The Clinical Dilemma of Autism Spectrum Disorder Diagnosis in a Child with 9p Deletion

Abstract

We reported on a 3-year-old girl child patient with the presence of trigonocephaly, broad nasal bridge, flattened occiput, and midface hypoplasia. Formal assessment of her development profile demonstrated expressive and receptive language delays, fine and gross motor delays, and no imaginative or symbolic representative play. Investigation of the etiology of her developmental delays revealed a genetic diagnosis of a 9p24 deletion by chromosomal microarray analysis. The possibility of an additional co-occurring disorder of autism spectrum disorder (ASD) was also raised by a referring clinician. This case report highlighted the clinical dilemma of diagnosing ASD in those with existing genetic syndromes.

Introduction

Patients with 9p deletion syndrome were first described in 1973, and the deletion is de novo in approximately half of the cases. ¹ Dysmorphic facial features are common including: trigonocephaly, midface hypoplasia, upgoing palpebral fissures, and a long philtrum. Deletions of 9p24 have been previously described to be associated with gonadal dysgenesis. ² To our knowledge, there is at least one related case of a child with a 9p24 deletion who exhibited behavioral and social-communication problems consistent with autism spectrum disorder (ASD). ¹ In this article, we present our case to illustrate the dilemma clinicians face differentiating the developmental trajectory of ASD versus non-ASD in a child with a 9p deletion.

Case Presentation

A 3-year-old girl, born at term to nonconsanguineous parents, was seen in a child developmental clinic to investigate her developmental delays. Her birth and neonatal course were unremarkable; however, by six months of age she was not meeting her gross motor milestones of rolling and sitting. The family history was noncontributory. Physical examination revealed the presence of trigonocephaly, flattened occiput, upgoing palpebral fissures, a broad nasal bridge, and midface hypoplasia. The neurological examination showed evidence of axial hypotonia. A visual assessment revealed equal and reactive pupils, normal visual fields, fundoscopy, and visual acuity. The patient was subsequently examined by an ophthalmologist with a normal evaluation. Developmental information noted severe expressive (second percentile) and receptive language delays (first percentile) measured using the Receptive-Expressive Emergent Language Test-Third Edition (REEL-3), a standardized measure relying on clinical observation and parental report. Detailed assessments from a physical therapist and occupational therapist were also completed using the Peabody Developmental Motor Scales-Second Edition (PDMS-2), a standardized assessment which targets balance skills, locomotion skills, and object manipulation, showing moderate developmental delays in both of these domains (Nineth percentile for gross motor tasks and fifth percentile for fine motor tasks). A detailed history based on the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) was completed along with an Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) Module 1. This module was selected based on language ability and chronological age. During the ADOS-2, single words were utilized, and the vocalizations were directed to caregivers. Intonation was appropriately varying, and there was no evidence of stereotyped language. Eye contact was used to initiate interactions, although was not consistently coordinated with gestures or other nonverbal communication. There was no imaginative or symbolic representative play, although she did show shared enjoyment in simple games such as peek-a-boo and used cause and effect toys. Similar developmental concerns were reflected on the DSM-5 based history and no unusual sensory interests or stereotypic behaviors were reported. Chromosomal microarray analysis was used to investigate the etiology of her developmental delays and a de novo interstitial deletion near the terminus of chromosome 9 [9p24.3p24.1 (204,090–7, 149, 842)] was detected.

Discussion

ASD As a Co-occurring Diagnosis in a Genetic Syndrome

The diagnosis of ASD in those with existing genetic syndromes is a challenging clinical dilemma. ³ The specific criteria developed within the DSM-5, including deficits in social communication and interaction, lack of nonverbal communication for social interaction, and restricted, repetitive patterns of behavior or interests (RRB), are difficult to differentiate from developmental delays in young children who are at a developmental age where social communication skills are not yet significantly developed. ³ Current clinical diagnostic tools such as ADOS, a semi-structured play-based tool, are not as reliable when the developmental age of a child is less than 18 months. ⁴ Additional limitations of the ADOS are found in the validity of scores for children with significant language delays and deficits in verbal communication. ⁵

In the context of this case presentation, the current developmental profile included: a recently developed wide-based walking pattern, scribbling utilizing a crayon in a fisted grip, an expressive vocabulary of approximately 15 words, and clear receptive response to name and simple one-step commands. Her social skills included initiation of joint attention, shared enjoyment in bubble play, and other physical interactions with caregivers, and engagement in mimicking games. Overall, her global developmental age was estimated at 15 months based on these skills as well as the multidisciplinary assessments conducted. Within the DSM-5, Criterion E for ASD requires that the differences in social communication ability and RRB “are not better explained by an intellectual disability or global developmental delay.” ⁶ Consideration of the overall platform of developmental skills may prove to be useful in the operationalization of this criterion since uniform delays in all developmental domains may point toward behavioral symptoms being attributed to low developmental age. ³ Delayed motor skills may also limit abilities to gesture, initiate social overtures, and interact in reciprocal play activities. The ADOS-2 Module 1 was conducted to obtain some further observation of specific behaviors that may be consistent with an ASD diagnosis; however, observed skills such as directing vocalizations toward caregivers, joint attention, making simple conventional gestures, and a lack of stereotypic mannerisms were in concordance with her developmental age. The presence of eye contact, directed facial expressions, gestures, sharing enjoyment during play, and engagement in reciprocal back and forth play were some of the most specific symptoms to differentiate ASD from other developmental disorders. ⁷

In an ideal situation, clinicians diagnosing ASD should have experience or knowledge of a typical developmental trajectory in patients with described genetic syndromes. This is not always possible for rarer syndromes such as 9p deletion or other de novo deletions with limited descriptions available. If the possibility exists to observe interactions amongst peers in a playroom setting, this helps provide additional information on spontaneous social play and interaction. When taking a developmental history, it is important to note differences between symptoms that are reported and those that are observed. These differences may provide useful probes for further questioning or observations. Specifically, observing and probing for shared affect, initiation, and response to joint attention, and response to the emotions of others, as well as obtaining information related to RRBs may provide specific information which would be useful in formulating an opinion regarding an ASD diagnosis. Evaluation for sensory impairments should be part of all assessments for ASD, especially in those with incompletely described chromosomal differences. Disorders of visual development may result in lack of spatial awareness, decreased ability to recognize facial expressions, and lack of ability to coordinate eye contact with vocalizations mimicking ASD symptoms. Further complicating the overlap of visual impairments with ASD is that children with visual impairments can present with stereotypic “blindisms” such as rubbing or pressing of the eyes. ⁸ An awareness of these features is essential for clinicians conducting assessments for neurodevelopmental disorders, as semi-structured observational assessments may need adaptation, and referrals for specialist ophthalmologic or other sensory evaluation may be required. ⁸

Conclusion

In rare genetic disorders, such as 9p deletion syndrome, clinicians often lack knowledge of longitudinal developmental trajectories which creates a challenge in diagnosing ASD as a co-occurring disorder. Our case presents a 9p24 deletion in a 3-year-old child who was screened for co-occurring ASD. Upon evaluation, her observed skills were fitting with her developmental age, and did not exceed the impairment expected from her developmental differences. These findings made the diagnosis of ASD less likely and her profile was in keeping with global developmental delay. Although the child did not receive a diagnosis of ASD, continued monitoring of her developmental trajectory in terms of intellectual functioning and social-communicative behavior will be maintained. Longitudinal follow-up is especially prudent given that in a study by Davidovitch et al, ⁹ it was reported that several patients were diagnosed with ASD after age 6 despite comprehensive early developmental evaluations being negative for ASD. Despite early evaluation, the diagnosis of ASD is often overshadowed by developmental language disorders and motor difficulties in children with significant developmental delays or genetic abnormalities. ⁹ As children acquire further cognitive, language, and motor skills, the social developmental trajectory may become clearer. ³ In children with chromosomal differences, ongoing evaluation of developmental status should be completed to ensure that appropriate specialized educational support programs and behavioral interventions are offered to support the child's development.

Clinical Pearls

1. Differences between observed developmental skills and reported skills provide an opportunity to probe further on developmental history taking.

2. Diagnosis of ASD as a co-occurring diagnosis relies on the clinician familiarizing themselves with typical developmental trajectories of genetic syndromes. As this may not always be possible, consideration of longitudinal follow-up before excluding or confirming a diagnosis is recommended.

3. Structured clinical tools, such as the ADOS-2, must be interpreted in the context of clinical observations and developmental status especially in children under 18-months developmental age or in children with visual/hearing disturbances.