Biomedical subjects
Publications and source records attributed to D Donnai.
Two sibs with a similar pattern of dysmorphic facial features and multiple structural abnormalities are reported. Both had a normal karyotype. The parents are first cousins and neither shows any stigmata of the disorder. In view of the consanguinity and pattern of malformations, autosomal recessive inheritance seems likely.
Isolated limb deficiencies are usually sporadic occurrences. However, if they are associated with other abnormalities or a family history, the risk to future pregnancies may be as high as 50%. A thorough history, examination and investigation of the baby as well as the parents is essential before assessing this recurrence risk. The syndromes associated with limb deficiencies are presented.
Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. We have studied 12 unrelated TCS families with multiple affected individuals for linkage to five chromosome 5 markers. There is strong evidence demonstrating linkage to three of these markers. Multipoint linkage analysis places the mutation causing TCS in the interval between the gene for the glucocorticoid receptor and the anonymous marker D5S22, with a maximum multipoint lod score of 9.1.
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OBJECTIVE: To determine the accuracy of midtrimester diagnosis of fetal abnormality by examination and investigation of fetuses after induced abortion. DESIGN: Prospective study over five years of fetuses aborted in the midtrimester because of abnormalities detected by ultrasonography and amniocentesis. Techniques included a full external examination by a clinical geneticist with experience in dysmorphology and other investigations including necropsy. SETTING: Regional genetic centre. PARTICIPANTS: Clinicians working within the North Western region who wished to use the service offered. RESULTS: 133 Fetuses were aborted because of abnormalities detected on ultrasonography and 115 because of abnormal findings on amniotic fluid analysis. In a further two cases fetal abnormality was diagnosed by molecular genetic and biochemical techniques. Among the fetuses with abnormal scans the pretermination diagnosis was changed or refined in a way which affected genetic counselling in 53 of 133 cases. Among the 115 fetuses diagnosed as abnormal by amniocentesis the pretermination diagnosis was confirmed in 112 cases and altered in three. CONCLUSION: Fetuses aborted because of abnormalities detected by screening should be examined by suitably experienced clinicians, both for accurate genetic counselling of the families and for quality control of the tests employed.
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Three cases of ankyloblepharon filiforme adnatum (AFA) in infants with Edwards syndrome are described. The case for a fifth subgroup of AFA is reinforced.
Three cases of congenital cranial hemihypertrophy are described. CT or ultrasound scans showed unilateral cerebral enlargement with dilatation of the ipsilateral ventricle. Seizures occurred in two patients and the neurodevelopmental outlook appears poor. These patients represent a poor prognosis subgroup of the congenital hemihypertrophies.
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Two sibs with a similar pattern of unusual facial features, limb malformations, and postnatal onset of ichthyosis are reported. The parents are first cousins and neither shows any stigmata of the disorder. The presence of ichthyosis suggests that there may be a metabolic component to this syndrome. In view of the consanguinity and pattern of the malformations, autosomal recessive inheritance seems likely.
The mouse mutant disorganisation (Ds) is a semidominant gene with variable penetrance in heterozygotes and lethality in homozygotes; 67% of heterozygotes have multiple defects and the rest have single defects. Fifty-three percent have cranioschisis and execephaly, 40% have hamartomas represented by papillae of variable size and shape protruding from the body, sometimes containing cartilage, and 33% have limb abnormalities. A child is presented with defects similar to those seen in mice heterozygous for Ds. He had shortening of the upper and lower segments of the right leg with a popliteal web and nine toes on the same side. A finger-like structure arose from the abdomen and one kidney was absent. The homology between this infant and Ds mice is discussed and published reports of human cases with similar abnormalities are reviewed.
The hypothesis of an intrinsic defect of germ plasma put forward by Streeter to explain the abnormalities observed in 'amniotic bands sequence' (ABS) was not supported by Torpin, who suggested that the bands derived from early amnion rupture, with formation of mesodermal strings and naked chorion, which then constricted or adhered to fetal parts. Recently, several authors have recorded and discussed possible mechanisms for 'non-band related' malformations in patients with otherwise typical limb constrictions and amputations. The mouse mutant disorganisation (Ds) is a semidominant with 72% of heterozygotes manifesting abnormalities, which include cranioschisis, limb duplications and deficiencies, gastro/thoracoschisis, and papillae protruding from other parts of the body. We report similar abnormalities including papillae in five fetuses and one newborn with ABS and, based on these observations and published reports, we suggest that a human homologue for Ds may be the cause of at least some examples of ABS.
Three children are described with severe Silver-Russell syndrome. Major medical problems occurred in the first two years of life in all three. Silver-Russell syndrome should be considered in the differential diagnosis of children with severe pre- and postnatal growth deficiency.
Three children are reported, a male and female sib pair of Sikh origin and a male child who was the offspring of first cousin Pakistani Muslims, with Hirschsprung's disease, hypoplastic nails, and similar minor dysmorphic features. We consider that they represent a distinct autosomal recessive syndrome.
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We describe three patients with the cutaneous manifestations of hypomelanosis of Ito. Two, with unusual abnormalities of their toes, had a mixture of diploid and triploid cells in cultured skin fibroblasts. The published clinical descriptions of hypomelanosis of Ito and diploid-triploid mosaicism are reviewed. Chromosome heteromorphisms, HLA types, and DNA fingerprints were studied in an attempt to elucidate the origin of the disease in our patients. We conclude that hypomelanosis of Ito is a manifestation of a heterogeneous group of disorders, the common factor being the presence of two genetically different cell lines. It can result from chromosomal mosaicism or chimerism, from a postzygotic mutation, or from X inactivation. The risk of recurrence is negligible if the proband is a male; if the proband is female the risk is also low but an X linked mutation must be considered.