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Re: Ivemark syndrome From: James S Smeltzer MD (gaperina@mindspring.com) Sun Jan 10 20:42:37 1999 Messages sorted by: [ date ][ thread ][ subject ][ author ] Next message: Ultravas99@aol.com: "Fwd: Uterine synechial porthole" Previous message: James S Smeltzer MD: "Re: Ivemark Syndrome" In reply to: Joshua Copel: "Re: Ivemark syndrome" Josh, 25% is much too high unless another affected individual in the kindred. Large majority are sporadic, I believe, although many kindred are reported: http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?208530 208530 ASPLENIA WITH CARDIOVASCULAR ANOMALIES Alternative titles; symbols IVEMARK SYNDROME POLYSPLENIA SYNDROME, INCLUDED POLYASPLENIA, INCLUDED HETEROTAXY, VISCEROATRIAL, AUTOSOMAL RECESSIVE, INCLUDED VAH, AUTOSOMAL RECESSIVE, INCLUDED TABLE OF CONTENTS •TEXT •REFERENCES •SEE ALSO •CONTRIBUTORS •CREATION DATE •EDIT HISTORY •CLINICAL SYNOPSIS Database Links <Picture: 15 MEDLINE Citations> Note: pressing the <Picture: Light Bulb> symbol will find the citations in MEDLINE whose text most closely matches the text of the preceding OMIM paragraph, using the Entrez MEDLINE neighboring function. TEXT Parental consanguinity in 3 families and 4 instances of multiple affected sibs (Simpson and Zellweger, 1973) support autosomal recessive inheritance. Hypoplasia of the spleen is sometimes the finding rather than aplasia. Congenital absence of the spleen is usually accompanied by complex cardiac malformations, malposition and maldevelopment of the abdominal organs, and abnormal lobation of the lungs. Heinz and Howell-Jolly bodies in the peripheral blood are hematologic signs of absent spleen. Most cases are sporadic. A patient with the typical asplenia syndrome had a sib who at autopsy showed multiple accessory spleens, persistent atrioventricularis communis and partial transposition of the abdominal viscera (Polhemus and Schafer, 1952). In another family, 3 sibs had asplenia with cyanotic heart disease (Ruttenberg et al., 1964). Chen and Monteleone (1977) reported 2 affected boys in one family and 2 first cousins in another. Overall empiric recurrence risk after birth of a single case is probably on the order of 5% or less. Hurwitz and Caskey (1982) reported affected brothers, bringing to 8 the number of families with multiple affected sibs. Congenital heart malformation and septicemia were features. They also reported an instance of parental consanguinity, bringing to 4 the number of such instances. They identified 32 cases among 4,059 autopsies done in a period of 21 years in the Texas Children's Hospital. All were seemingly sporadic. A male excess was noted in both familial and autopsy cases. The authors favored autosomal recessive inheritance with male preponderance. The designation polysplenia syndrome is used for a complex association of abnormalities of the spleen and of visceral lateralization with congenital heart malformations (Moller et al., 1967; Rose et al., 1975). Visceral and cardiac situs may be disparate--so-called situs ambiguus. Polysplenia suggests bilateral 'left-sidedness' (Moller et al., 1967) and mirror imaging of the lungs is frequent such that both lungs have the appearance of the left lung, with 2 lobes and hyparterial bronchi. Anomalous pulmonary venous return is frequent. The hepatic segment of the inferior vena cava is often missing. Return of blood from the lower part of the body is by the azygous or hemiazygous system, a venous defect that occurs almost only in this syndrome. Cardiac defects include atrial and ventricular septal defects, pulmonic stenosis, endocardial cushion defects, and others. <Picture: 30 MEDLINE Neighbors> Cesko et al. (1997) described 2 sibs with Ivemark syndrome. In both cases, absent spleen, symmetric liver, and trilobed lungs were associated with complex cardiac malformations. In the first infant, minor facial abnormalities were noted, including hypertelorism, low-set ears, and choanal stenosis. In the second case, the syndrome was diagnosed prenatally by fetal echocardiography at 20 weeks. Cesko et al. (1997) noted that fetal echocardiography is an effective means of prenatal detection of Ivemark syndrome. <Picture: 5 MEDLINE Neighbors> Rose et al. (1975) reported 2 sisters with the polysplenia syndrome, and Hallett et al. (1979) described 2 affected brothers. Arnold et al. (1983) reported an Amish family in which 5 persons in 2 generations showed congenital cardiac and visceral defects consistent with the polysplenia syndrome. The parents of 4 affected sibs were fourth cousins; a deceased sister of the father was affected. Families in which 1 person had the developmental complex with polysplenia and another person had it with asplenia (Polhemus and Schafer, 1952; Zlotogora and Elian, 1981; Niikawa et al., 1983) suggest that the asplenia and polysplenia syndromes are a single entity. Asplenia and polysplenia have similar cardiac anomalies, although asplenia tends to be associated with severe atrioventricular canal malformations and marked deficiency of the interventricular septum whereas with polysplenia the AV canal defects are usually less severe and there are greater abnormalities of the interatrial septum (Hutchins et al., 1983). In mice, a recessive mutation, iv, causes a malformation syndrome like asplenia/polysplenia in man (Layton, 1976). De la Monte and Hutchins (1985) reported sisters with polysplenia syndrome. Affected sibs were also reported by Arnold et al. (1983), Hallett et al. (1979), Niikawa et al. (1983), and Kawagoe et al. (1980). Rodriguez et al. (1991) reported a patient with polyasplenia and caudal deficiency including imperforate anus, ambiguous external genitalia, multiple contractures of the lower limbs with short femora, and agenesis of the corpus callosum. Although this patient apparently represents the first recognized case of agenesis of the corpus callosum in association with polyasplenia and caudal deficiency, the literature on 7 additional patients with polyasplenia and caudal deficiency was reviewed. The association of a laterality sequence with caudal deficiency may represent a distinct autosomal recessive entity. <Picture: 30 MEDLINE Neighbors> In 6 children in whom orthotopic cardiac transplantation had been performed for severe visceroatrial heterotaxia, Britz-Cunningham et al. (1995) found mutations in the gene encoding connexin 43 (CX43; 121014). Four of 6 patients were compound heterozygotes for CX43 mutations, indicating autosomal recessive inheritance. However, several groups were unable to find CX43 mutations in patients with heterotaxy. Gebbia et al. (1996) studied a total of 38 cases of sporadic and familial heterotaxy and found no mutations in CX43. Splitt et al. (1997) found no mutations in 48 patients with visceroatrial heterotaxy attending U.K. Regional Paediatric Cardiology Centres. Debrus et al. (1997) screened the entire coding sequence and direct flanking sequences of the CX43 gene in a selected group of 25 patients (19 familial cases) with a wide variety of lateralization defects and cardiovascular malformations. They detected only a single bp insertion in the 3-prime untranslated region of 1 patient. To test the possibility of mutations in other parts of the CX43 gene, the gene was located on the physical map of chromosome 6, and flanking polymorphic markers were genotyped. Haplotype analysis excluded the CX43 gene locus in nearly all of the familial cases of lateralization defects. Thus, the results of did not support the suggestion that this gene is implicated in human autosomal recessive lateralization defects. On the basis of analysis in the 3 previous reports and in 11 patients of their own, Toth et al. (1998) concluded that 'it is more and more likely that the results reported by Britz-Cunningham et al. (1995) were a laboratory artifact.' There had been a total of 78 cases of heterotaxy in which no CX43 mutation could be found in the 200 basepairs containing all of the nucleotide changes reported by Britz-Cunningham et al. (1995). <Picture: 30 MEDLINE Neighbors> Freeman et al. (1996) described a 6-year-old girl with a balanced 11;20 translocation (46,XX,t(11;20)(q13.1;q13.13)pat), asplenia, pulmonic stenosis, Hirschsprung disease, minor anomalies, and mental retardation. Fukushima et al. (1993) also reported an individual with situs abnormalities and a balanced chromosome rearrangement involving a breakpoint at 11q13. Freeman et al. (1996) stated that PCR analysis of microsatellite markers excluded uniparental disomy for chromosomes 11 and 20. Segregation analysis of markers in the 11q13 region in the proposita and her phenotypically normal carrier sibs did not show a unique combination of maternal and paternal alleles in the patient. Freeman et al. (1996) discussed several possible explanations for the simultaneous occurrence of situs abnormalities and a balanced 11;20 translocation: chance, further chromosome rearrangement in the patient, gene disruption and random situs determination, and gene disruption plus transmission of a recessive or imprinted allele from the mother. <Picture: 3 MEDLINE Neighbors> SEE ALSO Ivemark (1955) REFERENCES 1. Arnold, G. L.; Bixler, D.; Girod, D. : Probable autosomal recessive inheritance of polysplenia, situs inversus and cardiac defects in an Amish family. Am. J. Med. Genet. 16: 35-42, 1983. PubMed ID : 6638068 2. Britz-Cunningham, S. H.; Shah, M. M.; Zuppan, C. W.; Fletcher, W. H. : Mutations of the connexin43 gap-junction gene in patients with heart malformations and defects of laterality. New Eng. J. Med. 332: 1323-1329, 1995. PubMed ID : 7715640 3. Cesko, I.; Hajdu, J.; Toth, T.; Marton, T.; Papp, C.; Papp, Z. : Ivemark syndrome with asplenia in siblings. J. Pediat. 130: 822-824, 1997. PubMed ID : 9152295 4. Chen, S.-C.; Monteleone, P. L. : Familial splenic anomaly syndrome. (Letter) J. Pediat. 91: 160-161, 1977. PubMed ID : 874654 5. Debrus, S.; Tuffery, S.; Matsuoka, R.; Galal, O.; Sarda, P.; Sauer, U.; Bozio, A.; Tanman, B.; Toutain, A.; Claustres, M.; Le Paslier, D.; Bouvagnet, P. : Lack of evidence for connexin 43 gene mutations in human autosomal recessive lateralization defects. J. Molec. Cell. Cardiol. 29: 1423-1431, 1997. 6. de la Monte, S. M.; Hutchins, G. M. : Sisters with polysplenia. Am. J. Med. Genet. 21: 171-173, 1985. PubMed ID : 4003441 7. Freeman, S. B.; Muralidharan, K.; Pettay, D.; Blackston, R. D.; May, K. M. : Asplenia syndrome in a child with a balanced reciprocal translocation of chromosomes 11 and 20 (46,XX,t(11;20)(q13.1;q13.13). Am. J. Med. Genet. 61: 340-344, 1996. PubMed ID : 8834045 8. Fukushima, Y.; Ohashi, H.; Wakui, K.; Fujiwara, M.; Nakamura, Y.; Ogawa, K.: Polysplenia syndrome and paracentric inversion of chromosome 11 ((46,XX,inv(11)(q13q25)). (Abstract) Am. J. Hum. Genet. 53 (suppl.): 1543, 1993. 9. Gebbia, M.; Towbin, J. A.; Casey, B. : Failure to detect connexin43 mutations in 38 cases of sporadic and familial heterotaxy. Circulation 94: 1909-1912, 1996. PubMed ID : 8873667 10. Hallett, J. J.; Gang, D. L.; Holmes, L. B. : Familial polysplenia and cardiovascular defects. (Abstract) Pediat. Res. 13: 344, 1979. 11. Hurwitz, R. C.; Caskey, C. T. : Ivemark syndrome in siblings. Clin. Genet. 22: 7-11, 1982. PubMed ID : 7172476 12. Hutchins, G. M.; Moore, G. W.; Lipford, E. H.; Haupt, H. M.; Walker, M. C.: Asplenia and polysplenia malformation complexes explained by abnormal embryonic body curvature. Path. Res. Pract. 177: 60-76, 1983. 13. Ivemark, B. I. : Implications of agenesis of the spleen on the pathogenesis of cono-truncus anomalies in childhood: analysis of the heart malformations in splenic agenesis syndrome, with fourteen new cases. Acta Paediat. 44 (suppl. 104): 1-110, 1955. 14. Kawagoe, K.; Hara, K.; Jimbo, T.; Mizuno, M.; Sakamoto, S. : Occurrence of Ivemark syndrome with polysplenia in sibs of a family. Proc. Jpn. Acad. 56: 633-637, 1980. 15. Layton, W. M., Jr. : Random determination of a developmental process: reversal of normal visceral asymmetry in the mouse. J. Hered. 67: 336-338, 1976. PubMed ID : 1021593 16. Moller, J. H.; Nakib, A.; Anderson, R. C.; Edwards, J. E. : Congenital cardiac disease associated with polysplenia, a developmental complex of bilateral 'left-sidedness.'. Circulation 36: 789-799, 1967. PubMed ID : 6050934 17. Niikawa, N.; Kohsaka, S.; Mizumoto, M.; Hamada, I.; Kajii, T. : Familial clustering of situs inversus totalis, and asplenia and polysplenia syndromes. Am. J. Med. Genet. 16: 43-47, 1983. PubMed ID : 6638069 18. Polhemus, D. W.; Schafer, W. B. : Congenital absence of spleen; syndrome with atrioventricularis and situs inversus: case reports and review of the literature. Pediatrics 9: 696-708, 1952. 19. Rodriguez, J. I.; Palacios, J.; Omenaca, F.; Lorente, M. : Polyasplenia, caudal deficiency, and agenesis of the corpus callosum. Am. J. Med. Genet. 38: 99-102, 1991. PubMed ID : 2012140 20. Rose, V.; Izukawa, T.; Moes, C. A. F. : Syndromes of asplenia and polysplenia: a review of cardiac and non-cardiac malformation in 60 cases with special reference to diagnosis and prognosis. Brit. Heart J. 37: 840-852, 1975. 21. Ruttenberg, H. D.; Neufeld, H. N.; Lucas, R. V., Jr.; Carey, L. S.; Adams, P., Jr.; Anderson, R. C.; Edwards, J. E. : Syndrome of congenital cardiac disease with asplenia. Distinction from other forms of congenital cyanotic cardiac disease. Am. J. Cardiol. 13: 387-406, 1964. 22. Simpson, J.; Zellweger, H. : Familial occurrence of Ivemark syndrome with splenic hypoplasia and asplenia in sibs. J. Med. Genet. 10: 303-304, 1973. PubMed ID : 4774542 23. Splitt, M. P.; Tsai, M. Y.; Burn, J.; Goodship, J. A. : Absence of mutations in the regulatory domain of the gap junction protein connexin 43 in patients with visceroatrial heterotaxy. Heart 77: 369-370, 1997. 24. Toth, T.; Hajdu, J.; Marton, T.; Nagy, B.; Papp, Z. : Connexin43 gene mutations and heterotaxy. (Letter) Circulation 97: 117-118, 1998. PubMed ID : 9443444 25. Zlotogora, J.; Elian, E. : Asplenia and polysplenia syndromes with abnormalities of lateralization in a sibship. J. Med. Genet. 18: 301-302, 1981. PubMed ID : 7277426 CLINICAL SYNOPSIS View Clinical Synopsis Entry CONTRIBUTORS Victor A. McKusick - updated : 7/24/1998 Moyra Smith - updated : 6/9/1997 CREATION DATE Victor A. McKusick : 6/3/1986 At 08:15 PM 1/9/1999 -0600, you wrote: > RE>Ivemark syndrome 1/9/99 > >Mary is correct. Ivemark syndrome is the eponym for the heterotaxia syndromes, which can involve bilateral right sidedness, bilateral left sidedness, or seemingly virtually any combination thereof. We have seen prenatal cases with as little as an interrupted inferior vena cava, and others with the fullblown picture of severe congenital heart disease with midline livers, asplenia and lots of other bizarre anatomy. It must be distinguished from Kartagener syndrome, which has situs inversus with a structurally normal heart, bronchiectasis and immotile cilia > >The genetics are interesting. The books say that autosomal dominant, autosomal recessive and X linked inheritance has been described. There is a mouse model for this mapped to an area of the mouse genome with a high degree of correspondence to part of the human genome. Affected mice can be indifferent to situs, rather than necessarily abnormal. In other words, an affected individual might have a 50-50 chance of normal situs or abnormal situs. Makes Mendel's rules go out the window. We would tell any family with a previously affected child that there may be as high as a 25% chance of recurrence, although if the above is true actual recurrence of clinical disease might only be 12.5%. > >If this family, or any other affected family is interested in contributing blood, amniotic fluid or tissue DNA for human studies ongoing at Yale please contact Dr. Peter Bowers at the cc address in the header of this message. Samples can be shipped from anywhere. (This study involves banking DNA for future evaluation. No clinical information about current pregnancies or patients is anticipated. Medical professionals only, please.) > >Original reference: Ivemark, B. I. : Implications of agenesis of the spleen on the pathogenesis of cono-truncus anomalies in childhood: analysis of the heart malformations in splenic agenesis syndrome, with fourteen new cases. Acta Paediat. 44 (suppl. 104): 1-110, 1955. > >More info via Online Mendelian Inheritance in Man <http://www3.ncbi.nlm.nih.gov/Omim/searchomim.html> > >Josh Copel (in house attending with too much time on my hands tonight, I guess) >Joshua.Copel@Yale.edu > >-------------------------------------- >Terry >-------------------------------------- >Ivemark Syndrome is Asplenia/bilateral right-sidedness. Severe A-V >-------------------------------------- >canal defects or univentricular heart,TAPVR, bilateral tri-lobed lungs, >absent spleen, midline stomach. >Mary C. Scarboro > Next message: Ultravas99@aol.com: "Fwd: Uterine synechial porthole" Previous message: James S Smeltzer MD: "Re: Ivemark Syndrome" In reply to: Joshua Copel: "Re: Ivemark syndrome"

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