Syndromic Hearing Loss
by Jamie Mleczko

In our society today there are many disabled people. They can be seen almost anywhere: shopping malls, restaurants, even amusement parks. One type of disability that is hard to spot is a person with hearing loss. Hearing loss may have a non-genetic cause, such as infection or excessive noise, but in about 50% of cases of severe to profound deafness, the cause is genetic. There are over 100 inherited types of genetic hearing loss arranged into two categories: syndromic and non-syndromic. Non-syndromic hearing loss is when there are no other significant features besides the hearing loss. Syndromic, on the other hand, involves other medical or physical findings in addition to the hearing loss. There are several ways in which hearing loss can be inherited: autosomal dominant, autosomal recessive, X-linked (dominant or recessive), multifactorial, or chromosomal. Genetic hearing loss may be present at birth ("congenital") or it may start later in life. It may be stable or progressive; it may be conductive, sensorineural, or mixed. Considering these modes of inheritance, this article will concentrate only on syndromic forms of hearing loss.

The human body is made up of complex pathways that often rely on each other. Hence, if there is a mutation or malfunction in one of these pathways, it can lead to problems in seemingly unrelated areas of the body. These biological errors can be caused by environmental conditions or inherited from ancestors. That is, a mutation can and will be passed on in the genetic code to future generations by any one of the above mentioned modes of inheritance. Once the genetic code has been altered it may or may not be observed, depending on the location of the mutation. Geneticists try to locate and track these genes by observing case studies, which provide them with information on diseases and their modes of inheritance.

The following are some diseases or conditions, their relation to hearing loss, and how they are inherited.

Diabetes mellitus is a common disorder that occurs when your pancreas either totally stops producing insulin or does not produce enough of the hormone for your body's needs. This lack of insulin results in a low absorption of glucose, both by the body's cells, which need it for energy, and by the liver, which stores it. Another result is an abnormally high level of glucose in your blood. Almost all people with adult-onset diabetes have bilateral sensorineural hearing loss associated with a point mutation in the mitochondrial genome. The mitochondrial DNA (mtDNA) mutation occurs at loci 3243, and is a point mutation from Adenine to Guanine. It is presumed that a mtDNA mutation results in mitochondrial dysfunction in cochlear tissues (i.e., hair cells and stria vascularis) and in neurons of the auditory pathway. The two diseases are linked together due to their high percentage of correlation between eachother. If a person developed this syndromic hearing loss by mutation, he or she would then be a carrier for the diseases, and thus pass the mutation on to his or her progeny by normal mendelian genetic methods.1,4

Usher Syndrome
The symptoms of Usher syndrome are hearing loss and gradual loss of vision. About 6-12% of all deaf and hard-of-hearing children have Usher syndrome. The eye disorder most common in Usher syndrome is Retinitis Pigmentosa (RP). RP affects the sensory cells in the retina, which is the layer lining the inside of the eye. The retina itself is made up of several layers of interconnecting cells, two of which are called rods and cones. The rods deteriorate first, then the cones. This means night blindness occurs first, followed by blind spots, and then slowly progressive tunnel vision during the day. All types of Usher syndrome are caused by autosomal recessive genes. (see Appendix 1) This means that each parent has one normal and one Usher gene, and each gives the affected child the Usher gene. For example, each parent would have a recessive gene so any of their children would have an equal (25%) chance of inheriting Usher syndrome. Two of these genes are on chromosome #11 and one on #14. Most people have the Usher genes on the long arm of chromosome #11, with Usher syndrome Type 2 people having a deficient gene on the long arm of chromosome #1. What this means is that there is more than one underlying biochemical cause for combined hearing loss and RP.2

Osteogenesis Imperfecta
Osteogenesis Imperfecta (OI), also known as the "brittle bone disease", is a disease that causes bone and connective tissue deformities and hearing loss. OI has been classified into four types based on the severity and other features that can accompany the condition.

Type 1: This type usually goes unnoticed until a baby has fractures as the result of minor trauma. Some symptoms of this type are blue color to the whites of the eyes (the sclerae), and discolored teeth with and "opalescent", milky color or brownish cast, that are more likely to get cavities or be easily broken. About 50% of the people with OI type 1 develop hearing loss in adulthood, with almost all older folks having some hearing loss. It generally appears as a conductive loss in the late teens or twenties, due to problems with the small bones of the middle ear (ossicles). They may be fragile and malformed, or the footplate of one of the bones, the stapes, may be unable to move, as in otosclerosis. A sensorineural loss may also develop.
Type 2: This type is called the "Lethal Perinatal" form of OI, because it is readily noticed at birth, and the baby usually does not survive. There are deformities of the ribs, vertebrae and bones, along with fractures. Ultrasound before the baby is born can even show fractures.
Type 3: Is more severe than type 1 but less severe than type 2. Babies may be born with fractures, and also have blue sclerae at birth, but they do not die from OI. As they get older, fractures continue and their arms and legs grow poorly becoming crooked; they often develop curvature of the spine as well. Hearing loss is similar to that shown in type 1 people.
Type 4: Similar to type 1 except that the sclerae are not blue. Fractures may be present at birth, but the course of the condition is not as severe as types 2 or 3. Hearing loss is a little less severe than in type 1.

The cause of OI is defects in collagen. Collagen is a protein in the body that is part of the connective tissue, the tissue that helps to hold the skin, tendons and bones together. It creates strong fibers which serve as "scaffolding" for the bones. A collagen fiber is made up of three separate molecules wound together like strands in a rope. It is this ropelike structure that gives collagen its strength. There are two A1 strands and one A2 strand in each collagen type 1 fiber, which are involved in bone structure. Each strand is made by a separate gene, and genetic flaws (mutations) in either can cause OI. Evidence has suggested that mutations in A1 are associated with hearing loss. The type of OI depends of the type and location of mutation. Families with the same type of OI can have defects in different strands, or even different defects in the same strand.

There is no cure for OI, but it has been found that all types of OI are caused by autosomal dominant genes (see Appendix 1), with a few exceptions in recessive forms of type 2. This suggests that a person with OI has a 50-50 chance of passing on the OI gene to his or her children. If neither parent has OI (as in the case of type 2), the cause of the OI in the baby is usually a new mutation, and there is very little chance that the parents would have another child with OI. Also, occasionally a parent will carry the OI gene in some of the egg or sperm cells, but not in other cells that affect their bones. As a result, the parent would not have any of the symptoms of OI, but could still pass it on to their children.3

Case studies of the diseases mentioned provide geneticists with much information of how they are related to hearing loss and their mode of inheritance between generations. Learning the patterns of inheritance is the easy part, finding the cause of the diseases and how to correct them are the hard tasks. The biochemical pathways of the human body are amazingly complex with intersections throughout the body, making them interrelated in function and purpose. These connections are the reason for the link between irregularities in homeostasis. Someone who has a disease, or may think he or she is a carrier of a disease, should seek advice from a genetics counselor to find out information on his or her particular situation.


1. Oshima T, Ueda N, Ikeda K, Abe K, Takasaka T. "Bilateral sensorineural hearing loss associated with the point mutation in mitochondrial genome." Laryngoscope 106: P. 43-48 (1996)

2. "Retinitis Pigmentosa in Usher Syndrome" and "Usher Syndrome & Retinitis Pigmentosa Referrals" Hereditary Hearing Impairment Resource Registry, c/o Boys Town National Research Hospital, 555 N. 30th st., Omaha, NE 68131
Internet Address:

3. "Osteogenesis Imperfecta and Hearing Loss" Osteogenesis Imperfecta Foundation, Inc. 5005 W. Laurel St., Suite 210 Tampa, FL 33607-8214
Internet Address: WWW URL:

4. American Medical Association, The. Family Medical Guide, New York: Random House. 1987. P. 529.

Appendix 1

Autosomal Recessive Inheritance - An autosomal recessive gene is one that is carried on one of the 22 pairs of chromosomes which are not sex chromosomes. A person with an autosomal hearing loss (HL) would have two recessive genes for HL in that particular pair of genes. A person with a normal gene and a HL gene would not have a HL, but would be considered a carrier. Generally the HL gene has been passed down through the carrier's family for generations. A carrier has no way of knowing that he or she has a HL gene until having a child with HL. Then it becomes apparent that the individual and the individual's spouse, each are a carrier. There is a 1 in 4 or 25% chance for the child of two carriers to receive both normal genes and the same amount of chance that the child will have both recessive HL genes and have a HL. An example is an albino man with a hearing impairment. Albinism is passed on by autosomal recessive inheritance. So if a mother and father are carriers for albinism, assuming his hearing impairment is autosomally recessive and not linked, then their children have a 1 in 8 or 12.5% chance of being albino and hard-of-hearing.

Autosomal Dominant Inheritance - A gene that is expressed regardless of the code in the other gene is said to be dominant. An autosomal dominant gene is carried on one of the 22 pairs of autosomes which means that males and females with the gene are equally likely to pass it on to male or female offspring. A person who has a dominant HL generally has one HL gene and one normal gene, in one pair of genes. There is a 50% chance the father will contribute the HL gene and a 50% chance he will contribute the normal gene. There can be variation in the expression of a dominant gene even within the same family. In other words, the gene may cause a profound loss for an individual and only a mild to moderate loss for that individual's child. Another phenomenon that is seen with some dominant genes is nonpenetrance. This means that there is no detectable evidence that an individual with a dominant gene has the gene. When the gene is nonpenetrant it appears that the gene has skipped a generation.

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