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University of Pittsburgh


Inheritance of Cutis Laxa

The instructions for how our bodies grow, develop, and function are contained in our genes, each of which codes for a particular protein involved in one or more of these processes. Differences or variation in these genes and their resulting proteins are responsible not only for why individuals all look different from one another, but also impact how our bodies function, such as why one person might be particularly flexible while another can eat as much as he or she wants without gaining any weight! Sometimes, however, harmful changes, called mutations, can occur which cause diseases or other health problems.

Genes are located on chromosomes, with each chromosome containing thousands of genes. Humans have 46 chromosomes which are divided into 23 pairs; 22 of those pairs are called autosomes and are numbered from 1 to 22, while the 23rd pair, called the sex chromosomes, are either X or Y. Females have two X chromosomes, while males have one X and one Y chromosome. Because both men and women have two copies of each autosome, they therefore have two copies of every autosomal gene. In addition, females have 2 copies of the X chromosome, so they also have two copies of each of the X chromosome genes. Males, on the other hand, have only one X chromosome, and therefore have only one copy of the X chromosome genes. Genes and chromosomes are inherited from our parents, with each child receiving one member of every chromosome pair from each parent. Whether the father contributes an X or a Y chromosome from his sex chromosome pair determines whether the child will be male or female.

Diseases such as cutis laxa, which can be caused by many different genes and mutations, can be inherited in different ways, depending on where the gene is located (an autosome or the X chromosome) and the type of mutation (whether it takes one or two mutated copies of the gene to cause disease). If only one altered or mutant copy of an autosomal gene is necessary to cause the disease, the condition will be inherited in what is called an autosomal dominant (AD) inheritance pattern. If an individual has an AD condition, such as autosomal dominant cutis laxa (ADCL), the chance of passing the mutated gene, and therefore the disease, to a child is 1 in 2 or 50% with each pregnancy. These odds are the same as getting "heads" in a coin toss. AD disorders are typically observed in several generations of a family.

If two mutant copies of an autosomal gene are required to cause the disease, that condition is inherited in an autosomal recessive (AR) manner. There are several autosomal recessive types of cutis laxa (ARCL1A, ARCL1B, ARCL2A, etc.). With AR inheritance, both parents have to be "carriers" of one mutation in the same gene, and their child would have to inherit the mutant copy of that gene from both parents. In these situations in which both parents are carriers, each child would have a 1 in 4 or 25% chance of inheriting both mutant gene copies and therefore the disease. Carriers are typically healthy with no symptoms of the disease because they each have one functional copy of the gene. However, they may have one or more children with the condition, which is typically not seen anywhere else in the family.

X-linked recessive (XLR) inheritance occurs with disease-causing mutations in genes located on the X chromosome, such as occipital horn syndrome (OHS), an XLR form of cutis laxa. These mutations typically only affect males, because carrier females will almost always have one functional copy of the gene on their other X chromosome. However, because males have only one X chromosome, if they inherit the gene mutation, they will also inherit the disease. If a woman is a carrier for a gene mutation on the X chromosome, each child has a 50% or 1 in 2 risk of inheriting the gene mutation. However, her daughters who inherit the mutation will be carriers, whereas her sons who inherit the mutation will have the disease. In other words, on average, half of her daughters will be healthy carriers and half of her sons will have the disease. Likewise, if a man has an XLR disease, ALL of his daughters will be carriers, because they all get his X chromosome, and NONE of his sons will have the disease, because they all receive their father's Y chromosome, with their sole X chromosome coming from their mother.