The thrombocytopenia with absent radius (TAR) syndrome is perhaps the most striking and most easily recognized of the congenital thrombocytopenias. Clinical recognition of the disorder occurs soon after birth in the infant with purpura and characteristic limb deformities. Although absence of the radius is the most consistent finding in this condition, cardiac, renal, and other skeletal malformations (e.g., complete or partial agenesis of other bones or joints, bony synostoses) also may occur. Leukoerythroblastic responses, often associated with severe diarrhea, often are observed in the neonatal period and infancy. The inheritance pattern appears to be autosomal recessive. Bone marrow specimens exhibit reduced numbers of megakaryocytes, which often appear dysplastic. Transfused platelets survive normally, and many patients can be maintained on weekly platelet transfusions for long periods. The risk of platelet allosensitization with chronic transfusions is low with modern blood banking methods; however, if allosensitization does occur, patients can be managed with human leukocyte antigen (HLA)–matched platelets. The thrombocytopenia tends to remit spontaneously in the second and third years of life.

Patients with amegakaryocytic thrombocytopenia may present without radial or other congenital abnormalities. These patients generally present with isolated thrombocytopenia. Associations with neurologic defects and generalized bone marrow dysfunction developing later in life have been documented. Mutations in the thrombopoietin receptor (Mpl) have been identified in patients with amegakaryocytic thrombocytopenia.

Other syndromes associated with marrow failure or aplastic anemias that may present with thrombocytopenia include Fanconi aplastic anemia, Shwachman syndrome, and dyskeratosis congenita. Both Fanconi aplastic anemia and Shwachman syndrome can present in the neonatal period, whereas dyskeratosis congenita usually manifests in the second decade of life. Although all three syndromes can be associated with congenital abnormalities, Shwachman syndrome is differentiated by exocrine pancreatic insufficiency, bony dysostoses, and neutropenia in most cases. Mutations in a gene of unclear function, SBDS, has been identified in the majority of these patients.

In Fanconi syndrome, a variety of congenital abnormalities may exist in addition to pancytopenia. Many patients have absent radii, mimicking the TAR syndrome, but in all reported cases of Fanconi syndrome, absence of the radius is associated with absence of the thumb. In the TAR syndrome, invariably the thumb is present despite the absence of the radius. The phenotype of patients with Fanconi syndrome often varies within the same family. Some patients exhibit no detectable congenital abnormalities, but the syndrome can be detected on the basis of characteristic chromosomal abnormalities. Chromosomes of patients with Fanconi syndrome are more susceptible to damage by DNA cross-linking agents such as diepoxybutane and mitomycin C and have more chromosomal breakages than healthy control subjects when they are exposed to these agents. To date, eight complementation groups (A, B, C, D1, D2, E, F, G) for Fanconi anemia have been described, and each complementation group is thought to represent a distinct Fanconi anemia gene. These genes appear to cooperate in a cellular pathway that participates in DNA repair. Patients with Fanconi syndrome are susceptible not only to bone marrow failure, but also to malignant diseases, particularly leukemias and squamous cell carcinomas.

Dyskeratosis congenita presents with the triad of hyperpigmentation of the skin, dystrophic nails, and oral leukoplakia. This syndrome is inherited in autosomal dominant, autosomal recessive, and sex-linked recessive patterns. Patients with dyskeratosis congenita have been found to have mutations in hTERC and DKC1; these genes are important for the function of the enzyme telomerase and thus chromosomal stability. As in Fanconi anemia, patients with dyskeratosis congenita are at risk to develop malignant diseases, especially epithelial cancers.

Certain chromosomal abnormalities have also been associated with thrombocytopenia. Patients with trisomy 13 and 18 can exhibit thrombocytopenia, as can patients with Down syndrome. Deletions of chromosome 22q11 are found in patients with velocardiofacial syndrome; many of these patients are also thrombocytopenic. Paris-Trousseau syndrome is characterized by clinodactyly, hypertelorism, mental retardation, and thrombocytopenia. These patients have deletions of chromosome 11q23.

Thrombocytopenias transmitted as autosomal dominant traits with and without normal platelet survival have been described. Autosomal recessive inheritance of thrombocytopenia has also been reported. These syndromes may be easily confused with idiopathic thrombocytopenic purpura. Several familial giant platelet syndromes with thrombocytopenia, such as May-Hegglin anomaly, Fechner syndrome, Sebastian syndrome, and Epstein syndrome, result from mutations in the nonmuscle heavy chain of myosin 9 (MYH9). Other inherited conditions associated with giant platelets and thrombocytopenia include Bernard-Soulier and gray platelet syndrome; Bernard-Soulier syndrome arises from defects in the platelet receptor (GPIb/IX) for von Willebrand factor (vWF), whereas
gray platelet syndrome results from a deficiency of platelet alpha granules. In contrast, small platelets are one of the most consistent findings in the Wiskott-Aldrich syndrome; this finding can be very helpful in the differential diagnosis of inherited thrombocytopenias, particularly when a sex-linked recessive inheritance pattern is elicited.

Patients with Wiskott-Aldrich syndrome have been found to have mutations in the WASP gene. A sex-linked recessive form of thrombocytopenia without the severe immunodeficiency of Wiskott-Aldrich syndrome has also been shown to result from WASP mutations. Another sex-linked recessive syndrome with thrombocytopenia has been described in families with mutations in the transcription factor, GATA1. These patients also have dyserythropoietic anemia. Noonan syndrome is often inherited in an autosomal dominant fashion and can be associated with mild thrombocytopenia. Thrombocytopenia also occurs in the Tn-polyagglutination syndrome, a rare clonal disorder caused by an abnormality in glycosylation of the MN blood group antigen.

Glanzmann thrombasthenia is a prototype of the qualitative platelet disorders. This abnormality is inherited as an autosomal recessive trait. Although the number and morphology of the platelets are normal, life-threatening hemorrhagic complications may be encountered. The spectrum of severity of bleeding symptoms is broad, ranging from mild to severe. Platelets from patients with Glanzmann disease do not aggregate in vitro in response to adenosine diphosphate, collagen, epinephrine, and thrombin, but they do agglutinate in the presence of ristocetin and vWF. Clot retraction may be abnormal. These abnormalities are caused by the partial or complete absence of a cytoadhesive protein, glycoprotein IIb/IIIa (the platelet fibrinogen receptor), from platelet membranes. The ability of these platelets to agglutinate in the presence of ristocetin and vWF can be attributed to the presence of normal amounts of another cytoadhesive membrane protein, glycoprotein Ib, the major vWF receptor. Transfusion of platelets is an effective therapy for severe bleeding, but in a minority of cases it may result in the development of antibodies directed against the glycoprotein IIb/IIIa complex and resistance to further platelet transfusions. Larger than predicted platelet transfusions may be required, presumably because of interference of abnormal platelets with transfused platelets. Epsilon-aminocaproic acid can be extremely helpful for oral or nasal hemorrhage.

In the past several years, growing experience has suggested that recombinant factor VIIa is effective treatment for bleeding in patients with Glanzmann thrombasthenia and other platelet dysfunctions. Patients with Glanzmann thrombasthenia are at high risk for iron deficiency anemia secondary to frequent bleeding episodes; in particular, iron supplementation should be considered for infants and adolescent female patients with Glanzmann thrombasthenia. Numerous mutations in both glycoprotein IIb and IIIa have been described that result in Glanzmann phenotypes.

In Bernard-Soulier syndrome, another autosomal recessive disease resulting in severe hemorrhagic complications, platelets aggregate in vitro in the presence of adenosine diphosphate, collagen, epinephrine, and thrombin. However, agglutination does not occur in the presence of ristocetin, even with vWF. Platelets are often described as large and bizarre. Platelet number is often reduced, sometimes out of proportion to the number observed on peripheral blood smear. Underestimation of platelet counts by electronic techniques can be caused by their abnormal size and density. The primary defect in Bernard-Soulier syndrome appears to be an absence of glycoproteins Ib, V, and IX from the platelet surface. The deficiency of glycoprotein Ib results in the inability to bind vWF or respond to ristocetin. As in Glanzmann thrombasthenia, platelet transfusion is the preferred therapy for severe bleeding, but adjunctive measures such as epsilon-aminocaproic acid may be useful in specific instances, such as mouth bleeding. Development of antibodies against the glycoprotein Ib in transfused platelets may render patients refractory to platelet transfusions. In these cases, recombinant factor VIIa may be useful therapy.

Several mutations, involving both subunits of glycoprotein Ib, have been identified as causing Bernard-Soulier syndrome. Atypical Bernard-Soulier disease caused by mutations of glycoprotein IX has also been described.

Abnormalities of the platelet granules have been described. In the gray platelet syndrome, washed-out or gray-appearing platelets are seen on Wright-stained peripheral blood smears, and a bleeding diathesis occurs that usually is apparent at birth. A specific deficiency of alpha granules has been implicated as the cause of this disorder. A reduction occurs in platelet levels of alpha-granule constituents, such as fibrinogen, vWF, factor V, high-molecular-weight kininogen, fibronectin, thrombospondin, beta-thromboglobulin, platelet factor 4, and platelet-derived growth factor.

Deficiencies of the adenine nucleotide-containing dense granules or their contents have been reported in a heterogeneous group of patients. These abnormalities often are referred to collectively as the storage pool disorders. Bleeding symptoms usually are not severe. The defect can be demonstrated in vitro by a diminished response of platelets to agonists such as collagen, which depend on release of endogenous platelet nucleotides (i.e., second phase of platelet aggregation) for completion of the aggregatory response or by electron microscopy. Dense body deficiencies have been described as part of Hermansky-Pudlak syndrome (i.e., large, bizarre platelets associated with oculocutaneous albinism and accumulation of ceroid in bone marrow macrophages), TAR syndrome, Chédiak-Higashi syndrome, Ehlers-Danlos syndrome, Wiskott-Aldrich syndrome, and osteogenesis imperfecta.

In addition to the storage pool disorders, several abnormalities associated with the defective release of platelet granular contents have been reported. Abnormalities of arachidonic acid metabolism affect some patients, and defects of calcium metabolism have been postulated for others.

Abnormalities of platelet function occur in other congenital disorders, such as type I glycogen storage disease, cyanotic congenital heart disease, and pseudoxanthoma elasticum. Platelet dysfunction also can be seen with megathrombocyte disorders, such as Epstein syndrome.