Early fatal course in siblings with CDG-Ia (caused by two novel mutations in the PMM2 gene): clinical, molecular and autopsy findings


We report on two siblings with a novel mutation of the PMM2 gene leading to early postnatal death secondary to cardiac failure after 3 and 8 weeks, respectively. In addition to the already described features, one of them had amegakaryocytic thrombocytopaenia. Both children (male and female) were born in 2000 and 2004 (patient 1 and 2) to the healthy, unrelated parents after 36 and 35 weeks of gestation, respectively. The pregnancies were complicated by a mirror syndrome (i.e. foetal hydrops with consecutive oedema and rapid weight gain in the pregnant) around 30 weeks of gestation. Postnatally, they presented with hydrops and had profound hypoglycaemia and thrombocytopaenia, requiring additional administration of glucose and platelet transfusions. Bone marrow examination showed only few megakaryocytes in patient 1 and an amegakaryocytic bone marrow in patient 2. Maternal and neonatal disorders that cause thrombocytopaenia in the neonate could be excluded. Both children developed progressive hypertrophic cardiomyopathy and died from acute cardiac failure at 3 and 8 weeks, respectively. Patient 2, in addition, had pericardial effusion, not responding to conservative therapy and ultrasound examination showed kidneys which were increased in size and echogenity. Cranial ultrasound in patient 2 exhibited cerebellar hypotrophy, especially of the vermis cerebellaris beyond the fourth week of life. When patient 1 died, no definite diagnosis could be established. When the hydrops in patient 2 cleared, we saw the typical signs of CDG-Ia: unusual fatpads around the buttocks, neck and arms (Fig. 1), inverted nipples and internal strabismus. Autopsy was performed on both children. Histopathological data is shown in Table 1. Patient 2, in addition, had an amegakaryocytic thrombocytopaenia. Screening for CDG-Ia using isoelectric focussing of transferrin showed a type 1 pattern and the activity of PMM2 in leukocytes was nearly absent. Genotyping of patient 2 revealed a compound heterozygosity, with the maternal allele showing a G insertion between nucleotides 161-162 in Exon 2, leading to a frame-shift. Paternal allele showed 385G>T (V129L) in Exon 5. After diagnosing CDG-Ia in patient 2, we performed a mutation analysis from embedded material of patient 1 showing the same genotype. The clinical picture of both patients shows many features already described [1, 2, 4, 6]. However, to the best of our knowledge, this is the first case of CDG-Ia with amegakaryocytic thrombocytopaenia. The genotype of our patients is Eur J Pediatr (2007) 166:377–378 DOI 10.1007/s00431-006-0240-y

DOI: 10.1007/s00431-006-0240-y

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@article{Wurm2006EarlyFC, title={Early fatal course in siblings with CDG-Ia (caused by two novel mutations in the PMM2 gene): clinical, molecular and autopsy findings}, author={Donald Wurm and Andrea H{\"a}nsgen and Yoo-Jin Kim and Angelika Lindinger and Ali Baghai and L Gortner}, journal={European Journal of Pediatrics}, year={2006}, volume={166}, pages={377-378} }