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) syndrome presented with a bleeding disorder. Studies showed an immune-mediatedqualitative 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 considers 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 dysfunction INTRODUCTION Hemostatic dysfunction has not been described previously 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 relationship 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-oldwhite girl who was referred for evaluation of a bleeding disorder. She is the second child of healthy unrelated parents and was delivered a t term via a planned cesarean section. 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 October 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.
0 1992 Wiley-Liss, Inc.
(50th centile). Her Apgar scores were 9 and 10 at 1and 5 min, respectively. She was noted to have multiple anomalies. These included 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 metatarsophalangeal 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) syndrome. When we evaluated her, the respiratory and cardiovascular system exams were normal. She had a normal vagina and normal anus. She was shy and had to be coaxed to talk. She was experiencing scholastic difficulties 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 quotient 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 problems 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 mucocutaneous bleeding. The patient has never undergone major surgery or received blood product transfusions. There is no history of a familial bleeding disorder.
Platelet Dysfunction in the Opitz (BBBG) Syndrome
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 agonists (Fig. 1). Peripheral smear. Platelet morphology was normal. Electron microscopy. Ultrastructural analysis of fresh platelets following normal fixation, embedding and staining following incubation with diaminobenzidine did not demonstrate any abnormalities. Specifically, the content of platelet granules was normal. DDAVP (desmopressin acetate) therapeutic trial. An infusion of 0.3 pg/kg of dDAVP failed to correct 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-reactive 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 (11years) and was approximately 81°/12 years.
DISCUSSION The Opitz (BBBG) syndrome is an autosomal dominant 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, cryptorchidism, and bifid scrotum [Opitz et al., 1965, 1969; Opitz, 1987; Wilson et al., 19881.The manifestations in affected patients may vary in severity. Characteristically, 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 documented in obligate carriers [Pederson et al., 1976; F’rias et al., 19721. Bleeding disorders have not been described in patients with the Opitz syndrome. In contrast, a number of inherited disorders such as the Wiskott-Aldrich [Grotturn 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., 19881have 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 thrombocytopenia probably resulted from immune mechanisms based on her response to corticosteroids. The presence of antiplatelet antibodies associated with platelet dysfunction, 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
Arachidonic acid
Ristocetin
I
1 100
20
I min
H
r
797
0 100
I
Ristocetin
Fig. 1. Platelet aggregation studies in a patient with the Opitz (BBBG) syndrome and immunemediated platelet dysfunction. Platelet aggregation responses of the patient (PI and control subject (C) to arachidonic acid (500 Fgiml) and ristocetin (1and 1.2 mg/ml) are shown. Responses to collagen and ADP were normal (not shown).
, 100
798
Kapoor and Rodgers
static defect is immune-mediated platelet dysfunction. An association between the Opitz syndrome and autoimmunity has not been described previously. The possibility 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 demonstrates 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 phosphatase in one of their 5 patients with autoantibodyinduced SPD. Hence, autoantibodies may lead to platelet 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 complex [Niessner et al., 19861and Gplb [Woods et al., 19841 have been described. Such antibody-platelet interactions may interfere with platelet aggregation, fibroinogen binding, and binding to the vessel wall, resulting 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) syndrome may be coincidental. We are in the process of studying additional cases. Since many children with the Opitz syndrome may require surgery, physicians involved 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, autoantibodies 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 corticosteroids may be necessary for patients with significant symptoms. REFERENCES Apitz-Castro R, Cruz M, Ledezema C, Merino F, Ramirez-Dugue P, Dangelmeier C, Holmsin H (1985): The storage pool deficiency in patients with Chediak-Higashi Syndrome: Study of six patients. Br J Hematol 59:471-483. Clancy R, Jenkins E, Firkin B (1972): Qualitative platelet abnormalities in idiopathic thrombocytopenia purpura. N Eng J Med 286:622-626. Day HS, Holmsen H (1972): Platelet adenine nucleotide storage pool deficiency in thrombocytopenic absent radii syndrome. JAMA 221:1053-1054. Frias JL, Rosenbloom AL (1972):Two new familial cases ofG syndrome. 1972 Birth Defects Conference. Malformations Syndromes. New York: Alan R Liss, Inc., for The National Foundation-March of Dimes BD:OAS 254-57. Grottum KA, Hovig T, Holmsen H, Abramhamsen AF, Jeremic M, Seip M (1969): Wiskott-Aldrich syndrome: Qualitative platelet defects and decreased platelet survival. Br J Hematol 17:373-388. Hardisty RM, Mills DCB, Ketsa-Ard K (1972): The platelet defect associated with albinism. Br J Hematol 23:679-692. Niessner H, Clemetson KJ, Panzer S, Mueller-Eckhardt C, Santoso S, Bettelheim P (1986): Acquired thrombasthenia due to GpIIbiIIIaspecific autoantibodies. Blood 68571-576. Opitz J M (1987): Editorial comment: G syndrome (hypertelorism with hypospadias-dysphagia or Opitz-Frias or Opitz-G Syndrome). Perspective in 1987 and bibliography. Am J Med Genet 28:275-285. Opitz JM, Frias J L , Gutenberger JE, Pellet J R (1969): The G syndrome of multiple congenital abnormalities. In Bergsma D (ed):“The Conference on the Clinical Delineation of Birth Defects.” New York. Alan R. Liss, Inc., for the National Foundation-March of Dimes BD:OAS V(2):95-101. Opitz JM, Smith DW, Summitt KRL (1965): Hypertelorism and hypospadias. (Abstract) J Pediat 67:968. Pederson IL, Middelson M, Oster J (1976): The G syndrome. A four generation family study. Hum Hered 26:6671. Weiss H J (1980): Congenital disorders of platelet function. Semin Hematol 17:228-241. Weiss HJ, Rosove MH, Lages BA, Kaplan KL (1980):Acquired storage pool deficiency with increased platelet-associated IgG: A report of five cases. Am J Med 69:711-717. Wilson GR, Oliver WJ (1988): Further delineation ofthe G syndrome. A manageable cause of infantile dysphagia. J Med Genet 25157-163. Witt DR, McGillivray BC, Allanson JE, Huges HE, Hathaway WE, Zipursky A, Hall J G (1988): Bleeding diathesis in Noonan syndrome: A common association. Am J Med Gen 35:305-317. Woods VL, Kurata Y, Montgomery RR, Tani P, Mason D, Oh EH, McMillan R 11984):Autoantibodies against platelet glycoprotein Ib in patients with chronic immune thrombocytopenic purpura. Blood 64:156-160. Zahavi J , Marder VJ (1974): Acquired “Storage Pool Diseases” associated with circulating antiplatelet antibodies. Am J Med 56:883890.
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) syndrome presented with a bleeding disorder. Studies showed an immune-mediatedqualitative 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 considers 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 dysfunction INTRODUCTION Hemostatic dysfunction has not been described previously 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 relationship 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-oldwhite girl who was referred for evaluation of a bleeding disorder. She is the second child of healthy unrelated parents and was delivered a t term via a planned cesarean section. 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 October 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.
0 1992 Wiley-Liss, Inc.
(50th centile). Her Apgar scores were 9 and 10 at 1and 5 min, respectively. She was noted to have multiple anomalies. These included 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 metatarsophalangeal 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) syndrome. When we evaluated her, the respiratory and cardiovascular system exams were normal. She had a normal vagina and normal anus. She was shy and had to be coaxed to talk. She was experiencing scholastic difficulties 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 quotient 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 problems 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 mucocutaneous bleeding. The patient has never undergone major surgery or received blood product transfusions. There is no history of a familial bleeding disorder.
Platelet Dysfunction in the Opitz (BBBG) Syndrome
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 agonists (Fig. 1). Peripheral smear. Platelet morphology was normal. Electron microscopy. Ultrastructural analysis of fresh platelets following normal fixation, embedding and staining following incubation with diaminobenzidine did not demonstrate any abnormalities. Specifically, the content of platelet granules was normal. DDAVP (desmopressin acetate) therapeutic trial. An infusion of 0.3 pg/kg of dDAVP failed to correct 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-reactive 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 (11years) and was approximately 81°/12 years.
DISCUSSION The Opitz (BBBG) syndrome is an autosomal dominant 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, cryptorchidism, and bifid scrotum [Opitz et al., 1965, 1969; Opitz, 1987; Wilson et al., 19881.The manifestations in affected patients may vary in severity. Characteristically, 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 documented in obligate carriers [Pederson et al., 1976; F’rias et al., 19721. Bleeding disorders have not been described in patients with the Opitz syndrome. In contrast, a number of inherited disorders such as the Wiskott-Aldrich [Grotturn 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., 19881have 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 thrombocytopenia probably resulted from immune mechanisms based on her response to corticosteroids. The presence of antiplatelet antibodies associated with platelet dysfunction, 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
Arachidonic acid
Ristocetin
I
1 100
20
I min
H
r
797
0 100
I
Ristocetin
Fig. 1. Platelet aggregation studies in a patient with the Opitz (BBBG) syndrome and immunemediated platelet dysfunction. Platelet aggregation responses of the patient (PI and control subject (C) to arachidonic acid (500 Fgiml) and ristocetin (1and 1.2 mg/ml) are shown. Responses to collagen and ADP were normal (not shown).
, 100
798
Kapoor and Rodgers
static defect is immune-mediated platelet dysfunction. An association between the Opitz syndrome and autoimmunity has not been described previously. The possibility 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 demonstrates 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 phosphatase in one of their 5 patients with autoantibodyinduced SPD. Hence, autoantibodies may lead to platelet 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 complex [Niessner et al., 19861and Gplb [Woods et al., 19841 have been described. Such antibody-platelet interactions may interfere with platelet aggregation, fibroinogen binding, and binding to the vessel wall, resulting 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) syndrome may be coincidental. We are in the process of studying additional cases. Since many children with the Opitz syndrome may require surgery, physicians involved 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, autoantibodies 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 corticosteroids may be necessary for patients with significant symptoms. REFERENCES Apitz-Castro R, Cruz M, Ledezema C, Merino F, Ramirez-Dugue P, Dangelmeier C, Holmsin H (1985): The storage pool deficiency in patients with Chediak-Higashi Syndrome: Study of six patients. Br J Hematol 59:471-483. Clancy R, Jenkins E, Firkin B (1972): Qualitative platelet abnormalities in idiopathic thrombocytopenia purpura. N Eng J Med 286:622-626. Day HS, Holmsen H (1972): Platelet adenine nucleotide storage pool deficiency in thrombocytopenic absent radii syndrome. JAMA 221:1053-1054. Frias JL, Rosenbloom AL (1972):Two new familial cases ofG syndrome. 1972 Birth Defects Conference. Malformations Syndromes. New York: Alan R Liss, Inc., for The National Foundation-March of Dimes BD:OAS 254-57. Grottum KA, Hovig T, Holmsen H, Abramhamsen AF, Jeremic M, Seip M (1969): Wiskott-Aldrich syndrome: Qualitative platelet defects and decreased platelet survival. Br J Hematol 17:373-388. Hardisty RM, Mills DCB, Ketsa-Ard K (1972): The platelet defect associated with albinism. Br J Hematol 23:679-692. Niessner H, Clemetson KJ, Panzer S, Mueller-Eckhardt C, Santoso S, Bettelheim P (1986): Acquired thrombasthenia due to GpIIbiIIIaspecific autoantibodies. Blood 68571-576. Opitz J M (1987): Editorial comment: G syndrome (hypertelorism with hypospadias-dysphagia or Opitz-Frias or Opitz-G Syndrome). Perspective in 1987 and bibliography. Am J Med Genet 28:275-285. Opitz JM, Frias J L , Gutenberger JE, Pellet J R (1969): The G syndrome of multiple congenital abnormalities. In Bergsma D (ed):“The Conference on the Clinical Delineation of Birth Defects.” New York. Alan R. Liss, Inc., for the National Foundation-March of Dimes BD:OAS V(2):95-101. Opitz JM, Smith DW, Summitt KRL (1965): Hypertelorism and hypospadias. (Abstract) J Pediat 67:968. Pederson IL, Middelson M, Oster J (1976): The G syndrome. A four generation family study. Hum Hered 26:6671. Weiss H J (1980): Congenital disorders of platelet function. Semin Hematol 17:228-241. Weiss HJ, Rosove MH, Lages BA, Kaplan KL (1980):Acquired storage pool deficiency with increased platelet-associated IgG: A report of five cases. Am J Med 69:711-717. Wilson GR, Oliver WJ (1988): Further delineation ofthe G syndrome. A manageable cause of infantile dysphagia. J Med Genet 25157-163. Witt DR, McGillivray BC, Allanson JE, Huges HE, Hathaway WE, Zipursky A, Hall J G (1988): Bleeding diathesis in Noonan syndrome: A common association. Am J Med Gen 35:305-317. Woods VL, Kurata Y, Montgomery RR, Tani P, Mason D, Oh EH, McMillan R 11984):Autoantibodies against platelet glycoprotein Ib in patients with chronic immune thrombocytopenic purpura. Blood 64:156-160. Zahavi J , Marder VJ (1974): Acquired “Storage Pool Diseases” associated with circulating antiplatelet antibodies. Am J Med 56:883890.
