American Journal of Medical Genetics 34:255-257 (1989)
Letter to the Editor
Familial Agnathia-Holoprosencephaly Caused by an Inherited Unbalanced Translocation and Not Autosomal Recessive Inheritance
To the Editor:
In 1983 Pauli et al. reported on two stillborn female infants with midline brain defects and severe micro- gnathia or agnathia in this Journal. Karyotypes of one affected child and both parents were interpreted as nor- mal, and inheritance pattern was presumed to be auto- soma1 recessive. To our knowledge, no other familial cases of agnathia have been reported. The mother of these 2 infants recently became pregnant and contacted the Prenatal Genetics Clinic. Repeat prometaphase chro- mosome studies detected a balanced t(6;18)(p24.1 or p24.2; p11.21) in the husband (Fig. 1). The balanced translocation has also been found in the husbands mother and a brother. Repeat investigation on stored fibroblasts kindly provided by the laboratory who had done the original testing showed that the second stillborn infant was chromosomally unbalanced with a 46, XX,der18,t(6;18) (pter -+ p24.1 or p24.2::p11.21 + qter) karyotype (Fig. 2). Tissue was no longer available from the other stillborn infant. Family history documented a sister of the husband who was small for gestational age, failed to thrive because of feeding difficulties, had large anterior and posterior fontanelles, left divergent strabis- mus, stridor and weak cry, microcephaly (3rd centile), suspected heart defect because of cardiac enlargement detected on chest film and excessive pigmentation of genitals, nipples, and knuckles. Her parents had been told that she was developmentally delayed. She was hos- pitalized for bronchopneumonia at age 3 weeks and died suddenly at age 3 months. Postmortem examination doc- umented a bicornuate uterus and probable aspiration pneumonia but no structural brain or heart defects. In retrospect, it is likely that she had laryngomalacia with a secondary cor pulmonale, but the pathogenesis of the excessive pigmentation is unclear. Review of family pho- tographs show that she had relatively large ears, micro- gnathia, and possible hypertelorism and that she resem- bles the patient described by Pearson et al. . We think that this girl and the first stillborn infant most likely had the same duplication 6p and monosomy 18p as the karyotyped stillborn fetus. Analysis of the amniotic
Received for publication October 14, 1988.
0 1989 Alan R. Liss, Inc.
fluid cells from the current pregnancy shows the same balanced translocation as in her father.
The unfolding story of this family illustrates the need for storage of tissue from and prometaphase banding in cases of atypical familial recurrence. Review by the au- thors of the original karyotypes done in another labora- tory did not detect the translocation either in the bal- anced or unbalanced form. Because this familial recur- rence has been referred to as evidence for an autosomal recessive form of agnathia, we think that it is necessary to correct the previously published information. In ad- dition, the survival of only females with the inherited chromosome imbalance is striking in this family, and a similar preponderance of females has been suggested for monosomy 18p [Schinzel, 19841 and for duplication 6p [Bernheim et al., 1979; Breuning et al., 1977; Chiyo et al., 1975; CBt6 et al., 1978; Ferrando et al., 1981; Fryns et al., 1983, 1986; Gouw et al., 1973; Muneer et al., 1984; Pagano et al., 1980; Pearson et al., 1979; Rosi et al., 1979; Schinzel, 1984; Smith and Pettersen, 1985; Therkelsen et al., 1971; Turleau et al., 1978; Yuksel et al., 19801. This probably reflects more deleterious effects of the chro- mosomal imbalance in males, although the total number of individuals identified is small.
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Letter to the Editor 257
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Natalie Krassikoff Department of Pediatrics and Medical Genetics University of Alabama-Birmingham Gurbax S. Sekhon Director of the Cytogenetic Laboratory Waisman Center for Mental Retardation Madison, Wisconsin