Olfactory Evaluation in Children: Application to the CHARGE Syndrome

Christel Chalouhi, MD*; Patrick Faulcon, MD‡; Christine Le Bihan, MD§; Lucie Hertz-Pannier, MD, PhD࿣; Pierre Bonfils, MD, PhD‡; and Ve´ronique Abadie, MD, PhD*

ABSTRACT. Objective. To find an efficient tool for ABBREVIATIONS. CHARGE, coloboma, congenital heart disease, testing olfactory function in children and use it to inves- choanal atresia, mental and growth retardation, genital anomalies, tigate a group of children with CHARGE (coloboma, and malformations and loss; PEA, phenylethylalcohol. congenital heart disease, choanal atresia, mental and growth retardation, genital anomalies, and ear malforma- tions and ) syndrome. lfaction has always been and remains the Methods. We adapted for children an olfaction test most neglected in studies of child de- that had just been validated in an adult French popula- Ovelopment and behavior, the main reasons tion and investigated a control group of 25 healthy chil- being the poor knowledge concerning the role of dren aged 6 to 13 years. We then tested the olfactory olfaction in development and behavior and capacity of a group of 14 children with CHARGE syn- the lack of available tools for investigating olfaction, drome, aged 6 to 18 years. A questionnaire was com- in particular in children. Development of the olfac- pleted with the parents about their children’s feeding tory system begins very early in the human embryo; difficulties and their ability to recognize in every- olfactory bulbs have their definitive structure at day day life. We recorded and scored the histories of feeding 56. Then, cells of the olfactory placode differentiate behavior anomalies, the visual and auditory status, and to gonadotropic cells and migrate to the hypotha- current intellectual levels. MRI of the olfactory tracts and lamic region along the terminal nerve (cranial nerve bulbs was analyzed for 9 of 14 children. 0), the (cranial nerve 1), and the Results. We showed that healthy children have sim- ilar olfactory function to that of the adult control group, vomeronasal nerve. One part of the which was representative of the general population, projects to the anterior part of the for without any difference for either gender or age. We also and discrimination; the other showed that all children with CHARGE syndrome had projects to the and the olfactory deficiency. Half of them were anosmic, and the for the behavioral impact of olfaction and olfactory others had olfactory residual function (hyposmic). We emotional memory.1 The Jacobson vomeronasal or- found no association between olfactory deficiency and gan is a fetal structure that reduces after birth and feeding behavior, visual or auditory impairment, or in- that allows the transmission of odors through aque- tellectual level. Parental subjective evaluations were ac- ous middles, in particular amniotic fluid.2 Several curate for only half of the group. All of the MRIs showed data have shown that olfaction is functional during anomalies of the olfactory tracts and bulbs varying from prenatal life.3–6 At birth, newborns have highly effi- moderate hypoplasia to complete aplasia, without any cient olfactory abilities, allowing them to discrimi- relation between the radiologic and the functional re- nate the odor of their mother’s skin or milk from sults. those of other mothers7,8 and to modify their feeding Conclusions. Olfaction can be assessed in children, behavior according to the milk .9,10 In mice, even the young and disabled. Our results support the proposition that anomalies should be olfaction is crucial at birth to lead the pups to their included as a major criterion for the diagnosis of mother’s nipples, and anosmic mice die shortly after 11 CHARGE syndrome. Pediatrics 2005;116:e81–e88. URL: birth because they cannot find them. All of these www.pediatrics.org/cgi/doi/10.1542/peds.2004-1970; data suggest that human neonatal olfaction probably CHARGE syndrome, olfaction in children, olfactory defi- plays a role both in mother-child bonding and in ciency. newborns’ feeding behavior. During the first years of life, the role of olfaction is probably important, al- though few studies have demonstrated this, princi-

From the *General Pediatrics Unit, §Pediatrics Radiology Unit, and ࿣Biosta- pally because olfaction evaluation is difficult in this tistics Unit, Hoˆpital Necker Enfants Malades, Paris, France; and ‡Depart- age range. Nevertheless, in a previous study, we ment of Otolaryngology Head Neck Surgery, Unite´Centre National de la showed that reproducible behavioral modifications Recherche Scientifique UPRESSA 7060, Hoˆpital Europeen Georges Pompi- (breathing rhythm, mobility, and sight) indicate that dou, Paris, France. Accepted for publication Nov 22, 2004. healthy infants and toddlers (3 months to 3 years) 12 doi:10.1542/peds.2004-1970 have good olfaction abilities. Several studies have No conflict of interest declared. shown that olfaction improves from the age when it Reprint requests to (V.A.) Hoˆpital Necker-Enfants Malades, 149 Rue de becomes testable (7–8 years of age) until the age of Se`vres, 75743 Paris Cedex 15, France. E-mail: [email protected] ϳ40 years.13–16 These observations may be attribut- hop-paris.fr PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- able to the methods of olfaction testing and are dis- emy of Pediatrics. cussed later. After puberty, girls have better olfaction

www.pediatrics.org/cgi/doi/10.1542/peds.2004-1970Downloaded from www.aappublications.org/news by guest PEDIATRICSon September 26,Vol. 2021 116 No. 1 July 2005 e81 abilities than boys.17,18 From the age of ϳ40 years, Patients With CHARGE Syndrome olfaction abilities decrease, which partly explains an- Fourteen children with CHARGE syndrome were included. orexia in the elderly.18 The role of olfaction in adults The group consisted of 8 girls aged 7.5 to 18 years (mean Ϯ SD: is likely involved in several fields, such as appetite, 12.5 Ϯ 4) and 6 boys aged 6 to 10 years (mean Ϯ SD: 7.8 Ϯ 1.4). The diagnosis of CHARGE syndrome was made according to Blake emotional memory, and sexual bonding. However, and Amiel’s criteria (5 major criteria or 4 major criteria and 3 few studies can prove these roles. Studies on behav- minor criteria30,31). We asked the families to participate when their ior in adults with olfaction disorders, in particular child had speech and mental age corresponding to a 5- or 6-year patients with Kallmann syndrome, are rare and do level. Their visual ability had to be good enough to allow them to not show major effects of , suggesting that recognize drawings representing the odors on 10 10-cm pictures. Six patients had peripheral risk factors for olfaction deficit: pa- hyposmic patients compensate for their deficit by tients 2 and 3 had cleft lip and palate; patients 2, 3, 8, and 9 had other sensorial and cognitive means.19–21 Moreover, transient tracheostomy; and patients 5, 9, and 14 had unilateral in , especially in Western and so-called de- choanal atresia. Patient 14 had previously been tested with a veloped cultures, the is not well taught different method. She was excluded from the results but included in the association calculation and the discussion. or stimulated. Parents and children of both groups all were volunteers for this CHARGE syndrome (coloboma, congenital heart prospective study. Consent of all of the families was obtained in disease, choanal atresia, mental and growth retarda- accordance with the ethics rules of our hospital. tion, genital anomalies, and ear malformations and hearing loss) is a congenital malformative picture Olfactory Tests that was described 25 years ago.22,23 In addition to The French Biolfa olfactory test, recently validated in healthy young adults, was adapted to children.29 The Biolfa test uses 2 the defects cited in the acronym, other anomalies series of 30-mL glass sniff bottles that contain odorous chemical have been described. Some of them have a high substances. The first series measure the olfactory thresholds of 3 frequency, such as vestibular anomalies, facial dys- different substances (eugenol, aldehyde C14, and phenyl ethyl morphism, asymmetrical facial palsy, and alcohol [PEA; quantitative trial]). The second series is an odor dysfunction, whereas others have a lower frequency, identification test to determine quality of olfactory function using a large panel of odors that are common to Southern European such as renal, esophageal, osseous, and cerebral mal- countries (qualitative trial). formations.24–26 Once the structural anomalies are repaired, children with CHARGE have to overcome Olfactory Thresholds multiple sensory impairments, such as visual, audi- The threshold test consisted of aqueous dilutions of 3 compo- tory, and balance impairments. Olfaction has never nents (eugenol, aldehyde C14, and PEA), the mean detection been investigated in patients with CHARGE syn- thresholds of which (0.5, 0.15, and 7.5 ppm, respectively) were published by the French Association for Normalization in 1989.32 drome, although several arguments suggest that ol- These concentrations defined the level 3 on the difficulty scale of faction dysfunction is crucial in this malformative 9 concentration levels used in the test (Table 1). The lowest con- condition. First, most children with CHARGE syn- centration at which 1 of these odors was detected was termed drome have initial, severe, and long-lasting feeding “detection threshold.” In each test, we asked the child which of 2 disorders that are poorly explained by their swallow- stimuli (an odor or a blank), presented sequentially and in random order, smelled stronger (the forced-choice procedure). The first ing disorders alone. Second, children with CHARGE test began at the third level of difficulty. When a child failed to syndrome may have genital anomalies as a result of detect an odor, the next test was performed at the next higher hypothalamic luteinizing hormone-releasing hor- concentration level. For normal patients, the threshold results are mone deficit.27 Some radiologic and anatomic data expressed in concentration (parts per million). This calculation cannot be used for anosmic patients because they cannot detect have already shown arhinencephaly in CHARGE any odor (infinite threshold). Then, for analyzing the olfactory 23,28 syndrome. Finally, children with CHARGE syn- function in such cases, a test score was calculated for each com- drome often have peripheral orofacial anomalies that ponent (eugenol, aldehyde C14, and PEA). For each child, the may impair olfaction, such as choanal atresia, cleft eugenol score was the value [1/eugenol threshold], the PEA score was the value [1/PEA threshold ϫ 100], and the aldehyde C14 palate, or upper airway anomalies that sometimes score was the value [1/aldehyde C14 threshold]. In anosmic pa- lead to tracheotomy. We wanted to evaluate an ad- tients, the olfaction threshold concentration tends to the infinite; ditional sense (olfaction) in children with other mul- thus, the test score tends to 0 and was estimated as 0. tiple sensorial deficits. Thus, the aims of this study were dual: first, to explore an olfactory test adapted Odor Quality Identification to young children (Ͼ5 years of mental age) or dis- The second part of the test is a qualitative evaluation in which abled children, and, second, to apply this test to a the patient was asked to recognize an odor presented at a concen- series of children with CHARGE syndrome.

TABLE 1. Odorant Concentration as a Function of the 9 Lev- METHODS els of the Test Patients Level PEA, Eugenol, Aldehyde C14, ppm ppm ppm Control Group 1 6.5 0.1 0.05 A control group of 25 healthy children who were aged 6 to 13 2 7 0.3 0.10 years and had no known history of olfactory disturbance were 3 7.5 0.5 0.15 investigated. The group was composed of 14 girls aged 7 to 13 4 8 0.7 0.20 years (mean Ϯ SD: 10.6 Ϯ 2.2) and 11 boys aged 6 to 13 years 5 8.5 1 0.25 (mean Ϯ SD: 9.5 Ϯ 1.9). Three girls had adenoidectomy, 1 boy had 6 10 1.5 0.50 adenoidectomy and tonsillectomy, and 1 girl was born prema- 7202 1 turely without intellectual sequelae. To compare these children’s 8305 2 olfactory test results with those of adults, we used the results of 52 940105 normal adults tested by Bonfils et al.29

e82 OLFACTION DEFICIENCYDownloaded IN from CHARGE www.aappublications.org/news SYNDROME by guest on September 26, 2021 tration corresponding to his or her own olfactory detection thresh- TABLE 2. Comparison Between Healthy Children and Adults. old previously measured. Among the 8 odors proposed for adults, we chose the 6 that are most familiar to children, to be sure that we Children Adults P* were specifically testing olfaction and not the cognitive processes PEA NS of the children: citronella (lemon), cis-3-hexenol (grass), l-carvone Mean (SD) 7.06 (0.46) 7.07 (0.40) (mint), 1-octene-3-ol (mushroom), vanillin (vanilla), and para- Median 7 7.0 cresyl acetate ( dung). Moreover, drawings representing 10 Minimum–maximum 6.5–8.0 6.5–7.5 odors were systematically presented to the child to help his or her Eugenol NS memory and oral expression. The test was scored as the number of Mean (SD) 0.364 (0.21) 0.410 (0.18) olfactory items out of 6 correctly identified. The same investigator Median 0.30 0.50 performed all of the tests. For children with CHARGE, 1 parent Minimum–maximum 0.1–0.7 0.1–0.7 was present during the test, to avoid communication difficulties Aldehyde C14 .03 with the investigator. Mean (SD) 0.148 (0.09) 0.104 (0.05) Median 0.15 0.10 Clinical Investigation in Patients With CHARGE Minimum–maximum 0.05–0.50 0.05–0.20 Syndrome Detection threshold concentrations (in parts per million) are In addition to the olfaction test, a questionnaire was discussed shown. with the parents on their child’s feeding difficulties and ability to * Wilcoxon test. smell and recognize odors in everyday life. This subjective eval- uation of their olfactory capacity was scored at 3 levels: normal olfaction, residual olfaction, and no olfaction. Factors that are detection thresholds (Fig 1). For the qualitative test, likely to decrease olfactory capacities, such as tracheostomy, cho- children tended to have better results than adults anal atresia, and cleft palate, were noted (even when they were no (Fig 2). The 2 odors that are the most familiar in longer present at the study time). The severity of 2 other sense impairments (auditory and visual) was noted. Because the group infancy (vanilla and mint) were recognized by 84% was small, they were scored in 2 grades. For visual ability, “mi- and 88%, respectively, of the healthy children, al- nor” impairment meant no coloboma, or unilateral coloboma, or though they were recognized by only 55% and 51% bilateral coloboma but outside the macula and the papilla; “major of the adults, respectively. Sixty-eight percent of ” impairment meant large, bilateral coloboma, including the mac- ula. For auditory ability, “minor” impairment meant hearing loss healthy children recognized lemon (63% for adults), Ͻ60-dB deficit, and “major” impairment meant Ͼ60 dB. The se- which was better recognized by the older children, verity of the feeding disorders was scored after analysis of the and 56% of all children (42% for adults) recognized medical history, taking into account both the duration of artificial horse dung (they all were city dwellers!). feeding (nasogastric tube or gastrostomy) and the abnormal feed- Overall, we found no difference between boys and ing behavior (poor appetite and delay before achieving normal chewing and swallowing). Feeding disorders were scored in 4 girls, and the younger children had results similar to grades: absent, minor, moderate, and major. The current intellec- older children. Results of children with a history of tual status of the children with CHARGE was evaluated according , , and throat problems were similar to those to their school level, school system, and rehabilitation programs. without such a history. Children of the control group They were scored in 5 classes, using a previous protocol, from class 0 (the best) to class 4 (the worst).33 had a very good understanding of the test whatever their age, showing that it was suitable for young Radiologic Data children and suggesting that it was valid for disabled children, provided that they have reached speech For ethical reasons, MRI was not performed only for this ϳ study. However, we reanalyzed previous MRIs, only 9 of which and intellectual levels of 5 years. pass through thin sections of coronal planes, correctly showing the olfactory tracts and bulbs. and tract anomalies were CHARGE Group scored as follows: normal, moderate, or major hypoplasia or ab- The control group and the group of children with sent. The radiologist was blinded to the results of the olfactory tests. CHARGE did not differ for age or gender. Quantitative Evaluation Statistical Methods To compare the olfactory thresholds of the children of the All children with CHARGE syndrome, except for control group (n ϭ 25) with the series of normal adults previously 1, had severely decreased olfactory thresholds. One investigated (n ϭ 52), we used the nonparametric Wilcoxon test. child has a detection threshold in the normal range To compare children with CHARGE syndrome with the control for aldehyde C14 and PEA (7.5 and 0.15 ppm, respec- group, because our sample was small, we used nonparametric tively) but no detectable threshold for the third com- tests, the Wilcoxon test for continuous data, and Fisher’s exact test for categorical data. Fisher’s exact tests were performed to test the ponent. Nine of the 13 children who were tested by relation among the olfactory deficiency and feeding disorders, Biolfa (70%) had 0 detection scores. Detection scores current intellectual levels, and radiologic results. Concordance differed highly between CHARGE and control chil- between objective olfaction test results and familial subjective dren (Table 3). evaluations was evaluated using the ␬ coefficient. Qualitative Evaluation RESULTS All children with CHARGE syndrome had severe Control Group olfactory discrimination difficulties. Only the patient We first showed that healthy children have olfac- who had correct detection threshold at the quantita- tory capacities similar to a control group of adults, tive evaluation had a qualitative score (4 of 6) in the representative of the general population. Compari- normal range. All of the others had lower scores. son between the children’s and adults’ threshold Seven of the 9 children who had a null detection concentrations for the 3 components (eugenol, alde- threshold could not recognize any odor. These 7 hyde C14, and PEA) showed no difference (Table 2). children can clearly be considered anosmic (7 of 13 ϭ There were no differences between girls’ and boys’ half of the series). The other 2 children (with a null

Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2004-1970 by guest on September 26, 2021 e83 Fig 1. Detection thresholds (in parts per million) for the 3 components in boys and girls of the control group of children.

detection threshold) were able to recognize only 1 considered hyposmic). Of the 6 children who had and 2 odors, respectively. The children who had hyposmia, 2 were severe, 3 were moderate, and 1 residual abilities in the quantitative evaluation could was mild. identify from 2 to 5 odors. The difference in scores To search for associations with the clinical param- between children with CHARGE syndrome and con- eters, because the sample was small, we divided the trol subjects is shown in Fig 3. Comparison of these results of the children with CHARGE syndrome into discrimination tests between children with CHARGE 2 groups: anosmic and hyposmic. We did not find syndrome and control subjects showed highly signif- any statistical relation between olfactory test and icant differences except for horse dung (Table 4). clinical parameters. Comparison between subjective To grade olfactory deficit is difficult because both evaluation (parents’ opinion) and objective results of threshold and discrimination have to be considered the Biolfa test showed a poor concordance (␬ Ͻ 0). and because the olfactory is not a linear The parents’ assessments agreed with the Biolfa re- variable. Nevertheless, results for our group of chil- sults for only 6 of 13 children (patient 14 tested with dren with CHARGE syndrome can be summarized another technique). Of the 6 children with peripheral as follows: half of the children were anosmic (n ϭ 7), risk factors for olfaction deficit, 3 were anosmic and the other half were hyposmic (n ϭ 6 ϩ the child who 3 were hyposmic. This ratio was not different from was previously tested with another test and who was that for the whole group. Surprising, we found no

e84 OLFACTION DEFICIENCYDownloaded IN from CHARGE www.aappublications.org/news SYNDROME by guest on September 26, 2021 Fig 2. Scores of the control group (children) and adults at the discrimination test.

relation between the olfactory deficits and the sever- ence than we know on children’s development and ity of the feeding disorders. We found no association behavior, especially on feeding behavior and maybe between the olfactory deficits and the current intel- on affective and psychological behavior. Olfaction is lectual levels of the children, despite that all of the a primitive sense that is efficient early in life but children of the low intellectual level groups were receives no training and must be forgotten or ne- anosmic. However, children of the high intellectual glected when higher methods of communication, level group could also have severe hyposmia or especially speech, set in. Nevertheless, it might be . We found no relation between the olfactory interesting to look for olfactory dysfunction in chil- deficit and either visual or auditory impairment. dren with disorders that affect appetite or behavior, All 9 MRIs showed anomalies of the rhinenceph- such as nonorganic failure to thrive, for which the alon. The and bulb anomalies varied decrease in ingested food is often not understood, from moderate hypoplasia to complete aplasia. No attention-deficit/hyperactivity disorder, and autism. association could be found between the radiologic Finally, the olfactory system could be impaired in and the functional results. children with congenital or acquired lesions of the forebrain or of the brain midline. Having an efficient test for olfactory evaluation may now change the DISCUSSION pediatrician’s approach to this question and lead to Olfactory evaluation of children is now possible additional studies on the effects of introducing olfac- using the French Biolfa test, which has been adapted tion stimulation in rehabilitation programs for chil- and validated in healthy children. We found no sta- dren with disabilities. tistical difference between the results of the healthy In CHARGE syndrome, olfaction seems to be a children and those of adults, although the qualitative crucial question. In this series, olfactory deficiency part of the test had been simplified for children. The and rhinencephalon radiologic anomalies were al- results of children were better than those of adults ways present. Our sample of MRIs is small, but the for the 2 infantile odors. We found no differences for results are very coherent. If this high frequency of either age or gender. Our results differ from those of radiologic rhinencephalon anomalies is confirmed in Richman et al,15 who tested children aged 3 to 17 larger series, then this radiologic feature could be- years. They showed better olfactory abilities in older come a major criterion for the diagnosis of CHARGE children than in younger and in girls than in boys. These differences may be attributable to method- ologic bias. Because the wider the age range is and TABLE 3. Comparison of the Detection Thresholds of Chil- the more complex the test, the more likely differences dren With CHARGE Syndrome and Control Subjects between the youngest and oldest children are. Even Odor Control CHARGE P* in our simplified procedure, we observed that the (n ϭ 25) (n ϭ 13) less usual odors, such as lemon or dung, were the least well recognized by normal children. This sug- PEA Ͻ.00001 Mean 14.22 1.67 gests that the main problem in child olfaction testing Median 14.29 0 is to determine whether the test evaluates olfaction Minimum–maximum 12.5–15.38 0–13.33 or cognitive function. No girl of our control group Eugenol Ͻ.00001 was pubescent, whereas some of the Richman’s Mean 4.34 0.07 group may have been because they were older than Median 3.33 0 Minimum–maximum 1.43–10 0–0.67 ours. This may also explain the lack of difference Aldehyde C14 Ͻ.00001 between genders in our study. Mean 9.37 0.64 The Biolfa test is an interesting tool for evaluating Median 6.67 0 olfaction in normal children as well as in children Minimum–maximum 2–20 0–6.67 with disabilities. Olfaction certainly has more influ- * Wilcoxon test.

Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2004-1970 by guest on September 26, 2021 e85 Fig 3. Scores of the children with CHARGE syn- drome and control subjects for the discrimination test.

syndrome. Rhinencephalon anomalies have already lar canal anomalies could be useful to confirm or been described in CHARGE syndrome, at autopsy or not CHARGE diagnosis. Moreover, endocrinologic in brain imaging, but these anomalies are not yet anomalies of Kallmann syndrome are useful for un- systematically sought.28 Thin sections of coronal derstanding and investigating genital anomalies of planes, showing olfactory bulbs and tracts, are now patients with CHARGE syndrome. The lack of rela- recommended in brain imaging of patients who are tionship that we found between functional and ra- suspected to have CHARGE syndrome. Rhinenceph- diologic anomalies in CHARGE syndrome is not sur- alon congenital anomalies are rare and are mostly prising, because the same observation has already observed in isolated congenital anosmia, holoprosen- been made in Kallmann neuroradiologic studies.40 cephaly spectrum, Kallmann de Morsier syndrome, Finally, several autosomal genes have been impli- and Johnson-McMillin syndrome. Isolated congeni- cated in Kallmann syndrome and may be candidate tal anosmia is usually described in adults who com- regions when a mutation in the CHD7 gene has been plain of smell disorders late in life, and very few excluded (ϳ40% of the patients with CHARGE).41–43 cases have been published in children.34,35 In this Our results suggest that olfactory deficiency of situation, the patients are otherwise healthy and CHARGE syndrome is attributable not only to cen- the differential diagnosis of CHARGE syndrome is tral anomalies but also to peripheral ones, which not considered. Johnson-McMillin is a rare autoso- worsen olfactory function. We observed children mal dominant syndrome associated with alopecia, with associated choanal atresia and different types of hypogonadotrophic hypogonadism, atresia of the rhinencephalon radiologic anomalies. No child of external auditory canal, tooth defects, cardiac de- this series had bilateral and complete choanal atresia, fects, and mental retardation. It induces embryologic explaining why 2 of the 3 children with choanal anomalies of the ectoderm and neuroectoderm of atresia had residual olfactory abilities. Only bilateral the first and second brachial arches, Rathke’s pouch, choanal atresia has been shown to be responsible for and the diencephalon.36,37 Overlaps between John- anosmia in a small sample, suggesting that choanal son-McMillin and CHARGE syndrome exist be- atresia plays a deleterious role by its reduction of cause CHARGE syndrome also induces anomalies airflow through the olfactory nasal .44 of neuroectoderm development and neural crest Similarly, tracheotomy and cleft palate in children migration. Overlaps between CHARGE and Kall- without central olfactory system anomalies have mann syndromes are interesting for several reasons. been incriminated in olfaction disorders.45,46 Kallmann syndrome, in its typical phenotype, is as- The consequences of olfactory deficiency in chil- sociated with hypogonadotropic hypogonadism and dren with CHARGE syndrome are difficult to quan- olfaction deficit. Some cases of Kallmann syndrome tify because these children have multiple causes ex- have been described with additional features such plaining their disabilities. That is probably why we as hearing loss, choanal atresia, and mental retarda- did not find any association between olfactory defi- tion.38,39 In these situations, searching for semicircu- ciency and most clinical aspects of our series. A more subtle analysis than ours that focuses on the descrip- TABLE 4. Qualitative Olfactory Acuity in Children With tion of feeding behavior and cognitive function CHARGE Syndrome Compared With Control Subjects could provide more information. Hence, it is possible Odor Control CHARGE P that olfactory deficiency participates in the pheno- Ͻ type of the affected children, especially regarding Vanilla 21/25 5/13 .01 their feeding disorders, mother-child attachment, be- Mint 22/25 3/13 .0001 Mushroom 22/25 3/13 .0001 havior disturbance, communication difficulties, and Grass 24/25 3/13 Ͻ.0001 maybe cognitive outcome. When it becomes pos- Lemon 17/25 0/13 Ͻ.0001 sible, evaluation of olfactory abilities of children with Horse dung 14/25 3/13 NS CHARGE syndrome should be included in the inves- Data are number of successes/number of children. tigations that are used to analyze their disabilities.

e86 OLFACTION DEFICIENCYDownloaded IN from CHARGE www.aappublications.org/news SYNDROME by guest on September 26, 2021 Even if olfactory deficiency cannot be measured in by defects in the olfactory system in genetic arhinencephaly mice. Biol children who have CHARGE syndrome and whose Neonate. 2000;78:293–299 12. Gordon Pomares C, Schirrer J, Abadie V. Analysis of the olfactory mental age and speech level are below 5 years, ra- capacity of healthy children before language acquisition. J Dev Behav diologic data could suggest functional anomalies and Pediatr. 2002;23:1–5 lead to various suitable actions. First, olfactory defi- 13. Richman RA, Post EM, Sheehe PR, Wright HN. Olfactory performance ciency has to be taken into account in the under- during childhood. I. Development of an odorant identification test for chil- standing of the abnormal feeding behavior of most dren. J Pediatr. 1992;121:908–911 children with CHARGE syndrome. For those who 14. Richman RA, Wallace K, Sheehe PR. Assessment of an abbreviated odorant identification task for children: a rapid screening device for have major difficulties in achieving normal feeding schools and clinics. Acta Paediatr. 1995;84:434–437 behavior, especially difficulties in swallowing solids 15. Richman RA, Sheehe PR, Wallace K, Hyde JM, Coplan J. Olfactory even after improvement of their organic swallowing performance during childhood II. Developing a discrimination task for disorders, it is likely that food texture plays an im- children. J Pediatr. 1995;127:421–426 portant role. Healthy children recognize and appre- 16. Doty RL. Olfaction. Annu Rev Psychol. 2001;52:423–452 ciate food by its visual aspect, , texture, and 17. Brand G, Millot JL. Sex differences in human olfaction: between evi- dence and enigma. Q J Exp Psychol B. 2001;54:259–270 smell. If vision and olfaction are impaired, then chil- 18. Doty RL, Shaman P, Applebaum SL, Giberson R, Siksorski L, Rosenberg dren surely give more value to taste and texture. L. Smell identification ability: changes with age. Science. 1984;226: Their preference for salty or spicy becomes 1441–1443 understandable, as well as their preference for 19. Schiffman SS. Taste and smell in disease. N Engl J Med. 1983;308: smooth textures. Moreover, children with olfaction 1275–1279 dysfunction may benefit from rehabilitation pro- 20. Mattes RD, Cowart BJ, Schiavo MA, Arnold C, et al. Dietary evaluation of patients with smell and/or taste disorders. Am J Clin Nutr. 1990;51: grams. Sense of smell does not pass exclusively via 233–240 olfactory bulbs, tracts, and nerve. Specific odors, 21. Parhar J, Pfaff D, Schwanzel-Fukuda M. Genes and behavior as studied such as lemon and vinegar, pass through the sensory through gonadotropin-releasing hormone (GnRH) neurons: compara- branch of the fifth cranial nerve. In CHARGE syn- tive and functional aspects. 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Int J Pediatr Otorhinolaryngol. 1995;33:23–42 programs that are essential for children with 26. Tellier AL, Cormier-Daire V, Abadie V, et al. CHARGE syndrome: CHARGE syndrome. report of 47 cases and review. Am J Med Genet. 1998;76:402–409 27. Wheeler PG, Quigley CA, Sadeghi-Nejad A, Weaver D. Hypogonadism and CHARGE association. Am J Med Genet. 2000;94:228–231 28. Lin AE, Siebert JR, Graham JM. Central nervous system malformations ACKNOWLEDGMENTS in the CHARGE association. Am J Med Genet. 1990;37:304–310 We thank Professor Lyonnet and Dr Amiel from the genetics 29. Bonfils P, Faulcon P, Avan P. Screening of olfactory function using the department for advice; all the patients, children, and parents, Biolfa olfactory test: investigations in patients with . Acta control and CHARGE, who participated in this study; and Alan Otolaryngol. 2004;124:1–9 Strickland for help in preparing the manuscript. 30. Blake KD, Davenport SLH, Hall BD, et al. 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Downloaded from www.aappublications.org/news by guest on September 26, 2021 Olfactory Evaluation in Children: Application to the CHARGE Syndrome Christel Chalouhi, Patrick Faulcon, Christine Le Bihan, Lucie Hertz-Pannier, Pierre Bonfils and Véronique Abadie Pediatrics 2005;116;e81 DOI: 10.1542/peds.2004-1970 originally published online June 15, 2005;

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