Ear Infection

Can a Mutation Predict Ear Infections?

By Regie Lyn P. Santos-Cortez, M.D., Ph.D.

Otitis media or middle ear infection is a common disease in childhood; in the United States, it is the most frequent reason for antibiotic use in children and pediatric office visits. Typically when children have otitis media it is usually acute. This means the duration of infection since the start of symptoms is under two weeks, and there is inflammation such as redness of the eardrum and pus in the middle ear, with or without the perforation of the eardrum (a hole in the eardrum).

In such cases, what causes the infection is usually a common bacterium such as Streptococcus pneumoniae (“strep”) or Haemophilus influenzae (including type B, or Hib). The infection can become chronic, so there is a persistent perforation that may not heal and a chronic or recurrent ear discharge.

Otitis media is typically treated with antibiotics and may require surgery. If left untreated, it can lead to complications, the most common of which is hearing loss. Today, there is a preventative vaccination available for bacteria (strep and some Hib) that cause acute otitis media.

Aside from young age, there are many risk factors that contribute to otitis media, such as lack of breastfeeding, allergies, upper respiratory infection, daycare attendance or overcrowding, exposure to tobacco smoke, low socioeconomic status, and family history. Over the past few years, the availability of new sequencing technologies has sped up the identification of novel genes associated with disease including infections and immune states.

Through funding from Hearing Health Foundation, our group studied an indigenous Filipino community that is relatively homogeneous, highly intermarried, and has about a 50 percent prevalence of otitis media. In this population quantitative age, sex, body mass index, breastfeeding, tobacco exposure or swimming in deep seawater were not associated with otitis media. All members of the indigenous community have poor access to health care and low socioeconomic status.


By using next-generation sequencing in two indigenous second cousins who have chronic otitis media, we identified a mutation in the A2ML1 gene that is shared by the two cousins. This gene encodes a protease inhibitor localized to the middle ear epithelium. (An inhibitor is a compound that traps protease—an enzyme that breaks up protein—and brings it to other cell structures for clearance.)

In this study, we reconstructed a large pedigree of 37 indigenous relatives with different forms of otitis media, and showed that each relative with the mutation has an 80 percent chance of having any form of otitis media. When the study was expanded to 85 community members, the A2ML1 mutation was the only significant predictor of otitis media within the community, and carriage of the mutation increases the risk of otitis media almost four-fold. Our study was published in American Academy of Otolaryngology–Head and Neck Surgery Foundation's journal on August 2, 2016.

Among A2ML1 mutation carriers, otitis media may be diagnosed within the first months of life, with chronic otitis media occurring in later childhood and persisting well into adulthood, suggesting that the mutation affects otitis media onset and recovery. Furthermore, mutation carriers with chronic otitis media have higher relative abundance of the bacteria Fusobacterium and Porphyromonas, which are relatively uncommon for the disease.

Taken together, these findings are consistent with the role of A2ML1 protein as a protective factor in the middle ear; defective A2ML1 protein makes the middle ear mucosa susceptible to damage from proteases produced by both bacteria and inflammatory cells. The mutation of the gene means its protease inhibitor action fails to trap and clear damaging enzymes.

Remarkably the same A2ML1 mutation that was found in the indigenous Filipinos was also identified in three European and Hispanic-American children, indicating that this mutation is not limited to the Filipinos. (It’s possible the same ancestor from Spain, estimated to be 1,800 years ago, introduced the variation to these populations.) The three U.S. children who carried the mutation also had early-onset otitis media that required surgery by six months. Additionally we also identified rare A2ML1 mutations in six other otitis-prone children in the U.S.

We have established A2ML1’s involvement in otitis media susceptibility and can use this knowledge to predict otitis media occurrence in mutation carriers. Now we are expanding our research by studying DNA and/or microbial samples from additional U.S. and Filipino families, and RNA and additional microbial samples from the indigenous Filipino population. Our goal is to identify additional genes and pathways that play a role in otitis media susceptibility and that may be targeted to develop novel treatments of chronic otitis media.

Regie Lyn P. Santos-Cortez, M.D., Ph.D., is an associate professor in the Department of Otolaryngology, University of Colorado Denver, Anschutz Medical Campus. A 2011 and 2012 Emerging Research Grants scientist, she also received the 2012 Collette Ramsey Baker Research Award (in memory of Collette Ramsey Baker, HHF’s founder).

The study “Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population” was published in the journal of Otolaryngology–Head & Neck Surgery online on August 2, 2016.

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Rare Gene Cariant Associated with Middle Ear Infections

By Baylor College of Medicine

Many parents have heard the night-time cry of “my ear hurts.” For some children, this might happen frequently beginning in infancy and even persist into adulthood. An international consortium led by those at Baylor College of Medicine may have taken the first step on the road to understanding why only some people get frequent painful or chronic middle ear infections. The culprit may be rare genetic variants in a gene called A2ML1.

A report on their work appears online in the journal Nature Genetics.


In studies led by Dr. Regie Lyn P. Santos-Cortez, assistant professor of molecular and human genetics at Baylor, researchers looked for a genetic component to the disorder. Santos-Cortez is not only a genetics researcher, she was also trained as an otolaryngologist in her native Philippines, and she knows the toll such infections take.

After graduation, she went on a medical missionary trip to an indigenous Filipino population in one area of the country where most of the people were related.

There she created a family tree or pedigree that identified, among other things, who within the same community suffered from recurrent ear infections and who did not.

“The pedigree was huge,” she said. “It was several pages long and wide.”

Everyone had similar socioeconomic status, swam in the same sea water, were or had been mostly breastfed, ate the same food, and had the same exposure to cigarette smoke, which made an environmental factor an unlikely cause.

Luckily, next-generation sequencing that allowed her to determine the genetic sequence of several people in the population was available. Without that technological advance, she said, she did not think they could have identified the gene.

Within the indigenous community, she found that 80 percent of those who carry the variant in the A2ML1 gene developed otitis media. They also found the same gene variant in three otitis-prone children in a group in Galveston, Texas.

So far, they have identified this rare genetic cause for susceptibility to middle ear infections in 37 Filipinos, one Hispanic-American and two European-Americans. It is likely that the variant has been present in the population in the Philippines and in Galveston at least 150 years and may even be the result of a “founder” effect, which suggests one person from outside the population, more likely from Spain, brought the gene variant into the two populations.

Additionally, rare A2ML1 variants were identified in six otitis-prone children who were Hispanic- or European-American, and none of these variants occurred in thousands of individuals without otitis media.

She does not think this is the only gene involved in predisposing children to middle ear infections, but it could be an important one. The protein involved may play a role in the immune system that protects the ear. Perhaps the variant somehow derails the protection the protein should provide.

Another gene called alpha 2-macroglobulin or A2M, which encodes a protein that is found at high levels in very infected ears, is formed in such a way that it can trap proteases, enzymes that can kill infectious microbes but can also damage the mucosa of the middle ear if left unchecked.

Because the protein sequences of A2M and A2ML1 are highly identical, they may have similar or overlapping functions and one might compensate for the other when it is non-functional. An antibiotic drug called bacitracin is used in drop form to treat the problem in Europe. However, because bacitracin dampens the effect of A2M it may not be the best treatment for people who have genetic variants in A2ML1, she said.

“There are many other antibiotic drops on the market,” said Santos-Cortez.

The finding of the variant is a start, she said. She and her colleagues hope to look further into the mechanism by which A2ML1 defects cause otitis media susceptibility.

Others who took part in this work include Xin Wang, Anushree Acharya, Izoduwa Abbe, Biao Li, Gao T. Wang and Suzanne M. Leal, all of Baylor; Charlotte M. Chiong, Ma Rina T Reyes-Quintos, Ma Leah C. Tantoco, Marieflor Cristy Garcia, Erasmo Gonzalo D V Llanes, Patrick John Labra, Teresa Luisa I. Gloria-Cruz, Abner L. Chan, Eva Maria Cutiongco-de la Paz and Generoso T. Abes, all of the University of the Philippines Manila-National Institutes of Health; Arnaud P. Giese, Saima Riazuddin and Zubair M. Ahmed, University of Maryland at Baltimore; Joshua D Smith, Jay Shendure, Michael J. Bamshad and Deborah A. Nickerson, all of the University of Washington at Seattle; E. Kaitlynn Allen and Michele M. Sale of the University of Virginia in Charlottesville; Kathleen A. Daly of the University of Minnesota in Minneapolis; Janak A. Patel and Tasnee Chonmaitree of the University of Texas Medical Branch at Galveston.

Funding for this work came from the Hearing Health Foundation; Action On Hearing Loss and the National Organization for Hearing Research Foundation (to R.L.P.S.-C.); the University of the Philippines Manila–National Institutes of Health (to G.T.A. and R.L.P.S.-C.); and U.S. National Institutes of Health (Grants U54 HG006493 (to D.A.N.), R01 DK084350 (to M.M.S.), R01 DC003166 (to K.A.D.), R01 DC005841 (to T.C.), R01 DC011803 and R01 DC012564 (to S.R. and Z.M.A.), and R01 DC011651 and R01 DC003594 (to S.M.L.).

The above post is reprinted from materials provided by Baylor College of Medicine.

Help us change the course of hearing research and find a cure for hearing loss and tinnitus! Hearing Health Foundation’s “Name a Research Grant” program enables donors to name and fund a specific research grant in their name or in honor or memory of a loved one.

We're currently planning for our 2016 grant cycle. If you're interested in naming a research grant in any discipline within the hearing and balance space, such as Usher Syndrome, hyperacusis, stria, or tinnitus, please contact development@hhf.org

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"Listen to Me, Right Now!"

By Yishane Lee

As a parent, I constantly think that my children aren’t listening. The number of times I repeat myself endlessly (usually accompanied by an escalation in volume) before I get an answer is enough to drive me bonkers. But a child who isn’t listening to you can be a sign of something more than a clash of wills.

If you find that your child doesn’t respond to repeated entreaties—especially when you’re not facing her—it could be a sign of a hearing loss.

It is one sign that Hearing Health magazine staff writer Barbara Jenkins, Au.D., BCABA, includes in her list of the most common signs of hearing loss in children of different ages, from infants to teenagers.

Despite universal newborn hearing screening in hospitals—an effort that HHF spearheaded in the 1990s that has been critical for early intervention treatment—hearing loss can be progressive and appear in children after you go home from the hospital and into the school years.

For instance, a baby who doesn’t react to a sudden noise, such as a toy dropping to the floor, may have a hearing loss. Evolutionarily speaking, humans (and all animals) make sounds in reaction to hearing sounds, so a hearing loss can be indicated when a baby does not make word-like sounds, such as “gaga” or “dada” by 10 months of age.

In fact, speech milestones are critical for making sure your child’s development—and hearing—are on track. (Also important is talking directly to your toddler, too, according to a new Stanford University study.) Talk to your pediatrician if you have any concerns, no matter how slight. A study in JAMA Otolaryngology-Head and Neck Surgery found that parental concern and school hearing screens helped diagnose hearing loss after passing the newborn hearing screening.

As your child ages, there’s more opportunity for social interaction as well as picking up illnesses. Ear infections (otitis media, or infection of the middle ear) are one of the most common childhood infectious diseases requiring antibiotics. In young children the Eustachian tube has not fully developed, leaving the middle ear more likely to retain fluid that in the ears of older children gravity flushes out.

Since infections can last one to three months, with fluid blocking the ear, during that time hearing and speech both become impaired.

This can delay language acquisition and lead to learning issues. Left untreated, children who are prone to chronic ear infections are at risk of permanent hearing loss. Some of our 2013 Emerging Research Grant recipients (Ravinder Kaur, Ph.D.; Ani Manichaikul, Ph.D.; and Merri J. Rosen, Ph.D.) are working on developing a vaccine, identifying genetic predispositions, or otherwise mitigating the effects of this serious health issue in children.

Placing ear tubes in the ear are a common remedy for children with chronic ear infections. It’s a simple surgery, but requires general anesthesia, and repeated surgeries may be required if the tubes fall out. Our otolaryngologist recommended that my son, then just over a year old, get tubes to help with chronic fluid in the ear (without infections). But I couldn’t bring myself to do surgery when the ailment was something he would eventually grow out of. That said, it is a common, safe surgery that many children have benefited from.

Ear infections can be an obvious sign of potential hearing loss. So can needing the TV or stereo volume turned up, tilting the head forward, or having difficulty at school. Your child may even tell you straight out that he can’t hear you. As Jenkins writes, “This may seem obvious, but many parents assume that their children are not paying attention when in fact there may be an unidentified hearing loss.”

Review the signs your child may have a hearing loss here, and share your experience parenting a child with hearing loss below.

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