Alternative titles; symbols
SNOMEDCT: 712922002; ORPHA: 182050; DO: 0060651;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q12.3 | Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss | 155100 | Autosomal dominant | 3 | MYH9 | 160775 |
A number sign (#) is used with this entry because macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MATINS) is caused by heterozygous mutation in the gene encoding nonmuscle myosin heavy chain-9 (MYH9; 160775) on chromosome 22q12.
Macrothrombocytopenia with or without granulocyte inclusions, nephritis, or sensorineural hearing loss was previously thought to comprise 4 distinct entities with overlapping features: Fechtner syndrome, May-Hegglin anomaly, Epstein syndrome, and Sebastian syndrome. Fechtner syndrome was characterized by the triad of thrombocytopenia, giant platelets, and Dohle body-like inclusions in peripheral blood leukocytes, with the additional Alport syndrome (301050)-like features of nephritis, hearing loss, and eye abnormalities, predominantly cataracts (Peterson et al., 1985). May-Hegglin anomaly was characterized by the triad of thrombocytopenia, giant platelets, and Dohle body-like inclusions in peripheral blood leukocytes. Epstein syndrome was characterized by thrombocytopenia, deafness, and nephritis, and lacked leukocyte inclusion bodies on classic staining of peripheral blood smears. Sebastian syndrome was similar to May-Hegglin anomaly, but had a different ultrastructural appearance of the leukocyte inclusions. Seri et al. (2003) suggested that these 4 disorders were not distinct entities, but rather represented a single disorder with a continuous clinical spectrum because variable phenotypic expression is observed not only between families but also within families having the same MYH9 mutation. In addition, Balduini et al. (2011) noted that all patients present leukocyte inclusion bodies, although of variable size. Seri et al. (2003) proposed the term 'MYH9-related disease' for the disorder; however, an isolated form of nonsyndromic deafness (DFNA17; 603622) is also caused by mutation in the MYH9 gene.
May (1909) described inclusion bodies in granulocytes from the peripheral blood of an asymptomatic 24-year-old woman. Hegglin (1945) observed the triad of thrombocytopenia, giant platelets, and inclusion bodies in the leukocytes in 2 generations of a family. The leukocyte inclusions consisted of cytoplasmic RNA-containing inclusions, so-called Dohle bodies, which can also be seen transiently during acute infections.
Oski et al. (1962) observed the same anomaly in a mother and her 2 children. Of 24 reported cases, 9 had thrombocytopenia.
Jenis et al. (1971) suggested a hypothetical model for the development of the May-Hegglin inclusions based on ultrastructural studies of marrow precursors containing the inclusions. They suggested that the filaments represent completely unfolded, i.e., depolymerized, ribosomes. Similar basophilic inclusions occurred in the Fechtner syndrome.
Epstein et al. (1972) described 2 unrelated families, each with 2 members with macrothrombocytopathia, nephritis, and deafness. In 1 family, a third member, a young child, had the platelet disorder and mild hearing loss. Except for the greater severity in females, the renal disease was indistinguishable from that of X-linked Alport syndrome (301050). Likewise, the high frequency sensorineural hearing loss was similar to that in Alport syndrome. Thrombocytopenia was present with giant platelets showing abnormal ultrastructure and defective adherence to glass, and the bleeding time was prolonged. Aggregation of platelets in response to collagen and epinephrine and release of phospholipids were all impaired, and the release of nucleotide after exposure to collagen was abnormally low.
Parsa et al. (1976) reported another kindred with the triad of hereditary nephritis, deafness, and thrombocytopenia with giant platelets. Electron microscopic studies of megakaryocytes led the authors to suggest that the giant platelets may result from a degenerative process in megakaryocytes leading to nuclear regression and cytoplasmic fragmentation, rather than from the normal blebbing process.
Peterson et al. (1985) reported a family in which 8 members of 4 generations showed nephritis, deafness, congenital cataracts, macrothrombocytopenia, and leukocyte inclusions in various combinations. The authors referred to the disorder as the 'Fechtner syndrome,' presumably from the surname of the family. The family differed from others reported, such as families with Epstein syndrome, in that their hematologic abnormalities included not only macrothrombocytopenia but also small, pale blue cytoplasmic inclusions in the neutrophils and eosinophils. Light microscopic appearance of the inclusions resembled that of toxic Dohle bodies and inclusions of May-Hegglin anomaly, but their ultrastructural appearance was unique. Deafness was high-tone sensorineural. Renal disease ranged from microscopic hematuria to end-stage renal failure necessitating dialysis and kidney transplantation. All affected adults had cataracts. Gershoni-Baruch et al. (1988) reported a second family with Fechtner syndrome; 16 members were affected.
In 6 members of 4 sibships in 3 generations of a kindred, Greaves et al. (1987) described thrombocytopenia with giant platelets. The proband was a 38-year-old white European male with a lifelong history of easy bruising. At the age of 18 months, he had suffered gastrointestinal hemorrhage, requiring blood transfusion. He had had prolonged hemorrhage after extraction of teeth, and vasectomy was complicated by hematomas. One patient underwent splenectomy for thrombocytopenia during childhood with no benefit. Greaves et al. (1987) described qualitative and quantitative platelet defects, which they suggested might be secondary to a disturbance of megakaryocyte cytoplasmic fragmentation.
Heynen et al. (1988) described the Fechtner syndrome in a female patient who had developed multiple ecchymoses from the time she started walking at the age of 1 year, due to severe thrombocytopenia. Hearing problems developing at the age of 8 years progressed to almost complete deafness. The blood smear showed giant platelets the size of granulocytes. The patient had moderate proteinuria, but there were no abnormalities in the urinary sediment or in renal function. Heynen et al. (1988) postulated an abnormality in the cytoskeleton of megakaryocytes such that formation of the demarcation membrane system and the expulsion of platelets do not occur normally.
Fujita et al. (1990) described the May-Hegglin anomaly in a 39-year-old male and his son and daughter. All 3 also had spastic paraplegia, which began in the offspring at about age 12 and in the father at about age 20. Renal function was normal.
Greinacher et al. (1990) described the Sebastian platelet syndrome, a variant of hereditary macrothrombocytopenia combined with the presence of neutrophil inclusions that differed from those found in patients with May-Hegglin anomaly, the Chediak-Higashi syndrome (214500), or individuals with septicemia, and toxic Dohle bodies in polymorphonuclear leukocytes. The inclusions in polymorphonuclear leukocytes were similar to those found in patients with Fechtner syndrome.
Greinacher and Mueller-Eckhardt (1990) referred to the Sebastian platelet syndrome as an autosomal dominant disorder characterized by the same hematologic changes as those in the Fechtner syndrome, but without the manifestations of Alport syndrome.
In a patient with end-stage renal failure being prepared for renal transplant and in his healthy brother, Nel et al. (1992) found the May-Hegglin anomaly. They concluded that there was no relation to the renal failure. Almost all neutrophils contained at least one inclusion body. These bodies were larger than toxic Dohle bodies found in septicemia, stained better, and were not accompanied by toxic granulation in the cytoplasm. Most of the inclusions were spindle shaped and occurred in any location in the cell cytoplasm as compared with the smaller, more irregular or rounded Dohle bodies, which tended to have a peripheral location in the cell. On electron microscopy, the bodies were shown to have parallel filaments oriented in the long axis of the inclusion.
Greinacher et al. (1992) described 2 families with May-Hegglin anomaly, one with 4 and the other with 3 affected persons. Platelet counts were markedly reduced and were correctly determined only in the counting chamber. Bleeding time and platelet aggregation were normal, but platelet nucleotide concentrations (ATP and ADP) were elevated. Giant platelets and spindle-shaped inclusion bodies were found in the granulocytes, which functioned normally. Both families were ascertained through a child who was found to have thrombocytopenia during acute infection. Misdiagnosis in such cases can lead to mismanagement, including the use of dangerous therapy.
Brodie et al. (1992) reported a kindred with hereditary macrothrombocytopenia and progressive sensorineural hearing loss. None of the family members had any evidence of renal dysfunction. The disorder was inherited by and through females in 4 generations. Hearing impairment began before the third decade and progressed to severe to profound bilateral hearing loss by the fourth decade. The platelet disorder manifested in early childhood and persisted lifelong, although it tended to remain asymptomatic.
Rocca et al. (1993) reported a 4-generation family in which 10 of 14 individuals had macrothrombocytopenia with leukocyte inclusions. Some, but not all, affected members had Alport-like symptoms, such as deafness, nephritis, and cataracts. For example, members aged less than 50 years had clinically silent ocular abnormalities, mainly lens opacities. These observations were consistent with 'reduced expression of Alport manifestations,' thus showing similarity to Sebastian syndrome.
Kelley et al. (2000) noted that about 25 to 50% of affected individuals with May-Hegglin anomaly have mild to moderate episodic bleeding.
Seri et al. (2003) found sensorineural hearing loss for high tones in 9 (82%) of 11 patients initially diagnosed as having May-Hegglin anomaly or Sebastian syndrome. Three patients with May-Hegglin anomaly or Sebastian syndrome were found to have cataracts. In addition, microscopic hematuria or proteinuria was found in 4 patients with May-Hegglin anomaly and 2 with Sebastian syndrome. These findings emphasized the phenotypic overlap among disorders caused by mutation in the MYH9 gene.
Using immunocytochemical analysis, Seri et al. (2003) detected an irregular distribution of myosin in neutrophil cytoplasm of all 22 patients with mutations in the MYH9 gene, including 5 patients with a diagnosis of Epstein syndrome. Large myosin aggregates appeared as Dohle-like bodies, whereas the smaller ones were not readily recognizable on Giemsa-stained peripheral blood smears.
Kunishima et al. (2005) reported a 45-year-old Japanese man with macrothrombocytopenia and severe bilateral sensorineural deafness, but no evidence of renal dysfunction. Leukocyte morphology on conventional Giemsa staining was ambiguous, but immunofluorescence staining showed abnormal subcellular localization of MYH9. The MYH9-positive structures showed a thread-like appearance, not punctuated or granular as often described in other MYH9-related disorders.
Utsch et al. (2006) reported a newborn girl diagnosed with Epstein syndrome who had a heterozygous mutation in the MYH9 gene (160775.0012). Although she did not show deafness or nephritis, she had macrothrombocytopenia and impaired platelet aggregation response to ADP and epinephrine. Bone marrow aspirate showed enhanced megakaryocytopoiesis with predominance of immature and dysplastic megakaryocytes. Erythropoiesis and granulocytopoiesis were normal. In addition, she had classic exstrophy of the bladder (600057). Prenatal ultrasound studies showed protrusion of the abdominal wall and a single umbilical artery. After birth, she was noted to have diastasis of the symphysis, epispadic open urethral groove, bifid clitoris and labia minora, an open laying bladder plate, and duplication of the vagina. The authors noted the young age of the patient and suggested that she may develop deafness and/or nephritis in the future. Utsch et al. (2006) suggested that although MYH9 mutations had not previously been associated with urogenital malformations, the mutation may have played a role in the bladder exstrophy in this patient.
Savoia et al. (2010) investigated 118 consecutive unrelated patients with a clinical presentation of macrothrombocytopenia with or without progressive sensorineural hearing loss, presenile cataract, and renal damage. All patients prospectively underwent immunofluorescence assay for myosin-9 aggregate dectection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of whom (98%) also had an MYH9 mutation. Neither aggregates nor an MYH9 mutation was identified in the remaining 36 patients. The authors concluded that neutrophil inclusions of myosin-9 are a pathognomonic sign of the disorder.
Rabbolini et al. (2018) noted the frequent misdiagnosis of this disorder as immune thrombocytopenia with subsequent mismanagement. Features resulting in misdiagnosis include a lack of family history due to the occurrence of de novo mutations in as many as 20 to 35% of cases; bleeding symptoms that are often mild and not always reported in childhood; failure of automated counters to reliably estimate platelet number and size (MPV) due to the presence of giant platelets; and pathognomonic neutrophil inclusions that are not always easily visible on Romanowsky-Giemsa-stained blood films.
Macrothrombocytopenia and granular inclusion bodies with or without nephritis or sensorineural hearing loss is inherited in an autosomal dominant manner (May-Hegglin/Fechtner Syndrome Consortium, 2000).
In a Japanese family with May-Hegglin anomaly, Kunishima et al. (1999) performed a genomewide linkage study using highly polymorphic short tandem repeat markers. Linkage was found with chromosome 22q12.3-q13.2, with a maximum 2-point lod score of 4.52 at a recombination fraction of 0.00 for markers D22S1142 and D22S277. Haplotype analysis mapped a critical region for the disease locus to a 13.6-cM region, between D22S280 and D22S272. The relative proximity of the GP1BB gene (138720) on 22q11.2, as well as its involvement in autosomal dominant isolated giant platelet disease (see 231200) (Kunishima et al., 1997), suggested a possible involvement of GP1BB in MHA. However, sequence analysis in 2 patients showed no abnormality in the GP1BB gene.
Martignetti et al. (2000) confirmed the assignment of the MHA locus to 22q12.3-q13.1, and determined that the physical size of the MHA region is 0.7 Mb.
In a genomewide linkage screen in 3 families with MHA, Kelley et al. (2000) found a maximum lod score of 3.91 at a recombination fraction of 0.076 for marker D22S683. Within the largest family, the maximum lod score was 5.36 at theta = 0.00 at marker D22S445. Fine mapping of recombination events using 8 adjacent markers indicated that the minimal disease region in this largest family alone is in a region of approximately 26 cM from D22S683 to the telomere. The maximum lod score for the 3 families combined was 5.84 at theta = 0.00 for marker IL2RB (146710), which maps to 22q11.2-q13.
In an extended Israeli family with Fechtner syndrome plus impaired liver functions and hypercholesterolemia in some individuals, Toren et al. (1999) mapped the disease-causing gene to the long arm of chromosome 22. Six markers yielded a lod score of more than 3.00. A maximum 2-point lod score of 7.02 was obtained with the marker D22S283 at a recombination fraction of 0.0. Recombination analysis placed the disease-causing gene in a 5.5-Mb interval between markers D22S284 and D22S1167. Toren et al. (1999) stated that no collagen genes or genes comprising the basement membrane had been mapped to this region, 22q12.1-q13.2. Toren et al. (2000) mapped Epstein syndrome to the same region of chromosome 22q, suggesting that it is allelic to Fechtner syndrome.
In linkage studies of the original family described by Epstein et al. (1972), Toren et al. (2000) found a maximum 2-point lod score of 3.41 with marker D22S683 at a recombination fraction of 0.00. Recombination analysis placed the disease-causing gene in a 3.37-Mb interval between the markers D22S284 and D22S693.
The May-Hegglin/Fechtner Syndrome Consortium (2000) identified 6 heterozygous MYH9 mutations in 7 unrelated probands with one or another of the 3 autosomal dominant giant platelet disorders: May-Hegglin anomaly (R1933X, 160775.0001 and E1841K, 160775.0002), Fechtner syndrome (D1424H, 160775.0005 and R792C, 160775.0006), and Sebastian syndrome (T1155I; 160775.0007).
Kelley et al. (2000) also identified mutations in the MYH9 gene in 10 unrelated patients with May-Hegglin anomaly: E1841K in 5 families, R1933X in 4 families, and T1155I in the last family.
In a family reported by Rocca et al. (1993) in which 10 of 14 individuals had macrothrombocytopenia with leukocyte inclusions and only some of the 10 had deafness, nephritis, and cataracts, Heath et al. (2001) identified a heterozygous mutation in the MYH9 gene (E1841K; 160775.0002) in all affected members.
Heath et al. (2001) found that the original family reported by Epstein et al. (1972) had a missense mutation (R702C; 160775.0006) in the MYH9 gene.
In affected members of the family with macrothrombocytopenia and progressive sensorineural hearing loss reported by Brodie et al. (1992), Mhatre et al. (2003) identified a missense mutation (D142N; 160775.0010) in the MYH9 gene. They noted that the same mutation has been found in May-Hegglin anomaly, Fechtner syndrome, and Sebastian syndrome.
In a Japanese patient with macrothrombocytopenia and deafness, Kunishima et al. (2005) identified a heterozygous deletion in the MYH9 gene (160775.0015).
In a study of 108 patients from 50 unrelated pedigrees with MYH9 mutations, Pecci et al. (2008) found that 68% of families carried mutations in 1 of 4 residues: 702 in the motor domain (12 families) and residues 1424, 1841, and 1933 in the tail domain (9, 7, and 6 pedigrees, respectively). All subjects with mutations in the motor domain of MYH9 developed severe thrombocytopenia, nephritis, and deafness before the age of 40 years. Patients with mutations at residue 1424 or 1841 had a much lower risk of these complications, significantly higher platelet counts, and an intermediate clinical picture. Patients with mutations at residue 1933 did not develop kidney damage or cataracts but did develop deafness late in life.
M'Rad et al. (1992) reported studies of 31 families with Alport syndrome. One family had a severe form of the disease with deafness and end-stage renal disease (ESRD) at the age of 14 but without ocular signs of Alport syndrome. M'Rad et al. (1992) considered the disorder to be X-linked in this family because the mother was less severely affected than the son. In both mother and son, macrothrombocytopathia and inclusions resembling Dohle bodies were observed. The segregation of the only informative marker was consistent with X-linkage.
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