The following is a case history of one family’s genetic history with LS- shared with the intention of educating readers about key genetic terms and inheritance patterns; please consult medical professionals in your area for information and advice regarding your situation.
By Ellen Ladau
The field of human genetics can be quite challenging to comprehend, but knowledge of key terms and basic rules can be essential to help you and your family understand the inheritance of LS in your particular situation, as well as the chances of inheritance in future offspring. When we want to learn more about a subject, the popular series of “Books for Dummies” often comes to mind. To learn key definitions and the basics of human inheritance patterns, click on this great “cheat sheet.” http://www.dummies.com/how-to/content/genetics-for-dummies-cheat-sheet.html No insult to anyone’s intelligence intended!
My family has been studied extensively as we have three occurrences of LS across two generations. I have letters in my files going back as far as 1974 from the Mount Sinai School of Medicine in NYC that summarize the inheritance of LS in first my younger brother and myself; however, the situation dramatically changed after the birth of my daughter who also has LS. Initially, the LS in my family was described as being inherited in a recessive manner. As per the letter written by Lynn Godmilow, A.C.S.W and Dr. Sara Kaffe to summarize our family evaluation:
recessive disorders are “those in which completely normal parents carry a mutant gene which is harmless to them in a single dose, but which in double dose causes the disease. These parents also carry a normal gene which is what protects them from the disease. When both parents are carriers of the same mutant gene, each of their children has a 1 in 4 or 25% chance of inheriting a mutant gene from each parent and therefore having the disease. Each child also has a 2 in 4 or 50% chance of only inheriting one mutant gene and being a carrier like the parents. Also each child has a 1 in 4 or 25% chance of not inheriting either mutant gene and therefore being completely normal.
Unlike recessive inheritance described above, dominant disorders are those that require only one abnormal gene to be passed on to a child from one parent for them to have the associated condition. Although I knew I had a 50% chance of passing on the LS gene to a child, the risk of me having an affected baby was stated as follows: “while no one would ever tell you 0% risk its certainly less than 1 in 1000 risk.” To put the risk of a baby being born with a major birth defect in perspective, in 1974, it was estimated that at least 2% or 1 in 50 of all children born had a major abnormality.
In 1988, after becoming engaged, I consulted with the Department of Genetics at Mt. Sinai Hospital again. I was advised that LS in my family was still considered to be recessively inherited and that the risk of a major birth defect in any pregnancy was increased to “1 in 40.”
Dr. Kurt Hirschhorn, Chairman of the Department, further stated that the “miniscule risk for a child with Larsen Syndrome disappears in comparison to this background risk of abnormalities in any couple.” I became pregnant in late 1990 and consulted specialists again, mainly due to concerns for managing the physical aspects of my pregnancy. I was told that there is an increase in joint laxity (looseness) during any pregnancy but, because in LS joints are already abnormal, my risk was even higher. I was also advised by my older brother (who is unaffected by LS), a physician, to consult a specialist in maternal and fetal medicine (an obstetrician who specializes in high risk pregnancies). I was informed that an ultrasound performed around week 16 of my pregnancy could check for some LS related malformations, although none were expected.
In April of 1991, a sonogram did indeed pick up evidence that my husband and I would have a daughter born with LS. Though still so small that I could barely recognize her physical features on the sonogram screen, the doctor recognized foot deformities and palate deformities typical of LS.
From that sonogram on, in addition to managing my pregnancy, the focus shifted to ensuring a safe delivery for the baby. A C-Section was already planned but additional precautions were put into effect. A medical journal article was published by my obstetrician, Dr. Burton Rochelson, about the prenatal diagnosis of my daughter’s LS and obstetrical management thereof; a full citation of the article will be provided below.
To get an explanation of how a once-described recessively inherited condition was now actually a dominant disorder, my family turned once again to the geneticists at Mt. Sinai Hospital in NYC. In a letter addressed to my parents, Dr. Hirschhorn and his colleague, Dr. Rena Petrella, reviewed the two possible theories they had discussed with them in terms of their passage of the LS gene to me which I in turn passed on to my daughter:
A situation called decreased penetrance seen in some autosomal dominant conditions in which a parent transmits the affected gene but does not show signs of the disorder was discussed as a remote possibility.
The other concept introduced to my entire family in 1991 is called “germline mosaicism.” In this situation, one of two normal-appearing people (my parents) carries a mutation (a change in genetic material that causes an abnormality) in a few cells of their body. The doctors further explain:
there are not enough affected cells present to cause clinical features of the disorder. However, the cells involved can include either the egg or the sperm. This parent would have an increased risk of passing on the affected gene to his or her children. The magnitude of this risk cannot cannot be determined because the number of affected cells is not known. However, if the affected gene is transmitted to a child, the child shows signs of the disorder because the affected gene now behaves in an autosomal dominant manner.
Based upon our new knowledge of the actual dominant inheritance of LS, my husband and I chose not to have any more children because there would be a 50% risk of having another baby with LS. My younger brother and his wife, who faced the same risk, chose to adopt a child. These are extremely personal decisions for each family to make and our decisions should in no way influence your own.
Please feel free to post questions about or comments regarding above case study.
Godmilow, Lynn, and Kaffe, Sara, Mt. Sinai School of Medicine, Department of Pediatrics, Letter to Mr. and Mrs. H. Klein. 15 Apr. 1974. TS.
Hirschhorn, Kurt, Mt. Sinai School of Medicine, Department of Pediatrics, Letter to author, 3 Feb. 1988. TS.
Petrella, Rena, and Hirschhorn, Kurt, Mt. Sinai School of Medicine, Department of Pediatrics, 4 Letter to Mr. and Mrs. H. Klein, 4 Dec. 1991. TS.
Rochelson B, Petrikovsky B, Shmoys S, Prenatal Diagnosis and Obstetric Management of Larsen Syndrome, Obstet Gynecol., 8 May 1993; 81(5(Pt2): 845-847.