Gastrointestinal Ulceration, Recurrent, With Dysfunctional Platelets

A number sign (#) is used with this entry because of evidence that recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP) is caused by homozygous or compound heterozygous mutation in the PLA2G4A gene (600522) on chromosome 1q31.

Description

Recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP) is an autosomal recessive disorder characterized by onset of severe gastrointestinal mucosal ulceration in early childhood. Affected individuals may have secondary iron deficiency anemia or malnourishment. Studies of platelet aggregation show a functional defect associated with decreased thromboxane-A2 production and decreased eicosanoid biosynthesis. The gastrointestinal disease is believed to result from decreased or absent production of prostaglandins that protect the gut mucosa (summary by Adler et al., 2008 and Faioni et al., 2014).

Clinical Features

Adler et al. (2008) reported a 45-year-old Italian man with a history of occult gastrointestinal blood loss, chronic anemia, iron deficiency, and abdominal pain as a child and young adult. He had multiple episodes of small bowel perforation necessitating 5 surgical interventions between 38 and 45 years of age. Histology showed multiple recurrent ulcerations of the gastrointestinal mucosa. Laboratory studies showed markedly reduced levels of thromboxane B2 and 12-hydroxyeicosatetraenoic acid (12-HETE) produced by platelets and leukotriene B4 released from calcium ionophore-activated blood, consistent with an almost complete absence of the release of arachidonic acid (AA) during platelet activation. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished, but normalized with the addition of AA.

Faioni et al. (2014) reported 27-year-old twins, a brother and sister, from a large Sardinian family, who had lifelong mucosal bleeding. The patients presented in the first years of life with epistaxis, gum bleeding, gastrointestinal bleeding, hematuria, and recurrent duodenal ulcers. The sister had menorrhagia resulting in iron deficiency anemia. Platelet function studies showed normal aggregation and secretion by AA, but impaired aggregation and secretion by collagen. Serum eicosanoids, including thromboxane-B2 (TxB2) and 12-HETE, were extremely low. The overall findings suggested a defect in the arachidonate pathway of platelet activation, with decreased production of thromboxane-A2 from endogenous AA. In addition, both patients and their mother had mildly decreased levels of coagulation factor XI (F11; 264900) (about 60% of normal values), which may have contributed to the bleeding. The brother also developed mildly impaired renal function at age 13 years; this remained stable. Faioni et al. (2014) suggested that the early onset of duodenal ulcers was likely due to the severe deficiency of eicosanoids that protect the gastrointestinal mucosa. Family members who were heterozygous carriers of the mutation had increased prevalence of duodenal ulcers before age 40 and showed borderline low serum levels of TxB2, but none had a bleeding diathesis.

Brooke et al. (2014) reported a brother and sister from a small region in Serbia with onset of severe gastrointestinal disease before 4 years of age. They first presented with peptic ulceration, bleeding, and pyloric stenosis, and both underwent vagotomy and eventually gastroenterostomy or gastrojejunostomy for disease recurrence. Over the following 40 years, both patients continued to have significant gastrointestinal mucosal ulcerations affecting the small bowel, esophagus, and bile duct, with fistulas, strictures, and adhesions from multiple surgeries. Both were malnourished. They were given a provisional diagnosis of 'cryptogenic multifocal ulcerating stenosing enteritis (CMUSE).' Brooke et al. (2014) noted that the lesions resembled those associated with the use of NSAIDs, which reduce prostaglandin production. In addition, the sister had recurrent infections with Candida albicans, Campylobacter, Salmonella, and Staphylococcus, which may implicate immune dysregulation. Patient platelet studies showed impaired aggregation in response to stimulation by collagen, but normal aggregation with the addition of AA, as well as decreased production of TxA2, indicating a defect in PLA2G4A-mediated AA release. These findings were similar to those observed in normal patients treated with aspirin.

Inheritance

The transmission pattern of GURDP in the family reported by Faioni et al. (2014) was consistent with autosomal recessive inheritance, although heterozygous mutation carriers had a mild phenotype.

Molecular Genetics

In a 45-year-old man with GURDP, Adler et al. (2008) identified compound heterozygosity for 2 missense mutations in the PLA2G4A gene (S111P, 600522.0001 and R485H, 600522.0002). His asymptomatic mother and sister, who were found to have intermediate levels of platelet-derived thromboxane B2 and 12-HETE that were below or at the lower end of the normal range, were each heterozygous for 1 of the mutations. respectively. A known SNP in the PLA2G4A gene, K651R, was also detected on the same allele as the R485H variant.

In twin sibs from a large Sardinian family with GURDP, Faioni et al. (2014) identified a homozygous missense mutation in the PLA2G4A gene (D575H; 600522.0003). Patient platelets showed normal PLA2G4A mRNA levels, but undetectable protein levels, suggesting instability of the mutant protein and consistent with a complete loss of function. Analysis of 35 other family members showed that 14 (40%) were heterozygous for the variant and 21 (60%) were homozygous wildtype. Heterozygotes for the variant did not have a bleeding diathesis, but had a relatively high prevalence of duodenal ulcers at a young age (less than 40 years).

In a Serbian brother and sister with GURDP, Brooke et al. (2014) identified a homozygous 4-bp deletion in the PLA2G4A gene (600522.0004). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Gastrointestinal mucosal tissue and peripheral blood cells from the patients showed complete absence of the PLA2G4A protein.