Renal Unit, Magna Graecia University of Catanzaro, Italy
Correspondence and offprint requests to: Michele Andreucci, MD, PhD, Via Giacomo Puccini 18, I-80127 Napoli, Italy. Email: andreucci{at}unicz.it
Keywords: Alport's syndrome; double nucleotidic mutation; end-stage renal disease
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Introduction |
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Alport-like syndromes identify a group of diseases characterized by thrombocytopaenia with giant platelets and autosomal dominant transmission. Their distinguishing features consist of the presence of nephritis, cataracts, hearing loss or deafness with or without leucocytic intracytoplasmatic inclusions (named Dhole bodies). This group of diseases includes: the MayHegglin anomaly, Fechtner syndrome, Sebastian syndrome and Epstein syndrome. Unlike in Alport's syndrome, the genetic mutations linked to this group of disorders are in the human non-muscle myosin IIA heavy chain gene (MYH9) [2].
The MayHegglin anomaly is a rare autosomal dominant disorder characterized by abnormally large platelets, leucocytic inclusions and thrombocytopaenia, which predisposes patients to bleeding disorders [3]. The Sebastian and Fechtner syndromes share these features, but patients with the Fechtner syndrome also show high-tone sensorineural deafness, cataracts and nephritis [4], while the MayHegglin anomaly and Sebastian syndrome are differentiated by an ultrastructural examination of leucocyte inclusions. The Epstein syndrome consists of deafness and nephritis in the absence of cataracts and leucocytic inclusions [2]. The clinical features of all of these genetic disorders are shown in Table 1.
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Case |
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In our unit, she underwent clinical and metabolic evaluations. Echocardiography showed an aneurysm of the interatrial septum. She was started on a low protein diet along with anti-hypertensive therapy with calcium antagonists and ACE inhibitors. Her renal function had been stable during the following 2 years. She did not have cataracts. Later, because of worsening renal function, an A-V fistula was created and haemodialysis was started. During the screening for renal transplantation, given the patient's age, a more complete evaluation was required to exclude nephropathies with high rates of recurrence. Thus, further examinations were performed, including genetic analysis for the gene responsible (COL-IV A5) for Alport's syndrome. COL-IV A5 was found to be a non-altered gene. Another genetic study was therefore performed to explain the thrombocytopaenia and the absence of leucocyte inclusion bodies. The gene MYH9 showed a double mutation: one of the two mutations had been previously reported [5] in a family suffering from the Fechtner disease; the other one was also found in the genome of the patient's mother. A further blood smear was inspected in a highly specialized laboratory and showed Döhle bodies in 97% of her neuthrophils.
An immunocytochemical study, performed as described by Dacie and Lewis [6], was done using monoclonal antibodies against the heavy chain of non-muscle myosin IIA. It showed the protein to be abnormally distributed in PMN and in platelets. While in normal subjects the cytoplasmic distribution of the protein is homogeneous, in this patient the protein had a spotty distribution (15 spots per cell; each spot: 0.96.8 µm). This pattern is very similar to the one of patients presenting with MYH9 gene mutations regardless of their diagnosis.
An NMR performed in our unit demonstrated a hypoplasia of the inferior vena cava with a compensatory dilatation of the azygos vein (an abnormality called azygos-like continuation of inferior vena cava).
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Discussion |
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The genetic analysis of our patient showed the presence of a double nucleotidic mutation in the MYH9 gene: the first one has been identified inside the 21st exon (2728 AC) that results in a substitution of a lysine with a glutamine [codon no. 910 (K910Q)]; the second one corresponds to a gene mutation already identified [5] in a family with the Fechtner syndrome, consisting of 4270 G
C, resulting in a substitution of an aspartic acid with a hystidine at codon no. 1424 (D1424H). Neither mutation was found in any of 50 normal subjects who were also analysed. Interestingly, the genetic analysis of the patient's mother revealed the presence of the mutation of the 21st exon which was not found in her father. The novelty of our finding is the presence of another mutation (never before reported in the literature) in a gene that already presents a previously reported mutation. It is not possible to assert that the double mutation in the MYH9 gene caused the hypoplasia of the inferior vena cava and the presence of a single kidney in our patient. The patient's mother had only microhaematuria as a sign of renal impairment with otherwise normal renal function and with no abnormalities in platelets' size and number. She did not have proteinuria or cataracts. (Renal biopsy was not performed and her blood smear was not studied.)
In conclusion, while the double mutation in the MYH9 gene of our patient was associated with end-stage renal disease, only asymptomatic haematuria was observed in her mother, in whom a single mutation in the same gene was found. The condition of our patient can be called an autosomal dominant hereditary nephritis with haematological abnormalities.
Conflict of interest statement. None declared.
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References |
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