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Bilateral cochlear implantation in children with Noonan syndrome
International Journal of Pediatric Otorhinolaryngology 73 (2009) 889–894
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Bilateral cochlear implantation in children with Noonan syndrome C. Scheiber a,*, A. Hirschfelder a, S. Gra¨bel a, H. Peters b, H. Olze a a b
Klinik fu¨r Hals-, Nasen- und Ohrenheilkunde, Charite´ – Universita¨tsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany Institut fu¨r Medizinische Genetik, Charite´ – Universita¨tsmedizin Berlin, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 October 2008 Received in revised form 16 February 2009 Accepted 18 February 2009 Available online 19 March 2009
Noonan syndrome is a mostly autosomal dominant inherited disorder, which can be accompanied by hearing disorders or deafness, coagulation disorders, combined heart defects and developmental disorders. We are reporting on two children with an established Noonan syndrome with a severe bilateral hearing loss of respectively 95 and 100 dB and proper findings in the CT/MRI of the petrous bone. After complete otologic and radiologic diagnostics, both children underwent bilateral cochlear implantation successfully. According to the authors’ knowledge, this is the first time that cochlear implant therapy is discussed in patients with Noonan syndrome. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Noonan syndrome Cochlear implant Hearing disorder Deafness Inherited disorder
1. Introduction ENT specialists are frequently confronted with hearing disorders in the context of syndromes. Noonan syndrome is one of these syndromes that has increasingly moved into focus due to new diagnostic developments. It was described for the first time in 1963 as an independent syndrome by Jacqueline A. Noonan, a pediatric cardiologist at the University of Iowa and Dorothy Emke, pediatrician, in a series of patients with characteristic facies and multiple abnormalities [1]. The syndrome is also known under the names of XX-Turner-phenotype, XY-Turner-phenotype and further synonymously used names (Table 1), as it is a complex familial abnormalities syndrome, which clinically resembles the Ullrich–Turner-syndrome in multiple characteristics and appears in both genders [2]. The syndrome’s symptoms can include short stature, facial dysmorphias and hearing disorders or even deafness (Table 2). Confirmation of possible hearing disorders and facial dysmorphias lead to consult an ENT specialist. The literature concerning epidemiologic data on the frequency of hearing disorders is rare and to the authors’ knowledge there is no comprehensive published data regarding the hearing evolution in patients with Noonan syndrome. Qui et al. [3] examined 20 patients (12 male, 8 female, age 5–65 years, mean 18.6 years) with Noonan syndrome and diagnosed a hearing loss for high
* Corresponding author. Tel.: +49 30 450 555 002; fax: +49 30 450 555 900. E-mail addresses: [email protected], [email protected] (C. Scheiber). 0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2009.02.016
frequencies in 50% and for low frequencies in 20% of the patients. In connection with tympanometry and bone conduction threshold, the hearing loss was sensorineural in 75%. The results of pure tone audiometry were widely spread, ranging from normal hearing to severe hearing loss. In a clinical study on Noonan syndrome, Sharland et al. [4] found hearing disorders in 40% of the 151 patients (83 male, 68 female, mean age 12.6 years). The levels of hearing loss were not specified, however. In comparison, numerous abnormalities of the petrous bone in Noonan syndrome have been described in the literature [5–7] (Table 1). According to the authors’ knowledge, this is the first time that the aspects of diagnostics and therapy are discussed and the literature is generated regarding cochlear implantation in patients with Noonan syndrome. In the case report, we present the successful bilateral implantation of a Cochlear Implant (CI) in two children with Noonan syndrome. 2. Case report 2.1. Clinical history and clinical findings We are reporting on two girls (2 years and 4 years) who have been diagnosed with Noonan syndrome at the Charite´ University Children’s Hospital in 2007 on the basis of a cytogenetic examination and the characteristic findings constellation. In both children the karyotype was normal with 46, XX and analysis confirmed the presence of mutation in gene PTPN11. Exons 1–15 of the PTPN11 gene and the flanking intronic sequences were amplified by PCR and bidirectionally sequenced. Apart from the
890
C. Scheiber et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 889–894
Table 1 Synonyms. Male Turner syndrome Familial Turner syndrome Female pseudo-Turner syndrome Pseudo-Turner syndrome Pseudo-Ullrich–Turner-syndrome Turner-like syndrome Turner’s phenotype with normal karotype Turner’s syndrome in female with X-chromosome Ullrich–Noonan syndrome XX Turner phenotype syndrome Turner phenotype syndrome
appearance which was characteristic for Noonan syndrome, the girls had multiple malformations of the cardio-vascular system (pulmonary valve stenosis, patent ductus arteriosus, atrial septal defect, patent foramen ovale), short stature and a general developmental delay. Weight and height constantly remained considerably under the 3rd percentile and a statomotoric retardation was found. 2.1.1. Case report 1 The 4-year-old girl, a premature infant (36 + 2 weeks of pregnancy [WOP]), was delivered via emergency cesarean section because of a suspected uterine rupture. Postpartum she demonstrated a respiratory adjustment disorder after initial
Table 2 wide clinical variability of symptoms. Symbols are indicating presence (+) and absence ( ) of symptoms.
Physical appearance Short stature Triangular contour of the face Short webbed neck with pterygium colli Hypertelorism Ptosis Epicanthus medialis High anterior hairline Low posterior hairline Curly hair Mild mental retardation Malformations of the cardio-vascular system Pulmonary valve stenosis Patent ductus arteriosus Atrial septal defect Patent foramen ovale ENT Features Hearing disorder Low set posteriorly angulated ears with thickened helix Anatomic middleand inner ear abnormalities Petrous bone: absence of the long process of the incus and atypical position of stapes [5] Dehiscence of a high jugular bulb, semicircular canal aplasia, extremely large mastoid emissary vein, small and dysplastic cochlea [6] Dehiscence of the facial canal, enlarged semicircular canal [7] Facial features: High nasal bridge Wide nasal base Deep philtrum Higharched palate Micrognathia Malalignment of the teeth Further symptoms Strabismus Amblyopia Refractive errors Cone shaped cornea Funnel chest Scoliosis Simian crease Pulmonary valve stenosis Testicular maldescent Testicular aplasia Cryptorchidism Seizure disorder Thrombocytopaenia and Partial deficiencies of coagulation factors XI, XII, XIII von Willebrand disease with lack of von Willebrand factor (vWF) and factor VIII Individual symptoms Leucopenia Clinodactyly Hypoplastic appearing outer genitals A plane occiput
Case report 1: the 4-year-old girl
Case report 2: the 2-year-old girl
+
+ + + + + + +
+ + + + + + +
+ +
+ + + +
+ + + +
+ + +
+ + +
+ + +
+ + +
+ + + +
+ +
+
+
+
+
+ + + +
C. Scheiber et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 889–894
inconspicuousness. The administration of oxygen allowed to achieve a stable saturation; however, there were still isolated falls in oxygen saturation during the first week of life. The girl showed individual stigmata on the face, acra and outer genitals. She is suspected of having von Willebrand disease with pronounced bleeding tendency. Cytogenetic analysis revealed a heterozygous transition from A to G at cDNA Position 922 in exon 8 of the PTPN11 gene. This change predicts the amino acid substitution from asparagine to aspartic acid (p.Asn308Asp c.922A > G) and is located in the tyrosine phosphatase (PTP) domain of the protein [8]. At the age of 20 months the neuropediatric evaluation revealed a statomotoric and mental retardation of approximately 8 months. The girl developed a progressive hearing loss. Right after birth normal transitory evoked otoacoustic emissions were recordable on both sides. Due to an absent development of language and general retardation, the auditory brainstem responses (ABRs) were registered at the age of 2 years and revealed a threshold of 50 dB. That is why hearing aids were adjusted. A progression in hearing loss became evident at the age of 4 years. The ABR measurement showed a threshold at 100 dB on the right side and 95 dB on the left side. These findings were confirmed twice with an interval of 2 months. 2.1.2. Case report 2 The 2-year-old girl was a premature infant (36 + 1 WOP), too. Postpartum she suffered from fetal hydrops with pronounced ascites and increasing respiratory insufficiency in a congenital CMV infection, confirmed in serum and ascites, with pneumonia and hepatitis. Due to secondary pulmonary hypoplasia, there was a long-term need for ventilation with several ineffective attempts to withdraw ventilation. Recurrent pneumonias and bronchitis required intensive care. A pronounced thrombocytopenia and leucopenia required several substitutions. In the first year of life a dysorexia with the feeding difficulty of an insufficient calorie intake and hydration added to the developmental disorders and pronounced muscle hypotonia. In the appearance of the 2-year-old an epicanthus, hypertelorism, a plane occiput, low set posteriorly angulated ears and a funnel chest were conspicuous. The cytogenetic analysis showed the heterozygous transversion c.853T > C in exon 7 of the PTPN11 gene, which predicts a phenylalanine to leucine (Phe285Leu) substitution [9]. At the age of 14 months the psychologic evaluation of development revealed a mean general retardation of 8 months at minimum. We supposed that profound hearing loss was present since birth. The neonatal screening with transitory evoked otoacoustic emissions after birth
891
showed no responses. In the ABR no responses were detected up to 60 dB bone conduction and 100 dB air conduction, either. 2.2. Cochlear implantation Both children were presented with so far absent development of speech – both were only articulating sounds. Complete diagnostics and cochlear implantation, however, could not be performed earlier because the 2-year-old girl suffered of recurrent respiratory infections, which needed intensive care treatment. The parents of the 4-year-old girl were initially very reluctant toward any medical examination, diagnostics and treatment, which explains the delay for cochlear implantation in this patient. In both girls we found a flat tympanogram. A paracentesis followed by an auditory brainstem response was performed under anesthesia due to the girls’ age. In the 4-year-old girl, up to 100 dB on the right side and up to 95 dB on the left and, in the 2year-old girl, up to 100 dB on both sides, no brain stem potentials were derivable. The electrically evoked amplitude modulation following responses (EAMFR) were derivable in both children with correct responses, as a sign of normal auditory nerve function. Under the same anesthesia a computerized tomography (CT) and magnetic resonance imaging (MRI) were performed. The acoustic nerves appeared to be correctly positioned as well as the cochlea and the semicircular canals, which appeared to be correctly filled with fluid on both sides. In the younger patient, expanded interior subarachnoid spaces were found with a moderately delayed myelinization along with a deficiency of white substance, as well as a corpus callosum hypoplasia. Both children received bilaterally sequentially a cochlear implant (nucleus freedom), with the interval until the 2nd operation being respectively 8 months (older girl) and 10 months (younger girl). The older girl was suspected to have von Willebrand disease and therefore received minirine (desmopressin), 2 mg/kg of body weight nasal, before the operation, haemate was kept ready in case of a bleeding. The remarkable benefit after cochlear implantation can be seen in the aided threshold with hearing aids of the older girl (Figs. 1 and 2) and after implantation of the right side of the younger girl (Fig. 3) (Figs. 4 and 5). 3. Discussion During the diagnostics for the CI, there was no deviation from our standard in either of the two patients. Although mild cognitive deficiency and developmental retardation related to their age was
Fig. 1. Audiometry, case 1, aided threshold with hearing aids in sound field.
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Fig. 2. Audiometry, case 1, after bilateral cochlear implantation.
Fig. 3. Audiometry, case 2, after unilateral cochlear implantation (right).
described by the caring pediatricians and psychologists no differences had been made for indication as well. Nevertheless a mild cognitive deficiency could be a difficulty in rehabilitation. That is why special efforts as in all patients with syndromes accompanied by mental retardation are necessary. Our two patients profit very much of day nursery with special-needs teachers, who report about encouraging progress in speech and general development already. Noonan syndrome has increasingly moved into focus due to new diagnostic developments. Recently, genetic markers have been used to establish a diagnosis. Even before that, the fact that patients with Noonan syndrome have normal karyotypes (46, XX and 46, XY) helped to differentiate it from the phenotipically similar Ullrich–Turner-syndrome [2]. The syndrome is relatively common with an incidence of 1:1000 to 1:2500 live-born children. The wide range in the literature can be explained by the fact that, over decades, there were no biochemical or genetic markers to establish a diagnosis and that it was just a clinical diagnosis. In big families in which Noonan syndrome is frequently inherited in an autosomal dominant pattern, a locus for the gene was narrowed down on the long arm of chromosome 12 in section 12q24. Sporadic appearance is explained by point mutations. In several patients, an autosomal recessive heredity is suspected [10]. In
2001, Tartaglia et al. [8] showed that mutations in gene PTPN11 are present in approximately 40–50% of the patients with Noonan syndrome. The same mutations found in gene PTPN11 of the two children in our report have already been described in patients with Noonan syndrome [8,9]. It is expected that, in the future, further genes will be detected, whose mutations cause changes in children which are similar to Noonan syndrome. One possible candidate is e.g., the KRAS gene [11]. This cytosolic protein–tyrosine–phosphatase SHP2, the gene product of PTPN11, seems to be important for the development of the pulmonary valve [8]. Due to the characteristics with facial dysmorphias and hearing disorders, patients with Noonan syndrome should be examined by an ENT specialist. The children in our case reports had a threshold value of 95 and 100 dB on both sides in the ABR. The CT and MRI imaging of the petrous bone and of the neurocranium showed normal findings leading to indication for a CI. In case of a suspected hearing disorder otoacoustic emission (OAE) should be measured and, in case of an unusual finding, the ABR should be measured, too. In order to achieve the best possible result for the language acquisition, we plead for an early implantation in the first year of life, after complete establishment of a diagnosis and indication. There should be no difference or delay during the diagnostics in comparison to children without Noonan syndrome. Should the
Fig. 4. A–L, case 1.
C. Scheiber et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 889–894
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Fig. 5. A–F, case 2.
operation not be possible at that time due to a concomitant disease or recurrent infections, the implantation of the CI should be performed as soon as possible. Due to the shorter operation duration of the individual intervention, the faster postoperative recovery of the children and the perioperative risk of bleedings in connection with coagulation disorders commonly associated with Noonan syndrome, we decided for a two-stage bilateral operation. Before cochlear implant surgery, the correct osteal inner ear structure, mastoid pneumatization and a possible bulbus elevation should always be evaluated with the help of a CT with highresolution. This way, abnormalities of the petrous bone, which are symptomatic for this syndrome, can be detected. Attention should be paid to possible central lesions. For this, we recommend a MRI of the head. Our patients did not show any contraindications for a CI in imaging. In addition, the situs, the appropriate impedance and the neural response telemetry (NRT) were normal during the operation. In Noonan syndrome, however, the wide spectrum of possible associated abnormalities in the petrous bone and the ossicle must be focused as well. Apart from the otolaryngological examination of these patients, a high-resolution computed tomography of the petrous bone is advisable, even before small operations on the ear. Cremers and van der Burgt [5] described, for example, a chain anomaly in a patient with Noonan syndrome presenting normal findings on the eardrum and a conductive hearing loss since early childhood. Furthermore, multiple abnormalities in the petrous bone have been described in computer tomographic and histopathologic findings [6,7]. 4. Remarks In patients who are suspected of having Noonan syndrome, it should be attempted to genetically confirm the mutation in gene PTPN11. As in all newborn babies, the sense of hearing is checked
in the first week of life by means of otoacoustic emissions and, if necessary, an ABR examination is performed. In case of a possible coincidence of Noonan syndrome and hearing disorders, audiometric and early brain stem audiometric tests should be performed at regular intervals, and, if it is indicated, hearing aids or CI should be used as soon as possible. Regarding indication for a CI no deviation should be made from patients without Noonan syndrome. The encouraging onset of developmental progress the two children underwent since implantation strengthens this. If a CI operation is indicated, a coagulation analysis including a multimer analysis with regard to von Willebrand disease is necessary. Coagulation needs to be optimized before the operation and blood reserves need to be ready in case of a bleeding. Pre-existing cardiac defects need to be taken into consideration and recurrent respiratory infections need to be treated before operation. This requires interdisciplinary co-operation, as it is possible in large hospitals. Then nothing will compromise a successful CI operation of these children. Conflict of interest The corresponding author certifies that there is no actual or potential conflict of interest in relation to this article. References [1] J.A. Noonan, Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease, Am. J. Dis. Child. 116 (1968) 373–380. [2] N. Stahnke, Ullrich–Turner-Syndrom und Noonan-Syndrom, Monatsschr. Kinderheilkd. 152 (2004) 517–527. [3] W.W. Qui, S.S. Yin, F.J. Stucker, Audiologic manifestations of Noonan syndrome, Otolaryngol. Head Neck Surg. 118 (1998) 319–323. [4] M. Sharland, M. Burch, W.M. McKenna, M.A. Paton, A clinical study of Noonan syndrome, Arch. Dis. Child. 67 (1992) 178–183.
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[5] C.W.R.J. Cremers, C.J.A.M. van der Burgt, Hearing loss in Noonan syndrome, Int. J. Pediatr. Otorhinolaryngol. 23 (1992) 81–84. [6] S. Naficy, N.T. Shepard, S.A. Telian, Multiple temporal bone anomalies associated with Noonan syndrome, Otolaryngol. Head Neck Surg. 116 (1997) 265–267. [7] M. Miura, I. Sando, Y. Orita, B.E. Hirsch, Temporal bone histopathological study of Noonan syndrome, Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 73–82. [8] M. Tartaglia, E.L. Mehler, R. Goldberg, G. Zampino, H.G. Brunner, H. Kremer, et al., Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome, Nat. Genet. 29 (2001) 465–468.
[9] M. Tartaglia, K. Kalidas, A. Shaw, X. Song, D.L. Musat, I. van der Burgt, et al., PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity, Am. J. Hum. Genet. 70 (6) (2002) 1555– 1563. [10] G. Schlu¨ter, M. Rossius, A. Wessel, B. Zoll, Das Noonan-Syndrom, Dtsch. Arztebl. 100 (2003) A 1192–1197 [Heft 18]. [11] B.D. Gelb, M. Tartaglia (2006) Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction 2 Human Molecular Genetics, 15: Review Issue No. 2, R220–R226.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Bilateral cochlear implantation in children with Noonan syndrome C. Scheiber a,*, A. Hirschfelder a, S. Gra¨bel a, H. Peters b, H. Olze a a b
Klinik fu¨r Hals-, Nasen- und Ohrenheilkunde, Charite´ – Universita¨tsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany Institut fu¨r Medizinische Genetik, Charite´ – Universita¨tsmedizin Berlin, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 October 2008 Received in revised form 16 February 2009 Accepted 18 February 2009 Available online 19 March 2009
Noonan syndrome is a mostly autosomal dominant inherited disorder, which can be accompanied by hearing disorders or deafness, coagulation disorders, combined heart defects and developmental disorders. We are reporting on two children with an established Noonan syndrome with a severe bilateral hearing loss of respectively 95 and 100 dB and proper findings in the CT/MRI of the petrous bone. After complete otologic and radiologic diagnostics, both children underwent bilateral cochlear implantation successfully. According to the authors’ knowledge, this is the first time that cochlear implant therapy is discussed in patients with Noonan syndrome. ß 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Noonan syndrome Cochlear implant Hearing disorder Deafness Inherited disorder
1. Introduction ENT specialists are frequently confronted with hearing disorders in the context of syndromes. Noonan syndrome is one of these syndromes that has increasingly moved into focus due to new diagnostic developments. It was described for the first time in 1963 as an independent syndrome by Jacqueline A. Noonan, a pediatric cardiologist at the University of Iowa and Dorothy Emke, pediatrician, in a series of patients with characteristic facies and multiple abnormalities [1]. The syndrome is also known under the names of XX-Turner-phenotype, XY-Turner-phenotype and further synonymously used names (Table 1), as it is a complex familial abnormalities syndrome, which clinically resembles the Ullrich–Turner-syndrome in multiple characteristics and appears in both genders [2]. The syndrome’s symptoms can include short stature, facial dysmorphias and hearing disorders or even deafness (Table 2). Confirmation of possible hearing disorders and facial dysmorphias lead to consult an ENT specialist. The literature concerning epidemiologic data on the frequency of hearing disorders is rare and to the authors’ knowledge there is no comprehensive published data regarding the hearing evolution in patients with Noonan syndrome. Qui et al. [3] examined 20 patients (12 male, 8 female, age 5–65 years, mean 18.6 years) with Noonan syndrome and diagnosed a hearing loss for high
* Corresponding author. Tel.: +49 30 450 555 002; fax: +49 30 450 555 900. E-mail addresses: [email protected], [email protected] (C. Scheiber). 0165-5876/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2009.02.016
frequencies in 50% and for low frequencies in 20% of the patients. In connection with tympanometry and bone conduction threshold, the hearing loss was sensorineural in 75%. The results of pure tone audiometry were widely spread, ranging from normal hearing to severe hearing loss. In a clinical study on Noonan syndrome, Sharland et al. [4] found hearing disorders in 40% of the 151 patients (83 male, 68 female, mean age 12.6 years). The levels of hearing loss were not specified, however. In comparison, numerous abnormalities of the petrous bone in Noonan syndrome have been described in the literature [5–7] (Table 1). According to the authors’ knowledge, this is the first time that the aspects of diagnostics and therapy are discussed and the literature is generated regarding cochlear implantation in patients with Noonan syndrome. In the case report, we present the successful bilateral implantation of a Cochlear Implant (CI) in two children with Noonan syndrome. 2. Case report 2.1. Clinical history and clinical findings We are reporting on two girls (2 years and 4 years) who have been diagnosed with Noonan syndrome at the Charite´ University Children’s Hospital in 2007 on the basis of a cytogenetic examination and the characteristic findings constellation. In both children the karyotype was normal with 46, XX and analysis confirmed the presence of mutation in gene PTPN11. Exons 1–15 of the PTPN11 gene and the flanking intronic sequences were amplified by PCR and bidirectionally sequenced. Apart from the
890
C. Scheiber et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 889–894
Table 1 Synonyms. Male Turner syndrome Familial Turner syndrome Female pseudo-Turner syndrome Pseudo-Turner syndrome Pseudo-Ullrich–Turner-syndrome Turner-like syndrome Turner’s phenotype with normal karotype Turner’s syndrome in female with X-chromosome Ullrich–Noonan syndrome XX Turner phenotype syndrome Turner phenotype syndrome
appearance which was characteristic for Noonan syndrome, the girls had multiple malformations of the cardio-vascular system (pulmonary valve stenosis, patent ductus arteriosus, atrial septal defect, patent foramen ovale), short stature and a general developmental delay. Weight and height constantly remained considerably under the 3rd percentile and a statomotoric retardation was found. 2.1.1. Case report 1 The 4-year-old girl, a premature infant (36 + 2 weeks of pregnancy [WOP]), was delivered via emergency cesarean section because of a suspected uterine rupture. Postpartum she demonstrated a respiratory adjustment disorder after initial
Table 2 wide clinical variability of symptoms. Symbols are indicating presence (+) and absence ( ) of symptoms.
Physical appearance Short stature Triangular contour of the face Short webbed neck with pterygium colli Hypertelorism Ptosis Epicanthus medialis High anterior hairline Low posterior hairline Curly hair Mild mental retardation Malformations of the cardio-vascular system Pulmonary valve stenosis Patent ductus arteriosus Atrial septal defect Patent foramen ovale ENT Features Hearing disorder Low set posteriorly angulated ears with thickened helix Anatomic middleand inner ear abnormalities Petrous bone: absence of the long process of the incus and atypical position of stapes [5] Dehiscence of a high jugular bulb, semicircular canal aplasia, extremely large mastoid emissary vein, small and dysplastic cochlea [6] Dehiscence of the facial canal, enlarged semicircular canal [7] Facial features: High nasal bridge Wide nasal base Deep philtrum Higharched palate Micrognathia Malalignment of the teeth Further symptoms Strabismus Amblyopia Refractive errors Cone shaped cornea Funnel chest Scoliosis Simian crease Pulmonary valve stenosis Testicular maldescent Testicular aplasia Cryptorchidism Seizure disorder Thrombocytopaenia and Partial deficiencies of coagulation factors XI, XII, XIII von Willebrand disease with lack of von Willebrand factor (vWF) and factor VIII Individual symptoms Leucopenia Clinodactyly Hypoplastic appearing outer genitals A plane occiput
Case report 1: the 4-year-old girl
Case report 2: the 2-year-old girl
+
+ + + + + + +
+ + + + + + +
+ +
+ + + +
+ + + +
+ + +
+ + +
+ + +
+ + +
+ + + +
+ +
+
+
+
+
+ + + +
C. Scheiber et al. / International Journal of Pediatric Otorhinolaryngology 73 (2009) 889–894
inconspicuousness. The administration of oxygen allowed to achieve a stable saturation; however, there were still isolated falls in oxygen saturation during the first week of life. The girl showed individual stigmata on the face, acra and outer genitals. She is suspected of having von Willebrand disease with pronounced bleeding tendency. Cytogenetic analysis revealed a heterozygous transition from A to G at cDNA Position 922 in exon 8 of the PTPN11 gene. This change predicts the amino acid substitution from asparagine to aspartic acid (p.Asn308Asp c.922A > G) and is located in the tyrosine phosphatase (PTP) domain of the protein [8]. At the age of 20 months the neuropediatric evaluation revealed a statomotoric and mental retardation of approximately 8 months. The girl developed a progressive hearing loss. Right after birth normal transitory evoked otoacoustic emissions were recordable on both sides. Due to an absent development of language and general retardation, the auditory brainstem responses (ABRs) were registered at the age of 2 years and revealed a threshold of 50 dB. That is why hearing aids were adjusted. A progression in hearing loss became evident at the age of 4 years. The ABR measurement showed a threshold at 100 dB on the right side and 95 dB on the left side. These findings were confirmed twice with an interval of 2 months. 2.1.2. Case report 2 The 2-year-old girl was a premature infant (36 + 1 WOP), too. Postpartum she suffered from fetal hydrops with pronounced ascites and increasing respiratory insufficiency in a congenital CMV infection, confirmed in serum and ascites, with pneumonia and hepatitis. Due to secondary pulmonary hypoplasia, there was a long-term need for ventilation with several ineffective attempts to withdraw ventilation. Recurrent pneumonias and bronchitis required intensive care. A pronounced thrombocytopenia and leucopenia required several substitutions. In the first year of life a dysorexia with the feeding difficulty of an insufficient calorie intake and hydration added to the developmental disorders and pronounced muscle hypotonia. In the appearance of the 2-year-old an epicanthus, hypertelorism, a plane occiput, low set posteriorly angulated ears and a funnel chest were conspicuous. The cytogenetic analysis showed the heterozygous transversion c.853T > C in exon 7 of the PTPN11 gene, which predicts a phenylalanine to leucine (Phe285Leu) substitution [9]. At the age of 14 months the psychologic evaluation of development revealed a mean general retardation of 8 months at minimum. We supposed that profound hearing loss was present since birth. The neonatal screening with transitory evoked otoacoustic emissions after birth
891
showed no responses. In the ABR no responses were detected up to 60 dB bone conduction and 100 dB air conduction, either. 2.2. Cochlear implantation Both children were presented with so far absent development of speech – both were only articulating sounds. Complete diagnostics and cochlear implantation, however, could not be performed earlier because the 2-year-old girl suffered of recurrent respiratory infections, which needed intensive care treatment. The parents of the 4-year-old girl were initially very reluctant toward any medical examination, diagnostics and treatment, which explains the delay for cochlear implantation in this patient. In both girls we found a flat tympanogram. A paracentesis followed by an auditory brainstem response was performed under anesthesia due to the girls’ age. In the 4-year-old girl, up to 100 dB on the right side and up to 95 dB on the left and, in the 2year-old girl, up to 100 dB on both sides, no brain stem potentials were derivable. The electrically evoked amplitude modulation following responses (EAMFR) were derivable in both children with correct responses, as a sign of normal auditory nerve function. Under the same anesthesia a computerized tomography (CT) and magnetic resonance imaging (MRI) were performed. The acoustic nerves appeared to be correctly positioned as well as the cochlea and the semicircular canals, which appeared to be correctly filled with fluid on both sides. In the younger patient, expanded interior subarachnoid spaces were found with a moderately delayed myelinization along with a deficiency of white substance, as well as a corpus callosum hypoplasia. Both children received bilaterally sequentially a cochlear implant (nucleus freedom), with the interval until the 2nd operation being respectively 8 months (older girl) and 10 months (younger girl). The older girl was suspected to have von Willebrand disease and therefore received minirine (desmopressin), 2 mg/kg of body weight nasal, before the operation, haemate was kept ready in case of a bleeding. The remarkable benefit after cochlear implantation can be seen in the aided threshold with hearing aids of the older girl (Figs. 1 and 2) and after implantation of the right side of the younger girl (Fig. 3) (Figs. 4 and 5). 3. Discussion During the diagnostics for the CI, there was no deviation from our standard in either of the two patients. Although mild cognitive deficiency and developmental retardation related to their age was
Fig. 1. Audiometry, case 1, aided threshold with hearing aids in sound field.
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Fig. 2. Audiometry, case 1, after bilateral cochlear implantation.
Fig. 3. Audiometry, case 2, after unilateral cochlear implantation (right).
described by the caring pediatricians and psychologists no differences had been made for indication as well. Nevertheless a mild cognitive deficiency could be a difficulty in rehabilitation. That is why special efforts as in all patients with syndromes accompanied by mental retardation are necessary. Our two patients profit very much of day nursery with special-needs teachers, who report about encouraging progress in speech and general development already. Noonan syndrome has increasingly moved into focus due to new diagnostic developments. Recently, genetic markers have been used to establish a diagnosis. Even before that, the fact that patients with Noonan syndrome have normal karyotypes (46, XX and 46, XY) helped to differentiate it from the phenotipically similar Ullrich–Turner-syndrome [2]. The syndrome is relatively common with an incidence of 1:1000 to 1:2500 live-born children. The wide range in the literature can be explained by the fact that, over decades, there were no biochemical or genetic markers to establish a diagnosis and that it was just a clinical diagnosis. In big families in which Noonan syndrome is frequently inherited in an autosomal dominant pattern, a locus for the gene was narrowed down on the long arm of chromosome 12 in section 12q24. Sporadic appearance is explained by point mutations. In several patients, an autosomal recessive heredity is suspected [10]. In
2001, Tartaglia et al. [8] showed that mutations in gene PTPN11 are present in approximately 40–50% of the patients with Noonan syndrome. The same mutations found in gene PTPN11 of the two children in our report have already been described in patients with Noonan syndrome [8,9]. It is expected that, in the future, further genes will be detected, whose mutations cause changes in children which are similar to Noonan syndrome. One possible candidate is e.g., the KRAS gene [11]. This cytosolic protein–tyrosine–phosphatase SHP2, the gene product of PTPN11, seems to be important for the development of the pulmonary valve [8]. Due to the characteristics with facial dysmorphias and hearing disorders, patients with Noonan syndrome should be examined by an ENT specialist. The children in our case reports had a threshold value of 95 and 100 dB on both sides in the ABR. The CT and MRI imaging of the petrous bone and of the neurocranium showed normal findings leading to indication for a CI. In case of a suspected hearing disorder otoacoustic emission (OAE) should be measured and, in case of an unusual finding, the ABR should be measured, too. In order to achieve the best possible result for the language acquisition, we plead for an early implantation in the first year of life, after complete establishment of a diagnosis and indication. There should be no difference or delay during the diagnostics in comparison to children without Noonan syndrome. Should the
Fig. 4. A–L, case 1.
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Fig. 5. A–F, case 2.
operation not be possible at that time due to a concomitant disease or recurrent infections, the implantation of the CI should be performed as soon as possible. Due to the shorter operation duration of the individual intervention, the faster postoperative recovery of the children and the perioperative risk of bleedings in connection with coagulation disorders commonly associated with Noonan syndrome, we decided for a two-stage bilateral operation. Before cochlear implant surgery, the correct osteal inner ear structure, mastoid pneumatization and a possible bulbus elevation should always be evaluated with the help of a CT with highresolution. This way, abnormalities of the petrous bone, which are symptomatic for this syndrome, can be detected. Attention should be paid to possible central lesions. For this, we recommend a MRI of the head. Our patients did not show any contraindications for a CI in imaging. In addition, the situs, the appropriate impedance and the neural response telemetry (NRT) were normal during the operation. In Noonan syndrome, however, the wide spectrum of possible associated abnormalities in the petrous bone and the ossicle must be focused as well. Apart from the otolaryngological examination of these patients, a high-resolution computed tomography of the petrous bone is advisable, even before small operations on the ear. Cremers and van der Burgt [5] described, for example, a chain anomaly in a patient with Noonan syndrome presenting normal findings on the eardrum and a conductive hearing loss since early childhood. Furthermore, multiple abnormalities in the petrous bone have been described in computer tomographic and histopathologic findings [6,7]. 4. Remarks In patients who are suspected of having Noonan syndrome, it should be attempted to genetically confirm the mutation in gene PTPN11. As in all newborn babies, the sense of hearing is checked
in the first week of life by means of otoacoustic emissions and, if necessary, an ABR examination is performed. In case of a possible coincidence of Noonan syndrome and hearing disorders, audiometric and early brain stem audiometric tests should be performed at regular intervals, and, if it is indicated, hearing aids or CI should be used as soon as possible. Regarding indication for a CI no deviation should be made from patients without Noonan syndrome. The encouraging onset of developmental progress the two children underwent since implantation strengthens this. If a CI operation is indicated, a coagulation analysis including a multimer analysis with regard to von Willebrand disease is necessary. Coagulation needs to be optimized before the operation and blood reserves need to be ready in case of a bleeding. Pre-existing cardiac defects need to be taken into consideration and recurrent respiratory infections need to be treated before operation. This requires interdisciplinary co-operation, as it is possible in large hospitals. Then nothing will compromise a successful CI operation of these children. Conflict of interest The corresponding author certifies that there is no actual or potential conflict of interest in relation to this article. References [1] J.A. Noonan, Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease, Am. J. Dis. Child. 116 (1968) 373–380. [2] N. Stahnke, Ullrich–Turner-Syndrom und Noonan-Syndrom, Monatsschr. Kinderheilkd. 152 (2004) 517–527. [3] W.W. Qui, S.S. Yin, F.J. Stucker, Audiologic manifestations of Noonan syndrome, Otolaryngol. Head Neck Surg. 118 (1998) 319–323. [4] M. Sharland, M. Burch, W.M. McKenna, M.A. Paton, A clinical study of Noonan syndrome, Arch. Dis. Child. 67 (1992) 178–183.
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[5] C.W.R.J. Cremers, C.J.A.M. van der Burgt, Hearing loss in Noonan syndrome, Int. J. Pediatr. Otorhinolaryngol. 23 (1992) 81–84. [6] S. Naficy, N.T. Shepard, S.A. Telian, Multiple temporal bone anomalies associated with Noonan syndrome, Otolaryngol. Head Neck Surg. 116 (1997) 265–267. [7] M. Miura, I. Sando, Y. Orita, B.E. Hirsch, Temporal bone histopathological study of Noonan syndrome, Int. J. Pediatr. Otorhinolaryngol. 60 (2001) 73–82. [8] M. Tartaglia, E.L. Mehler, R. Goldberg, G. Zampino, H.G. Brunner, H. Kremer, et al., Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome, Nat. Genet. 29 (2001) 465–468.
[9] M. Tartaglia, K. Kalidas, A. Shaw, X. Song, D.L. Musat, I. van der Burgt, et al., PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity, Am. J. Hum. Genet. 70 (6) (2002) 1555– 1563. [10] G. Schlu¨ter, M. Rossius, A. Wessel, B. Zoll, Das Noonan-Syndrom, Dtsch. Arztebl. 100 (2003) A 1192–1197 [Heft 18]. [11] B.D. Gelb, M. Tartaglia (2006) Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction 2 Human Molecular Genetics, 15: Review Issue No. 2, R220–R226.