American Journal of Medical Genetics 43796-798 (1992)

Brief Clinical Report

Platelet Dysfunction in a Patient With the Opitz (BBBG) Syndrome &hit Kapoor and George M. Rodgers Division of Hematology and Oncology, The University of Utah School of Medicine, and The Veterans Affairs Medical Center, Salt Lake City, Utah

An 11-year-old girl with Opitz (BBBG) syn- drome presented with a bleeding disorder. Studies showed an immune-mediated qualita- tive platelet dysfunction in the absence of thrombocytopenia. This is the first report of hemostatic dysfunction in a patient with the Opitz (BBBG) syndrome. This report con- siders the possible relationship of the platelet dysfunction to the Opitz (BBBG) syndrome and its treatment. o 1992 Wiley-Liss, Inc.

KEY WORDS: Opitz syndrome, platelet dys- function

INTRODUCTION Hemostatic dysfunction has not been described previ-

ously in patients with Opitz syndrome. We report on a patient with the Opitz (BBBG) syndrome who also has a lifelong bleeding disorder due to immune-mediated platelet dysfunction. We consider the possible relation- ship of platelet dysfunction to the Opitz syndrome and discuss the therapeutic strategies to prevent bleeding in this case.

CLINICAL REPORT H.C. is an 11-year-old white girl who was referred for

evaluation of a bleeding disorder. She is the second child of healthy unrelated parents

and was delivered at term via a planned cesarean sec- tion. At the time of her birth, her mother was 26 years old and her father was 25 years old. The pregnancy and the delivery were uncomplicated. Her birth weight was 3.4 kg (50th percentile) and her length was 48.75 cm

Received for publication April 22, 1991; revision received Octo- ber 4, 1991.

Address reprint requests to Fbhit Kapoor, M.D., Division of HematologyiOncology, Department of Medicine, University of Utah School of Medicine, 50 N Medical Drive, Salt Lake City, UT 84132.

(50th centile). Her Apgar scores were 9 and 10 at 1 and 5 min, respectively.

She was noted to have multiple anomalies. These in- cluded ocular hypertelorism with an antimongoloid slant of the palpebral fissures. Other features included a high-arched palate, severe malocclusion of teeth, and a receding chin. She had fine brown hair with a prominent widow’s peak. On examination of her extremities, long fingers with syndactyly of the 4th and 5th metatar- sophalangeal joints were noted. Webbing of fingers and toes was absent and her palmar and plantar creases were normal. As an infant, she had a normal suck reflex, but had difficulties with swallowing thick liquids. She also suffered from constipation. With advancing age the dysphagia and constipation abated. These findings were consistent with the diagnosis of the Opitz (BBBG) syn- drome. When we evaluated her, the respiratory and car- diovascular system exams were normal. She had a nor- mal vagina and normal anus. She was shy and had to be coaxed to talk. She was experiencing scholastic diffi- culties and had an (WIS) I& of 88 (20th centile). On the Denman neuropsychology memory scale, she obtained a full scale memory quotient of 43, verbal memory quo- tient of 46, and a nonverbal memory quotient of 55. Based on these results, H.C. is likely to continue to experience scholastic difficulties. There was no family history of congenital abnormalities. Both parents were normal on physical exam. She had 3 sibs who were also normal.

At age 4 years, she was evaluated for easy bruisability and was thrombocytopenic. She was treated successfully with prednisone for the next year with return of normal platelet counts. She did not have further bleeding prob- lems and no other diagnostic studies were done at that time. At age 10 years, she underwent tooth extractions which were complicated by excessive bleeding. Over the last year H.C. has had continuing problems with easy bruising, although she has not had any episodes of mu- cocutaneous bleeding.

The patient has never undergone major surgery or received blood product transfusions. There is no history of a familial bleeding disorder.

0 1992 Wiley-Liss, Inc.

Platelet Dysfunction in the Opitz (BBBG) Syndrome 797

LABORATORY INVESTIGATIONS Hematologic and Coagulation Parameters

WBC 6,400/mm3, hemoglobin 14.2 g/dl, hematocrit 41.9%, platelet count 242,000/mm3. Bleeding time (Ivy Method) 25 min, PT 12.7 sec (range 11.2-14.8 sec), PTT 41 sec (range 30-45 sec). Factor VII1:C activity 94% (range 50-200%), vWF antigen 81% (range 43-150%), ristocetin cofactor activity 100% (52-160%), results of vWF multimeric analysis were normal.

Platelet aggregation studies. Normal responses to 3 concentrations of collagen and 2 concentrations of ADP, but diminished responses to arachidonic acid and ristocetin, with disaggregation occurring with both ago- nists (Fig. 1).

Peripheral smear. Platelet morphology was nor- mal.

Electron microscopy. Ultrastructural analysis of fresh platelets following normal fixation, embedding and staining following incubation with diaminoben- zidine did not demonstrate any abnormalities. Specifi- cally, the content of platelet granules was normal.

DDAVP (desmopressin acetate) therapeutic trial. An infusion of 0.3 pg/kg of dDAVP failed to cor- rect the prolonged bleeding time.

Antiplatelet antibodies. Platelet-associated IgG was 829 molecules/platelet (range 0-300) and IgM 663 molecules/platelet (range 0-300). Indirect platelet-reac- tive antibodies were absent.

Blood chemistry. Results of SMA-20 studies were normal.

G-banded karyotype. 46,XX. Metabolic and organic screens. Serum FSH, LH,

17-hydroxyprogesterone, B-HCG stimulation test, growth hormone, and urine metabolic screen for amino and organic acids were normal.

Radiology. Her bone age was retarded in reference to her chronologic age (11 years) and was approximately 81°/12 years.

DISCUSSION The Opitz (BBBG) syndrome is an autosomal domi-

nant disorder associated with multiple congenital anomalies. The syndrome was first described by Opitz et al. [19651. The manifestations include hypertelorism, down-slanting palpebral fissures, cleft lip and palate, widow’s peak, and malformations of the facial skeleton. Other manifestations include laryngeal “dysplasia,” dysphagia and in affected males hypospadias, cryp- torchidism, and bifid scrotum [Opitz et al., 1965, 1969; Opitz, 1987; Wilson et al., 19881. The manifestations in affected patients may vary in severity. Characteristi- cally, patients with the Opitz (BBBG) syndrome have swallowing difficulties which often improve with age.

The diagnosis of the Opitz (BBBG) syndrome in this case was based on the characteristic physical anomalies and dysphagia. This patient apparently represents a new mutation since her parents are normal. However, variable penetrance of the mutant gene has been docu- mented in obligate carriers [Pederson et al., 1976; F’rias et al., 19721.

Bleeding disorders have not been described in pa- tients with the Opitz syndrome. In contrast, a number of inherited disorders such as the Wiskott-Aldrich [Grot- turn et al., 19691, Chediak-Higashi [Apitz-Castro et al., 19851, Hermansky-Pudlak [Hardisty et al., 19721, TAR syndrome [Day et al., 19721, and Noonan syndrome [Witt et al., 19881 have been associated with a bleeding diathesis. In all of these disorders bleeding is often due to platelet dysfunction.

Our patient has a history of a bleeding tendency since early childhood. Her earlier episodes of thrombocyto- penia probably resulted from immune mechanisms based on her response to corticosteroids. The presence of antiplatelet antibodies associated with platelet dysfunc- tion, abnormal platelet aggregation studies, normal von Willebrand studies, and the lack of response to dDAVP all strongly suggest that the basis for her current hemo-

I 100 Arachidonic acid 1

I min 20 H

0

r I 100 I , 100 Ristocet in Ristocetin

Fig. 1. Platelet aggregation studies in a patient with the Opitz (BBBG) syndrome and immune- mediated platelet dysfunction. Platelet aggregation responses of the patient (PI and control subject (C) to arachidonic acid (500 Fgiml) and ristocetin (1 and 1.2 mg/ml) are shown. Responses to collagen and ADP were normal (not shown).

798 Kapoor and Rodgers

static defect is immune-mediated platelet dysfunction. An association between the Opitz syndrome and autoim- munity has not been described previously. The possi- bility that the hemostatic defect is from an alloantibody is unlikely because she has not received transfusions.

The spectrum of autoimmune platelet defects includes both quantitative and qualitative abnormalities. The functional analysis of this patient’s platelets demon- strates some similarities with a platelet storage pool defect (SPD). Characteristically, these patients have a decreased content of platelet dense bodies and a failure of normal platelet aggregation to collagen, ADP and epinephrine [Clancy et al., 19721. Acquired storage pool defects from antibody-mediated storage pool depletion have been reported [Weiss, 19801. Weiss et al. 119801 described antibodies to membrane-bound acid phos- phatase in one of their 5 patients with autoantibody- induced SPD. Hence, autoantibodies may lead to plate- let dysfunction by either causing an SPD, or as in the case mentioned above, by binding with platelet surface membrane proteins. Antibodies to the GpIIb/IIIa com- plex [Niessner et al., 19861 and Gplb [Woods et al., 19841 have been described. Such antibody-platelet interac- tions may interfere with platelet aggregation, fibroinogen binding, and binding to the vessel wall, re- sulting in a bleeding tendency. The abnormal response to ristocetin coupled with the normal von Willebrands panel suggests that autoantibodies may be interacting with Gplb, the platelet membrane receptor required for the ristocetin response. Further studies are needed to characterize the exact nature of the autoantibodies in this patient.

This observation of autoimmune-mediated platelet dysfunction in a patient with the Opitz (BBBG) syn- drome may be coincidental. We are in the process of studying additional cases. Since many children with the Opitz syndrome may require surgery, physicians in- volved in their care need to be aware of this potential association. Until the nature of this disorder is detailed further, we recommend that aspirin and other drugs known to interfere with platelet function be used with caution in these patients. It should be noted that in addition to causing a hemorrhagic diathesis, autoan- tibodies may activate platelets and induce secretion and aggregation, leading to paradoxical thrombosis [Zahavi et al., 19741. Thus, the patient with Opitz syndrome who develops bleeding or thrombotic symptoms should be evaluated for immune-mediated platelet dysfunction.

Treatment with immunosuppressive agents such as cor- ticosteroids may be necessary for patients with signifi- cant symptoms.

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