Autism Spectrum Disorder, Klinefelter Syndrome, and Chromosome 3p21.31 Duplication: A Case Report

Scott W. Stuart, MD, MS; Casey H. King, BA; G. Shashidar Pai, MD

In This Article

Case Presentation

The patient was a 7-year-old white boy who presented with a long history of a mixed receptive-expressive language disorder, fine motor impairment, attention deficit hyperactivity disorder (ADHD), sleep initiation disorder, nocturnal enuresis, disruptive behavior, poor school performance, repetitive/compulsive tendencies, and poor social skills. He was born at full term, weighing 6 pounds 3 ounces, to nonconsanguineous parents. He attained fine and gross motor skills in a normal sequence with mild delay; however, significant delays in verbal and nonverbal skills were noted by 12 months. He had clinically significant hyperactive and impulsive behaviors by age 5 years that responded poorly to pharmacotherapy. Aberrant social skills with strict adherence to routine were significant by 6 years of age, prompting further evaluation for an ASD by a multidisciplinary team.

The review of systems was otherwise noncontributory. The family history revealed that the father had a distant history of ADHD and had received stimulant medications for 2 years. The mother had a long history of academic impairment and left school in 10th grade. She also had a long history of severe mood variability that included periods of severe depression followed by periods of impulsive spending with minimal need for sleep. However, the mother repeatedly declined psychiatric care to establish a formal diagnosis.

On physical examination, the patient was cooperative and healthy, with a height at the 25th percentile, but weight and head circumference were below the 3rd percentile. He made minimal eye contact, but several times he spontaneously spoke 3-word phrases with no immediate echolalia. The cranium was microcephalic with dense, coarse hair. Examinations of the ears, nose, and throat and pulmonary, cardiac, gastrointestinal, and neurologic systems were normal. The genitourinary examination demonstrated a Tanner 1 circumcised male with both testes in the inguinal canal that could easily be brought into the scrotum. Extremity examination was notable for bilateral fifth digit clinodactyly. Skin examination was notable for coarse hair on the lower extremities with no other evidence of advancing sexual maturation.

Multiple behavioral questionnaires and scales were administered during the ASD evaluation. The Preschool Language Scales, 4th edition, demonstrated a receptive language standard score of 84 (14th percentile), expressive language score of 71 (3rd percentile), and total language standard score of 75 (5th percentile). The Behavior Assessment System for Children, 2nd edition, parent form demonstrated clinically significant concerns for hyperactivity, attention deficits, conduct disturbances, atypicality, aggression, withdrawal, and abnormal social and adaptive skills. The Kaufman Brief Intelligence Test, 2nd edition, was given and demonstrated a verbal IQ of 79 (8th percentile), nonverbal IQ of 114 (82nd percentile), and full-scale IQ of 96 (39th percentile). This showed a significant split with weakness in verbal abilities. The Vineland Adaptive Behavior Scales II demonstrated a communication standard score of 75 with age equivalent of 4 years 2 months, daily living skills standard score of 83 with age equivalent of 5 years 6 months, socialization standard score of 66 with age equivalent of 2 years 2 months, and Adaptive Behavior Composite standard score of 73 with age equivalent of 4 year 0 months. The Lifetime Social Communication Questionnaire score was 27, indicating risk for an ASD. The Autism Diagnostic Observation Schedule-Module 2 was administered to accommodate for the level of language impairment, which was below the level necessary for Module 3 administration). The results demonstrated a Communication Domain score of 2 (within normal limits), Qualitative Impairments in Reciprocal Social Interaction score of 7 (above autism cut-off), and total score of 9 (above ASD threshold, but below autism threshold). On critical review of the DSM-IV Criteria Checklist for Autistic Disorder, the patient met the full criteria for a diagnosis of autism (1a, 1b, 2a, 2d, 3a, 3b).

Given the constellation of autism, a maternal family history of academic underachievement and multiple subtle physical findings, genetic testing was pursued. High-resolution chromosomes demonstrated classic KS with a 47,XXY karyotype. In addition, CGH microarray analysis (SignatureChip Version 4.0, Signature Genomic Laboratories, Spokane, Washington) showed a duplication of 3p21.31(RP11-68104, RP11-578F5). The parents' blood samples also had microarray CGH analysis and demonstrated that the mother had the same duplication of 3p21.31.


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