eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Inner Ear

Inner Ear, Genetic Sensorineural Hearing Loss

Author: Stephanie A Moody Antonio, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School
Coauthor(s): Barry Strasnick, MD, FACS, Chairman, Professor, Department of Otolaryngology - Head and Neck Surgery, Eastern Virginia Medical School
Contributor Information and Disclosures

Updated: Jun 1, 2009

Introduction

Background

Of the more than 4000 infants born deaf each year, more than half have a hereditary disorder. Hereditary disorders must be differentiated from acquired hearing losses. Not all hereditary hearing loss is present at birth; some children inherit the tendency to develop hearing loss later in life.

Genetic sensorineural hearing loss (SNHL) includes a broad range of disorders that affect infants, children, and adults. Affected individuals may have unilateral or bilateral hearing loss ranging from mild to profound. This article, like most related discussions, focuses on childhood hearing loss, with consideration of a few forms of adult-onset hearing loss.

Pathophysiology

Volumes of texts and journals are dedicated to the pathophysiology of genetic hearing loss and can not be easily summarized in a few paragraphs. Interestingly, note that as our understanding of the molecular basis of genetic hearing loss increases, so does our understanding of the molecular basis of hearing itself, although it remains still largely unsolved.1,2

First, we must understand that genetic hearing loss seems to breach all categories of hearing loss, including the following: congenital, progressive, and adult onset; conductive, sensory, and neural; syndromic and nonsyndromic; high-frequency, low-frequency, or mixed frequency; and mild or profound. Genetic hearing loss may show patterns of recessive, dominant, or sex-linked inheritance and may be a result in mutation of both cellular or mitochondrial DNA (and RNA, in the case of mitochondrial genes). Genetic hearing loss may be subject to environment and aging, such as noise-induced or age-induced hearing loss.

New genetic mutations are linked to hearing loss every year. More than 100 loci have been identified involving genes that code for proteins involved in the structure and function of hair cells, supporting cells, spiral ligament, stria vascularis, basilar membrane, spiral ganglion cells, auditory nerve, and virtually every structural element of the inner ear.3

Dysfunctional proteins have been identified in the impaired molecular-physiologic processes of potassium and calcium homeostasis,4 apoptotic signaling,5 stereocilia linkage,6 mechanicoelectric transduction, electromotility, and other processes.1 Eisen and Ryugo provide an excellent review of the molecular pathophysiology of genetic hearing loss.1

Frequency

United States

According to the National Institute on Deafness and Other Communication Disorders (NIDCD), hearing loss affects approximately 28 million Americans and approximately 17 in 1000 children and adolescents younger than 18 years. The average incidence of hearing loss in neonates in the United States is 1.1 per 1000 with variability among states ranging between 0.22 and 3.61 according to Mehra et al.7 In the study by Mehra et al, the prevalence of childhood and adolescent hearing loss was 3.1%, with higher rates in Hispanic Americans and in families with lower incomes.7

Congenital hereditary hearing loss must be differentiated from acquired hearing loss. More than half of all cases of prelingual deafness are genetic. The remaining 40-50% of all cases of congenital hearing loss are due to nongenetic effects, such as prematurity, postnatal infections, ototoxic drugs, or maternal infection (with cytomegalovirus [CMV] or rubella). Most cases of genetic hearing loss are autosomal recessive and nonsyndromic. Hearing loss that results from abnormalities in connexin 26 and connexin 30 proteins likely account for 50% of cases of autosomal recessive nonsyndromic deafness in American children.

The incidence of hearing loss increases with age. Loss affects 314 in 1000 people older than 65 years and 40-50% of people aged 75 years or older. Adult-onset hearing loss can be attributed to normal aging processes and environmental triggers. However, an individual's genetic predisposition should not be underestimated, as illustrated by aminoglycoside-induced ototoxicity and the predisposition to noise-induced hearing loss.

Current statistics can be found on the Early Hearing Detection & Intervention (EHDI) Program Web site published by the Centers for Disease Control and Prevention.

International

Genetic sensorineural hearing loss (SNHL) appears to occur twice as often in developed countries as in underdeveloped countries. Hearing impairment affects up to 30% of the international community, and estimates indicate that 70 million persons are deaf. In addition to ancestry and race, the proportions of hereditary versus acquired and syndromic versus nonsyndromic hearing losses across populations is highly variable and is heavily influenced by multiple factors, some likely not yet identified, including drift of populations, frequency of consanguinity, and health status.

Estimating the prevalence of hereditary hearing loss in populations across the world is very difficult because access to health care, poor health conditions, and a low level of awareness of hearing loss is compounded by a higher frequency of complicating risk factors such as neonatal distress, prematurity, high fever, otitis media, meningitis, ototoxic medications, and illnesses such as rubella.8

An estimated 30,000 infants are born with sensorineural hearing loss each year in China, which has a population of about 1.3 billion, but the percentage of these hearing losses attributable to heredity is not known.9 Saunders et al demonstrated a prevalence of significant hearing loss of 18% in a group of school-aged children in rural Nicaragua with a familial history of hearing loss in 24% of the children with hearing loss .8  Large-scale epidemiologic studies are needed and will become more feasible as molecular testing is made available to the world’s populations.

Mortality/Morbidity

The 350,000 individuals who are profoundly deaf in the United States earn approximately 30% less than the general population. Among school-aged children with hearing loss, approximately 52,000 attend schools or programs for the deaf, 100,000 are enrolled in special deaf-education classes, and 250,000 participate in standard public school settings. The overall cost for deafness education is estimated to be $121 billion.

Race

Genetic hearing loss does have significant ethnic links. Angeli recently reviewed the ethnic variability of DGNB1 and showed greater allelic variability in Hispanics.10 Schimmenti et al showed a lower prevalence of connexin-related hearing loss in Hispanic infants.11

Age

Before universal hearing screening for newborns, less than 50% of children who had hearing impairment were identified before the age of 3 years. Detection of risk factors (eg, prematurity, low birth weight, low Apgar scores) helps in identify less than 50% of infants who have or who are at risk for hearing loss. In one study, 78% of infants identified with hearing loss were in the well-baby nursery and not the neonatal intensive care nursery.12  This finding emphasized the ineffectiveness of screening on the basis of risk identification alone. Thirty-six states now mandate universal screening of newborns resulting in earlier identification and treatment.  Hereditary hearing loss may also be progressive or adult in onset.

Clinical

History

Genetic hearing loss may be congenital, prelingual, or postlingual in onset and may present with progressive, fluctuating, or stable patterns. Congenital hearing loss is potentially identifiable with newborn screening. High-risk indicators should be used to identify children who are at risk for developing hearing loss after birth. Attention to high-risk indicators, to achievement of speech and language milestones, and to the family history are essential in evaluating a child for hearing loss.

Failure to achieve the following speech and language milestones may indicate hearing loss and necessitate a hearing evaluation:13

  • Birth to 3 months
    • Startles to loud noise
    • Awakens to sounds
    • Blinks or widens eyes in response to noises
  • 3-4 months
    • Quiets to mother's voice
    • Stops playing, listens to new sounds
    • Looks for source of new sounds that are not in sight
  • 6-9 months
    • Enjoys musical toys
    • Coos and gurgles with inflection
    • Says "mama"
  • 12-15 months
    • Responds to his or her name and the word "no"
    • Follows simple requests
    • Uses expressive vocabulary of 3-5 words
    • Imitates some sounds
  • 18-24 months
    • Knows body parts
    • Uses expressive vocabulary with 2-word phrases (minimum of 20-50 words)
    • 50% of speech intelligible to strangers
  • By 36 months
    • Uses expressive vocabulary of 4- to 5-word sentences (approximately 500 words)
    • 80% of speech intelligible to strangers
    • Understands some verbs

Potential sources of acquired hearing loss should be considered including the following: in utero infection associated with genetic sensorineural hearing loss (SNHL; eg, toxoplasmosis, rubella, CMV infection, herpes, syphilis), hyperbilirubinemia at levels that require exchange transfusion, birth weight of less than 1500 g, bacterial meningitis, low Apgar scores (0-3 at 5 minutes, 0-6 at 10 minutes), respiratory distress (eg, due to meconium aspiration), mechanical ventilation for more than 10 days, and exposure to ototoxic medication (eg, gentamicin) administered for more than  5 days or used in combination with loop diuretics.

In older children, additional confounding factors include otitis media, mumps, measles, and head trauma. A history of visual impairment, syncope spells, kidney disease, or other system issues should be identified as potential indicators of a syndromic etiology. A detailed family history to identify affected parents, siblings, and relatives is imperative in the evaluation of the patient with hearing impairment.

Physical

Because genetic sensorineural hearing loss (SNHL) is associated with effects on virtually every organ, the physician must be familiar with the constellation of physical findings that may elucidate the etiology of a patient's hearing impairment.

Physical examination should include a complete evaluation of the ears, nose, throat, head, and neck, along with an overall assessment of the child's general physical and neurologic status.

Findings associated with hearing loss include microtia or atresia of the ear canal, cleft lip or palate, craniofacial abnormalities (eg, micrognathia, facial asymmetry, microcephaly, or craniosynostosis), cranial nerve weakness, heterochromia of the iris or other abnormalities of the ocular structures, vision impairment, goiter, and skeletal abnormalities.

Causes

Approximately 50% of all cases of congenital deafness are genetic. Approximately 70% of cases of hereditary deafness are nonsyndromic, and the remaining 30% are syndromic, associated with specific deformities or medical problems. Of nonsyndromic hearing losses, 75-85% are inherited in an autosomal recessive pattern, 15-20% are inherited in an autosomal dominant pattern, and 1-3% are inherited in an X-linked pattern. Genetic hearing loss is differentiated from acquired hearing loss with identification of a perinatal infection, such as toxoplasmosis, rubella, cytomegalovirus and herpes (TORCH), or another source such as trauma or noise. Although generally thought of as a childhood condition, genetic hearing loss can result in adult-onset hearing loss. A genetic basis or a genetic-environmental interaction appears to predispose some patients to noise or age-related hearing loss.

Syndromic hearing impairment

More than 400 genetic syndromes are associated with hearing impairment. These disorders are categorized as autosomal dominant, recessive, or X-linked.

Syndromic hearing impairment, autosomal dominant

  • Waardenburg syndrome is the most common cause of autosomal dominant syndromic hearing loss. The syndrome includes dystopia canthorum, a broad nasal root, confluence of the medial eyebrows, heterochromia irides, a white forelock, and bilateral or unilateral SNHL. Expressivity is extremely variable.
    • Four subtypes of Waardenburg syndrome are defined, as follows:
      • Type I includes dystopia canthorum (ie, lateral displacement of the inner canthus of the eye) and is caused by mutations in PAX3.
      • Type II is characterized by the absence of dystopia canthorum and is caused by mutations in MITF.
      • Type III has associated upper-limb abnormalities and is caused by mutations in PAX3.
      • Type IV is thought to be caused by mutations in EDNRB, EDN3, and SOX10, and patients with type IV have Hirschsprung disease.
  • Branchio-oto-renal syndrome is the second most common cause of autosomal dominant syndromic HL. This condition manifests as renal abnormalities, preauricular pits, deformed auricles, and lateral branchial cysts. The hearing loss may be conductive, SNHL, or mixed. Some patients have Mondini anomalies of the cochlea. Penetrance is high, but expressivity is extremely variable. Mutations in the EYA1, SIX1, and SIX5 genes have been identified.
  • Neurofibromatosis type 2 (NF2) is associated with vestibular schwannomas, meningiomas, ependymomas, juvenile cataracts, and other intracranial and spinal tumors. The gene for NF2 has been mapped to chromosome 22q12.2 and is thought to be a tumor-suppressor gene. It has about 50% penetrance. In the Wishart type of NF2, the disease manifests in childhood or early adulthood. As vestibular schwannomas and other tumors develop, this subtype becomes rapidly progressive and often severely disabling. In the Gardner type of NF2, disease is more limited, less disabling, and presents later (in the third or fourth decades) that it is in the Wishart type.
  • Sticker syndrome is defined by the association of cleft palate, progressive genetic sensorineural hearing loss (SNHL), and spondyloepiphyseal dysplasia (SED). Defects in COL result in 3 different types STL1 (COL2A1), STL2 (COL11A1), and STL3 (COL11A2). Related morbidity of SED includes atlantoaxial instability, scoliosis, osteoarthritis, myopia, and retinal detachment.
  • Otosclerosis is a genetic disorder generally associated with adult-onset conductive hearing loss. However, advanced otosclerosis may cause SNHL. The genes responsible for otosclerosis have not been found, but foci on chromosomes 6, 7, and 15 have been implicated.
  • Achondroplasia may be associated with mixed hearing loss.
  • Paget disease may result in progressive, adult-onset conductive hearing loss, genetic sensorineural hearing loss (SNHL), or both. Other common findings of this bone disorder are enlargement of the skull, kyphosis, and shortening of stature. The hearing loss is thought to be due to a cochlear process. Genetic and environmental factors are likely to be contributing factors.

Syndromic hearing impairment, autosomal recessive

  • Usher syndrome is the most common cause of autosomal recessive syndromic SNHL. Usher syndrome results in both hearing and visual impairments, and it is the etiology in at least 50% of persons with deafness and blindness. It may represent 3-6% of children born deaf and an additional 3-6% of children with milder hearing loss. The incidence is 4 in 100,000 births.
    • Three main types of Usher syndrome are described, as follows:
      • Type I is characterized by congenital severe-profound hearing loss and vestibular dysfunction. Retinitis pigmentosa (RP) develops in childhood and progresses from night blindness and loss of peripheral vision to blindness, through progressive degeneration of the retina. Vestibular dysfunction results in delayed motor milestones and may not walk until after 18 months.
      • Type II Usher syndrome is characterized by congenital mild-to-severe SNHL but normal vestibular function. Associate RP develops during the later teen years and tends to progress slower than in type I.
      • Children with Type III Ushers have normal hearing at birth that progresses during the teen years, requiring hearing aids by adulthood. Vestibular function is usually fairly normal, but may decline over time. RP begins at puberty and progresses into adulthood.
    • Early diagnosis is important in Usher syndrome and will impact management. Patients with Type I Usher syndrome who rely on manual communication may be more significantly impacted with development of visual impairment, at which time auditory rehabilitation will be less complete than if initiated earlier. Electroretinogram can be performed after the age of 2 years and may aid in identifying retinal problems earlier than fundoscopic examination and visual field tests. Genetic testing is now available and should be considered. Early identification and early cochlear implantation may mitigate the effect of dual sensory impairment if auditory-oral skills are developed prior to the onset of visual impairment.14
    • Twelve loci have been found to cause Usher syndrome. Genes and the proteins that they encode have been identified for 7 of the 12 loci. The genes that cause Usher syndrome are MY07A, USH1C, CDH23, PCDH15, and SANS, which cause USH1, USH2A (which causes USH2), and USH3A (which causes USH3). A mutation, named R245X, of the PCDH15 gene may account for a large percentage of USH1 cases in today's Ashkenazi Jewish population.
  • Pendred syndrome is the second most common type of AR syndromic hearing loss. It is characterized by congenital severe-to-profound sensorineural hearing impairment and euthyroid goiter. Goiter develops in early puberty or adulthood. Affected individuals have an abnormal perchlorate test indicating delayed organification of iodine by the thyroid. Mondini dysplasia and dilated vestibular aqueduct are commonly found during radiographic evaluation. Mutations in SLC26A4, which codes for pendrin, have been identified. Genetic testing is available and can be suggested if a Mondini malformation is found during evaluation.
  • Jervell and Lange-Nielsen syndrome results in congenital genetic sensorineural hearing loss (SNHL) and a prolonged QT interval. Affected individuals have syncopal episodes and may have sudden death. High-risk children (ie, those with a family history that is positive for sudden death, SIDS, syncopal episodes, or long QT syndrome) should have a thorough cardiac evaluation. EKG is commonly included in screening protocols for congenital hearing loss.
    • Mutations in the KCNE1 and KCNQ1 genes cause Jervell and Lange-Nielsen syndrome. About 90% of cases of Jervell and Lange-Nielsen syndrome are caused by mutations in the KCNQ1 gene; KCNE1 mutations are responsible for the remaining 10% of cases.
    • These genes are responsible for coding potassium channel proteins critical for maintaining the normal functions of the inner ear and cardiac muscle. Mutations in these genes alter the usual structure and function of potassium channels or prevent the assembly of normal channels. These changes disrupt the flow of potassium ions in the inner ear and in cardiac muscle, leading to the hearing loss and irregular heart rhythm characteristic of Jervell and Lange-Nielsen syndrome.
  • Refsum disease is a rare condition manifested by severe progressive genetic sensorineural hearing loss (SNHL) and retinitis pigmentosa due to abnormal phytanic acid metabolism. Because it can be treated with dietary modification and plasmapheresis, identification may be helpful

X-linked syndromic hearing loss

  • Alport syndrome is a result of mutations in type IV collagen genes that result in faulty basement membranes of the kidney and cochlea. The incidence is thought to be 1 in 5000 persons and is more common in males. The HL is bilateral and slowly progressive often starting in late childhood in the high frequencies. Deafness is common by age 25 years. In males, proteinuria progresses to end-stage renal disease before age 40 years.
    • In females, end-stage renal disease is less frequent until later decades. Diagnostic criteria include family history of hematuria progressing to end-stage renal disease, progressive high frequency genetic sensorineural hearing loss (SNHL), thickening of the renal basement membrane by electron microscopy, and anterior lenticonus and perimacular flecks.
    • In 80% of patients with Alport syndrome, the inheritance is X-linked dominant. Patients with Alport syndrome have mutations in COL4A3, COL4A4, or COL4A5 near Xq22. Other forms are autosomal dominant or recessive and, in these cases, the severity is equal between the sexes.

Nonsyndromic genetic sensorineural hearing loss

An estimated 70-80% of hereditary hearing loss is nonsyndromic. Approximately 75% of nonsyndromic genetic sensorineural hearing loss (SNHL) is autosomal recessive, 15-20% is autosomal dominant, and 1-3% is X-linked. As highlighted by Van Laer et al, some genes may be associated with both autosomal dominant and recessive hearing loss. Some variability may be seen in the phenotype, based on the location and type of mutation of a gene and effects of modifying genes and environmental factors.15

When a gene locus for hearing loss is identified, it is named for the inheritance pattern and a consecutive number. DFNA indicates autosomal dominant gene loci, DFNB indicates autosomal recessive loci, and DFN indicates X-linked loci. Mitochondrial disorders also exist. New gene loci are discovered every year.

Autosomal recessive nonsyndromic hearing loss is usually prelingual, nonprogressive, and severe to profound. Mutations in the connexin 26 gene at locus DFNB1 on chromosome 13 are thought to account for about 50% of recessive nonsyndromic hearing loss. 35delG is the most common mutation, but at least 90 different GJB2 mutations have been described.

The gene GJB2 codes for connexin 26, a gap junction beta2 protein. These proteins form intercellular channels in the plasma membrane and facilitate the exchange of molecules between cells. Connexin 26 is expressed in the stria vascularis, spiral ligament, spiral limbus, and in supporting cells of the cochlea. It appears to have a role in recycling of potassium. The hearing loss is usually prelingual and varies from mild to profound. It is usually predominantly high frequency and sloping but may also present with a flat audiometric curve. It is most often bilateral and symmetric, but unilateral cases have been identified. The ear is usually radiologically normal. Connexin 26-related hearing loss can be inherited by autosomal recessive or dominant patterns.

Autosomal dominant nonsyndromic hearing loss is more likely to be postlingual than autosomal recessive nonsyndromic hearing loss and is more variable in frequency distribution and severity. A common X-linked nonsyndromic mutation at gene locus DFN3 causes a mixed hearing loss. These patients are prone to perilymph gushers during stapedectomy that will result in profound postoperative SNHL. The related gene is POU3F4.

An interesting mitochondrial gene mutation is that for aminoglycoside-induced genetic sensorineural hearing loss (SNHL). The mutation A1555G in the 12s rRNA gene makes a person susceptible to hearing loss after treatment with gentamicin, neomycin, or other aminoglycosides.

Several websites are devoted to cataloging gene mutations, including The Hereditary Hearing Loss Homepage and those of the Harvard Medical School Center for Hereditary Deafness and GeneTests.

More on Inner Ear, Genetic Sensorineural Hearing Loss

Overview: Inner Ear, Genetic Sensorineural Hearing Loss
Differential Diagnoses & Workup: Inner Ear, Genetic Sensorineural Hearing Loss
Treatment & Medication: Inner Ear, Genetic Sensorineural Hearing Loss
Follow-up: Inner Ear, Genetic Sensorineural Hearing Loss
Multimedia: Inner Ear, Genetic Sensorineural Hearing Loss
References
Further Reading
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Further Reading

GeneReviews is a comprehensive web site with reviews for specific genetic disorders with searchable database.

The Hereditary Hearing Loss website provides an up-to-date resource for gene research.

The Harvard Medical School Center for Hereditary Deafness maintains a database of gene mutations.

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Keywords

sensorineural hearing loss, genetic sensorineural hearing loss, inner ear, hearing loss, SNHL, deafness, hearing impairment, hereditary hearing disorder, inner ear problems, hearing

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Contributor Information and Disclosures

Author

Stephanie A Moody Antonio, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School
Stephanie A Moody Antonio, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Medical Association, American Neurotology Society, and Virginia Society of Otolaryngology-Head and Neck Surgery
Disclosure: Nothing to disclose.

Coauthor(s)

Barry Strasnick, MD, FACS, Chairman, Professor, Department of Otolaryngology - Head and Neck Surgery, Eastern Virginia Medical School
Barry Strasnick, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Auditory Society, American College of Surgeons, American Medical Association, American Tinnitus Association, Ear Foundation Alumni Society, Norfolk Academy of Medicine, North American Skull Base Society, Society of University Otolaryngologists-Head and Neck Surgeons, Vestibular Disorders Association, and Virginia Society of Otolaryngology-Head and Neck Surgery
Disclosure: Nothing to disclose.

Medical Editor

Robert A Battista, MD, FACS, Assistant Professor of Otolaryngology, Northwestern University Medical School; Physician, Ear Institute of Chicago, LLC
Robert A Battista, MD, FACS is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Neurotology Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Gerard J Gianoli, MD, Clinical Associate Professor, Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine; Vice President, The Ear and Balance Institute; Chief Executive Officer, Ponchartrain Surgery Center
Gerard J Gianoli, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Neurotology Society, American Otological Society, Society of University Otolaryngologists-Head and Neck Surgeons, and Triological Society
Disclosure: Nothing to disclose.

CME Editor

Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders
Christopher L Slack, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation unstricted gift unknown; Axis Three Corporation Ownership interest Consulting; Omni Biosciences Ownership interest Consulting; Sentegra Ownership interest Board membership; Syndicom Ownership interest Consulting; Oxlo  Consulting; Medvoy Ownership interest Management position

 
 
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