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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 6  |  Page : 1304-1307
Macrothrombocytopenia, psychomotor retardation, and nephropathy: A novel familial syndrome

Department of Pediatrics, Jordan University Hospital, College of Medicine, University of Jordan, Amman, Jordan

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Date of Web Publication10-Nov-2014

How to cite this article:
Akl KF, Qudah AK, Awidi A, Suleiman MJ, Ababneh N, Bsoul N, Magablah A. Macrothrombocytopenia, psychomotor retardation, and nephropathy: A novel familial syndrome. Saudi J Kidney Dis Transpl 2014;25:1304-7

How to cite this URL:
Akl KF, Qudah AK, Awidi A, Suleiman MJ, Ababneh N, Bsoul N, Magablah A. Macrothrombocytopenia, psychomotor retardation, and nephropathy: A novel familial syndrome. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2022 Nov 28];25:1304-7. Available from: https://www.sjkdt.org/text.asp?2014/25/6/1304/144273
To the Editor,

The congenital thrombocytopenia syndrome may be associated with familial nephritis. The gene involved encodes non-muscle myosin heavy chain 9 (MYH9). This is different from the Alport's syndrome, which consists of hereditary nephritis with deafness. The underlying defect in the latter is in the type-4 collagen of the glomerular basement membrane. [1] There are several congenital thrombocytopenia syndromes, many of which are associated with large platelets. [1],[2],[3] Herein, we describe a syndrome consis­ting of recurrent megathrombocytopenia, psychomotor retardation, and speech defect, in three siblings. Two developed proteinuria and hypertension. To the best of our knowledge, this syndrome has not been previously reported.

Case 1

A 16-year old female, was diagnosed with idiopathic thrombocytopenic purpura (ITP) at the age of two years, in a regional hospital. At the age of ten years, the patient presented to our hospital with easy bruisability and recurrent epistaxis. Her family history revealed two sim­ilar siblings (cases 2 and 3), in addition to three normal ones, apart from two female cousins, who also had thrombocytopenia and proteinuria. The parents were first cousins (pedigree, [Figure 1]).
Figure 1: Pedigree of a consanguineous family with a novel syndrome of megathrombocytopenia, nephropathy, psychomotor retardation, gait disturbance, and speech defect. The solid symbols denote the affected family members. The squares and circles represent male and female family members, respectively. The arrow indicates the index patient.

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On physical examination, the patient was found to have developmental delay, with an IQ of 50. She developed steroid-resistant nephrotic range proteinuria. Renal biopsy showed mesangial proliferative glomerulonephritis and interstitial fibrosis, with immunoglobulin IgG and IgM deposits. Electron microscopic examination was not performed. Brain magnetic resonance imaging (MRI) was normal. The patient did not benefit from steroids.

Case 2

A ten-year-old female (sibling of case 1), who had recurrent easy bruisability associated with persistent thrombocytopenia, since infancy, had a developmental delay with a speech defect (four to five word sentences) and an abnormal gait. The blood pressure was 135/80 mm Hg (above normal for age). The facies were normal.

The leukocyte count was normal and the last platelet count was 75,000/mm 3 . Even as the initial urinalysis was normal, a subsequent test showed 2+ protein and no red cells. The serum creatinine was 0.55 mg/dL and albumin was 4.2 g/dL.

Case 3

A 17-year-old male (sibling of cases 1 and 2) who was diagnosed as ITP at the age of eight months was noted to sit up and walk at a delayed age of two years. He started to talk at three years (Mama, Papa). At six to seven years, he talked two to three word sentences. He was admitted to our hospital because of bilateral hip joint pain.

On physical examination (age 17 years), he had slight facial asymmetry, his IQ was 50, he was alert, laughed inappropriately, and communicated verbally with unintelligible two- to three-word sentences. He had a slight postural tremor and bilateral simian creases. There were exaggerated deep tendon reflexes all over, with an awkward gait. There was no ataxia.

The leukocyte count was normal and the platelet count was 540,000/mm 3 . The blood film showed giant platelets. His serum creatinine was 0.7 mg /dL and urine analysis was normal. An MRI, hearing test, chromosomal karyotyping, and electroencephalogram were all nor­mal. An echocardiogram revealed mild mitral regurgitation.

A complete blood count (CBC) was tested on all siblings and parents. The intelligence quotient was estimated for the parents and siblings.

The results are shown in [Table 1] and [Table 2].
Table 1: Hematological data of the propositus and affected siblings.

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Table 2: Data of the parents of the study patients.

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Following informed consent and approval by the Ethics Committee of the Jordan University Hospital, we obtained blood samples from the family members (parents, propositus, and siblings). Genomic DNA was isolated using a PureGene DNA isolation kit.

The entire 40 coding exons and exon-intron boundaries of MYH9 were amplified using polymerase chain reaction (PCR) and the pro­ducts were subjected to direct sequence ana­lysis. The primers used for the amplification of all 40 coding exons have been published previously. [4]

The PCR samples for sequencing were puri­fied using the PCR purification kit (Qiagen, Germany) and were sequenced using ABI BigDye terminator sequencing (Applied Bio-systems), on an ABI 3310 genetic analyzer (Applied Bio-system, Germany). Data were analyzed and compared with the normal MYH9 reference sequence (human GenBank accession number 3135984). There were no MYH9 muta­tions in the propositus, parents or siblings.

Our study patients had recurrent thrombocytopenia with giant platelets, psychomotor retardation, nephropathy, an abnormal gait, and a speech defect. The chronicity of the symp­toms, age at presentation, the presence of mental retardation, and the lack of response to corticosteroids, point to a congenital rather than an acquired platelet disorder. [1] Initially, we thought that our patients represented a variant of the known megathrombocytopenia syndromes. All three cases had large platelets, which were usually not detected in the routine counting chambers. [5]

Leukocyte inclusions, which occur in many of the large megathrombocytopenia syndromes have not been seen in any of our patients. These may be easily missed if only Wright or Giemsa stains are used. The yield is much better with heavy chain-A (NMMHCA) localization immunofluorescence analysis of neutrophil non-muscle myosin than conventional staining. [3],[5]

Some of the megathrombocytopenia syndromes, such as, the Fechtner [6] and Epstein [7] syndromes and the May Hegglin anomaly, also have nephropathy. [8],[9],[10] In addition to macrothrombocytopenia and leukocyte inclusions, patients with the Fechtner syndrome have congenital cataracts and hearing loss. [6] The Fechtner syndrome does not have type IV collagen disease, and it is no longer considered a variant of the Alport's syn­drome, as previously thought. [2],[7] The Fechtner syndrome is an autosomal dominant disease associated with MYH9 gene mutation, which encodes the non-muscle myosin heavy chain-A (NMM HCA). The MYH9 defect controls the macrothrombocytopenia, but it is not known how it causes nephritis, [7] which may progress to end-stage renal failure. [8]

Contrary to the Fechtner syndrome, the mode of inheritance in our cases was autosomal recessive. Proteinuria was the initial mani­festation of the nephropathy in our patients. The fact that it appeared only in the females and spared the male sibling, leads one to speculate that nephropathy is more severe in females. However, a meticulous search for future renal involvement is important.

In the Alport's syndrome, hematuria rather than proteinuria is the initial laboratory finding and hypertension develops at a later stage, usually after the onset of chronic renal insufficiency. [9] In our patients, proteinuria without hematuria was the initial renal laboratory fin­ding and hypertension developed before dete­rioration of the renal function.

We feel that our patients represent a new, autosomal recessive syndrome consisting of thrombocytopenia with large platelets, mental retardation, and nephropathy. Additional fin­dings include gait disturbance and a speech defect. A literature search did not reveal a similar entity. One limitation in our study was lack of electron microscopy.

The frequency of this novel syndrome remains unknown. It should be looked for in countries with a high prevalence of consanguinity, such as, the Middle East.

Conflict of interest: None

   Acknowledgment Top

The authors would like to thank the support given by the Deanship of Academic Research at The University of Jordan.

   References Top

Drachman JG. Inherited thrombocytopenia: When a low platelet count does not mean ITP. Blood 2004;103:390-8.  Back to cited text no. 1
Seri M, Pecci A, Di Bari F, et al. MYH9-related disease. May- Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine 2003;82:203-15.  Back to cited text no. 2
Kunishima S, Saito H. Congenital macrothrombocytopenias. Blood Rev 2006;20:111-21.  Back to cited text no. 3
Heath KE, Campos-Barros A, Toren A, et al. Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet 2001;69:1033-45.  Back to cited text no. 4
Kunishima S, Matsushita T, Kojima T, et al. Immunofluorescence analysis of neutrophil non-muscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations. Lab Invest 2003;83:115-22.  Back to cited text no. 5
Peterson LC, Rao KV, Crosson JT, White JG. Fechtner syndrome-a variant of Alport's syn­drome with leukocyte inclusions and macro thrombocytopenia. Blood 1985;65:397-406.  Back to cited text no. 6
Knebelmann B, Fakhouri F, Grünfeld JP. Here­ditary nephritis with macrothrombocytopenia: No longer an Alport syndrome variant. Nephrol Dial Transplant 2001;16:1101-3.  Back to cited text no. 7
Moxey-Mims MM, Young G, Silverman A, Selby DM, White JG, Kher KK. End-stage renal disease in two pediatric patients with Fechtner syndrome. Pediatr Nephrol 1999;13:782-6.  Back to cited text no. 8
Gubler MC. Inherited diseases of the mem­brane. Nat Clin Pract Nephrol 2008;4:24-37.  Back to cited text no. 9
Basile C, Schiavone P, Heidet L, Grünfeld JP. Hereditary nephritis with macrothrombocytopenia: Phenotypic variety and the genotypic defect. J Nephrol 2002;15:320-3.  Back to cited text no. 10

Correspondence Address:
Dr. Kamal F Akl
Department of Pediatrics, Jordan University Hospital, College of Medicine, University of Jordan, Amman
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.144273

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  [Table 1], [Table 2]


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