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 husband‘s 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. [1979]. 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.

REFERENCES Bernheim A, Berger R, Vougier G, Thieffry JC, Matet Y (1979): Partial

trisomy 6p. Hum Genet 4813-16. Breuning MH, Bijlsma JB, de France HF (1977): Partial trisomy 6p due

to familial translocation t(6;20)(p21; p13). Hum Genet 387-13. Chiyo H, Kuroki Y, Matsui I, Yanagida K, Nakagome Y (1975): A 6p

trisomy detected in a family with a “giant satellite.” Humangenetik 30:63-67.

C6t6 GB, Papadakou-Lagoyanni S, Sbyrakis S (1978): Partial trisomy 6p with karyotype 46,XY,der(22), t(6;22)(p22; ql3)mat. J Med Genet 6: 4 79-481.

Ferrando P, San Roman C, Rodriquez de Cordoba S, Arnaiz-Villena A (1981): Partial trisomy 6p: 46,XX,-lO,der(lO),t(6;lO)(p22;26)pat and HLA localization. J Med Genet 18%-233.

Fryns JP, Petit P, Jaeken J, Eggermont E, Kleckowska A, van den Berghe H (1983): Partial trisomy 6p: A clinical entity. Ann Genet 2650-52.

Fryns JP, Kleckowska A, Moerman F, van den Berghe K, van den Berghe H (1986): Partial distal trisomy 6p in a malformed fetus. Ann Genet 2953, 54.

Gouw WL, Ten Kate LP, Ander GJPA (1973): A case of 18q- in a family with a translocation t(6p+;18q-) identified by Giemsa banding tech- nique. Hum Genet 19:123-126.

Muneer R, Sarale D, Keppen L, Rennert 0 (1984): Familial partial trisomy of different segments of chromosome 6p and choanal atresia

6

2" I I

18 Fig. 1. Schematic of breakpoints on chromosomes 6 and 18 in the balanced translocation carrier.

Fig. 2. Duplication 6p and monosomy 18p as detected in the stillborn (upper line) and the balanced translocation in the carrier (bottom line). Arrows point to the abnormal chromosomes and the respective breakpoints.

Letter to the Editor 257

in 2 female patients. Am J Hum Genet. 36(Suppl): 1068. Pagano L, Fioretti G, Vetrella M, Risolo E, Casullo C, Celona A, Renda

S, Rinalda A, Ventruto S (1980): Hereditary 3;6 translocation: Three cases of multiple malformations with partial trisomy 6p21 + pter. Ann Genet 23:173-175.

Pauli RM, Pettersen JC, Arya S, Gilbert EF (1983): Familial agnathia- holoprosencephaly. Am J Med Genet 14577-698.

Pearson G, Mann JD, Bensen J, Bull RW (1979): Inversion duplication of chromosome 6 with trisomic codominant expression of HLA antigens. Am J Hum Genet 31:29-34.

Rosi G, Venti G, Migliorini Bruschelli G, Donti E, Bocchini V, Armellini R (1979): Trisomy 6p22 + 6pter due to familial t(6;13)(p22; q34 or 33) translocation. Hum Genet 51:67-72.

Schinzel A (1984): “Catalogue of Unbalanced Chromosome Aberrations in Man.” Berlin: Walter de Gruyter, p 604.

Smith BS and Pettersen JC (1985): An anatomical study of a duplication 6p based on two sibs. Am J Med Genet 20549-663.

Therkelsen AJ, Klinge T, Henningsen K, Mikkelsen M, Schmidt G (1971): A family with a presumptive C/F translocation in five gen- erations. Ann Genet 14:13-21.

Turleau C, Chavin-Colin F, de Grouchy J (1978): La trisomie 6p par- tielle. Ann Genet 21:88-91.

Yuksel M, Jones LA, Taysi K, Henry CG (1980): Partial trisomy of the short arm of 6: A case due to paternal balanced translocation. Turk J Pediatr 22:65-71.

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