Richard A. McPherson MD, MSc , in Henry's Clinical Diagnosis and Management by Laboratory Methods , 2022
May-Hegglin Anomaly
This is characterized by pale-blue inclusions resembling Döhle bodies in neutrophils, by giant platelets and, in some persons, by thrombocytopenia(Fig. 34.3). The inclusions are larger and more prominent than the Döhle bodies found in infections. They have been described in eosinophils, basophils, and monocytes as well as in neutrophils. The blue staining of the inclusions is due to RNA. Granulocyte function is normal. May-Hegglin is a rare autosomal-dominant condition involving the nonmuscle myosin heavy chain 9 gene (MYH9) linked to chromosome 22q12-13. The mutations appear to alter the assembly and stability of myosin and may be responsible for the underlying pathophysiology and changes seen in leukocyte and platelet structure and function. Varied mutations inMYH9 are responsible for a phenotypic spectrum of illness, including May–Hegglin anomaly, Sebastian, Fechtner, and Epstein platelet syndromes (Pecci et al., 2014;Saposnik et al., 2014).
Disorders affecting megakaryocytes and platelets
JG White , in Blood and Bone Marrow Pathology (Second Edition), 2011
May–Hegglin anomaly (MHA)
May–Hegglin anomaly (MHA) has an autosomal dominant pattern of inheritance.120,121 Platelet counts are reduced to about 50 000/mm3 in these patients, but the MPV is 5–7 times that of normal cells (Fig. 32.25). If one multiplies the platelet number by MPV to obtain the platelet mass in circulating blood, there is little difference between the values obtained in MHA and normal individuals.78 Thus, patients with MHA are not really thrombocytopenic. The number of megakaryocytes present in bone marrow of MHA patients is not increased, and their mean volume is similar to that of normal megakaryocytes.
A characteristic feature of MHA, in addition to giant platelets, is the presence of spindle-shaped bodies in all types of granulocytes and in monocytes122 (Figs 32.25–32.27). The inclusions are referred to as Dohle bodies, but are not to be confused with the enlarged azurophilic granules in neutrophils of patients with severe infections123 (Fig. 32.28), even though they are referred to by the same name. Dohle bodies in MHA leukocytes are basophilic on Wright-stained blood smears and react positively when stained with methylgreen pyronine.124 The immature nature of the inclusions suggested by these staining reactions is borne out in ultrastructural studies.125 Short segments of RER, clusters of ribosomes, and a framework of parallel filaments are the principal constituents of May–Hegglin inclusions viewed in thin section126 (Fig. 32.27). The filaments are 8–9 nm in diameter and resemble intermediate filaments found in many cell types.127 Light and electron microscopic studies suggest that MHA inclusions result from a failure to completely disassemble and resorb the RER and ribosome clusters characteristic of early states in the development of mature circulating cells.
MHA inclusions may also be related in some way to giant platelet formation in the megakaryocyte128 (Fig. 32.29). Although channels of the demarcation membrane system (DMS) derived from the surface membrane may appear in primitive megakaryocytes, the tortuous mass of membrane does not reach its full stage of development in the form of platelet-sized fields until protein synthesis is virtually complete.118 At this stage the channels of RER have ordinarily been converted to smooth endoplasmic reticulum (SER), and are distributed evenly throughout the cytoplasm. Only by removal or drastic modification of the massive membrane barrier imposed by the RER is it possible for the surface-derived DMS to penetrate into and subdivide the deepest recesses of megakaryocyte cytoplasm.
Yet the mere disappearance of one membrane system and development of another does not explain the fine balance of interaction between the DMS and SER. In every platelet, close associations between the surface-derived channels and residual elements of SER can be identified. We have called these specialized associations membrane complexes (MC).53 Since MCs are intrinsic features of normal platelet anatomy, it is clear that their development in the parent megakaryocyte requires a balanced distribution of elements from the two channel systems throughout the cytoplasm.
What would happen if the timing of these events leading to sequestration of megakaryocyte cytoplasm was thrown off? If demand for platelets was greatly increased so they had to be delivered from immature megakaryocytes to circulating blood before completion of protein synthesis, what would they look like? One would expect their cytoplasm to be less mature and to contain at least some RER. Indeed, the platelets in the peripheral blood of patients with idiopathic thrombocytopenic purpura (ITP) often have this appearance. Also, on the basis of the rationale given above, one would expect ITP platelets to be large. Indeed they are, and the name 'megathrombocyte' was coined to describe them.129 Thus, shortening of the time interval for development and interaction of the DMS and SER can result in large platelets with immature features.
MHA platelets, despite their large size, do not resemble the megathrombocytes of ITP (Fig. 32.30). The giant MHA thrombocytes are almost uniformly huge, while ITP platelets are irregular in size, with only a few large cells present in peripheral blood.130 Characteristics of immaturity are lacking in the MHA platelets. Organelles, including alpha granules, lysosomes, dense bodies, mitochondria and peroxisomes, are present in normal numbers and distribution. The basophilia and occasional segments of RER found in left-shifted ITP129 platelets are absent in MHA cells.
In fact, the only apparent difference between huge MHA platelets and normal-sized cells is the increased amount of internalized membrane and the size of the membrane complexes (Figs 32.30 and 32.31). Clearly, there is no defect in the ability of MHA megakaryocytes to invaginate the surface membranes and form the DMS; nor does there appear to be a problem of interaction between DMS and SER to form membrane complexes. These intricate mazes formed by the two channel systems in MHA megakaryocytes are very prominent in circulating platelets. Thus, the membrane systems and their interactions appear to be involved in some way in the pathogenesis of the giant platelets of the MHA.131
The precise mechanism is still uncertain. Since both the DMS and SER are fully developed in MHA megakaryocytes, an imbalance of some form in their interaction would seem to be a likely possibility.132 The inclusions in MHA leukocytes may provide a clue to the defective process in the megakaryocytes. MHA inclusions appear to represent collections of RER, ribosomes, and filaments which have failed to disappear during the maturation sequence. Their tendency to remain in aggregates into mature stages may be reflected in developing MHA megakaryocytes. If channels of RER remain associated for prolonged periods during conversion to SER, the interaction with the wave of advancing DMS could be perturbed. As a result, excessive interaction may occur between the two types of channels to form large membrane complexes with a consequent reduction in the interactions of DMS to form sequestration zones. The imbalance could result in giant platelets and increased membrane complex formation, precisely the characteristic features of circulating MHA platelets.
There is a second way in which persistence of channels of RER or clusters of SER could result in giant platelet formation. As mentioned above, the RER during the stage of protein formation presents a formidable barrier to penetration by DMS pushing in from the cell surface. If it fails to disassemble, even though conversion to SER takes place, barriers may remain, and result in a decreased number of very large sequestration zones.132
There may be other possible ways in which an imbalance of membrane interaction could result in evolution of the giant MHA platelets. However, the two suggested have the advantage of bringing together the pathogenesis of the MHA inclusions in leukocytes and the development of giant platelets in megakaryocytes. Some of the individuals with MHA have prolonged bleeding times and hemorrhagic symptoms which cannot be explained on the basis of reduced platelet numbers alone. However, tests of platelet function and aggregation have, in general, been normal and the platelet defect responsible for excessive bleeding in MHA has not been defined.127
Basil J. Zitelli MD , in Zitelli and Davis' Atlas of Pediatric Physical Diagnosis , 2018
White Blood Cells
Increases, decreases, and physical alterations in WBCs are common pediatric problems. In general, these are due to increases or decreases in specific types of WBCs. Most cases of neutrophilia (Fig. 12.37), neutropenia, eosinophilia (Fig. 12.38), lymphocytosis (Fig. 12.39), lymphopenia, or monocytosis (Fig. 12.40) in the pediatric population do not represent primary hematologic disorders. These abnormalities often represent bone marrow responses to varied conditions. Normal values for total WBC number and differential counts are age related (Table 12.5). African-American patients may have lower granulocyte counts than white patients of the same age.
Neutropenia is one of the most common white cell disorders seen in pediatrics. Differing levels of neutropenia, reflected by a diminished absolute neutrophil count (ANC), confer differing risks of infection. Neutropenia can be seen in response to medications, in congenital deficiencies (Kostmann syndrome), or in response to infections. Autoimmune neutropenia develops in response to antibody-mediated destruction of neutrophils, most commonly in a postinfectious setting. This is generally self-limited and resolves in a matter of months. Chronic benign neutropenia has an unclear etiology but can persist for years. Its name can be somewhat misleading, because children are still at risk for severe, and potentially fatal, infections. Cyclic neutropenia, a disorder in which the ANC drops at regular intervals, is extremely rare but can be tested for on a genetic level. During periods of neutropenia, children may develop mucosal ulcerations or breakdown. Children with neutropenia generally do not require isolation or prophylactic antibiotics on a regular basis. However, if febrile, those children do warrant prompt medical evaluation to rule out a more serious infection. Hormonal stimulation with granulocyte colony-stimulating factor (G-CSF) to increase the ANC usually is required only in settings of severe infections or prominent symptoms.
Morphologic abnormalities of the granulocytic series, although less common than neutropenia, may provide clues to the diagnosis. The hypersegmented neutrophil, which may be an early clue to vitamin B12 deficiency, has been noted previously (seeFig. 12.10). This needs to be distinguished from familial hypersegmentation by looking at the peripheral smears of family members. On occasion, mature neutrophils may be abnormally large in members of a given family—so-calledhereditary giant neutrophils. The Pelger-Huët anomaly (Fig. 12.41) is usually a benign morphologic inherited anomaly in children, but it is sometimes acquired in adults as an association with leukemia and lymphoma. Increased numbers of nuclear appendages may also be seen in the neutrophils of patients with trisomy 13 (Fig. 12.42). These, however, may be difficult to distinguish from normal neutrophil "drumsticks," which are nuclear appendages that occur in 2% to 10% of neutrophils of normal girls.
Megakaryocyte Development and Platelet Formation
Joseph E. ItalianoJr., John H. Hartwig , in Platelets (Second Edition), 2007
3 Nonmuscle Myosin Heavy Chain A
May-Hegglin anomaly (MHA), the most common form of inherited giant platelet disorders, was first described by May in 1909161 and later by Hegglin162 in 1945. This rare autosomal dominant platelet disorder is characterized by giant platelets, thrombocytopenia, leukocyte inclusions, and mild bleeding tendency (see Chapter 54). Giant platelets have a dispersed organization of microtubules. The disease appears to be the result of a mutation in the gene encoding nonmuscle heavy chain 9 (MYH9), which encodes a 224-kD polypeptide that makes up 2 to 5% of the total platelet protein.84,85,163 Myosin II is an ATPase motor molecule that binds to actin filaments and generates force for contraction. Each myosin has two heads and a long, rodlike tail. The major function of the rodlike tail of myosin II is to permit the molecules to assemble into bipolar filaments. This assembly is crucial for the function of myosin II, and the hematological phenotype of MHA may be the result of a block in the polymerization of myosin II into filaments during megakaryocyte development and platelet formation. The most common mutations in MYH9 — lesions in the rod — cause defects in nonmuscle myosin IIA assembly in vitro.164 Mutations in MYH9 are also responsible for Fechtner and Sebastian syndromes, which are also autosomal dominant macrothrombocytopenias characterized by thrombocytopenia, leukocyte inclusions, and giant platelets (see Chapter 54).85,163 In contrast to MHA, Fechtner syndrome is associated with cataracts, nephritis, and hearing disability.165 Sebastian syndrome can be differentiated from MHA by ultrastructural leukocyte inclusion properties.166
Assessment of Thrombocytopenia, Thrombocytosis, and Platelet Morphology
A blood smear is essential to validate the cell count whenever an automated count shows thrombocytopenia (e.g., a count <60 × 109/L) (Chapter 163). This should be done quickly before patient management is altered, such as by postponing surgery or initiating further diagnostic workup. A platelet transfusion should never be given for an unexpected thrombocytopenia without microscopic confirmation of the count. A factitiously low platelet count is often the result of in vitro platelet aggregation (Chapter 162) and is occasionally the result of platelet satellitism, possibly also with platelet phagocytosis. To detect aggregates reliably, the edges and the tail of the smear should be examined. The presence of fibrin strands also suggests the activation of coagulation and an erroneous platelet count.
If a low platelet count is confirmed, the film may give clues to the cause (Chapter 163).12c Giant platelets (Figs. 148-22 and148-23) occur in a number of inherited thrombocytopenias, including Bernard-Soulier syndrome and MYH9-related disorders (the May-Hegglin anomaly and related conditions).13 Small platelets are less common but are a feature of Wiskott-Aldrich syndrome and familial platelet disorder with propensity to myeloid malignancy. Agranular platelets occur in the gray platelet syndrome and platelets with a reduced number of larger than normal granules are seen in Jacobsen/Paris-Trousseausyndrome. The presence of May-Hegglin inclusions (Döhle-like bodies; seeFig. 148-19) in neutrophils indicates that the cause of the thrombocytopenia is a mutation inMYH9. In acquired thrombocytopenias, increased platelet turnover is often accompanied by the presence of large platelets, whereas bone marrow failure is associated with platelets of normal size. It is important to look for red cell fragments to confirm or exclude a diagnosis of thrombotic thrombocytopenic purpura and atypical hemolytic-uremic syndrome in any patient with the apparent recent onset of thrombocytopenia; because platelet transfusions are usually contraindicated in these conditions, the smear should be examined before platelet transfusion is contemplated. Occasionally the smear reveals clinically unsuspected malaria.14 The smear of any patient with the apparent recent onset of severe thrombocytopenia should be examined carefully for evidence of acute promyelocytic leukemia; the leukemic cells may be infrequent in the circulating blood. Hemorrhagic manifestations and a low platelet count can also be indicative of meningococcal septicemia; in some patients, organisms are seen in the blood smear and the diagnosis is confirmed; in other patients, only marked toxic changes in neutrophils are detected.
Thrombocytosis should also be confirmed on a smear. Factitiously elevated counts may be the result of the presence of red cell fragments (in microangiopathic or mechanical hemolytic anemia, burns, or accidental in vitro heating of the blood sample), white cell fragments (in acute leukemia and, less often, in lymphoma), cryoglobulin precipitates, or microorganisms (particularlyCandida species). If the count is confirmed, the blood smear may be useful to indicate a likely cause (e.g., features of hyposplenism or the presence of basophilia in a myeloproliferative disorder).
Megakaryocyte Development and Platelet Formation
Joseph E. ItalianoJr., John H. Hartwig , in Platelets (Third Edition), 2013
4 Nonmuscle Myosin Heavy Chain A
May–Hegglin anomaly (MHA), the most common form of inherited giant platelet disorders, was first described by May in 1909178 and later by Hegglin179 in 1945. This rare autosomal dominant platelet disorder is characterized by giant platelets, thrombocytopenia, leukocyte inclusions, and a mild bleeding tendency (see Chapter 47). The giant platelets have a dispersed organization of microtubules. The disease is the result of a mutation in the gene encoding nonmuscle heavy chain 9 (MYH9), which encodes a 224-kD polypeptide that makes up 2 to 5% of the total platelet protein.89,90,180 Myosin II is an ATPase motor molecule that binds to actin filaments and generates force for contraction. Each myosin has two heads and a long, rod-like tail. The major function of the rod-like tail of myosin II is to permit the molecules to assemble into bipolar filaments. This assembly is crucial for the function of myosin II, and the hematological phenotype of MHA may be the result of a block in the polymerization of myosin II into filaments during megakaryocyte development and platelet formation. The most common mutations in MYH9—lesions in the rod—cause defects in nonmuscle myosin IIA assembly in vitro.181 Mutations in MYH9 are also responsible for Fechtner and Sebastian syndromes, which are also autosomal dominant macrothrombocytopenias characterized by thrombocytopenia, leukocyte inclusions, and giant platelets (see Chapter 47).90,180 In contrast to MHA, Fechtner syndrome is associated with cataracts, nephritis, and hearing disability.182 Sebastian syndrome can be differentiated from MHA by ultrastructural leukocyte inclusion properties.183
Recent studies have implicated myosin IIA in constraining proplatelet formation until megakaryocytes reach full maturity. Loss of myosin IIA function via dominant inhibitory mutations in humans, targeted gene disruption in mice, or genetic manipulation of megakaryocytes appears to speed up proplatelet production.184–186 As a result, production of platelets is disorganized and generates platelets that fluctuate broadly in shape, content, and diameter. These observations also indicate that the Rho-ROCK-myosin light chain pathway regulates myosin IIA.187
Molecular Basis of Hemostatic and Thrombotic Diseases
Alice D. Ma , Nigel S. Key , in Essential Concepts in Molecular Pathology, 2010
The MYH9-Associated Disorders
The May-Hegglin anomaly is the prototype of a family of disorders now known to be due to a defect in the MYH9 gene. May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias that are distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear inclusions known as Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes.
Molecular Basis of Hemostatic and Thrombotic Diseases
Karlyn Martin MD , ... Nigel S. Key MD , in Molecular Pathology (Second Edition), 2018
The MYH9-Associated Disorders
The May-Hegglin anomaly is the prototype of a family of disorders due to a defect in the MYH9 gene [46]. Other MYH9 gene disorders include Sebastian syndrome [47], Fechtner syndrome [48], and Epstein syndrome [49]. Autosomal dominant mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all of these syndromes. The hallmark of these disorders is macrothrombocytopenia and characteristic Dӧhle-like inclusions within the leukocytes. The various disorders are distinguished by different combinations of clinical and laboratory findings. The Fechtner syndrome includes the triad of sensorineural deafness, ocular abnormalities, and nephritis seen in Alport syndrome [48]. Epstein syndrome differs from Fechtner syndrome by the lack of cataract and the lack of leukocyte inclusions [49]. Both the May-Hegglin anomaly and the Sebastian syndrome manifest macrothrombocytopenia with leukocyte inclusions, but may be distinguished by ultrastructural analysis of the inclusions: in the May-Hegglin anomaly, the Dӧhle-like bodies are composed of cytoplasm surrounding parallel microfilaments with clustered ribosomes, whereas the inclusion bodies in the Sebastian syndrome are composed of highly dispersed microfilaments with few ribosomes [47].
S. Nagalla , P.F. Bray , in Reference Module in Biomedical Sciences, 2014
Inherited Thrombocytopenia with Large Platelets
May–Hegglin anomaly, Fechtner, Sebastian, and Epstein syndromes are a part of the MYH9-related disorders. Affected individuals have a mutation in the MYH9 gene, which encodes for nonmuscle myosin heavy chain IIA. These are autosomal dominant disorders that are associated with macrothrombocytopenia. The platelet function is usually normal in these disorders. In addition to the large platelets, Döhle-like inclusion bodies seen in some of the white blood cells (neutrophils, monocytes, and/or eosinophils). These disorders may be associated with other phenotypic abnormalities like renal problems, cataracts, and sensorineural hearing loss. Thrombocytopenia is usually mild to moderate, but rarely may be severe. Clinical bleeding is usually minimal because of the mild-to-moderate decrease in platelet counts with normal platelet function. Patients are usually supported with platelet transfusion, as needed. Thrombopoietin-receptor agonists (TPO-RA) may play a role in the treatment of these disorders.
2.
Bernard–Soulier syndrome (BSS)
BSS is an autosomal recessive bleeding disorder caused by quantitative or qualitative defects in the platelet GPIb-IX-V receptor. The GPIb-IX-V receptor complex is composed of gene products from GP1BA, GP1BB, GP9, and GP5 and most BSS mutations involve GPIbα, the platelet VWF receptor. BSS patients have macrothrombocytopenia and LTA shows absent or decreased agglutination of platelets to ristocetin. Affected patients have mild-to-moderate bleeding and are usually transfused platelets for bleeding or procedures.
3.
Platelet-type von Willebrand disease and von Willebrand disease type 2B can be associated with macrothrombocytopenia. Platelet type von Willebrand disease is an autosomal dominant disorder resulting in a gain-of-function mutation in the GPIbα receptor causing increased binding of platelets to the VWF, platelet clumping, and mild-to-moderate macrothrombocytopenia. LTA demonstrates increased platelet agglutination to low-dose ristocetin. A similar clinical phenotype is seen in type 2B von Willebrand disease, but in this case there is a gain-of-function mutation in ∖WF-causing enhanced binding to GPIbα. These platelets also show increased agglutination to low-dose ristocetin in the LTA. These two disorders are differentiated by doing mixing studies in LTA to determine whether the defect is in the platelets or the plasma.
4.
Other inherited macrothrombocytopenias
Mediterranean macrothrombocytopenia is an autosomal dominant disorder with mutations in GP1BA resulting in mild macrothrombocytopenia. Though Glanzmann thrombasthenia (GT) does not normally cause thrombocytopenia, there are a few GT-like disorders involving mutations in the ITGA2B and ITGB3 genes that can result in platelet dysfunction and thrombocytopenia. β1-tubulin-related and filamin-A-related thrombocytopenias are also autosomal dominant disorders that can result in macrothrombocytopenia. Gray platelet syndrome (GPS) is characterized by the absence of platelet alpha granules and can also result in large platelets with platelet dysfunction. GPS may also result in myelofibrosis and splenomegaly and this disorder can be inherited in an autosomal dominant or recessive fashion. Splenectomy and platelet transfusions are some of the treatments used to raise the platelet count in the affected individuals. Mutations in the GATA-1 gene can lead to macrothrombocytopenia, platelet function defect, and dyserythropoiesis resulting in anemia and thalassemia in some patients. Paris-Trousseau syndrome is an autosomal dominant disorder resulting in macrothrombocytopenia with abnormal platelet granules, facial abnormalities, and psychomotor retardation.
Michelle P. Lambert , Mortimer Poncz , in Platelets (Third Edition), 2013
E MYH9-Related Diseases (May–Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome)
Although May–Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome were previously considered to be separate but overlapping rare syndromes, they are now grouped together because they have all been shown to involve mutations in the MYH9 gene that encodes for the nonmuscle myosin heavy chain IIA (myosin IIA).149–151 Clinically, patients may present at birth with macrothrombocytopenia and spindle-shaped Döhle leukocyte inclusions (Fig. 47-2). These inclusions stain positively for myosin II when immunostaining is performed, suggesting that the abnormal protein precipitates and forms these inclusions.152 In childhood or adult life, patients may develop sensorineural hearing loss, cataracts, and glomerulonephritis that may progress to severe renal failure.153 Thrombocytopenia is usually noted incidentally or on routine screening as patients with MHY9-related disease and does not usually cause a symptomatic bleeding diathesis, although a few patients may have severe bleeding.154 Reports suggest there may be a correlation between the particular mutation and phenotype: mutations of the C-terminal region appear to result in predominantly hematologic manifestations, whereas mutations of the head ATPase domain are more commonly associated with nephropathy or hearing loss.155
Figure 47-2. Peripheral blood smears from a patient with MYH9-related disease.
A. Normal blood smear with a leukocyte present (thin arrow) and platelets (thick arrows). B and C. Blood smears from a patient with MHY9-related disease and a platelet count of 24×109/L and an MPV of 20.6 μm3. Thin arrows indicate blue spindle Döhle bodies in the leukocyte. The thick arrow points to a platelet larger than the adjacent red cell. Hematoxylin and eosin stain, original magnification ×500.
On laboratory evaluation, patients present with variable thrombocytopenia with platelet counts ranging from 10 to 150×109/L.154 Macrothrombocytes are always present, but to a variable degree (Fig. 47-2). Platelets larger than a red cell can vary from 3% to 45% of all platelets.149 Audiometric evaluation identified hearing loss in approximately 75% of patients identified with MHY9-related disease143 and, interestingly, approximately 80% of patients initially diagnosed with MYH9-related develop multiorgan involvement.155 The same study also revealed microscopic hematuria and proteinuria even in patients initially identified as having only hematologic abnormalities;156 therefore, it is important to continue to screen affected individuals for hearing loss and renal disease even if the only obvious phenotype to date has been macrothrombocytopenia. Variable phenotypic expression in this disorder is seen in those with the same mutation and even within the same family.156 Platelet survival is normal although bone marrow examination shows increased numbers of megakaryocytes.157In vitro platelet aggregation studies are usually normal, although shape change as a result of activation may be abnormal.157,158
0 Response to "Study Blue What Abnormal Findings Are Found in Mayhegglin Anomaly"
Post a Comment