American Journal of M e d i c a l Genetics M246-247 (1992)
Letter to the Editor Human Situs Determination Is Probably Controlled by Several Different Genes To The Editor: In their excellent paper, Wilson et al. [19911report on a balanced translocation (12/13) which “highlights a locus on chromosome 12 of significance to human situs, symmetry and cardiac development.” This report, especially in view of paucity in literature on chromosome aberrations associated with the laterality sequence or with situs abnormalities, prompted us to report on two such cases ascertained through the Baltimore-Washington Infant Study of congenital cardiovascular malformations confirmed before one year of age [Ferencz, 19901. CLINICAL REPORTS Case 1 Full term white male with the birthweight of 2,380 g and OFC of 35.25 cm (< 5th centile) and length of 52.5 cm (5th centile) a t age 9 weeks. Anomalies noted a t birth were omphalocele, midline cleft lip and palate and heart defect. Minor facial anomalies included small epicanthal folds, broad nasal tip, mild micrognathia, small c-shaped ears, prominent occiput; the infant also had mild pectus excavatum. Fundoscopic eye examination showed small maculae with some optic nerve hypoplasia. Renal US was normal and sonographic examination of the brain showed a subependymal cyst. Borderline hearing was found on audio evoked EEG. Chromosome analysis documented an interstitial deletion of proximal lOq:46,XX,del(lO)(pter+q2l::q23-+ qter) (Fig. 1).Both parents had normal chromosomes. The infant died at age 20 months. Autopsy findings were as follows: partial atrioventricular canal, muscular VSD, single atrial chamber with left sided superior and inferior vena cava, right cardiac apex, left liver, complete intestinal malrotation, absent appendix, 2 accessory spleens. No other abnormalities were found. Case 2
This full term, small for gestational age (BW 1,910 g, OFC 27.2 cm, length 43 cm) black female, was born after a pregnancy complicated with oligohydramnios. Physical examination showed microcephaly, hypertelorism with flat nasal bridge, flat occiput, and high-arched palate. Both thumbs were absent with hypoplastic 5th fingers and bilateral single palmar crease. Labia majora
Received for publication January 21, 1992. Address reprint requests to Dr. Rivka Carmi, University of Maryland at Baltimore, Division of Human Genetics, 405 W. Redwood St., Suite 400, Baltimore, MD 21201.
0 1992 Wiley-Liss, Inc.
were hypoplastic with posterior vaginal tag. A complex cardiovascular malformation was diagnosed. The infant died at one week due to intractable heart failure. Autopsy examination of the heart showed common atrioventricular (AV) canal, large atrial septa1 and infracristal ventriculo-septa1 defects separated from AV canal, unclassified transposition of great vessels, dextrorotation of heart, levoposition of right atrial appendage, right aortic arch, persistent left superior vena cava, anomalous origin of left pulmonary artery from innominate artery, marked hypoplasia of pulmonary valve and arteries, as well as hypoplastic right ductus arteriosus. Other findings were: bilobed right lung, absent thymus, small spleen weighing 2.5 g (predicted normal weight 5.2 & 2.1 g). Chromosome analysis showed a derivative chromosome 13 formed by a terminal deletion of the region 13q31+qter:46,XX, - 13 fder(13)(q3l-+qter) (Fig. 2). Parental chromosomes were normal. DISCUSSION Accumulating literature suggests that the early embryonal process of determination of body asymmetry and thus the accomplishment of normal situs is complex and probably controlled by several different genes. Since the clinical delineation of the laterality sequence, a considerable amount of information on familial cases has documented autosomal recessive, autosomal dominant and X-linked recessive inheritance [Simpson and Zellweger, 1973; Katcher, 1980; Hurwitz and Caskey, 1982; Niikawa et al., 1983;Arnold et al., 1983;de la Monte and Hutchins, 1985; Opitz, 1985; and Mathias et al., 19871, thus implying at least 3 different major genes involved with lateralization. The mapping of the iu locus to mouse chromosome 12 [Brueckner et al., 19891 further suggested the existence of a human counterpart gene, possibly localized to the analogous chromosome number 14. Chromosome rearrangements, which have been proved so useful in guiding molecular studies [Worton et al., 19841, are rare in the laterality sequence or in isolated situs abnormalities. To the best of our knowledge, apart from the case reported by Wilson et al. 119911, there is only a statement on the association of trisomy 13 and situs inversus mentioned by Schinzel[19831,a case of monosomy 22 with, among other anomalies, mesocardia, midline liver and accessory spleen [DeCicco et al., 19731, and an unpublished case of 18p- with cranial meningocele and situs inversus mentioned by Meinecke [1990]. However, including our two cases, even this small number of cases suggest that chromosomes 13,18, and 10 could also be involved with lateralization and situs determination.
Letter to the Editor
Fig. 1. del(lO)(pte1-q21::q23+qter).
247
Fig. 2. del(l3)(q3l+qter).
One possible explanation for the paucity of such re- DeCicco F, Steele MW, Pau S, Park SC (1973):Monosomy of chromosome No. 22: A case report. J Pediatr 83:836-838. ported cases might be an underestimation of the signifiMonte SM, Hutchins GM (1985):Brief clinical report: sisters with cance of subtle findings (usually in autopsies) such as de lapolysplenia. Am J Med Genet 21:171-173. abnormal lung lobation, abnormal anatomical course of Ferencz C (1990):A case-control study of cardiovascular malformations the main bronchi in relation to the pulmonary artery in live-born infants: The morphogenetic relevance of epidemiologic and midline location of the liver, as incomplete forms of findings. In Clark EB, Takao A, (eds): “Developmental Cardiology, Morphology and Function.” New York: Raven Press, pp 523-539. situs inversus. Indeed, none of our cases had a complete form of the laterality sequence or complete situs in- Hurwitz RC, Kaskey CT (1982): Ivemark syndrome in siblings. Clin Genet 22:7-11. versus. They both had some cardiac heterotaxy with Katcher AL (1980):Familial asplenia, other malformations and sudden partial or complete AV canal. In the partial monosomy death. Pediatrics 65:633-635. 13q case “left isomeric” right lung and a suggestion of a Mathias RS,Lacro RV, Jones KL (1987):X-linked laterality sequence: hypoplastic spleen (form fruste of asplenia which is actuSitus inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:lll-116. ally considered at right isomerism?) were present. Although a thorough evaluation of this case by Dr. Van Meinecke P, Padberg B, Laas R (1990): Agnathia, holoprosencephaly and situs inversus-A 3rd report. Am J Med Genet 37:286-287. Praagh led her to the conclusion that this is not a case of situs abnormality (personal communication), we think Niikawa N, Koshaka S, Mizumoto M, Mamada I, Kajii T (1983):Familial clustering of situs inversus totalis and asplenia and polysplenia that the combination of abnormal heart placement and syndromes. Am J Med Genet 16:43-47. lung lobation with hypoplastic spleen is not a chance Opitz J M (1985):Editorial comment on the paper by de la Monte and occurrence and is rather an incomplete form of the latHutchins on familial polyasplenia. Am J Med Genet 21:175-176. erality sequence. The monosomy 1Oq case had a left Ruben GD, Templeton JM, Ziegler MM (1983): Situs inversus: The complex inducing neonatal intestinal obstruction. J Pediatr Surg liver as an only manifestation of abdominal situs in18:751-756. versus. However, this infant had polysplenia and intestiSchinzel A (1983): “Catalogue of Unbalanced Chromosome Aberranal malrotation, the latter occurring in 50-70% of cases tions in Man.” Berlin, New York: W. deGruyter, p. 913. with situs inversus [Ruben et al., 19831. Thus, this inJ, Zellweger H (1973): Familial occurrence of Ivermark synfant also had part of the laterality sequence spectrum. Simpson drome with splenic hypoplasia and asplenia in sibs. J Med Genet While situs abnormalities have not been previously re10:303-304. ported with either monosomy 1Oq or 13q, other findings Wilson GN, Stout JP, Schneider NR, Zneimer SM, Gilstrap LC (1991): Balanced translocation 12/13 and situs abnormalities: Homology of presented by our cases, such as cleft lip and palate for early pattern formation in man and lower organisms? Am J Med monosomy 1Oq and thumbs and thymic aplasia for Genet 38:601-607. monosomy 13q have been noted [Schinzel,19831. Future Worton RG, Duff C, Sylvester J E , Schmickel AD, Willard H F (1984): recognition of association patterns between various parDuchenne muscular dystrophy involving translocation of the dmd tial manifestations of situs anomalies and chromosome gene next to ribsosomal RNA genes. Science 224:1447-1449. aberrations might further contribute to the understandRivka Carmi ing of the roles played by various genes in order to bring Joann A. Boughman about the normal body asymmetry and situs. Division of Human Genetics Division of Epidemiology and REFERENCES Preventive Medicine Arnold GL, Bixler D, Girod D (1983): Probable autosomal recessive University of Maryland at Baltimore inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am J Med Genet 16:35-42. Brueckner M, D’Eustachio P, Horwich AL (1989):Linkage mapping of a mouse gene, IV, that controls left-right asymmetry of the heart and viscera. Proceedings of the National Academy of Sciencesof the United States of America. 86(13):5035-5038.
Kenneth R. Rosenbaum Division of Genetics Children’s Hospital National Medical Center Washington, D.C.
Letter to the Editor Human Situs Determination Is Probably Controlled by Several Different Genes To The Editor: In their excellent paper, Wilson et al. [19911report on a balanced translocation (12/13) which “highlights a locus on chromosome 12 of significance to human situs, symmetry and cardiac development.” This report, especially in view of paucity in literature on chromosome aberrations associated with the laterality sequence or with situs abnormalities, prompted us to report on two such cases ascertained through the Baltimore-Washington Infant Study of congenital cardiovascular malformations confirmed before one year of age [Ferencz, 19901. CLINICAL REPORTS Case 1 Full term white male with the birthweight of 2,380 g and OFC of 35.25 cm (< 5th centile) and length of 52.5 cm (5th centile) a t age 9 weeks. Anomalies noted a t birth were omphalocele, midline cleft lip and palate and heart defect. Minor facial anomalies included small epicanthal folds, broad nasal tip, mild micrognathia, small c-shaped ears, prominent occiput; the infant also had mild pectus excavatum. Fundoscopic eye examination showed small maculae with some optic nerve hypoplasia. Renal US was normal and sonographic examination of the brain showed a subependymal cyst. Borderline hearing was found on audio evoked EEG. Chromosome analysis documented an interstitial deletion of proximal lOq:46,XX,del(lO)(pter+q2l::q23-+ qter) (Fig. 1).Both parents had normal chromosomes. The infant died at age 20 months. Autopsy findings were as follows: partial atrioventricular canal, muscular VSD, single atrial chamber with left sided superior and inferior vena cava, right cardiac apex, left liver, complete intestinal malrotation, absent appendix, 2 accessory spleens. No other abnormalities were found. Case 2
This full term, small for gestational age (BW 1,910 g, OFC 27.2 cm, length 43 cm) black female, was born after a pregnancy complicated with oligohydramnios. Physical examination showed microcephaly, hypertelorism with flat nasal bridge, flat occiput, and high-arched palate. Both thumbs were absent with hypoplastic 5th fingers and bilateral single palmar crease. Labia majora
Received for publication January 21, 1992. Address reprint requests to Dr. Rivka Carmi, University of Maryland at Baltimore, Division of Human Genetics, 405 W. Redwood St., Suite 400, Baltimore, MD 21201.
0 1992 Wiley-Liss, Inc.
were hypoplastic with posterior vaginal tag. A complex cardiovascular malformation was diagnosed. The infant died at one week due to intractable heart failure. Autopsy examination of the heart showed common atrioventricular (AV) canal, large atrial septa1 and infracristal ventriculo-septa1 defects separated from AV canal, unclassified transposition of great vessels, dextrorotation of heart, levoposition of right atrial appendage, right aortic arch, persistent left superior vena cava, anomalous origin of left pulmonary artery from innominate artery, marked hypoplasia of pulmonary valve and arteries, as well as hypoplastic right ductus arteriosus. Other findings were: bilobed right lung, absent thymus, small spleen weighing 2.5 g (predicted normal weight 5.2 & 2.1 g). Chromosome analysis showed a derivative chromosome 13 formed by a terminal deletion of the region 13q31+qter:46,XX, - 13 fder(13)(q3l-+qter) (Fig. 2). Parental chromosomes were normal. DISCUSSION Accumulating literature suggests that the early embryonal process of determination of body asymmetry and thus the accomplishment of normal situs is complex and probably controlled by several different genes. Since the clinical delineation of the laterality sequence, a considerable amount of information on familial cases has documented autosomal recessive, autosomal dominant and X-linked recessive inheritance [Simpson and Zellweger, 1973; Katcher, 1980; Hurwitz and Caskey, 1982; Niikawa et al., 1983;Arnold et al., 1983;de la Monte and Hutchins, 1985; Opitz, 1985; and Mathias et al., 19871, thus implying at least 3 different major genes involved with lateralization. The mapping of the iu locus to mouse chromosome 12 [Brueckner et al., 19891 further suggested the existence of a human counterpart gene, possibly localized to the analogous chromosome number 14. Chromosome rearrangements, which have been proved so useful in guiding molecular studies [Worton et al., 19841, are rare in the laterality sequence or in isolated situs abnormalities. To the best of our knowledge, apart from the case reported by Wilson et al. 119911, there is only a statement on the association of trisomy 13 and situs inversus mentioned by Schinzel[19831,a case of monosomy 22 with, among other anomalies, mesocardia, midline liver and accessory spleen [DeCicco et al., 19731, and an unpublished case of 18p- with cranial meningocele and situs inversus mentioned by Meinecke [1990]. However, including our two cases, even this small number of cases suggest that chromosomes 13,18, and 10 could also be involved with lateralization and situs determination.
Letter to the Editor
Fig. 1. del(lO)(pte1-q21::q23+qter).
247
Fig. 2. del(l3)(q3l+qter).
One possible explanation for the paucity of such re- DeCicco F, Steele MW, Pau S, Park SC (1973):Monosomy of chromosome No. 22: A case report. J Pediatr 83:836-838. ported cases might be an underestimation of the signifiMonte SM, Hutchins GM (1985):Brief clinical report: sisters with cance of subtle findings (usually in autopsies) such as de lapolysplenia. Am J Med Genet 21:171-173. abnormal lung lobation, abnormal anatomical course of Ferencz C (1990):A case-control study of cardiovascular malformations the main bronchi in relation to the pulmonary artery in live-born infants: The morphogenetic relevance of epidemiologic and midline location of the liver, as incomplete forms of findings. In Clark EB, Takao A, (eds): “Developmental Cardiology, Morphology and Function.” New York: Raven Press, pp 523-539. situs inversus. Indeed, none of our cases had a complete form of the laterality sequence or complete situs in- Hurwitz RC, Kaskey CT (1982): Ivemark syndrome in siblings. Clin Genet 22:7-11. versus. They both had some cardiac heterotaxy with Katcher AL (1980):Familial asplenia, other malformations and sudden partial or complete AV canal. In the partial monosomy death. Pediatrics 65:633-635. 13q case “left isomeric” right lung and a suggestion of a Mathias RS,Lacro RV, Jones KL (1987):X-linked laterality sequence: hypoplastic spleen (form fruste of asplenia which is actuSitus inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:lll-116. ally considered at right isomerism?) were present. Although a thorough evaluation of this case by Dr. Van Meinecke P, Padberg B, Laas R (1990): Agnathia, holoprosencephaly and situs inversus-A 3rd report. Am J Med Genet 37:286-287. Praagh led her to the conclusion that this is not a case of situs abnormality (personal communication), we think Niikawa N, Koshaka S, Mizumoto M, Mamada I, Kajii T (1983):Familial clustering of situs inversus totalis and asplenia and polysplenia that the combination of abnormal heart placement and syndromes. Am J Med Genet 16:43-47. lung lobation with hypoplastic spleen is not a chance Opitz J M (1985):Editorial comment on the paper by de la Monte and occurrence and is rather an incomplete form of the latHutchins on familial polyasplenia. Am J Med Genet 21:175-176. erality sequence. The monosomy 1Oq case had a left Ruben GD, Templeton JM, Ziegler MM (1983): Situs inversus: The complex inducing neonatal intestinal obstruction. J Pediatr Surg liver as an only manifestation of abdominal situs in18:751-756. versus. However, this infant had polysplenia and intestiSchinzel A (1983): “Catalogue of Unbalanced Chromosome Aberranal malrotation, the latter occurring in 50-70% of cases tions in Man.” Berlin, New York: W. deGruyter, p. 913. with situs inversus [Ruben et al., 19831. Thus, this inJ, Zellweger H (1973): Familial occurrence of Ivermark synfant also had part of the laterality sequence spectrum. Simpson drome with splenic hypoplasia and asplenia in sibs. J Med Genet While situs abnormalities have not been previously re10:303-304. ported with either monosomy 1Oq or 13q, other findings Wilson GN, Stout JP, Schneider NR, Zneimer SM, Gilstrap LC (1991): Balanced translocation 12/13 and situs abnormalities: Homology of presented by our cases, such as cleft lip and palate for early pattern formation in man and lower organisms? Am J Med monosomy 1Oq and thumbs and thymic aplasia for Genet 38:601-607. monosomy 13q have been noted [Schinzel,19831. Future Worton RG, Duff C, Sylvester J E , Schmickel AD, Willard H F (1984): recognition of association patterns between various parDuchenne muscular dystrophy involving translocation of the dmd tial manifestations of situs anomalies and chromosome gene next to ribsosomal RNA genes. Science 224:1447-1449. aberrations might further contribute to the understandRivka Carmi ing of the roles played by various genes in order to bring Joann A. Boughman about the normal body asymmetry and situs. Division of Human Genetics Division of Epidemiology and REFERENCES Preventive Medicine Arnold GL, Bixler D, Girod D (1983): Probable autosomal recessive University of Maryland at Baltimore inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am J Med Genet 16:35-42. Brueckner M, D’Eustachio P, Horwich AL (1989):Linkage mapping of a mouse gene, IV, that controls left-right asymmetry of the heart and viscera. Proceedings of the National Academy of Sciencesof the United States of America. 86(13):5035-5038.
Kenneth R. Rosenbaum Division of Genetics Children’s Hospital National Medical Center Washington, D.C.
