Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 6 Issue: 1

Neurocognitive Functioning in a Young Female with Weaver Syndrome

Wise JM*, Cooper A, Crenshaw ML and Katzenstein JM
Johns Hopkins All Children’s Hospital, St. Petersburg, Florida
Corresponding author : Jillian M Wise, PhD
Johns Hopkins All Children’s Hospital, Child Development and Rehabilitation Center, 880 Sixth Street South, Suite 420, Saint Petersburg, Florida 33701, USA
Tel:
727-767-7445
E-mail: [email protected]
Received: December 10, 2016 Accepted: December 31, 2016 Published: January 04, 2017
Citation: Wise JM, Cooper A, Crenshaw ML, Katzenstein JM (2017) Neurocognitive Functioning in a Young Female with Weaver Syndrome. J Genet Disor Genet Rep 6:1. doi: 10.4172/2327-5790.1000148

Abstract

Weaver Syndrome is a low frequency syndrome caused by mutations in the EZH2 gene. Individuals with Weaver Syndrome have similar physical abnormalities as well as overall low cognitive functioning, motor deficits, and difficulties with independent living skills. This is a case study that presents the neurocognitive profile of n 11 year old female diagnosed with Weaver Syndrome. This was the child’s first neuropsychological evaluation following a long-standing history of concerns regarding her cognitive abilities, academic achievement, and independent living skills. Results of the evaluation revealed extremely low range cognitive functioning, as well as below age expectation performance across a majority of cognitive domains. While the child’s neurocognitive profile was similar to prior research regarding cognitive outcomes in children with Weaver Syndrome, additional research on the neurocognitive profile of children with Weaver Syndrome is indicated. 

Keywords: Weaver syndrome; Neurocognitive function; Child; Genetics; Neuropsychology

Keywords

Weaver syndrome; Neurocognitive function; Child; Genetics; Neuropsychology

Introduction

To date, the medical literature does not include a full clinical description of the neurocognitive presentation of individuals diagnosed with Weaver syndrome, an extremely rare genetic disorder caused by mutations in the histone methyltransferase, EZH2 [1]. There have been approximately 50 reported cases of Weaver syndrome in the medical literature worldwide [2]. This rare anomaly was first discovered in 1974 by Weaver and colleagues and was described as having characteristics of accelerated growth and bone age maturation as well as dysmorphic facial appearances [3,4]. Other known characteristics of Weaver syndrome can include macrocephaly, hypertonia, camptodactyly (permanently bent fingers), hypertelorism (increased width between the eyes), telecanthus, long philtrum, micrognathia (undersized jaw), and tall stature [1,5]. Umbilical hernia is commonly reported, as well as increased risk for tumors [1,6]. Variable intellectual disability was reported ranging from normal intelligence to severe intellectual disability [1]. One case study reported severe developmental and motor delays in a patient who died at age 16 months of sepsis, congestive heart failure, and respiratory arrest [5]. Another case study reported borderline cognitive impairment on verbal and visuospatial tasks [7]. In a case study where both siblings were born with Weaver syndrome, the first sibling was unexpectedly found dead within 48 hours of life, the second sibling survived and was reported to be severely delayed and attended a school for the severely mentally handicapped [8].

Case Report

An 11 year old female was referred for a neuropsychological evaluation to assess her neurocognitive strengths and weaknesses due to her medical history significant for Weaver syndrome. Specifically, the child’s mother reported concerns that have been present since she was a young child, including learning difficulties, slow processing speed, and difficulty independently completing activities of daily living.
Birth and medical histories
The child was the second child born to non-consanguineous parents. She was born at 32 weeks gestation at a birth weight of 5 pounds, 8 ounces via caesarean section delivery. No prenatal exposure to drugs or other toxins were reported. Due to prematurity, the child remained in the hospital for 2 months and required the use of a feeding tube. Motor and cognitive developmental milestones were reportedly delayed, though the child did not receive any early developmental therapies until age 3. Following her third birthday, she was enrolled in speech therapy and slowly began to acquire language. By age 6, the child was reportedly using 3-4 word sentences.
She was identified to have Weaver syndrome when she was 8 years old and has experienced medical and cognitive sequelae that is common in individuals with Weaver syndrome, including: umbilical hernia, vision problems, and accelerated bone maturation. This child’s medical history was also notable for vision problems, hearing problems with tube placement, asthma, peanut allergies, and ear infections. As a young child, she had difficulty falling and remaining asleep, although at the time of this neuropsychological evaluation her mother did not indicate concerns with sleep or appetite.
Given her features of macrocephaly and developmental delay and facial features suggestive of an overgrowth syndrome, genetic testing for PTEN, NSD1 as well as EZH2 were performed. The EZH2 sequencing showed a mutation which has been found in one patient with Weaver syndrome previously. This is denoted as c. 2233G>A or p.Gly745Lys. This is presumed a de novo mutation in the proband as her parents are not symptomatic and confirms the diagnosis of Weaver syndrome as the cause for her overgrowth and delayed milestones.
At the time the child presented for a neuropsychological evaluation she resided with her biological parents and older brother (age 21). There was no reported family history of psychological or learning disorders. Spanish was the primary language spoken in the child’s home. However, the child preferred to communicate in English. Socially, the child was said to get along well with her older brother and peers, although she reportedly preferred to spend time with children who were younger.
The child was placed in 4th grade at the time of the evaluation. She was educated entirely in English, her preferred language. The child was previously retained in 3rd grade due to poor academic performance and slow developmental progress. She was provided educational accommodations and supports through an Individualized Education Program (IEP). Her mother indicated that the child received additional individualized support in reading and mathematics, as well as Physical Therapy once a week and Speech/Language Therapy once a week through her school. Significant concerns with the child’s learning abilities were reported, as it takes her much longer to learn and retain new information, as well as difficulty with expressive and receptive language.
Diagnostic procedures and test interpretation
The child was administered standardized tests across the domains of intellectual functioning, academic skills, language, memory, attention, executive functioning, fine motor skills, behavioral functioning and visual motor integration. Additionally, her mother completed the parent-report forms of behavioral/emotional functioning and adaptive skills. Throughout the evaluation the child demonstrated an overall slow response speed, taking significantly more time to provide her responses in comparison to same-age peers. Attention, hyperactivity and impulsivity were judged to be age appropriate. She made good eye contact, but demonstrated a blunted affect with limited reciprocal and spontaneous conversation. No assistive devices were used during testing.
Intellectual abilities
As a measure of her overall level of cognitive functioning, the child was administered the Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) as a measure of her core intellectual abilities. The WISC-V is an individually administered assessment measure used to assess a child’s level of cognitive functioning [9]. This child completed 10 of the subtests that comprise her Full Scale IQ (FSIQ): Block Design (ScS=4, 2nd percentile), Similarities (ScS=7, 16th percentile), Matrix Reasoning (ScS=3, <1st percentile), Digit Span (ScS=8, 25th percentile), Coding (ScS=6, 9th percentile), Vocabulary (ScS=3, <1st percentile), Figure Weights (ScS=6, 9th percentile), Visual Puzzles (ScS=4, 2nd percentile), Picture Span (ScS=5, 5th percentile), and Symbol Search (SS=2, <1st percentile). On this measure, she evidenced extremely low range abilities overall (Full Scale IQ=69, 2nd percentile). She performed slightly better on tasks of verbal intelligence (i.e., identifying similarities between words, vocabulary, etc.) and working memory (i.e., ability to hold information in mind while problem solving), as both were measured in the borderline range (Verbal Comprehension Index=73, 4th percentile; Working Memory Index=79, 8th percentile). Her nonverbal intelligence, or ability to utilize visual details to identify common rules among objects and engage in visual problem solving (Visual Spatial Index=67, 1st percentile; Fluid Reasoning Index=69, 2nd percentile), and psychomotor processing speed (Processing Speed Index=66, 1st percentile) all fell within the extremely low range, consistent with her overall level of cognitive functioning.
Learning and memory
Overall, the child’s learning and memory abilities were delayed, consistent with her cognitive abilities. To assess her verbal learning and memory, subtests from the Wide Range Assessment of Memory and Learning – Second Edition (WRAML-2) were administered. The WRAML-2 is an individually administered test used to assess immediate and delayed verbal memory [10]. On a measure of story memory, in which the child was read two short stories and then asked to freely recall each story individually, her performance fell in the borderline range when required to immediately recall story details (WRAML-2 Story Memory Immediate ScS=5, 5th percentile), as well as following a 20 min delay (WRAML-2 Story Memory Delayed ScS=4, 2nd percentile). Her ability to recognize story elements (i.e., identify if a statement was true or false based on her recall of story details) was in the average range (WRAML-2 Story Memory Recognition ScS=8, 25th percentile). The child was also asked to repeat back meaningful sentences, her performance on this task fell in the borderline range (WRAML-2 Sentence Memory ScS=5, 5th percentile). On a measure of her rote verbal learning and memory skills (WRAML-2 Verbal Learning), in which she was read a list of 15 words over four trials, she evidenced extremely low range learning and recall of a list of words (WRAML-2 Verbal Learning Immediate ScS=2, <1st percentile). Furthermore, her ability to recall the list after a 20 min delay, as well as her ability to accurately recognize words from the list, was in the borderline range (Verbal Learning Delayed ScS=4, 2nd percentile; Verbal Learning Recognition ScS=5, 5th percentile). To assess the child’s visual memory, she was administered the Memory for Designs task on the NEPSY-II. The NEPSY-II is an individually administered assessment measure that is often used to assess a range of neurocognitive processes in children (i.e., attention, executive functions, language, visual spatial abilities, learning and memory, etc.). However, for the purposes of this evaluation, the subtest Memory for Designs was utilized, in which the child was shown a grid with designs on a page and then asked to recall the content and spatial locations of the designs when removed from view [11]. Her performance fell in the extremely low to borderline range overall during learning trials (Memory for Designs Immediate Recall: Content ScS=4, 2nd percentile; Spatial ScS=1, <1st percentile; Total ScS=1, <1st percentile) and after a 20 min delay (Memory for Designs Delayed Recall: Content: ScS=4, 2nd percentile; Spatial=7, 16th percentile; Total=4, 2nd percentile) for both the content and spatial location of the designs.
Language
The child’s level of receptive and expressive language skills were also measured at the neuropsychological evaluation. The Peabody Picture Vocabulary Test, Fourth Edition (PPVT-4) measures an individual’s receptive language skills by asking the individual to select a picture (out of an array of four pictures) that best fits the meaning of the word [12]. On this task, the child’s receptive language skills were measured in the borderline range (PPVT-4 SS=72, 3rd percentile). Furthermore, her expressive vocabulary was measured with the use of the Expressive Vocabulary Test, Second Edition (EVT-2). The EVT-2 measures an in individual’s ability to label or identify a synonym to an image shown by the examiner [13]. Similar to her receptive language skills, the child’s expressive language was measured in the borderline range (EVT-2 SS=76, 5th percentile). On a task of complex receptive language skills (i.e., the ability to follow increasingly complex instructions) (NEPSY-II Comprehension of Instructions), she also performed in the borderline range (NEPSY-II Comprehension of Instructions ScS=5, 5th percentile).
Attention and executive functioning
To measure her attentional abilities, she was administered a task of sustained visual attention (Connors Continuous Performance Test 3rd Edition, CPT-III), which required her to respond to specific stimuli, but inhibit her responding when viewing different stimuli. The CPT-III is a computer-based assessment that assesses attention in children 8 and older [14]. Her performance on this task indicated errors of omission (failing to respond when a target was present) indicating inattention (CPT Omissions T-Score=84; HRT=70; HRT SD=61). Her commission rate (responding incorrectly to non-targets) was in the average range (CPT Commissions T-Score=54). On a task of problem-solving, which was assessed with the use of the Tower of London, Drexel University, 2nd Edition (TOL-Drexel-2). The TOLDrexel- 2 is a measure of executive functioning and planning abilities [15]. On the TOL-Drexel-2, her overall performance was variable, as she demonstrated greater difficulty following the rules of the task (TOL-Drexel-2 Total Rule Violation SS=72, 3rd percentile), took longer to solve the problems (TOL-Drexel-2 Total Execution Time SS=72, 3rd percentile), and got fewer tasks correct in comparison to her same-age peers (TOL-Drexel-2 Total Correct SS=82, 12th percentile). On a task of speeded number sequencing (Trail Making Test), she evidenced extremely low range performance (Trails A SS=68, 2nd percentile). Additionally on a task requiring her to rapidly alternate between sequencing numbers and letters, she performed in the low average range (Trails B SS=85, 16th percentile). On a task of verbal fluency (Controlled Oral Word Association), her performance fell in the extremely low range for phonemic (i.e., letter) (COWA Phonemic SS=45, <1st percentile) and semantic (i.e., category) (COWA Animals SS=70, 2nd percentile; COWA Food SS=65, <1st percentile) fluency.
Visual-motor functioning/fine motor
On a test of visual-motor integration skills, the Beery-Buktenica Developmental Test of Visual-Motor Integration, Sixth Edition (VMI-6), the child was asked to copy a sequence of geometric figures of increasing complexity. This task was created to assess an individual’s ability to integrate their visual and motor, or hand and eye, coordination [16]. The child performed in the low average range on this measure (VMI SS=86, 18th percentile). Additionally, to evaluate her fine motor speed and dexterity, she was administered the Grooved Pegboard Test, where she was required to place small pegs into holes using her right then left hand. On this task, she demonstrated extremely low performance with her dominant (right) (Grooved Pegboard Dominant Hand SS=<40, <1st percentile) and when using her non-dominant (left) (Grooved Pegboard Nondominant Hand SS=42, <1st percentile) hand. As a result, the child demonstrated significant difficulty with fine motor control.
Academic skills
As a measure of the child’s attainment of academic skills, she was administered three subtests from the Wechsler Individual Achievement Test - Third Edition (WIAT-III). The WIAT-III is an academic achievement test for children in Prekindergarten through 12th grade [17]. For this evaluation, the child completed the Word Reading subtest, in which she was asked to read words as they became increasingly difficult. On this task her performance fell within the low average range (WIAT-III Word Reading SS=86, 18th percentile). Her computational math and spelling skills fell in the borderline range (WIAT-III Numerical Operations SS=75, 5th percentile; Spelling SS=78, 7th percentile).
Behavioral/emotional/social functioning
Rating scales were also completed by the child’s mother. All rating scales were completed in Spanish, the mother’s preferred language. The child’s mother complete a broad measure of emotional and behavioral functioning, the Behavioral Assessment System for Children, Second Edition (BASC-2) [18]. On this measure, the child’s mother endorsed significant concerns with her leadership skills (T = 29, 2nd percentile), activities of daily living (T = 24, 1st percentile) and functional communication (T=25, 1st percentile). In addition, she indicated mild concerns with somatization (T=67, 93rd percentile), withdrawal (T=65, 91st percentile), adaptive skills (T=30, 3rd percentile), and social skills (T=39, 16th percentile). Her mother also completed the Adaptive Behavior Assessment System, 2nd edition (ABAS-II), a measure of adaptive functioning and ability to independently complete daily living skills [19]. On this measure, the report provided by the child’s mother rated her overall adaptive functioning to be in the extremely low range (GAC SS=40, <1st percentile), indicating that the child requires more assistance to complete tasks across the domains of Conceptual (SS=49, <1st percentile), Social (SS=53, <1st percentile) and Practical (SS = 40, <1st percentile) skills than same-age peers. This rating of her adaptive functioning was consistent with the mother’s report during clinical interview in which she indicated that the child needed significant help and prompting to completed daily tasks.

Discussion

Overall, the child’s cognitive and adaptive functioning profile is consistent with a diagnosis of Intellectual Disability, Mild. This is consistent with the current research base which indicates that many children diagnosed with Weaver Syndrome often have lower levels of cognitive functioning, spanning from severely to moderately impaired [1]. The child’s performance on tasks across a majority of the cognitive domains measured also fell well below age expectations. She demonstrated difficulties with both receptive and expressive language, though evidenced language commensurate with her intellectual abilities, which is consistent with prior research on this population.
Another area of significant difficulty for this young woman was on tasks requiring her to utilize her fine motor speed and dexterity. Clumsiness, which was identified by the child’s mother, as well as through observation and objective testing, has commonly been noted as an area of difficulty for individual’s with Weaver syndrome [1,5]. It is important to note that this child had not received any occupational therapy to support the development of her fine motor skills at the time of this evaluation.
Overall, findings from the neuropsychological evaluation indicate that her cognitive functioning and academic achievement was below age expectations, at approximately the 7 year old age level. These results suggest that the child will need a significant amount of support to continue to make cognitive and academic gains. Functionally, the child may be expected to have difficulty taking in new information in everyday settings, fully understanding abstract concepts and independently doing many tasks that others her age seem to do without a great deal of assistance. Recommendations for the development of daily living skills, occupational therapy, as well as consideration for vocational training in the future, were provided. Furthermore, it was recommended that the child return in two years for a full neuropsychological re-evaluation to continue to track her neurocognitive development.

Limitations

One limitation of this study is the sample size. While a case study provides important information regarding low frequency syndromes, such as Weaver syndrome, the low sample size impacts the external validity and generalizability to the results without additional participants. In addition, this evaluation was the first neuropsychological evaluation the child participated in, limiting the amount of information regarding the child’s functioning during early childhood. Another limitation of the current study was the language barrier. While the child’s preferred language was English, her mother speaks in Spanish to her in the home which may have had an impact on her development of receptive and expressive language and also impacted the amount of information obtained during clinical interview.

Future Research

Additional research is needed to further identify the neurocognitive functioning of individual’s diagnosed with Weaver syndrome. Additional case series, or studies with larger sample sizes, in which similar neuropsychological batteries are administered to obtain information about a child’s functioning across a number of neurocognitive domains (i.e., intellectual abilities, academic achievement, learning and memory, language, attention, executive functioning, motor skills, social-emotional/behavioral functioning, and adaptive functioning) are necessary. Serial neuropsychological evaluations to follow a child’s progress across the lifespan are also recommended for researchers to identify the developmental progression of a child with Weaver syndrome and long-term outcomes.

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