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Transfus Med Hemother. 2010 October; 37(5): 248–258.
Published online 2010 September 15. doi:  10.1159/000320279
PMCID: PMC2980509

Language: English | German

Current Strategies in Diagnosis of Inherited Storage Pool Defects

Summary

Inherited platelet defects lead to bleeding symptoms of varying severity. Typically, easy bruising, petechiae, epistaxis, and mucocutaneous bleeding are observed in affected patients. The platelet defects are classified into disorders affecting either platelet surface receptors or intracellular organelles of platelets. The latter are represented by platelet storage pool diseases (SPD) which share a defect of platelet granules. Platelet α-granules, δ-granules, or both may be affected resulting in the clinical picture of α-SPD (e.g. Gray platelet syndrome, Quebec platelet disorder, arthrogryposis, renal dysfunction, and cholestasis syndrome), δ-SPD (e.g. Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome), or αδ-SPD (e.g. X-linked thrombocytopenia, Wiskott-Aldrich syndrome). Diagnosis of SPD is very extensive and requires platelet aggregation and flow cytometry analyses with interpretation from a specialist. Many of these disorders share common treatments, however, efficacy can vary between different patients. Therapy regiments with tranexamic acid, DDAVP, activated FVIIa, and platelet transfusions have been published. Stem cell or bone marrow transplantations are preserved for severe defects. Here, we describe the pathophysiology, clinical manifestations, and diagnosis of the major human SPDs.

Keywords: Storage pool disease, SPD; Platelet granules; Platelet dysfunction

Zusammenfassung

Angeborene Thrombozytopathien führen zu Blutungssymptomen unterschiedlichen Schweregrades. Typischerweise werden bei den betroffenen Patienten Hämatomneigung, Petechien, Nasenbluten sowie Schleimhautblutungen beobachtet. Die Thrombozytopathien werden durch Störungen der Thrombozytenrezeptoren oder der thrombozytären intrazellulären Organellen verursacht. Letztere werden durch die Storage-Pool-Defekte (SPD) repräsentiert, die einen Defekt der thrombozytären Granula aufweisen. Es können α-Granula, δ-Granula oder beide betroffen sein, die jeweils das klinische Bild der α-SPD (z.B. Gray-Platelet-Syndrom, Quebec-Platelet-Defekt, Arthrogrypose, renale Dysfunktion und Cholestasen), δ-SPD (z.B. Hermansky-Pudlak-Syndrom, Chediak-Higashi-Syndrom, Griscelli-Syndrom) oder αδ-SPD (z.B. X-chromosomale Thrombozytopenie, Wiskott-Aldrich-Syndrom) aufweisen. Die Diagnostik von SPD ist sehr aufwendig und benötigt eine Untersuchung der Thrombozytenaggregation sowie durchflusszytometrische Analysen, die von einem Spezialisten interpretiert werden sollten. Die Therapien mit Tranexamsäure, DDAVP, aktiviertem Faktor FVIIa oder Thrombozytentransfusionen sprechen bei Patienten mit Thrombozytopathien nicht gleich gut an. Stammzelloder Knochenmarkstransplantationen sind schweren Formen vorbehalten. In diesem Review werden Pathophysiologie, klinische Manifestation und Diagnostik der wichtigsten SPDs zusammengefasst.

Introduction

Inherited defects of platelet function are classified according to their effect on the various steps of platelet function and involve membrane receptor defects and storage pool deficiencies. Severe forms of platelet dysfunction are associated with deficiencies in platelet membrane receptors, but defects in the number and distribution of secretory granules can also cause significant bleeding. Storage pool disease (SPD) is a heterogeneous group of congenital disorders that have a deficiency of granules or their constituents in common. Absence of platelet granules results in a defective secretion (e.g. ADP) from activated platelets as well as abnormal secretion-dependent platelet aggregation [1]. In some disorders, such as Chediak-Higashi (CHS), Hermansky-Pudlak (HPS), or Wiskott-Aldrich (WAS) syndromes, the molecular lesion extends to other cells.

Platelet granules are classified into α-granules and δ-granules (dense bodies). The α-granules are storage sites for proteins that are either synthesized in megakaryocytes (MKs) or endocytosed from plasma [2]. α-granules contain numerous proteins involved in platelet adhesion (von Willebrand factor (VWF), P-selectin, fibronectin, fibrinogen), coagulation factors (factors V and XIII), growth factors (platelet-derived growth factor, transforming growth factor-β), and platelet factor-4. The δ-granules contain primarily calcium, ATP, ADP, serotonin, histamine, and epinephrine.

According to the storage pool-deficient platelets, which have decreased amounts of α-granules, δ-granules, or both, and their specific constituents, the clinical syndrome is called α-SPD, δ-SPD, or combined αδ-SPD. These disorders, affecting the extension phase of clot formation, are associated with impaired platelet function as indicated by decreased aggregation responses. This review gives an overview about the known clinical phenotypes of SPDs associated with the absence of α- and/or δ-granules (table (table1).1). Careful clinical and molecular diagnosis is essential to differentiate the complex disorders of lysosomal trafficking.

Table 1
Inherited storage pool diseases (SPD): genetic mutations and associated phenotypes

α-Storage Pool Disease

Gray Platelet Syndrome

Introduction

Gray platelet syndrome (GPS) was first described by Raccuglia in 1971 as a qualitative defect in platelets [3]. The rare inherited disorder presents with bleeding tendency, moderate thrombocytopenia associated with a marked decrease, or absence of platelet α-granules and their contents. Hallmark of the disease is the failure of MK proteins to enter into the secretable storage pools that characterize α-granules of normal platelets. GPS platelets specifically lack α-granules probably due to their failed maturation during MK differentiation [4]. Numbers of mitochondria, dense bodies, peroxisomes, and lysosomes are normal.

Case reports suggesting autosomal dominant [5] as well as autosomal recessive [6] inheritance have been described, indicating that GPS is probably a genetically heterogeneous disorder. The molecular defect(s) responsible for GPS remain(s) to be determined.

Pathophysiology

MKs show defective α-granule production, with impaired up-take and storage of endogenously synthesized proteins, such as platelet factor-4, β-thromboglobulin, VWF, or multimerin (a multimeric factor V-binding protein), and defective storage of exogenous proteins, such as fibrinogen, albumin, or factor V.

Clinical Manifestations

GPS patients present with mild to moderate bleeding symptoms such as easy bruising, petechiae, and epistaxis. Mucosal membrane bleeding may also occur. Bleeding time is prolonged. While platelets of some patients aggregate normally, for other patients thrombin- and/or collagen-induced platelet aggregation is impaired. A feature of most patients is the early onset of myelofibrosis, a disorder attributed to the spontaneous release of newly synthesized growth factors from MKs [7]. Jantunen et al. [8] reported on a GPS patient with myelofibrosis and splenomegaly indicating extramedullary hematopoiesis. Splenectomy has produced a temporary or even longstanding rise in platelet counts, however, without significant effect on bleeding tendency. The patient has been followed for more than 15 years without apparent progression of myelofibrosis.

Granule abnormalities in granulocytes have been reported in one family, indicating that the defect may not be restricted to platelets [9]. Nurden et al. [6] report a novel case of GPS where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical GPS symptoms such as bleeding diathesis and enlarged gray platelets. However, no mutations were identified in the GPVI gene. In addition, decreased levels of platelet membrane TLT1 (TREM-like transcript-1), which is located in the α-granule membrane, and decreased levels of P-selectin were found in this patient [10]. The authors postulate that excess activity of metalloproteases may have caused the decrease of these proteins. Taken together, GPS patients exhibit much heterogeneity concerning biochemical, phenotypic, and molecular characteristics.

Diagnosis

Blood smear typically reveals mild to moderate thrombocytopenia and enlarged (but not giant) platelets that have a gray appearance. Platelet aggregation studies are variable with no classical response pattern to ADP, epinephrine, thrombin, or collagen [7].

Quebec Platelet Disorder

Introduction

Quebec platelet disorder (QPD) is a rare, autosomal dominant bleeding disorder described in two families from the province of Quebec in Canada [11, 12]. The disorder is characterized by mild thrombocytopenia, moderately reduced platelet factor V clotting activities, and bleeding risk. In addition, QPD α-granule proteins are decreased in amount probably due to significant degradation [13]. Interestingly, protein degradation is restricted to α-granules, but does not occur in blood plasma.

Pathophysiology

α-Granule protein levels such as factor V, fibrinogen, VWF, thrombospondin, fibronectin, P-selectin, and osteonectin are significantly degraded in QPD platelets [13]. In contrast, platelet factor-4 and β-thromboglobulin do not appear to be affected. QPD platelets also showed quantitative deficiency in the α-granule protein multimerin with a normal multimer pattern [14].

Unlike normal platelets, QPD platelets contain increased amounts of the fibrinolytic serine protease urokinase-type plasminogen activator (u-PA, PLAU) without increased plasma u-PA or systemic fibrinolysis [15]. During clot formation, u-PA released by QPD platelets leads to increased platelet-dependent fibrinolysis. These data implicate u-PA in the pathogenesis of α-granule protein degradation and bleeding diathesis in QPD. Remarkably increased transcript levels of u-PA mRNA during MK differentiation were linked to a mutation in an uncharacterized regulatory element near the PLAU allele as cause of QPD [16]. Recently, QPD patients were identified to have a direct tandem duplication of a 78-kb genomic segment including PLAU and all of its characterized regulatory elements [17]. It is possible that the QPD duplication mutation further increases PLAU expression during megakaryopoiesis by other mechanisms such as alternative transcription, splicing, and/or histone binding.

Clinical Manifestations

Typically, QPD manifests as delayed-onset bleeding following hemostatic challenges (12–24 h after traumata) that responds to fibrinolytic inhibitor therapy, with or without increased bruising, episodic joint bleeds, and spontaneous hematuria [18]. Other symptoms may include excessive bleeding after cuts and delayed wound healing. QPD life expectancy appears to be similar to other family members since fatal bleeding episodes are rare.

Diagnosis

QPD platelets show protease-related degradation of many α-granule proteins even though α-granule ultrastructure is preserved. Thrombocytopenia is sometimes observed. QPD platelets fail to aggregate in response to epinephrine with or without reduced aggregation with ADP and collagen.

Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome

Introduction

ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is a severe autosomal recessive multisystem disorder associated with arthrogryposis multiplex congenita and abnormalities in polarized liver and kidney cells. This association was first reported in 1973 by Lutz-Richner and Landolt and again in another family by Nezelof et al. in 1979 [19]. ARC syndrome leads to death in infancy (by the age of about 6 months). Those patients surviving longer have shown severe developmental delay [20]. Soluble as well as membrane-bound α-granule proteins were significantly decreased or undetectable, i.e. both the releasable protein pools and membrane components of α-granules were absent.

Pathophysiology

By elucidating the molecular basis of ARC, germline mutations in the VPS33B gene were identified [21]. VPS33B (vacuolar protein sorting 33 homolog B) demonstrates a homolog of the class C yeast vacuolar protein sorting protein (Vps33) that contains a Sec1-like domain and belongs to the family of SM (Sec1/Munc18-like) proteins. SM proteins are important in the regulation of SNARE(soluble N-ethylmaleimide-sensitive factor attachment receptor)-dependent complex formation and subsequent membrane fusion. VPS33B may be involved in intracellular vesicle trafficking, being essential for the development of platelet α-granules but not for granule secretion (fig. (fig.1)1) [22]. Because some ARC patients showed no mutation in the VPS33B gene, the evidence for a possible second ARC locus was postulated [23]. Recently, Cullinane et al. [24] identified mutations in VIPAR (VPS33B-interacting protein involved in polarity and apical protein restriction) in ARC patients without VPS33B defects. VPS33B and VIPAR may function as part of a complex that is involved in apical membrane protein sorting.

Fig. 1
Post-Golgi sorting in conventional cell types and melanocytes: The role of HPS proteins as well as VPS33B in vesicle trafficking is demonstrated. These proteins affect the synthesis of lysosomes and LROs in the endocytic pathway. The different BLOC protein ...

Clinical Manifestations

Patients with ARC syndrome present with arthrogryposis, renal tubular dysfunction (Fanconi syndrome), and cholestasis with a low γGT (γ-glutamyltransferase) activity. However, cases may stay undiagnosed as not all patients present with the three cardinal features. Typically, patients present with recurrent fever, infections (e.g. pneumonia), and failure to thrive. Further clinical symptoms such as ichthyosis, central nervous system (CNS) defects, neurogenic muscular atrophy, nephrogenic diabetes insipidus, anemia, and diarrhea have been reported [25]. Case reports showed that ARC patients may have a bleeding tendency. It has become apparent that there is notable clinical variability, even within the same family. No clear genotype-phenotype correlations were identified.

Diagnosis

Blood smear revealed abnormally large platelets with pale appearance, absent α-granules, and increased number of δ-granules. Low concentrations of β-thromboglobulin, platelet factor-4, and thrombospondin can be measured [26]. ARC platelets demonstrate reduced aggregation with arachidonic acid and ADP [22]. Diagnosing ARC syndrome by liver biopsy is associated with a substantial risk of morbidity and mortality. However, none of the patients with abnormal platelet function had episodes of spontaneous bleeding, but patients may suffer from severe hemorrhage after organ biopsy [23]. Thus, direct sequencing of VPS33B and VIPAR is an alternative method to provide molecular diagnosis in ARC patients.

δ-Storage Pool Disease

δ-Storage pool deficiency (δ-SPD) can develop isolated or in combination with complex disorders such as HPS, CHS, WAS, or thrombocytopenia-absent radius (TAR) syndrome.

Typically, δ-SPD is associated with reduced adenine nucleotide (AN) and serotonin levels while ABCC4 (ATP-binding cassette, sub-family C, member 4 protein) is quantitatively normal. However, recently, patients with a δ-SPD-like phenotype were described demonstrating absence of ABCC4 as well as reduced AN but normal serotonin levels. The authors postulate that impaired expression of ABCC4 mediates the defect in AN storage [27]. However, the genetic basis of the new δ-SPD phenotype remains to be determined.

Hermansky-Pudlak Syndrome

Introduction

HPS, a rare autosomal recessive disorder, was first described by the Czechoslovakian physicians Hermansky and Pudlak in 1959 [28]. They reported on two unrelated patients with oculocutaneous albinism, congenital nystagmus, lifelong bleeding tendency, and unusual pigmented macrophages in bone marrow and lymph nodes. In addition, one patient had interstitial pulmonary fibrosis and died at the age of 34 years.

Since then, HPS has been recognized as a group of genetically distinct diseases resulting from abnormal formation or trafficking of intracellular vesicles. The specific organelles affected in HPS are the lysosomes and lysosome-related organelles (LROs), such as the melanosomes and the platelet dense bodies, which all share certain integral membrane proteins [29, 30]. Impairment of melanosome formation results in oculocutaneous albinism [31] and absence of platelet dense bodies causes a bleeding diathesis. Most probably, due to mistrafficking of a subset of lysosomes, some HPS patients accumulate ceroid lipofuscin, an amorphous lipid-protein complex thought to be stored within cellular lysosomes, leading to granulomatous colitis or severe pulmonary fibrosis.

Patients of nearly all ethnic groups have been diagnosed with HPS. However, this disorder is frequent in Puerto Rico and in an isolated mountain village high in the Swiss Alps [32, 33].

Pathophysiology

While at least 15 distinct genes were cloned in the mouse, in humans 8 genes (HPS1HPS8) have been found causing hypopigmentation and platelet storage pool deficiency. It is likely that additional human HPS genes will be discovered, corresponding to the known mouse strains. All HPS proteins are associated in multi-protein complexes essential for biogenesis and intracellular trafficking of LROs [34] (fig. (fig.1).1). The defined function of the particular subunits of these multi-protein complexes is not yet determined. The BLOC-1 (biogenesis of lysosome-related organelle complex-1) includes as subunits HPS7 (Dysbindin), HPS8 (BLOS3), and the mouse gene products of pallidin, muted, cappuccino, snapin, BLOS1 and BLOS2. BLOC-2 contains HPS3, HPS5, and HPS6. BLOC-3 involves HPS1 and HPS4 as subunits. The adapter protein complex AP-3 comprises the HPS2 (β3A)-, δ-, μ3- and σ3-subunits. Mutations within particular HPS genes can lead to dysfunction of the corresponding protein complex and thus to defective maturation of melanosomes and platelet dense bodies. The human HPS subtypes (HPS1–HPS8) have in part different clinical features. Patients with those defects of HPS proteins that belong to the same multi-protein complex (e.g. BLOC-3) show a similar clinical HPS phenotype (HPS1, HPS4) (table (table22).

Table 2
Hermansky-Pudlak syndrome (HPS) subtypes and clinical phenotypesa

Clinical Manifestations

All HPS phenotypes present with oculocutaneous albinism, decreased visual acuity, congenital nystagmus, and mild to severe bleeding symptoms including easy bruising, epistaxis, petechiae, and prolonged bleeding after surgery or trauma. Skin diseases can include solar keratoses, squamous cell and basal cell carcinoma. HPS1 and HPS4 patients may additionally show restrictive lung disease (78% of HPS1 patients / 14% of HPS4 patients) or granulomatous colitis (15%/43%) [35].

Neutropenia and susceptibility to recurrent infections, primarily respiratory illness, have been exclusively observed in HPS2 patients so far. In addition, hip dislocations secondary to dysplastic acetabulae, neurological abnormalities including poor balance, and conductive hearing loss can occur in HPS2 patients. So far, one patient with HPS2 who developed fulminant hemophagocytic lymphohistiocytosis (HLH) has been described [36].

HPS3 is clinically mild compared with HPS1. Interestingly, most HPS5 patients demonstrate elevated cholesterol and triglyceride levels as well as increased creatinine clearance. The first three HPS6 patients did not show severe phenotypes. However, a recent study reports on a 36-year-old female patient with a history of multiple abdominal surgeries requiring several red blood cell and platelet transfusions, four miscarriages, endometriosis, heavy menses, urinary and rectal incontinence with neurogenic bladder dysfunction, frequent migraines, and hearing loss [37]. A 13-year-old patient presented with global developmental delay with a handicap in both motor function and speech/language. A 52-year-old man has a history of esophageal dysmotility, hiatal hernia, and other gastrointestinal complications including gastro-esophageal reflux disease and dysphagia [37].

The only known HPS7 patient, a 48-year-old Portuguese woman, showed mild shortness of breath on exertion and reduced lung compliance. However, pulmonary function and computed tomography (CT) chest scans were normal [38]. Interestingly, DTNBP1 (dystrobrevin-binding protein 1, HPS7) gene variants were shown to be associated with schizophrenia; however, this correlation is controversial [39, 40]. A Pakistani family with several HPS8 patients, all carrying the same mutation, did not demonstrate further clinical complications except the common clinical HPS phenotype (bleeding symptoms, oculocutaneous albinism, decreased visual acuity) [41].

Diagnosis

Striking clinical symptoms in HPS patients are the tyrosinasepositive oculocutaneous albinism, nystagmus, decreased visual acuity, and a bleeding diathesis (fig. (fig.2A).2A). Bleeding time is prolonged. Electron microscopy and peripheral blood smear should reveal normal platelet count with absent or few platelet dense bodies. Platelet agglutination/aggregation after stimulation with ristocetin, ADP, collagen, epinephrine, and arachidonic acid typically shows a significantly impaired second wave. HPS patients’ platelets demonstrate the absence of platelet δ-granule secretion whereas α-granule secretion is normal (fig. (fig.2B).2B). Molecular genetic analysis allows the confirmation of the diagnosis as well as the classification into a particular HPS subtype (HPS1–8) which is important for therapy and prognosis.

Fig. 2
Clinical phenotype of a HPS patient. A Photo of a HPS1 patient demonstrating oculocutaneous albinism. B Expression of CD63 agonist on patient's platelets showing impaired δ-granule secretion was detected by flow cytometry.

Chediak-Higashi Syndrome

Introduction

Sato (1955) reported ‘Chediak and Higashi's disease’, the probable identity of a new leukocyte anomaly (Chediak) and congenital gigantism of peroxidase granules (Higashi) [42]. Donohue and Bain, using the specific designation CHS, described a lethal familial disease with anomalous inclusions in the leukocytes and constitutional stigmata [43]. In CHS, a rare autosomal recessive disease, the bleeding diathesis is associated with severe immunologic defects and progressive neurological dysfunction if the patient survives to adulthood.

Pathophysiology

The CHS gene (LYST; lysosomal trafficking regulator) was identified as responsible for CHS [44, 45]. The LYST protein regulates LRO size and movement, although its defined role is not known yet. LYST is predicted to be a cytosolic protein that mediates membrane interactions. Multiple LYST frameshift and nonsense mutations were initially described resulting in a truncated CHS protein and a severe phenotype [46, 47]. Rarely, missense mutations are associated with a milder form of the disease.

Clinical Manifestations

Like HPS, CHS is also characterized by oculocutaneous albinism and dense granule deficiency leading to platelet disorder and prolonged bleeding tendency. In addition, CHS patients present with severe immunodeficiency leading to life-threatening bacterial infections. The clinical picture of CHS is similar to that of HPS2. In the so-called accelerated phase of CHS, approximately 85% of CHS patients develop HLH with fever, anemia, neutropenia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. If CHS patients survive until adulthood, they develop neurological defects including neuropathies, autonomic dysfunction, atrophy, sensory deficits, cerebellar signs, seizures, and cognitive defects. Only hematopoietic stem cell transplantation (HSCT) has been shown to improve the long-term outcome of this otherwise fatal disease [48]. In contrast to the immunological disorders, the neurological symptoms seem not to be prevented by HSCT.

Diagnosis

The hallmark of CHS is the presence of giant inclusion bodies in a variety of granule-containing cells (fig. (fig.3).3). Lysosomes, melanosomes, platelet dense granules, and cytolytic granules are affected. Platelet counts are normal. Interestingly, the secondary wave of platelet aggregation is impaired and platelets show an increased ATP- to ADP-ratio and a decreased amount of serotonin and calcium. Molecular genetic analysis of the LYST gene allows the confirmation of the diagnosis. The type of the LYST mutation may influence the severity of the disease.

Fig. 3
Blood smear of a CHS patient demonstrating giant inclusion bodies in the cytoplasm of leukocytes.

Griscelli Syndrome

Introduction

Griscelli syndrome (GS), a rare autosomal recessive disorder, was first described in 1978 [49, 50]. GS is characterized by pigmentary dilution of the skin, a silver-grey shine of the hair, large clumps of pigment within hair shafts (fig. (fig.4),4), and the accumulation of large and abnormal end-stage melanosomes in the centre of melanocytes.

Fig. 4
Large pigmentary clumps in the hair shaft of a GS patient.

Patients with GS can be categorized in 3 types. Type 1 (GS1) manifests with severe primary neurological impairment including developmental delay and mental retardation. Mutations within the MYO5A (myosin Va) gene, which encodes an organelle motor protein, myosin Va (MYO5A), were identified as causing GS1 [51, 52]. Type 2 (GS2) is associated with potentially lethal immunodeficiency and HLH. GS2 is associated with mutations in RAB27A which encodes a small GTPase protein (Rab27a) involved in the function of the intracellular-regulated secretory pathway [53]. Type 3 (GS3) only has dermatological manifestations and results from mutations in the gene encoding melanophilin (MLPH) [52].

Pathophysiology

Inside the melanocytes, mature melanosomes are transported from the cell centre to the cell periphery. This bidirectional transport takes place along microtubule tracks and the sublemmal actin-network. The latter process involves the processive motor protein MYO5A, which attaches to melanosomes through interaction with MLPH and Rab27a [54]. Several molecular studies have already revealed that mutations within any member of the Rab27a-MLPH-MYO5A tripartite complex cause one of the three GS subtypes.

MYO5A functions as a dimeric, actin-based molecular motor protein containing ATP-binding sites as well as actinbinding capability. The ATP-binding sites can convert energy through ATP hydrolysis, generating a mechanical movement along the actin filaments. Rab27a, a member of the Ras super family of small GTPases, is essential for membrane trafficking by targeting, docking, and fusion of transport vesicles with their appropriate acceptor membranes in different mammalian cell types. In addition to its role in melanocytes, the Rab27a protein also functions in granule release within cytotoxic T lymphocytes. Therefore, defective Rab27a in GS2 patients also leads to immunodeficiency. The recently identified MLPH belongs to a novel class of the family of the synaptotagmin-like protein (SLP). MLPH is the specific linker protein between MYO5A and Rab27a.

Clinical Manifestations

In patients with GS1 (hypotonia, statomotoric, and mental retardation, without a history of infections), MYO5A mutations were identified [55]. Since the second series of Elejalde syndrome patients [56] had clinical and histologic features similar to GS1, it was suggested that in some patients Elejalde syndrome and GS1 represent the same entity [57, 58]. Patients with Elejalde syndrome as well as with GS1 present with mental retardation and profound neurologic dysfunction including severe muscular hypotonia, ocular alterations, and seizures.

As the original patients described by Griscelli manifested partial albinism, frequent pyogenic infections, and acute episodes of fever, neutropenia, and thrombocytopenia, these patients were expected to have GS2 [49]. While most GS2 patients also develop uncontrolled T lymphocyte and macrophage activation syndrome, often associated with HLH, leading to death in the absence of HSCT [53], some show severe neurologic impairment early in life without apparent immune abnormalities. Although the ashen mouse which lacks Rab27a presents with platelet storage pool deficiency including prolonged bleeding time [59], reports on prolonged bleeding in GS2 patients were missing.

The neurologic manifestation in GS1 and GS2 seems to have a distinct origin: several reports established that neuroslogic manifestations in patients with GS caused by RAB27A mutations (GS2) were related to lymphocyte infiltration of the CNS [53, 55], whereas patients with GS caused by MYO5A mutations (GS1) exhibited a primary neurologic disease unrelated to the hematopoietic lineage [56].

In one patient with hypopigmentation without any immunologic or neurologic manifestations, a homozygous mutation in the MLPH gene was identified and referred to GS3 [52]. So far, it is unclear why GS3 only presents with hypomelanosis but not with neurologic or immunologic defects.

Diagnosis

Three types of human GS are recognized, all displaying pigment dilution of the hair and skin. Different subtypes include neurological defects (GS1) or severe immunodeficiency with a defective cytotoxic activity of lymphocytes (GS2). GS patients do not have an obvious bleeding tendency; whether they have a defect in platelet δ-granules is not known. Differential diagnosis of GS2 with HPS2 can be difficult.

αδ-Storage Pool Disease

In the combined α- and δ-storage pool disease (αδ-SPD), δ-granules are always decreased, while the number of α-granules varies. Patients’ platelet population is typically inhomogeneous; some platelets may have significantly more α- and/or δ-granules than others [60].

X-Linked Dyserythropoietic Anemia with Thrombocytopenia/X-Linked Macrothrombocytopenia

Introduction

The X-linked dyserythropoietic anemia with thrombocytopenia/ X-linked macrothrombocytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe and can include platelet dysfunction, β-thalassemia, neutropenia, and congenital erythropoietic porphyria. Since the disorder is inherited in an X-linked dominant matter, all male family members carrying the mutated allele are affected. Several inherited mutations in GATA1 are associated with distinct clinical phenotypes such as ‘familial dyserythropoietic anemia with thrombocytopenia’ [61, 62], ‘X-linked macrothrombocytopenia’ (with or without anemia), and ‘congenital erythropoietic porphyria’ [63].

Pathophysiology

Vertebrate erythroid cells contain the tissue-specific transcription factor GATA1 as the founding member of the GATA factor family, which is known to regulate the expression of a large number of genes in multiple cell types. Since GATA1 has been shown to be essential for normal hematopoiesis, especially for erythropoiesis and megakaryopoiesis, mutations within GATA1 cause characteristic hematologic disorders. Both inherited and acquired hematological diseases due to GATA1 mutation have been reported in several families [64]. A low transcription of the GATA-1 target genes, GPIbα and GPIX, is a characteristic of GATA-1 pathologies.

Clinical Manifestations

The clinical picture of X-linked dyserythropoietic anemia with thrombocytopenia/X-linked macrothrombocytopenia varies. Thrombocytopenia was observed in all patients, however, anemia did not occur in all patients [65, 66]. Typically, in infancy the patients present with easy bruising, mucosal bleeding, and epistaxis. Female carriers may have menorrhagia. Anemia ranges from minimal (mild dyserythropoiesis) to severe (hydrops fetalis). Severe hemorrhage and/or erythrocyte transfusion dependence may be present lifelong. In a milder phenotype, anemia and the risk for bleeding decrease spontaneously with age.

Diagnosis

Diagnostic laboratory findings usually include macrothrombocytopenia and normochromic anemia. In contrast to δ-SPD, laboratory analyses revealed impaired primary platelet aggregation in addition to the absence of secondary aggregation. Because of the lack of specificity in aggregation studies, the diagnosis also requires measurement of α- and δ-granule contents and/or electron microscopy to confirm the absence of platelet α-granules and the dysplastic features in platelets and MKs [67]. Family history is important as according with X-linked inheritance.

Wiskott-Aldrich Syndrome

Introduction

WAS is a rare X-linked recessive disease characterized by eczema, thrombocytopenia, increased risk of developing autoimmune disease and malignancies, and bloody diarrhea [68]. The clinical picture results from defective platelet and lymphocyte function. The immune deficiency is caused by decreased antibody production, although T cells are also affected. Isolated X-linked thrombocytopenia (XLT) with small platelets but without immunodeficiency is a clinically mild allelic variant. The three German patients originally described by Wiskott in 1937 died early in life from intestinal bleeding and sepsis [69]. In 1994, WAS was linked to mutations in a gene on the short arm of the X chromosome, encoding Wiskott-Aldrich syndrome protein (WASP). A frameshift mutation in the WAS gene was found in family members of the originally described patients [70]. The symptomatic individuals were all male, consistent with an X-linked recessive inheritance.

Pathophysiology

WAS could be considered as a pathology of the cytoskeleton. The WAS gene, encoding for the protein WASP, is mainly expressed in hematopoietic cells and displays a key regulator of actin polymerization. WASP seems to be involved in signal transduction pathways in which tyrosine phosphorylation and adapter protein function have been suggested. Deficiency of WASP induces premature proplatelet formation in the bone marrow where a lack of actin-rich podosomes abrogates MK migration [71]. Both classical and mild forms of WAS result from loss-of-function mutations of WAS, of which hundreds have been described. WAS mutations that confer constitutive WASP activation with increased actin polymerizing activity give rise to an X-linked form of neutropenia with an intrinsic disruption of myelopoiesis through defective mitosis and cytokinesis [72].

Clinical Manifestations

Patients with WAS present with microthrombocytopenia, moderate to severe eczema, and recurrent infections. Autoimmune disorders are also found in WAS patients. WAS platelets, which are small and do not function properly, are removed by the spleen leading to low platelet counts. Splenomegaly is not an uncommon finding. Platelets may increase in size following splenectomy [73, 74].

Diagnosis

The diagnosis is made on the basis of clinical parameters, blood smear, and low immunoglobulin levels. Typically, serum immunoglobulin (Ig) M level is reduced while IgG and IgA levels are normal or occasionally elevated. IgE levels may be elevated [75]. WAS platelets aggregate poorly and have a low granule number. T lymphocytes also show impaired function. Decreased levels of WASP and/or confirmation of a causative mutation provide the most definitive diagnosis.

Disclosure

The authors declared no conflict of interest.

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