May–Hegglin anomaly (MHA), Sebastian syndrome (SBS) and Fechtner syndrome (FTNS) are autosomal‐dominant macrothrombocytopenias with Döhle‐like leucocyte inclusions. These diseases are due to ...mutations of the MHY9 gene, encoding the heavy chain of non‐muscle myosin IIA (NMMHC‐A). We investigated the NMMHC‐A localization in blood cells from eight MHA, SBS or FTNS patients with known MYH9 mutations. All the patients showed an altered localization of NMMHC‐A in granulocytes and platelets, suggesting that Döhle‐like bodies are due to the aggregation of NMMHC‐A in the cytoplasm. Therefore, immunocytochemistry for NMMHC‐A is a simple and sensitive method to detect pathological phenotypes of granulocytes and platelets in the diagnosis of MYH9‐related disorders.
The autosomal dominant, giant-platelet disorders, May-Hegglin
anomaly (MHA; MIM 155100), Fechtner syndrome
(FTNS; MIM 153640) and Sebastian syndrome (SBS), share the
triad of thrombocytopenia, large ...platelets and characteristic leukocyte inclusions
(?Döhle-like? bodies). MHA and SBS can be differentiated
by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished
by the additional Alport-like clinical features of sensorineural deafness,
cataracts and nephritis. The similarities between these platelet
disorders and our recent refinement of the MHA (ref. 6)
and FTNS (ref. 7) disease loci to an overlapping
region of 480 kb on chromosome 22 suggested that all three disorders are allelic.
Among the identified candidate genes is the gene encoding nonmuscle myosin
heavy chain 9 (MYH9; refs 8?10),
which is expressed in platelets and upregulated during granulocyte
differentiation. We identified six MYH9 mutations (one
nonsense and five missense) in seven unrelated probands from MHA, SBS and
FTNS families. On the basis of molecular modelling, the two mutations affecting
the myosin head were predicted to impose electrostatic and conformational
changes, whereas the truncating mutation deleted the unique carboxy-terminal
tailpiece. The remaining missense mutations, all affecting highly conserved
coiled-coil domain positions, imparted destabilizing electrostatic and polar
changes. Thus, our results suggest that mutations in MYH9 result in
three megakaryocyte/platelet/leukocyte syndromes and are important in the
pathogenesis of sensorineural deafness, cataracts and nephritis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We studied a family with a suspected diagnosis of MYH9-related disease, which is one of the most common forms of autosomal dominant macrothrombocytopenias associated with hearing impairment, ...cataracts and nephritis. No mutation of the MYH9 gene was identified. Moreover, the A156V variant of the GPIbalpha gene, responsible for 30% of macrothrombocytopenias in Italy, was not detected in the family. Therefore, we hypothesized that the clinical symptoms were caused by mutations in different genes. The screening of the candidate genes for deafness and/or cataract allowed us to identify two variants, M34T and S19T, of the GJB2 gene in family members with hearing impairment. Because of the relatively common occurrence of inherited hearing loss and, at least in the Mediterranean area, of platelet macrocytosis, the two traits occurred by chance in the same family and mimicked the MYH9-related disease.
May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory ...signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear 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. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
Prenatal Diagnosis of Cloacal Anomaly Sebastiano Cacciaguerra, Lucia Lo Presti, Luciano Di Leo, Samoa Grasso, Simone Gangarossa, Vincenzo Di Benedetto, Aurelio Di Benedetto
Scandinavian journal of urology and nephrology,
1998, Letnik:
32, Številka:
1
Journal Article
The authors present a case of prenatal diagnosis of cloacal anomaly, characterized by the presence of oligohydramnios and cystic pelvic mass with changing features during observation. Postnatal study ...confirmed the presence of a recto-cloacal fistula, with a high confluence of the urinary, genital and intestinal systems. Both parents had a chromosome 9 inversion (p11q13), but the child was chromosomally normal.
Becker nevus syndrome is a phenotype characterised by the simultaneous occurrence of: (1) a circumscribed patch of (light or dark brown) hyperpigmentation with a sharply outlined but irregular border ...(resolving into small spots reminiscent of an archipelago) and hypertrichosis (with increased smooth muscle bundles) with slight acanthosis (the so-called Becker’s nevus); (2) associated unilateral hypoplasia of one or more of the following: breast, underlying musculature (mostly the shoulder girdle), underlying adipose tissue (lipoatrophy) and limb (usually the arm); and (3) underlying skeletal anomalies including vertebral defects and scoliosis, fused or accessory cervical ribs, pectus excavatum or carenatum, and internal tibial torsion (Danarti et al. 2004, Happle et al. 1997, Sugarman 2004). All of these anomalies tend to show a regional correspondence to the nevus and are mostly ipsilateral (Danarti et al. 2004).
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