Ivemark syndrome
Ivemark syndrome is a rare genetic disorder characterized by abnormal left-right body symmetry and developmental anomalies of abdominal and thoracic organs. It primarily involves conditions such as asplenia (absence or underdevelopment of the spleen) or polysplenia (multiple spleens) and is often associated with complex congenital heart defects. The syndrome can arise sporadically, but familial cases suggest potential inheritance patterns, including autosomal recessive and X-linked traits. Risk factors for Ivemark syndrome include a family history of related conditions and certain prenatal exposures, such as maternal diabetes or cocaine use.
Diagnosis typically involves imaging techniques like ultrasound and MRI, which can reveal characteristic organ placement abnormalities. Infants diagnosed with Ivemark syndrome may require treatments such as prophylactic antibiotics and corrective surgeries for associated heart defects. The prognosis varies greatly, often depending on the severity of the congenital heart issues, with asplenia linked to higher risks of severe complications. While early mortality rates were high, advances in medical care have improved the life expectancy of affected individuals. Overall, Ivemark syndrome signifies a complex interplay of genetic factors that warrant thorough investigation and multidisciplinary management for those affected.
Ivemark syndrome
ALSO KNOWN AS: Asplenia syndrome; right isomerism sequence; polysplenia syndrome; left isomerism; asplenia with cardiovascular anomalies; visceroatrial heterotaxy; situs ambiguus; bilateral right-sidedness sequence
DEFINITION Ivemark syndrome is a disorder associated with both abnormal right-left symmetry and abnormal development of abdominal and thoracic organs. The condition originally was defined as asplenia with cardiovascular anomalies but has been expanded to include both asplenia and polysplenia and other anomalies of left-right body symmetry. While most cases of the disorder are sporadic, familial cases consistent with autosomal recessive, autosomal dominant, and X-linked inheritance have been reported.
Risk Factors
A family history of asplenia/polysplenia or any form of heterotaxia, the abnormal arrangement of body parts, indicates an increased risk. A family history of congenital heart defects such as transposition of the great vessels or double outlet right ventricle may also indicate an increased risk. Some data suggest that maternal diabetes, prenatal cocaine exposure, and twinning increase the risk for a laterality defect.
Etiology and Genetics
Autosomal recessive inheritance has been inferred from the findings of consanguinity in some families with Ivemark syndrome, and multiple affected siblings in other families. X-linked inheritance has also been inferred from a small number of families with numerous affected males in multiple generations. Rarely, chromosome disorders such as 13, trisomy 18, or deletion 22q11 may cause heterotaxy. Left-right symmetry is established in the developing embryo early in the first trimester before organ development. Numerous genes are involved in establishing the left-right axis, providing single gene candidates for heterotaxia. Despite advances in determination of laterality genes, few mutations have actually been found in humans with a laterality defect. Additionally, when mutations have been found, they are usually present in form, which is inconsistent with autosomal recessive inheritance.
The genetic of Ivemark syndrome appears complex, due in part to multiple loci and variable gene penetrance and expressivity. Thus far, a single causative gene has not been identified to account for the majority of either familial or sporadic cases. However, recent literature has focused on expansion of the heterotaxy phenotype to include a family history of apparently isolated congenital heart defects or other midline defects, suggesting that wide variability in and severity may exist. A possible association between heterotaxy and the connexin 43 gene on chromosome 6 was reported in 1995; however, numerous subsequent studies failed to find an association. Mutations within an X-linked locus encoding the ZIC3 gene (a protein) may account for up to 1 percent of sporadic heterotaxia. Five autosomal loci linked to visceroatrial heterotaxy have been identified, including the CFC1 gene on chromosome 2, which is involved in intracellular signaling; the activin receptor, type IIB (ACVR2B) and CRELD1 genes on chromosome 3; the NKX2-5 cardiac gene on chromosome 5; and the LEFTYA gene on chromosome 1. These genes, however, have not been implicated in the majority of individuals with either familial or sporadic Ivemark syndrome.
Symptoms
By definition, Ivemark syndrome involves abnormalities of splenic and cardiovascular formation/placement as a result of randomization of left-right body symmetry. Splenic anomalies include both asplenia (either absent or underdeveloped spleen) or polysplenia (multiple spleens or lobes). Cardiovascular anomalies include complex congenital heart defects and cardiac conduction defects. Lobation of lungs is often abnormal. Development and placement of the gallbladder, liver, stomach, and other abdominal organs may also be affected. Defects of the midline involving almost all other organ systems, including gastrointestinal, genitourinary, and central nervous systems, are also seen.
Screening and Diagnosis
Ivemark syndrome overall is presumed to be rare. Statistical estimates reported in 2023 that Ivemark syndrome occurred in 1 in 10,000 to 1 in 40,000 live births and was responsible for 1 to 3 percent of all cardiac defects in infants. Prenatal ultrasound demonstrating abnormalities with orientation of the fetal stomach and cardiac apex may be the first indication of an abnormality with right-left symmetry. After birth, ultrasound and radiography can identify abnormal left-right symmetry of abdominal organs. Echocardiography or MRI detects congenital heart defects. Heinz and Howell-Jolly bodies in peripheral blood indicate absence of the spleen. A barium swallow study is suggested to rule out gastrointestinal malformation. Vertebral X-rays and central nervous system and genitourinary imaging are also recommended.
Treatment and Therapy
Infants with asplenia should receive prophylactic antibiotics. Pneumococcal vaccination should also be considered at age two. Corrective surgery of congenital heart defects or cardiac transplantation is often required. Additional surgical correction of intestinal malrotation and other congenital anomalies may be needed. Pacemakers may be required for correction of arrhythmia.
Prevention and Outcomes
Methods to prevent the majority of cases of Ivemark syndrome are not currently known. Good control of maternal and avoidance of prenatal exposures such as cocaine may prevent some cases. Prenatal diagnosis may improve neonatal survival. Prognosis often depends upon the severity of the congenital heart defect. Asplenia is more commonly associated with severe cardiac disease and is more likely to result in neonatal death due to the risk of overwhelming infection and severity of cardiac anomaly. However, complete heart block and polysplenia is often lethal. The presence of other significant congenital anomalies is also a poor prognostic factor. Early studies indicated a significant percentage of individuals died in early childhood; however, life expectancy has increased with improved cardiac surgery techniques.
Bibliography
Chen, Harold. Atlas of Genetic Diagnosis and Counseling. 2d ed. New York: Springer, 2012. Digital file.
Ivemark, B. I. “Implications of Agenesis of the Spleen on the Pathogenesis of Cono-truncus Anomalies in Childhood.” Acta Paediatrica 44, suppl. 104 (1955): 1–110. Print.
"Ivemark Syndrome." National Organization for Rare Disorders, 24 Aug. 2010, rarediseases.org/rare-diseases/ivemark-syndrome/. Accessed 4 Sept. 2024.
McKusick, Victor A., and Cassandra L. Kniffin. "#208530 Right Atrial Isomerism; RAI." OMIM.org, 19 Sept. 2013, www.omim.org/entry/208530. Accessed 4 Sept. 2024.
Molineux, Aimee. "What is Ivemark Syndrome?" News-Medical.Net, 10 Dec. 2023, www.news-medical.net/health/What-is-Ivemark-Syndrome.aspx. Accessed 4 Sept. 2024.
Zhu, Lirong, John W. Belmont, and Stephanie M. Ware. “Genetics of Human Heterotaxias.” European Journal of Human Genetics 14 (2006): 17–25. Print.