Clinical elements
This case report describes a 44-month-old (3 years and 8 months) Caucasian girl who was the second child of healthy and non-consanguineous parents. The family history was negative. She was born at term after an uncomplicated pregnancy and delivery, and the birth parameters were normal.
At 6 months of age, her parents noted behavioral anomalies, including avoidance of gaze, absence of turning when called by her name, and retreating into repetitive, self-centered games. In addition, she had delayed gross motor development. She began sitting at 12 months and walking at 19 months of age. Her medical history was otherwise unremarkable except for recurrent episodes of bronchiolitis. The day care center staff noticed socialization difficulties and the appearance of motor mannerisms with rocking back and forth. Thus, ASD was suspected. At 2 years and 8 months of age, she was referred to a referral center for developmental problems because the pediatrician suspected Angelman syndrome. A clinical examination showed facial dysmorphism with coarse features, full cheeks, anteverted nares, and a large mouth. Her height and weight were in the normal range, with a head circumference (HC) at −1 standard deviation (SD). A neurological examination was normal.
When she was 3 years and 8 months old, a multidisciplinary diagnostic evaluation was conducted at a referral center (PACA Autism Resource Center) using standardized tools. A global psychomotor delay was found, with a developmental age of 23 months in fine motor skills and 27 months in overall motor skills. In addition, subtle global hypotonia was also noted. An electroencephalogram (EEG) and cerebral magnetic resonance imaging (MRI) with spectroscopy showed no anomalies. An ear, nose, and throat (ENT) workup revealed physiological audition.
The diagnosis was performed according to the DSM-5 criteria with the help of the following multidisciplinary workups and standardized tools (refer to Table
1): the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) [
22]; the Autism Diagnostic Interview-Revised (ADI-R) [
23]; and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) [
24].
Table 1
The autism scales
ADOS-2 in French [ 22] (module 1): | |
• Social affect, 17 (communication, 4; reciprocal social interaction, 13) | |
• Restricted and repetitive behaviors, 5 | |
• Overall total, 22 (ASD threshold, 11; autism threshold, 16) | |
• ADOS-2 comparison score, 7 (moderate) | |
| |
• Reciprocal social interactions, 18 (autism threshold, 10) | |
• Nonverbal communication, 10 (threshold, 7) | |
• Repetitive behaviors and stereotyped patterns, 7 (threshold, 3) | |
• Developmental anomalies at or before 36 months, 5 (threshold, 1) | |
Vineland-II/VABS-II [ 24] standard scores: | |
• Communication, 32 | |
• Daily life, 38 | |
• Socialization, 42 | |
• Motor skills, 50 | |
• Composite score of adaptive behavior, 26 | |
The results of ADOS-2 module 1 led to the diagnosis of autism with a moderate level of symptomatology. She was nonverbal and was tested with module 1, which is the specific module for preverbal children. During the administration of the ADOS-2, we noticed that gesturing was poor and response to her name was lacking. She had no spontaneous initiation of joint attention. However, she was able to have directed vocalizations and presented a large variety of directed facial expressions. Her eye contact was of acceptable quality. There was a shared pleasure observed in the interactions, and she presented directed smiles.
The results of the ADI-R showed scores greater than the cut-off for autism in the three domains, with developmental anomalies noted before 36 months. It should be noted that the ADI-R was performed even though she presented a global level of development lower than 24 months, and the results contributed to the diagnostic assessment.
The VABS-II evaluates adaptive behavior. The test result showed a low composite score of adaptive behavior (standard score 26). Adaptation was low in all domains, namely, motor, socialization, daily life, and communication.
Her communication competencies were evaluated using the Early Social Communication Scales (ESCS), which allows evaluation of development in three domains of early communication [
25]. Her level of SI was similar to that of an 18-month-old child.
Her level of conjoined attention (CA) was 13 months. Her regulation of behavior was equivalent to 12 months. Overall, this child presented a social communication development level of 14 months.
Her level of development was evaluated using the Psychoeducational Profile, Third Edition (PEP-3) [
26]. The results revealed overall delay. Her verbal and preverbal cognition levels were at 16 months.
Her receptive and expressive language level corresponded to that of a child younger than 12 months of age. Her developmental age was 19 months in global motor skills. She does not present any clear lateralization and has difficulties with static equilibrium. Her developmental age was 20 months for fine motor skills. She cannot coordinate her two hands and has difficulties grasping objects with two fingers. However, she spontaneously engages in scribbling. Her oculomotor imitation was similar to that of a 22-month-old child. She can engage in imitation through the manipulation of objects and actions. However, her imitation of gestures and sounds is weaker.
The overall result of the tests indicated ASD associated with developmental delays. Her strengths included imitation and interactions with other people through gaze and smiling.
Genetic analyses
Genetic analyses were conducted at the referral center for developmental problems. The pediatrician initially suspected Angelman syndrome due to the developmental delay and frequent smiling. However, analysis of chromosome 15 methylation invalidated this hypothesis and excluded 15q11.2 microdeletion or uniparental chromosome 15 disomy.
The aCGH was performed using a 4 × 180 K whole-genome oligonucleotide microarray following the manufacturer’s protocol (Agilent Technologies, Santa Clara, CA, USA). The results were interpreted with Cytogenomics software v3.0.1.1 (ADM2 method). A CNV was considered if at least three contiguous oligonucleotides presented an abnormal mean log ratio (> 0.25 or ≤ 0.25). This analysis identified a 1.7 Mb interstitial
de novo microdeletion in chromosomal region 2q13 (on the long arm of chromosome 2) between proximal chromosomal position 111,399,243 and distal position 113,102,535 (hg19/GRCh37). Using the International System for Human Cytogenetic Nomenclature 2016, the deleted region identified by the microarray analysis was designated as follows: arr[GRCh37] 2q13(111399243_113102535)× 1 dn. The region encompasses the following nine genes:
BUB1,
ACOXL,
BCL2L11,
MERTK,
FBLN7,
TMEM87B,
ANAPC1,
ZC3H8, and
ZC3H6. Fluorescent
in situ hybridization (FISH) analysis with probes RP11-438 K19 confirmed this rearrangement. Previous studies reported that recurrent CNVs of this chromosomal region are implicated in the 2q13 microdeletion/microduplication syndrome [
12,
13].