Response to desmopressin is strongly dependent on F8 gene mutation type in mild and moderate haemophilia A.

Desmopressin causes two- to six-fold increase of factor VIII (FVIII) in mild or moderate haemophilia A patients. However, responses are variable and little is known whether this is associated with F8 gene mutation. The study objective was to assess the relationship between F8 gene mutation and desmopressin response in haemophilia A patients. Desmopressin response (absolute and relative) was determined in 97 hemophilia A patients. Four amino acid changes (Arg2169His, Pro149Arg, Asn637Ser, and Arg612Cys) and a number of other mutations leading to an aberrant FVIII protein or FVIII deficiency were analysed. Patients with Arg2169His showed significantly lower FVIII levels before and after desmopressin compared to all other mutations (p<0.001). Pro149Arg amino acid change showed significantly lower FVIII levels 1 hour after desmopressin compared to all other mutations (p<0.005). An absolute response with FVIII≥0.50 IU/ml after 1 hour was observed in 41% (9 of 22) of patients with Arg2169His; however, this was not sustainable after 6 hours in any of these subjects. No patients with Pro149Arg mutation (n=6) showed an absolute response with FVIII≥0.50 I U/ml. Patients with other mutations showed significantly more complete and partial responses. Relative responses did not differ between mutations. Our study shows that haemophilia A patients with amino acid change Arg2169His or Pro149Arg have a decreased desmopressin response with regard to FVIII levels as compared to other mutations. Our results indicate that response to desmopressin is dependent on the F8 gene mutation type, despite the fact that multiple factors influence the desmopressin response, even within families.

Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations.

Opitz syndrome (OS; MIM 145410 and MIM 300000) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal (LTE) abnormalities, imperforate anus, developmental delay, and cardiac defects. The X-linked form (XLOS) is caused by mutations in the MID1 gene, which encodes a microtubule-associated RBCC protein. In this study, phenotypic manifestations of patients with and without MID1 mutations were compared to determine genotype-phenotype correlations. We detected 10 novel mutations, 5 in familial cases, 2 in sporadic cases, and 3 in families for whom it was not clear if they were familial or sporadic. The genotype and phenotype was compared for these 10 families, clinically diagnosed OS patients found not to have MID1 mutations, and 4 families in whom we have previously reported MID1 mutations. This combined data set includes clinical and mutation data on 70 patients. The XLOS patients with MID1 mutations were less severely affected than patients with MID1 mutations reported in previous studies, particularly in functionally significant neurologic, LTE, anal, and cardiac abnormalities. Minor anomalies were more prevalent in patients with MID1 mutations compared to those without mutations in this study. Female MID1 mutation carriers had milder phenotypes compared to male MID1 mutation carriers, with the most common manifestation being hypertelorism in both sexes. Most of the anomalies found in the patients of the present study do not correlate with the MID1 mutation type, with the possible exception of LTE malformations. This study demonstrates the wide spectrum of severity and manifestations of OS. It also shows that XLOS patients with MID1 mutations may be less severely affected than indicated in prior reports.