Biomedical subjects
Publications and source records attributed to J L Tolmie.
Thirty one patients with the putative diagnosis of Prader-Willi syndrome were reassessed clinically and by DNA analysis. Eleven patients were judged not to have Prader-Willi syndrome and 20 to have the condition. This was confirmed by DNA analysis in all but one case. The diagnosis of Prader-Willi syndrome, especially in early infancy, should be made with caution unless confirmed by molecular genetic studies.
Sparse, brittle, sulphur-deficient hair is an excellent marker for several autosomal recessive neurocutaneous syndromes. The term 'trichothiodystrophy' is commonly used in publications on such syndromes and the best characterized trichothiodystrophy syndrome is associated with skin photosensitivity and intellectual impairment. Patients with these three cardinal signs usually have an underlying DNA repair defect. Here we describe clinical and laboratory findings in two patients with trichothiodystrophy and defective DNA repair alongside findings in three other cases who have different trichothiodystrophy syndromes without defective DNA repair. These patients' features are discussed in the light of a practical classification scheme which is based upon a check-list of clinical abnormalities associated with trichothiodystrophy syndromes (Van Neste, 1991).
We describe three cases of prenatal infantile cortical hyperostosis (Caffey's disease) from two families, all associated with maternal polyhydramnios. Case 1 (family 1) was an early early neonatal death after delivery at 27 weeks gestation, case 2 (family 2) an intrauterine death at 33 weeks. Case 3 (family 2) had limited skeletal involvement and followed a course typical for Caffey's disease. Only six cases of prenatal Caffey's disease with extensive skeletal involvement have previously been described. Polyhydramnios was reported in all but one and the condition was lethal unless pregnancy reached term. To our knowledge cases 2 and 3 reported here represent the first description of Caffey's disease in which the prenatal lethal form was not sporadic.
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Of 821 consecutive admissions to a paediatric intensive care unit, 47 (5.7%) were for chromosomal or monogenic disorders. These patients had more readmissions, longer mean stays, and a higher mortality rate than the group as a whole. In two of the four cases that died of single gene disorders, failure to store DNA made genetic counseling difficult.
The tendency for sibs affected by non-syndromal neural tube defect (NTD) to have the same type of lesion was assessed retrospectively in a series of 66 affected sibships from the west of Scotland. Different schemes were used to classify the lesions: in the simplest classification into either anencephaly (including anencephaly-spina bifida) or spina bifida there was a tendency for spina bifida to breed true. More detailed description of the NTD in 48 sibships permitted classification according to location on the neuraxis; in this scheme sibs had dissimilar lesions. In 48 sets of affected sibs the lesions were separable into high NTD, which had involvement above vertebral level T12, and low NTD, which did not extend above T12. Low lesions comprised a minority of the total and each one occurred in a sibship with a high lesion. These results do not support the idea that NTDs occurring above and below vertebral level T12 have a different genetic basis.
Clinical, chromosomal and molecular studies of a group of 15 XX males confirm the presence of two main groups. A Y + ve group of ten patients exhibit sex reversal as the result of transfer of the distal end of the short arm of the Y chromosome, including testis determining factors, to the short arm of one X-chromosome, presumably by accidental crossing-over in paternal meiosis. The ten patients have Klinefelter's syndrome but differ from XXY cases in that they are short and shown no impairment of intelligence. The four Y-ve XX males have no demonstrable Y sequences and differ from Y + ve cases in abnormality of the external genitalia and invariable gynaecomastia; in this, they more closely resemble XX true hermaphrodites than XY males. These observations on Y - ve XX males and an additional exceptional Y + patients suggest that the ZFY locus is not essential for male differentiation and is not the primary testis determining factor. Male sex determination in sporadic, and familial Y-ve XX males and true hermaphrodites is likely to be the result of mutation in an X-linked TDF gene and its consequent escape from the constraints of X-inactivation. It seems premature to abandon the dosage model of sex determination on the recent evidence that ZFX does not show dosage compensation.
The cardinal features of the Baller-Gerold syndrome (MIM *21860) are craniosynostosis and radial aplasia. Only 12 cases have been published and these are roughly divisible into two groups: cases without any additional abnormalities and cases with a broad range of additional features. We describe a boy with craniosynostosis and radial aplasia alone and highlight genetic counselling difficulties presented by a sporadic case of this rare syndrome.
We report three infants with a rare syndrome of restrictive dermopathy, in which rigidity of the skin at birth is associated with characteristic facial anomalies, generalised arthrogryposis, bony abnormalities, and lung hypoplasia. The skin has a distinctive pathology with compaction of the dermal collagen and fibrosis of the subcutaneous tissue. The inheritance is likely to be autosomal recessive and the condition appears to be fatal in the early neonatal period.
A proximal 15q deletion, del(15) (q11:q13), was detected in a child with Angelman syndrome by cytogenetic analysis of peripheral lymphocytes. The chromosomes of both parents appeared normal. Flow karyotype analysis carried out on lymphoblastoid cell lines derived from the child and her parents confirmed the presence of a de novo 15 deletion. The estimated size of the deleted segment ranged from 6.1-9.5% of chromosome 15 (approximately 6-9.3 million base pairs). The parental origin of the deleted chromosome could not be resolved by flow cytometry, but cytogenetic evidence suggested that it was derived from the smaller chromosome 15 homologue in the mother.
We describe findings in a 29-year-old woman with Oliver McFarlane syndrome after 25 years of follow-up, and we review findings in six other reported cases. Pigmentary retinal degeneration, trichomegaly, prenatal onset growth failure, anterior pituitary deficiencies, and peripheral neuropathy characterize the condition.
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A child with impaired intelligence, minor dysmorphisms, obesity and genital hypoplasia was found to have an apparently balanced translocation, 46,XY,t(4;14)(q12;q13), following cytogenetic analysis. The same rearrangement was also detected in the child's father, who had similar phenotypic abnormalities to his son. Detailed study of flow karyotypes produced from lymphoblastoid cell lines established that in both patients the translocation was in fact unbalanced with approximately 11 million base pairs of DNA (corresponding to about 6.0% of chromosome 4 or 11.0% of chromosome 14) being lost.
We report a mother and two of her children, one female and the other male, who have ptosis, hypertelorism, epicanthic folds, downward slanting palpebral fissures, broad nasal bridge, and minor digital anomalies (fig 1); the children had delayed closure of a large anterior fontanelle. All three affected persons were born prematurely.
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We report male and female siblings with extreme microcephaly and mental retardation, growth retardation, and multiple chromosome mosaicism. Mental retardation associated with chromosome mosaicism does not always carry a low recurrence risk.