Abstract
Objective
The aim of the study was to assess the audiological findings of a 4-year-old child with a homozygous COL11A2 mutation and to point out the role of continuous follow-ups in children with craniofacial syndromes after the newborn hearing screening.
Methods
A 4-year-old boy with otospondylomegaepiphyseal dysplasia (OSMED) was followed up after birth for hearing loss. Transient Otoacoustic Emissions (TEOAE’s), Distortion Product Otoacoustic Emissions (DPOAE’s), Automated and Clinical Auditory Brainstem Response (AABR and ABR) measurements, Visual Reinforcement Audiometry, immitansmetric measurements and hearing threshold measurements were performed for audiological evaluation.
Results
The patient developed sensorineural hearing loss at 11 months of age while his hearing was normal at birth. Because of auditory-verbal training with hearing aids started at 20 months of age, he now has normal verbal communication with his peers.
Conclusions
This study clearly demonstrates that hearing loss developes in infancy in patients with OSMED and underscrores the importance of contunied hearing screening beyond newborn period for early intervention of hearing impairment and communication problems.
Keywords: Newborn hearing screening, COL11A2 mutations, OSMED, sensorineural hearing loss
Introduction
Otospondylomegaepiphyseal (OSMED; MIM 215150) dysplasia is an autosomal resessive disorder characterized by sensorineural hearing loss, shortness of the limbs, and spondyloepiphyseal dysplasia with large epiphyses [1-4]. Typical facial features are mid-face hypoplasia with depressed nasal bridge and a small nose. General view of the body is disproportionate short stature with short limbs.
A total of 12 different mutations in the COL11A2 gene (GenBank NG_011589.1; MIM 120290) have been identified in patients with OSMED [3; according to the Human Gene Mutation Database Professional 2010.3 accessed in October 2010]. COL11A2 is located at 6p21.3 and contains 66 exons coding for 1736 amino acids. Mutations or polymorphisms in COL11A2 have also been reported to be associated with micrognathia, glossoptosis, nonsyndromic cleft palate, Kawasaki disease, and development of coronary artery lesions without hearing loss [5-7]. Hearing loss due to COL11A2 mutations is the result of tectorial membrane dysfunction. A knock-out mice model with a homozygous deletion of Col11a2 showed that the organization and strength of the fibers in the tectorial membrane were disrupted [8].
In this report we present the clinical findings with an emphasis on hearing loss associated with a novel homozygous COL11A2 mutation in a 4-year-old child.
Clinical Report
This 4-year-old boy was born to consanguineous (second cousin) Turkish parents. Clinical features of the patient were summarized in Table 1. There was no family history of hearing loss. The study was approved by the Ethics Committee of Ankara University and by the IRB at the University of Miami. An informed consent from and permission for the publication of clinical photographs were signed by both parents.
Table 1.
Clinical features of the proband.
| Characteristic | Status of the case |
|---|---|
| Age | 4 years |
| Height | 97,5 cm (between the 3rd- 10th centile) |
| Weight | 11 kg (less than the 3rd centile) |
| Disproportionately short limbs | + |
| Cleft palate | - |
| Micrognathia/retrognathia | + |
| Midface hypoplasia | + |
| Nose deformities | Short nose, flat nasal bridge, anteverted nares. |
| Long philtrum | + |
| Hypertelorism | + |
| Midfacial hemangioma | - |
| Auricle deformities | Sulcus anthelix rearwards, low set ears |
| Sensorineural hearing loss | 48 dB HL in the right, 60 dB HL in the left ear |
| Enlarged joints | + |
| Pectus excavatum | - |
| Vertebral body anomalies | + |
| Kyphosis | - |
| Lumbar lordosis | + |
| Ocular changes | - |
| High myopia | - |
The patient was first seen at the Pediatric Genetics Clinic of Ankara University when he was 3-1/2 months old. The diagnosis of OSMED was established based on midfacial hypoplasia with a flat nose and short upper extremities (Fig. 1a and b). Skeletal radiographs revealed shortening of the long bones and metacarpals as well as enlarged and flared metaphyses. The hights of anterior part of lower thoracal vertebral bodies were decreased (Fig. 2a, 2b and 2c). DNA sequencing of all coding exons and intron-exon boundaries of the COL11A2 gene using a DNA sample obtained from peripheral blood of the proband revealed a homozygous c.3329delC (p.Pro1110Leufs235) mutation. Both parents were heterozygous for the mutation. The ophthalmological examination was first performed when the child was 9-1/2 months old and was normal. A recent examination showed normal findings as well.
Figure 1.
a and b: Current appearance of the proband.
Figure 2.
a and b: Left upper and lower extremity radiographs show short and dumbbell shape humerus and tibia. Metaphyses of long bones are enlarged (megametaphyses) and flared.
c: Lateral spine radiography demonstrates mild platyspondyly.
Audiological findings
Newborn hearing screening results of the patient were normal for both Transient Evoked Otoacoustic Emissions (TEOAE’s) and Automated Auditory Brainstem Response (AABR) measurements as recommended by the National Institutes of Health Consensus Development Conference in 1993 for Universal hearing screening [9]. One of them is the AABR measures average neural response to repeated sound signals, and the other is otoacoustic emissions detecting sound produced by movements of outer hair cells of the cochlea. This protocol typically has a sensitivity of % 92, and a specificity of % 98 [10].
At 3 and 1/2 months, TEOAEs and AABR measurements were bilateraly positive again. TEOAEs and Distortion Product Otoacoustic Emissions (DPOAEs) were measured with ILO-92 equipment (Institute for Laryngology and Otology, London, England). AccuScreen PRO (MADSEN-GN Otometrics, Taastrup, Denmark) was used for AABR measurements. Bilateral midle ear pressure were 0 daPa and acoustic reflexes were positive.
At 11 months, results of TEOAEs and DPOAEs showed no emissions in either ear. Results of tympanometry were -64 daPa atmospheric pressure in the right ear, -108 daPa atmospheric pressure in the left ear. Bilateral acoustic reflex were positive.
At 17 months, hearing threshold levels were obtained with bilateral sensorineural hearing loss of 70 dB HL (with visual reinforcement audiometry), which are shown in Fig. 3. Hearing mesurement was performed within soundproof rooms, using an AC-40 audiometer (Interacoustics, Assens, Denmark). Clinical ABR threshold measurement was obtained at a threshold of 50 dB HL for click stimulation. Results of tympanometry were 0 daPa atmospheric pressure in both ears. AZ-26 (Interacoustics, Assens, Denmark) was used for immitansmetric measurements. Bilateral hearing aids were prescribed to the child at 20 months.
Figure 3.
Hearing thresholds of the proband with Visual Reinforcement Audiometry while the case was at 17 months.
Current audiological findings at 4 years of age showed moderate sensorineural hearing loss of 48 dB Hearing Level (HL) in the right ear and moderate-severe sensorineural hearing loss of 60 dB HL in the left ear. Pure tone hearing threshold measurements were done between 125 and 6000 Hz, according to International Standards Organisation (ISO), 1964. Hearing thresholds of both ears are shown in Fig. 4. Speech Awereness Threshold (SAT) was 40 dB HL in the right ear and 50 dB HL in the left ear. He used hearing aids on regular basis after 20 months of age and his verbal communication was the same level as that in peers.
Figure 4.
Hearing thresholds of the proband at 4 years old.
Clinical ABR measurements were done with ECLIPSE EP25 model Brainstem Evoked Response Audiometer (Interacoustics, Assens, Denmark). Clinical ABR outcomes were obtained for click stimulation and are shown in Fig. 5.
Figure 5.
Clinical ABR outcomes for click stimulation.
Educational Findings
The patient has attended auditory-verbal training with his mother regularly for two years. There were no behaviour and attention problems during the training. He was assessed in terms of general development, receptive and expressive language skills, speech intelligibility and auditory performance. Preschool Language Scale (PLS) is used to evaluate the language skills of patient and targets receptive and expressive language skills [11]. As the PLS test scores, his age of receptive and expressive language were found to be consistent with his chronologic age. Denver II is the most widely used developmental screening tests in the world and is used to evaluate the general development of the child [12]. As the Denver II test scores, his gross/fine motor, personal-social and language development were found to be consistent with his chronologic age. Speech Intelligibility Rating is a time effective global outcome measure of speech production in real-life situations [13,14]. His Speech Intelligibility Rating was 4 during the assessment, according to Speech Intelligibility Rating criteria (Table 2). His auditory performance was assessed by Categories of Auditory Performance test comprises a hierarchical scale of auditory perceptive ability [15,16]. His categories of auditory performance was 5 according to the Categories of Auditory Performance (Table 3).
Table 2.
| Category Speech Intelligibility Rating | |
|---|---|
| 1 | Connected speech is unintelligible. Prerecognizable words in spoken language, primary mode of communication may be manual. |
| 2 | Connected speech is unintelligible. Intelligible speech is developing in single words when context and lip-reading cues are available. |
| 3 | Connected speech is intelligible to a listener who concentrates on lip-reading. |
| 4 | Connected speech is intelligible to a listener who has little experience of a deaf person’s speech. |
| 5 | Connected speech is intelligible to all listeners. |
Table 3.
| Categories of Auditory Performance | |
|---|---|
| 1 | No awareness of responds to environmental sounds/voice. |
| 2 | Awareness of responds to environmental. |
| 3 | Responds to speech sounds. |
| 4 | Recognises environmental sounds. |
| 5 | Discrimination of speech sounds. |
| 6 | Understands common phrases without lip reading. |
| 7 | Understands conversation without lip reading. |
| 8 | Can use telephone with known speaker. |
Discussion
The Joint Committee on Infant Hearing determined 10 risk indicators (one of them is the presence of syndromic findings) for audiologic monitoring in infants until two years of the age with normal hearing on newborn screening [17]. Accordingly, this child was continued to be followed for hearing loss with the diagnosis of a syndrome, OSMED. As a result, hearing loss was identified as early as possible and the child received successful intervention.
Although hearing loss is a known finding in OSMED, details of hearing phenotype are not well described. Audiological findings in this study and those of previously reported patients with COL11A2 mutations in the literature are summarized in Table 4. Mutations in COL11A2 are associated with two other syndromes that are autosomal dominantly inherited, nonocular Stickler syndrome type III (MIM 184840) and Weissenbacher-Zweymuller syndrome (also referred to as heterozygous OSMED; MIM 277610) and with non-syndromic autosomal dominant (DFNA13; MIM 601868) as well as autosomal recessive (DFNB53; MIM 609706) sensorineural hearing loss. Some details of hearing phenotype are missing in publications related to COL11A2 mutations. Our study is the only one where newborn hearing screening results and ABR measurements are available, which clearly demonstrate the age of onset of sensorineural hearing loss in OSMED. An excellent outcome due to early detection and intervention of hearing loss in our patient underscores the importance of longitudinal follow ups in children with syndromic findings.
Table 4.
Audiological findings associated with COL11A2 mutations.
| Present Study | OSMED Syndrome [3, 4, 18, 19] | Stickler Syndrome [20, 21, 22] | Weissenbacher-Zweymuller Syndrome [2, 23] | DFNB53 (nonsyndromic deafness) [24] | DFNA13 (nonsyndromic deafness) [25, 26, 27, 28] | |
|---|---|---|---|---|---|---|
| Inheritance Pattern | Autosomal Recessive | Autosomal Recessive | Autosomal Dominant | Autosomal Dominant | Autosomal Recessive | Autosomal Dominant |
| Number of Mutations up to date | 1 | 12 | 2 | 1 | 1 | 2 |
| Newborn-screening | Normal | Not available | Not available | Not available | Not available | Not available |
| Onset age | 11 months | Early onset, early childhood, or not available. | Early childhood or not available. | 5 years or not available | Prelingual | Congenital, early childhood or 2nd-4th decade |
| Progression | Progressed until 11 months; afterwards non progressive (thus far) | Non progressive or not available | Progressive or not available. | Not available | Non progressive | Progressive, progressive at 4th decade or non progressive |
| Severity | Moderate to severe | Moderate to profound | Mild to severe | Severe or not available | Profound | Mild to severe |
| HL type | SNHL | SNHL | Mixed or SNHL | SNHL | SNHL | SNHL |
| Audiogram shape | Gently slopping | Flat, high Frequencies or not available | U-shaped, flat, gently/steply slopping or not available | Not available | Not available | Mid or High frequencies |
SNHL: Sensorineural Heaing Loss
Acknowledgments
This work was supported in part by grants R01DC009645 from the National Institute of Deafness and other Communication Disorders of the NIH and 108S045 from the Scientific and Technological Research Council of Turkey.
Footnotes
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References
- 1.Giedion A, Brandner M, Lecannellier J, et al. Oto-spondylo-megaepiphyseal dysplasia (OSMED) Helv Paediatr Acta. 1982 Sep;37(4):361–380. [PubMed] [Google Scholar]
- 2.Pihlajamaa T, Prockop DJ, Faber J, et al. Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymuller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome) Am J Med Genet. 1998 Nov 2;80(2):115–120. doi: 10.1002/(sici)1096-8628(19981102)80:2<115::aid-ajmg5>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
- 3.Melkoniemi M, Brunner HG, Manouvrier S, et al. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet. 2000 Feb;66(2):368–377. doi: 10.1086/302750. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Temtamy SA, Mannikko M, Abdel-Salam GM, Hassan NA, Ala-Kokko L, Afifi HH. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical and radiological findings in sibs homozygous for premature stop codon mutation in the COL11A2 gene. Am J Med Genet A. 2006 Jun 1;140(11):1189–1195. doi: 10.1002/ajmg.a.31205. [DOI] [PubMed] [Google Scholar]
- 5.Melkoniemi M, Koillinen H, Mannikko M, et al. Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia. Eur J Hum Genet. 2003 Mar;11(3):265–270. doi: 10.1038/sj.ejhg.5200950. [DOI] [PubMed] [Google Scholar]
- 6.Nikopensius T, Jagomagi T, Krjutskov K, et al. Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate. Birth Defects Res A Clin Mol Teratol. 2010 Sep;88(9):748–756. doi: 10.1002/bdra.20700. [DOI] [PubMed] [Google Scholar]
- 7.Sheu JJ, Lin YJ, Chang JS, et al. Association of COL11A2 polymorphism with susceptibility to Kawasaki disease and development of coronary artery lesions. Int J Immunogenet. 2010 Dec;37(6):487–492. doi: 10.1111/j.1744-313X.2010.00952.x. [DOI] [PubMed] [Google Scholar]
- 8.Masaki K, Gu JW, Ghaffari R, et al. Col11a2 deletion reveals the molecular basis for tectorial membrane mechanical anisotropy. Biophys J. 2009 Jun 3;96(11):4717–4724. doi: 10.1016/j.bpj.2009.02.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Morton CC, Nance WE. Newborn hearing screening--a silent revolution. N Engl J Med. 2006 May 18;354(20):2151–2164. doi: 10.1056/NEJMra050700. [DOI] [PubMed] [Google Scholar]
- 10.Kennedy C, McCann D, Campbell MJ, Kimm L, Thornton R. Universal newborn screening for permanent childhood hearing impairment: an 8-year follow-up of a controlled trial. Lancet. 2005 Aug 20-26;366(9486):660–662. doi: 10.1016/S0140-6736(05)67138-3. [DOI] [PubMed] [Google Scholar]
- 11.Zimmerman IL, Castilleja NF. The role of a language scale for infant and preschool assessment. Ment Retard Dev Disabil Res Rev. 2005;11(3):238–246. doi: 10.1002/mrdd.20078. [DOI] [PubMed] [Google Scholar]
- 12.Frankenburg WK, Dodds J, Archer P, Shapiro H, Bresnick B. The Denver II: a major revision and restandardization of the Denver Developmental Screening Test. Pediatrics. 1992 Jan;89(1):91–97. [PubMed] [Google Scholar]
- 13.Allen MC, Nikolopoulos TP, O’Donoghue GM. Speech intelligibility in children after cochlear implantation. Am J Otol. 1998 Nov;19(6):742–746. [PubMed] [Google Scholar]
- 14.Calmels MN, Saliba I, Wanna G, et al. Speech perception and speech intelligibility in children after cochlear implantation. Int J Pediatr Otorhinolaryngol. 2004 Mar;68(3):347–351. doi: 10.1016/j.ijporl.2003.11.006. [DOI] [PubMed] [Google Scholar]
- 15.O’Donoghue GM, Nikolopoulos TP, Archbold SM, Tait M. Cochlear implants in young children: the relationship between speech perception and speech intelligibility. Ear Hear. 1999 Oct;20(5):419–425. doi: 10.1097/00003446-199910000-00005. [DOI] [PubMed] [Google Scholar]
- 16.Yang HM, Lin CY, Chen YJ, Wu JL. The auditory performance in children using cochlear implants: effects of mental function. Int J Pediatr Otorhinolaryngol. 2004 Sep;68(9):1185–1188. doi: 10.1016/j.ijporl.2004.04.011. [DOI] [PubMed] [Google Scholar]
- 17.Joint Committee on Infant Hearing. Year 2007 position statement: principles and guidelines for early hearing detection and intervention program. Pediatrics. 2007;120(4):898–921. doi: 10.1542/peds.2007-2333. [DOI] [PubMed] [Google Scholar]
- 18.van Steensel MA, Buma P, de Waal Malefijt MC, van den Hoogen FH, Brunner HG. Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet. 1997 Jun 13;70(3):315–323. doi: 10.1002/(sici)1096-8628(19970613)70:3<315::aid-ajmg19>3.3.co;2-y. [DOI] [PubMed] [Google Scholar]
- 19.Avcin T, Makitie O, Susic M, et al. Early-onset osteoarthritis due to otospondylomegaepiphyseal dysplasia in a family with a novel splicing mutation of the COL11A2 gene. J Rheumatol. 2008 May;35(5):920–926. [PubMed] [Google Scholar]
- 20.Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, Robin NH. Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen. J Pediatr. 1998 Feb;132(2):368–371. doi: 10.1016/s0022-3476(98)70466-4. [DOI] [PubMed] [Google Scholar]
- 21.Admiraal RJ, Brunner HG, Dijkstra TL, Huygen PL, Cremers CW. Hearing loss in the nonocular Stickler syndrome caused by a COL11A2 mutation. Laryngoscope. 2000 Mar;110(3 Pt 1):457–461. doi: 10.1097/00005537-200003000-00025. [DOI] [PubMed] [Google Scholar]
- 22.Vuoristo MM, Pappas JG, Jansen V, Ala-Kokko L. A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. Am J Med Genet A. 2004 Oct 1;130A(2):160–164. doi: 10.1002/ajmg.a.30111. [DOI] [PubMed] [Google Scholar]
- 23.Harel T, Rabinowitz R, Hendler N, et al. COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED) Am J Med Genet A. 2005 Jan 1 1;132A:33–35. doi: 10.1002/ajmg.a.30371. [DOI] [PubMed] [Google Scholar]
- 24.Chen W, Kahrizi K, Meyer NC, et al. Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus. J Med Genet. 2005 Oct;42(10):e61. doi: 10.1136/jmg.2005.032615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Ensink RJ, Huygen PL, Snoeckx RL, Caethoven G, Van Camp G, Cremers CW. A Dutch family with progressive autosomal dominant non-syndromic sensorineural hearing impairment linked to DFNA13. Clin Otolaryngol Allied Sci. 2001 Aug;26(4):310–316. doi: 10.1046/j.1365-2273.2001.00477.x. [DOI] [PubMed] [Google Scholar]
- 26.Kunst H, Huybrechts C, Marres H, Huygen P, Van Camp G, Cremers C. The phenotype of DFNA13/COL11A2: nonsyndromic autosomal dominant mid-frequency and high-frequency sensorineural hearing impairment. Am J Otol. 2000 Mar;21(2):181–187. doi: 10.1016/s0196-0709(00)80006-x. [DOI] [PubMed] [Google Scholar]
- 27.McGuirt WT, Prasad SD, Griffith AJ, et al. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13) Nat Genet. 1999 Dec;23(4):413–419. doi: 10.1038/70516. [DOI] [PubMed] [Google Scholar]
- 28.Brown MR, Tomek MS, Van Laer L, et al. A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p. Am J Hum Genet. 1997 Oct;61(4):924–927. doi: 10.1086/514892. [DOI] [PMC free article] [PubMed] [Google Scholar]