n d / or accelerated catabolism of intrinsicalIy abnormal platelets are more likely causes of the thrombocytopenia in this family. The small size of the patients' platelets and the presence of platelet fragments are consistent with this conclusion. A similar mechanism has been reported to be responsible for the thrombocytopenia of the Wiskott-Aldrich syndrome?S, ~, 57 Thus these brothers appear to possess the sex-linked recessive inheritance, the eczema, and possibly the platelet defect of the Wiskott-Aldrich syndrome, as well as certain of the immunologic defects, e.g., low natural antibody titers and negative intradermal skin tests. They are unlike patients with classical Wiskott-Aldrich syndrome in that they are able to mount a significant immune response when appropriately stimulated, e.g., ability to make antibody in response to polysaccharide antigens and to develop contact sensitivity to DNCB. The younger brother's immunoglobulin levels and in vitro lymphocyte transformation were more characteristic of Wiskott-Aldrich syndrome, but his serum protein catabolism was not. Under normal circumstances neither developed serious infection, but following splenectomy the older brother developed multiple infections leading to death. Ahhough no definite conclusion can be reached, it is clear that splenectomy in any child with sex-linked thrombocytopenia should be approached with caution. T h e enthusiastic recommendations of others 1~ 11 for splenectomy in such cases should perhaps be tempered by the significantly increased possibility of serious infectious sequelae. Similarly the presence of eczema a n d / o r any of the immunologic defects associated with the Wiskott-Aldrich syndrome, even if insufficient to make that diagnosis, should lead one to consider splenectomy only in extraordinary circumstances. Splenectomy is usually considered in the management of childhood thrombocytopenia

Volume 80 Number 2

only after at least several m o n t h s of disease, since most cases resolve within a y e a r ? 3, 40, 54 As the usual i n d i c a t i o n for splenectomy is fear of life-threatening hemorrhage, it is pertinent to consider t h e 278 children with thrombocytopenic purpura reviewed by K o m r o w e r a n d Watson. 4~ O f 19 deaths in this series, 17 occurred within the first m o n t h of illness; one child died of u n r e l a t e d cause a n d one died with persistent h e m o r r h a g e in spite of splenectomy. T h e rarity of fatal or cerebral h e m o r r h a g e , especially in m o r e chronic cases, has been confirmed by others?a, 54, ~s O n the other hand, chronic t h r o m b o c y t o p e n i a in children has recently been associated with m i n i m a l cerebral dysf u n c t i o n J 9 Nevertheless, the low risk of lifet h r e a t e n i n g h e m o r r h a g e , the c u r r e n t availability of specific platelet r e p l a c e m e n t in the event of h e m o r r h a g e , a n d the finite risk of sudden, c a t a s t r o p h i c infectious sequelae following splenectomy l e a d us, on balance, to urge a conservative a p p r o a c h to the m a n a g e m e n t of persistent t h r o m b o c y t o p e n i a , especially in boys. REFERENCES

1. Blaese, R. M., Strober, W., Brown, R. S., and Waldmann, T. A.: The Wiskott-Aldrich syndrome: A disorder with a possible defect in antigen processing or recognition, Lancet 1: 1056, 1968. 2. Cooper, M. D., Chase, H. P., Lowman, J. T., Krivit, W., and Good, R. A. : Wiskott-Aldrich syndrome: An immunological deficiency disease involving the afferent limb of immunity, Am. J. Med. 44: 499, 1968. 3. Ellis, E. F., and Smith, R. T.: The role of the spleen in imrnunity: With special reference to the post-splenectomy problem in infants, Pediatrics 37:111, 1966. 4. Erickson, W. D., Burgert, E. O., and Lynn, H. B.: The hazard of infection following splenectomy in children, Am. J. Dis. Child. 116: 1, 1968. 5. Eraklis, A. J., Kevy, S. V., Diamond, L. K., and Gross, R. E.: Hazard of overwhelming infection after splenectomy in childhood, N. Engl. J. Med. 276: 1225, 1967. 6. Robinson, T. W., and Sturgeon, P.: Postsplenectomy infection in infants and children, Pediatrics 25: 941, 1960. 7. Huntley, C. C., and Dees, S. C.: Eczema associated with thrombocytopenia purpura and purulent odtis media, Pediatrics 19: 351, 1957. 8. Krivit, W., and Good, R. A.: Aldrich's syn-

Hereditary thrombocytopenia

9.

10.

t 1.

12. 13.

14, [5.

16.

17.

18.

19.

20. 21.

22.

23.

233

drome (thrombocytopenia, eczema and infection in infants), Am. J. Dis. Child, 97: 137, 1959. Berglund, G., FinnstrSm, O., Johansson, S. G. O., and M6Iler, K. L.: Wiskott-Aldrich syndrome--a study of 6 cases, Acta Pediatr. Scand. 57: 89, 1968. Murphy, S., Oski, F. A., and Gardner, F. H.: Hereditary thromhocytopenia with an intrinsic platelet defect, N. Engl. J. Med. 281: 857, 1969. Schaison, G., Najean, Y., Loureiro, M., ArdallIou, N., Chavelet, F., Betigmann, M., and Bernard, J.: Thrombopenic famillale chronique par trouble de production, Arch. Fr. Pediatr. 25: 365, 1968. Vestermark, B., and' Vestermark, S.: Familial sex-linked thrombocytopenia, Acta Paediatr. 53: 365, 1964. Canales, L., and Mauer, A. M.: "Sex-linked hereditary thrombocytopenia as a variant of Wiskott-Aldrich syndrome, N. Engl. J. Med. 277: 899, 1967. Ata, M., Fisher, O. D., and ttolman, C, A.: Inherited thrombocytopenia, Lancet 1: 119, 1965. Cohen, P., Gardner, F. H., and Barnett, G. O.: Reclassification of the thrombocytopenias by means of the Cr 51 labeling method for measuring platelet life span, N. Engl. J. Med. 264: 1294, 1961. Najean, Y., Ardaillou, N., Caen, J., Larrieu, M., and Bernard, J.: Survival of radiochron'liurn-labeled platelets in thrombocytopenias, Blood 22" 718, 1963. Shulman, N. R., Watkins, S. P., Itscoitz, S. B-, and Students, A. B.: Evidence that the spleen retains the youngest and hemostatieally most effective patelets, Trans. Assos. Am. Phys. 81: 302, 1968. Gr6ttum,. K. A., Hovig, J., Holmsen, H., Abrahamsen, A. F., Jeremi% M., and Seip, M.: Wiskott-Aldrich syndrome: Qualitative platelet defects and short platelet survival, Br. J. Haematol. 17: 373, 1969. Baldini, M., Kim, B., Steiner, M., Kuramoto, A., Okuma, M., and Otridge, B. W.: Metabolic platelet defect in the Wiskott-Aldrich syndrome, Pediatr. Res. 3: 377, 1969.. Krivit, W., Yunis, E., and White, J. G.: Platelet survival studies in Aldrich syndrome, Pediatrics 37: 339, 1966. Pearson, H. A., Shulman, N. R., Oski, F. A., and Eitzman, D. V.: Platelet survival in Wiskott-Aldrich syndrome, J. PEmATm 68: 751, 1966. Blaese, R. M., Strober, W., Levy, A. L., and Waldmann, T. A.: I-Iypercatabolism of IgG, IgA, IgM and[ albumin in the Wiskott-Aldrich syndrome: A unique disorder of serum protein metabolism. In press. Oppenhelm, J. J., Blaese, R. M., and Waldmann, T. A.: Defective lymphocyte transformation and delayed hypersensitivity in Wiskott-Aldrich syndrome, J. Immunol. 104: 835, 1970.

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The Journal o] Pediatrics February 1972

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