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ARTICLE |
a National Institute of Health and Medical Research and Department of Genetics, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
b National Institute of Health and Medical Research, Mixed Unit of Research 0205, Atomic Energy Commission, Orsay, France
c National Institute of Health and Medical Research and Department of Psychiatry, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
d Paris 11 University, Paris 5 University, Mixed Unit of Research-S0669, Paris 10 University, Nanterre and Department of Obstetrics and Gynaecology, Assistance Publique-Hôpitaux de Paris, Paris, France
e National Center for Scientific Research, Mixed Unit of Research 7114, Paris, France
f Department of Genetics, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. We assessed neuromotor, sensory, language, communication, and social development and performed cerebral MRI and study of regional cerebral blood flow measured by positron emission tomography in 8 children carrying the 22q13.3 deletion.
RESULTS. Despite variability in expression and severity, the children shared a common developmental profile characterized by hypotonia, sleep disorders, and poor response to their environment in early infancy; expressive language deficit contrasting with emergence of social reciprocity from ages 
3 to 5 years; sensory processing dysfunction; and neuromotor disorders. Brain MRI findings were normal or showed a thin or morphologically atypical corpus callosum. Positron emission tomography study detected a localized dysfunction of the left temporal polar lobe and amygdala hypoperfusion.
CONCLUSIONS. The developmental course of the 22q13.3 deletion syndrome belongs to pervasive developmental disorders but is distinct from autism. An improved description of the natural history of this syndrome should help in recognizing this largely underdiagnosed condition.
Key Words: 22q13.3 deletion • pervasive developmental disorders • autism • regression • language deficit • neuromotor disturbances • sensory abnormalities • thin corpus callosum
Abbreviations: ADI-R—Autism Diagnostic Interview-Revised • DSM-IV—Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition • rCBF—cerebral blood flow • PET—positron emission tomography
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Yet, the 22q13.3 deletion remains largely underdiagnosed because of the lack of clinical specificity. Here we reported on the neuromotor, sensory, language, communication, and social development, as well as brain imaging, of 8 children carrying a 22q13.3 deletion. This study was aimed at improving the description of the neurobehavioral phenotype and brain abnormalities of this microdeletional syndrome.
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METHODS |
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On the basis of microsatellite genotyping (D22S276, D22S274, D22S1169, ALO22327, and Z82189), fluorescence in situ hybridization analysis,19 and dosage analysis of SHANK3 using multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, Netherlands), the size of the 22q13.3 deletions was found to span from 150 kb to >9 megabases. Four of the children had a deletion breakpoint within the intron 8 of SHANK3 gene. The 4 others had a deletion that extended beyond SHANK3 and involved other more centromeric genes (Table 1).
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Clinical Evaluation
Clinical evaluation included various approaches to allow quantitative and qualitative evaluation, namely, standardized or semistandardized assessments (parent's interview and test battery), careful observation and interactions with patients, and nondirective in-depth interviews with parents according to the single-case method. A detailed history of the pregnancy, birth, neuromotor and language development, behavior, and neurologic symptoms was obtained from parents. A direct observation of the children was made, and various available records were collected (language and physical therapy, school reports, home movies, videos, and medical files).
We used the items of the Autism Diagnostic Interview-Revised20 (ADI-R), a standardized semistructured interview with the child's parents, to obtain detailed descriptions of behavioral symptoms related to reciprocal social interaction, play, communication, and repetitive behaviors and stereotyped patterns. This instrument could diagnose autism, according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),21 when the child met the cutoff criteria for each of the 3 areas and when the developmental deviance started before 3 years old. However, in our study, it was more useful for description than for diagnosis.
Motor function and praxis were evaluated through quantitative assessment using standardized neuropsychomotor test batteries,22–25 which measure postural-motor, locomotor, and eye-hand grip coordination; spatial and temporal basic notions; posturomotor and locomotion acquisitions (static and dynamic balance); visuomanual prehension coordination; distal gnosopraxia; finger and tactile gnosis; manual and oral praxis; bimanual and visuomotor coordination; ocular pursuit; and visual motor integration.
We used developmental quotients from the Psychoeducational Profile-Revised26 that assess development of children functioning at levels between 6 months and 7 years. The instrument produces developmental scores in 7 areas (imitation, fine motor, gross motor, eye-hand integration, perception, cognitive performance, and cognitive verbal), which can be used to estimate age-equivalent scores.27 When possible, general intellectual level was assessed by using the Wechsler Intelligence Scale for Children, Third Edition.28
Brain Imaging Protocol and Statistical Analyses
Cerebral blood flow (rCBF) was measured by positron emission tomography (PET) (Siemens ECAT Exact HR + 962 [Siemens, Knoxville, TN]) after intravenous injection of H215O. Data were collected during a period of 80 seconds. PET studies were performed during sleep induced by premedication with 4 mg/kg of sodium pentobarbital to obtain complete motionlessness. A previous study showed that sedation does not change either the global or the local distribution of rCBF.29 A high-resolution brain MRI (1.5-T Sigma system [General Electric, Milwaukee, WI]) was also obtained for all of the children.
The rCBF images were analyzed using the statistical parametric mapping software (SPM 96 [Wellcome Department of Cognitive Neurology, London, United Kingdom]). This software was used for image realignment, transformation into standard stereotactic anatomic Talairach space, smoothing, and statistical analysis.30 The 8 children carrying he 22q13.3 deletion were compared with 13 children with idiopathic mental retardation. Comparisons between groups were performed with the t statistic, further transformed into the z statistic (statistical parametric mapping [z]). The resulting z maps were thresholded at a P < .001. Clusters with spatial extent probability of <5% are reported (corrected for multiple comparisons).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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4 to 5 months, sleep problems (hypersomnia or insomnia), excessive crying, unusual fussiness, unresponsive to environment, lack of attention to voice, overt sensitiveness to touch, and visual scrutiny at 8 to 9 months. Some of these symptoms were considered as warning signs of autism in all of the subjects but 1 (patient 6).
Psychomotor Development
The ability to sit unaided was acquired between 9 and 13 months (mean: 10 months), and independent walking between 16 and 36 months (mean: 24 months). Postural or tonus abnormalities were noted, including the absence of anticipation movement when falling, arms in the candlestick position during walking, very persistent floor sitting with the legs in a "W" position, walking on the knees, and persistent dribbling and/or hypersalivation. Daytime bladder control was acquired by 5 of 8 patients between the age of 4 and 6 years and night bladder control by only 2 of 8 between the age of 4 and 8 years.
Language, Communication, and Social Skill Development
Babbling was absent or very poor in all but 1 (patient 1). Between 1 and 2 years, the children did not seem to understand speech or failed to orient in response to their name. Half of the patients suffered recurrent otitis media. From age 3 years, the children displayed no apparent desire to be alone: direct gaze was clearly present, although unstable. They used their eyes to communicate, then made vague gestures as pointing or taking the parent's chin to draw attention. Nevertheless, it was sometimes difficult to understand the child's intents because of the lack of emotion or inappropriate facial expression (grimace). Their gestures were also rather rough or clumsy (eg, squeezing the neck of other children). Sometimes, children enjoyed overstepping relational limits and dominating the situation, and their behaviors were regarded as provocative or even aggressive (eg, pulling the hair of their mother or sibling while smiling).
For those who acquired verbal language, the first words appeared between 2 and 6 years and the first sentences from age 5 years. In 2 of 8 subjects, the first words appeared normally around 15 to 18 months, and then a total loss of speech occurred for many months, followed by recovery of language. The first utterances were long limited to guttural or inarticulate sounds or monosyllabic words. They had difficulty using orofacial muscles, and vocalic modulations were recognizable, but speech could be difficult to understand without the context. Utterances tended to be repetitive because of their limited language but were consistently appropriate to the situation. The patient's verbal comprehension was also severely impaired. When the message was unclear, they occasionally repeated what the interlocutor had just said, as is the case in young children learning to speak. Overall this indicated the will to communicate.
Language development was slow, and included episodes of regression. The outcome ranged from total absence of language to functional language with minor pronunciation difficulties. None of the children of our cohort showed signs of atypical language development: delayed echolalia, pronoun reversal, or neologism.
Behavior and Activities
Behavior changed rapidly during the first years. During their second year, the children showed various behavioral problems, including hyperactivity, short attention span, and rapid shifts from 1 uncompleted activity to another. Incessant restlessness associated with clumsiness led them to bump into objects or people and to endanger themselves because they failed to anticipate consequences of their movements. They showed resistance to change and had many habits (eg, taking the same path in the park), exaggerated reaction to minor changes in their environment, and troubles accepting transitions from 1 activity to another (eg, they routinely had to take their bag to accept to go out). They displayed repetitive activities, such as switching the light on/off, turning the tap on/off, or locking/unlocking the door. Two had unusual jigsaw puzzle skills (they rotated pieces and attempted to attach them at different angles). None of them exhibited complex motor mannerisms (finger wiggling or finger flicking).
Sensory Processing Abnormalities
All of the children had sensory processing abnormalities. They displayed unusual responses to the environment and sensory stimuli: lack of responsiveness to verbal or pain stimuli but, paradoxically, exaggerated reaction to tactile stimuli or overarousal to the environment (eg, panic at sudden noises, telephone, or rapid movements in the visual field). They tended to seek stimulation: oral (paper mouthing or licking glasses or iron objects), olfactory (smelling objects or people), or proprioceptive (lying on the floor or walking on the knees). All of these behaviors tended to decrease with developmental age. There were neither atypical visual exploratory behaviors (eg, lateral glance orientated toward parts of objects or strange fascination with moving stimuli) nor auditory hypersensitivities.
Neurologic Features
All of the children suffered from impaired fine and gross motor skills, including deficits in the maintenance of balance. Basic spatial and temporal notions, posturomotor acquisitions, and locomotion acquisitions (static and dynamic balance) were consistently impaired, as were visual-manual prehension coordination, distal gnosopraxia, finger and tactile gnosis, digital praxis, visual and bimanual motor integration, visual-motor coordination, and ocular pursuit (–2 standard deviation). Synkineses were also quantitatively too large for chronological age in all of the children (–2 standard deviation).
As far as neuromotor assessment is concerned, the patients fell into 2 groups. A first group (patients 1, 2, and 3) showed a deficit of orofacial praxis, abnormal postural reactions, distal pyramidal signs ("phasic stretch"), and impaired voluntary motor control. The second group (patients 6, 7, and 8) had hypotonia of lower limbs and orthopedic disorders.
Episodes of neuromotor disorders were reported and included acute episodes of hypotonia without altered consciousness, which regressed into 5 or 6 hours, tongue movements including rolling-up and rotation inside the mouth, eyelid flutter, vagal syncope, and standing still at attention for short periods. No one had clinical epilepsy. However, because of severe language impairment or periods of regression, many of them underwent electroencephalograms. One of them had electroencephalogram abnormalities with bifrontal spikes and slow spike waves increased by sleep. Sleep problems of all types were very frequent (6 of 8), ranging from excessive sleep during the first 18 months of life to fragmented nocturnal sleep because of frequent awakening.
Cognitive Assessment
Cognitive skills were investigated using Psychoeducational Profile-Revised in 7 of 8 patients and revealed mild-to-severe delay in all of the developmental milestones. The pattern was largely identical in all of the subjects and included a severe deficit of imitation and verbal cognition and a less severe delay of gross motor skills (Table 1).
At age 8 years and 8 months, patient 1 had a full-scale IQ of 51 on the Wechsler Intelligence Scale for Children, Third Edition, with a verbal IQ score of 46 and a performance IQ score of 60 with interscale and intrascale homogeneity and a peak of fitness in the subtest of object assembly (11/20).
Pervasive Developmental Disorders
All of the children had high ADI-R scores in the domain of reciprocal social interaction, play, and communication, but none scored in the area of repetitive behaviors and stereotyped patterns and, therefore, did not fulfill DSM-IV criteria for autistic disorder (Table 1). Significant ADI-R items included articulation trouble, paucity of mimicry, absence of offer to share, failure to develop peer relationships, unusual sensory behaviors, resistance to change personal routines, and response to trivial changes in the environment.
None of the children scored significantly for the following ADI-R items: delayed echolalia, verbal rituals, unusual attachments, hand and finger mannerisms, unusual preoccupations, head banging, or self-mutilation. Detailed analysis of the ADI-R items showed that significant ADI-R items resulted mainly from behaviors related to developmental delay of reciprocal social interactions and communication (eg, failure to develop peer relationships) and relatively few resulted from the deviant behaviors related to social interactions or communication (delayed echolalia) or restricted and repetitive behaviors (eg, interest in nonfunctional elements of materials).
Brain Imaging Abnormalities
Brain MRI findings were normal in 3 of 8 patients with a deletion size <270 kb. In the other 5 of 8 patients, brain abnormalities were diffuse (Table 1). Corpus callosum was either thin (4 of 5) or morphologically atypical (1 of 5). PET study revealed a localized dysfunction of the left temporal polar lobe and amygdala hypoperfusion in the group of 8 children carrying 22q13.3 deletion compared with the group of 13 mentally retarded children (Table 2 and Fig 1).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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3 to 5 years; (3) impairments in communication: although there was development of nonverbal communication (looking or pointing), their intents were frequently difficult to understand because of the lack of emotion or inappropriate facial expression in particular; (4) sensory processing dysfunction; disturbing touch, oral, pain, smell, and proprioception rather than visual and auditory perceptions; and improving with age; (5) neuromotor disorders consisting of impaired fine and gross motor control and praxis associated with unusual features, such as inability to anticipate movements when falling, walking on the knees, acute attacks of hypotonia, eyelid flutter, tongue movements (rolling-up and rotation), frequent vasovagal syncopes, and episodes of fixed facial expression for several minutes; and (6) hyperactivity, resistance to change, and nondeviant repetitive activities (not associated with oscillating of the extremities or intense visual fixation) related to developmental delay. Several features described here have been reported previously in the literature, namely, expressionless face,6 "to stand still for several minutes with a fixed facial expression, without saying a word, in an almost catatonic state,"12 tactile defensiveness,6 absence of hypersensitivity to noise,16 and high pain threshold.7,12 Autism or autistic behavior were also reported in several observations of patients with the 22q13.3 deletion syndrome.4,5,7,8,11,13–16
In our cohort, autism was suspected in 7 of 8 patients in their first years of life. However, clinical evaluation using DSM-IV criteria did not confirm autism and showed that the relationship pattern, development of language, and nature of repetitive behaviors were distinct from autism.
For example, nondescribed "motor stereotypies" have been reported in 2 patients with the 22q13.3 deletion.8,16 Particular stereotypies (nature, involving or not an object, context, etc) could be suggestive of syndromes. Hand-washing stereotypies with loss of purposeful hand movements have been reported in Rett syndrome, spasmodic upper body squeeze in Smith-Magenis syndrome,31 rolling movements of the head in Pitt-Hopkins syndrome,32 or atypical visual exploratory behavior in autism.33 In our series, we observed repetitive activities (eg, such as turning the pages of a book or putting objects in a line), stereotyped behaviors at the time of transitions from 1 activity to another, and hand flapping when happy in early infancy. None of these behaviors were characteristic of autism.34
In addition, several features often associated with autism were never observed in any of our children, and their absence could help us to recognize this deletion syndrome. The consistently absent features in this syndrome included atypical language development, unusual attachments or preoccupations, atypical visual exploratory behavior, seeking out vestibular stimulation (whirling themselves around and around), head banging or self-mutilation, auditory hypersensitivity, and complex motor mannerisms. Finally, these children could have a combination of paradoxical features: they could have both pain insensitivity and tactile hypersensitivity, hyporeactivity to the environment in early infancy and overarousal later, episodes of fixed facial expression and hyperactivity, hypotonia and hypertonic movements, excessive sleepiness, and fragmented nocturnal sleep.
It is interesting to note that scores in the Vineland Adaptation Behavior Scale35 have been reported in 2 patients5,15,36: their socialization coefficient and their daily living skills score were much better than their communication score, which is not typical of autism. Moreover, a severe regression during later teenage years (with a death in 1 case), which is also an uncommon feature in pervasive developmental disorders, was noted in 3 patients.8,16
Because of the small size and the cytogenetic heterogeneity of the 22q13.3 deletion of our patients, this above-described developmental course needs to be confirmed in other patients carrying a 22q13.3 deletion. All of the children of our cohort had simple deletions, and the neurobehavioral profile may be different in case of 22qter deletions deriving from balanced translocations with duplication of other chromosomal material.
Evaluations based on test batteries, checklists of symptoms, questionnaires, and observational studies are recommended to delineate specific phenotypes.37 We think that these approaches must be associated with nondirective interviews with parents and therapists to reveal the nature of symptoms, as well as additional symptoms that could be pertinent for diagnosis.
Regarding brain imaging, MRI abnormalities were only found in our patients with a large deletion, which is consistent with previous studies.2,3,6,11,14 No specific abnormality, but a thin or morphologically atypical corpus callosum, was observed in 5 subjects of our cohort and in 2 case subjects in the literature.11,14
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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We express our gratitude to the patients and their families. We thank Dr Geneviève Haag for discussion about patients.
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FOOTNOTES |
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Address correspondence to Anne Philippe, MD, PhD, INSERM U781, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France. E-mail: anne.philippe{at}necker.fr
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject The 22q13.3 deletional syndrome remains underdiagnosed, because affected children frequently do not present with distinctive physical features, and this cryptic deletion is often overlooked by a high-resolution karyotype.
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| What This Study Adds Our study improves the description of the neurobehavioral phenotype of the 22q13.3 deletion. It is particularly important to perform appropriate genetic tests (multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and SHANK3 gene sequencing) to diagnose this microdeletional syndrome.
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