Female haemophilia A in a family with seeming extreme bidirectional lyonization tendency: abnormal premature X-chromosome inactivation?
We studied a female child with mild classical haemophilia A, presenting with a F VIII deficiency similar to that detected in her maternal grandfather. Investigations on several occasions showed that the obligate carrier mother of the proposita had normal VIII:C activity, whereas her likewise obligate carrier sister had a typical carrier VIII:C/vWf:Ag pattern. The child was a phenotypically normal female with normal karyotype. Her father had no clinical or biochemical signs of haemophilia A. RFLP-analysis using DX13 and St14 probes each elicited one allele (5.8 and 3.4 kb, respectively) segregating along with the affected F VIII gene from the hemizygous grandfather to both his daughters and further to the haemophilic female child. The paternity of the child was analyzed using various red cell and HLA antigens and RFLP by p29C, a probe detecting polymorphic hypervariable TaqI and PstI fragments in the pseudoautosomal areas of the X- and Y-chromosomes. All results obtained were concordant with the declared paternity. RFLP-analysis, using single (Pst I) and double digestion (Pst I/Hha I) of DNA and a PGK probe, revealed a remarkable difference in hybridization fragments, strongly suggesting hypermethylation, and in consequence, preferential X-chromosome inactivation in the proposita. This points to extreme lyonization as the most plausible explanation for haemophilia A in this female child. A familial tendency to abnormal premature X-chromosome inactivation is speculated.
Ingerslev
J
J
Department of Clinical Immunology, University Hospital, Aarhus, Denmark.
Schwartz
M
M
Lamm
L U
LU
Kruse
T A
TA
Bukh
A
A
Stenbjerg
S
S
D002675:Child, Preschool; D015342:DNA Probes; D005169:Factor VIII / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D012729:Sex Chromosome Aberrations / Q000235:genetics*; D014960:X Chromosome; D014841:von Willebrand Factor / Q000235:genetics
D015342:DNA Probes; D014841:von Willebrand Factor; D005169:Factor VIII