Investigation of inflicted injury in a young girl reveals mild haemophilia A and Turner's syndrome.

A 2-year-old girl presented to casualty with a right knee effusion after apparently minor trauma. Inflicted injury was suspected and full forensic coagulation studies were performed which revealed a mild deficiency of factor VIII. Screening of the exons and intron/exon boundaries of F8 gene indicated that the child appeared to be homozygous for the missense mutation c.5123G>A (p.Arg1708His) in exon 14 of the F8 gene. This mutation has been reported to be associated with mild haemophilia A. The possibility of hemizygosity had been masked by the test kit employed but referral to the genetics service and subsequent array CGH resulted in a diagnosis of Turner syndrome.

A clinical, cytogenetic and molecular study of 47 females with r(X) chromosomes.

We studied 47 patients with a 45,X/46,X,r(X) karyotype to identify phenotypic differences between these patients and 45,X patients, and to determine whether these differences could be explained by the status of genes within the ring. Only 2 patients had the 'severe' r(X) phenotype, and both were consistent with this resulting from functional disomy of genes normally subject to X inactivation. A further 7 patients also carried active rings but these patients did not have a more severe phenotype than those whose rings were inactivated, probably because their rings were smaller and did not contain the (as yet unidentified) genes whose functional disomy is particularly damaging. Patients with a r(X) did not show clear physical differences when compared with a 45,X series, except for a possible reduction in the frequency of oedema in those whose r(X) had an Xq breakpoint distal to DXS128E, at Xq13.2. Thus some protection from oedema may be provided by the presence of two copies of Xq13.2.

A study of females with deletions of the short arm of the X chromosome.

We have undertaken a clinical and molecular study of 25 females with deletions of the short arm of the X chromosome. We have determined the deletion breakpoints, the parental origin and the activation status of the deleted X chromosomes. Genotype-phenotype correlations suggest that the presence of a single copy of the DFFRX gene, previously postulated as a gene involved in the ovarian failure seen in Turner syndrome, may be compatible with normal ovarian function, and that there may be a gene for Turner-like features located in distal Xp22.3.

Three patients with a 45,X/46,X,psu dic(Xp) karyotype.

Few cases of isochromosomes for the short arm of the X have been reported and all are dicentric with variable portions of the long arms interposed between the two centromeres. This paper reports three cases of complete short arm duplication of one X chromosome in unrelated female patients. All patients also have a 45,X cell line and present with some characteristic features of Turner syndrome. We used conventional cytogenetics, in situ hybridisation, and molecular genetics to describe all three structurally abnormal chromosomes and the parental origin of two of them. We briefly discuss the "inactivation enhancement" theory; however, any genotype-phenotype correlation is complicated by the presence of the 45,X cell line.

Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis).

The multiple lentigines syndrome is an autosomal dominant condition which has many similarities to Noonan syndrome, except in the most striking feature from which its name is derived. The less neutral but very apt mnemonic, LEOPARD syndrome, was first used by Gorlin et al to whom the major debt in the definition of this syndrome lies, that is, Lentigines, ECG abnormalities, Ocular hypertelorism/Obstructive cardiomyopathy, Pulmonary valve stenosis, Abnormalities of genitalia in males, Retardation of growth, and Deafness. Not previously included in the mnemonic is cardiomyopathy which is an important feature because it is associated with significant mortality.

Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function.

Turner's syndrome is a sporadic disorder of human females in which all or part of one X chromosome is deleted. Intelligence is usually normal but social adjustment problems are common. Here we report a study of 80 females with Turner's syndrome and a single X chromosome, in 55 of which the X was maternally derived (45,X[m]) and in 25 it was of paternal origin (45,X[p]). Members of the 45,X[p] group were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. Our observations suggest that there is a genetic locus for social cognition, which is imprinted and is not expressed from the maternally derived X chromosome. Neuropsychological and molecular investigations of eight females with partial deletions of the short arm of the X chromosome indicate that the putative imprinted locus escapes X-inactivation, and probably lies on Xq or close to the centromere on Xp. If expressed only from the X chromosome of paternal origin, the existence of this locus could explain why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females.

Extending the overlap of three congenital overgrowth syndromes.

We present the case of a male infant, born prematurely (at 33 weeks gestation) with macrosomia, disproportionate macrocephaly, facial dysmorphism, short penis and a small umbilical defect. He had a large ASD and was ventilated from birth for respiratory distress syndrome. He died at 12 hours of age despite neonatal ITU care. Post-mortem examination showed highly lobulated kidneys with nodules of blastema and foci of hamartomatous change in the medulla. Prominence of pancreatic islet cells and expansion of hepatic portal tracts were also noted. His mother has minor cervical spine abnormalities. We discuss the differential diagnosis and the difficulty in confidently assigning a diagnosis to this patient, as considerable overlap is becoming evident between Simpson-Golabi-Behmel syndrome and Perlman syndrome.

Evidence for a cryptic 46,XX cell line in a 45,X/46,X,psu idic(Xq) patient with normal reproduction.

Gonadal dysgenesis resulting in primary infertility is one of the most common features of Turner syndrome. There have been a number of cases described of pregnancy in 45,X subjects, but whether or not the fertility is associated with a 46,XX cell line in the germ cells is not known. We describe a 45,X/46,X,psu idic(Xq) female with normal fertility, in whom a cryptic 46,XX cell line was found in the germ cells.