A 4-year-old boy is brought to the office by his parents due to behavioral difficulties at preschool. The patient's teacher has concerns that his speech is difficult to understand and that he hits other children for no clear reason. His mother says, "He is generally a happy kid but gets easily upset sometimes. It takes a long time to calm him down." The patient was born at term with no complications and has no significant medical history. Family history includes autism spectrum disorder in his older brother. Vital signs are within normal limits, and his height and weight track at the 60th percentile. On physical examination, the patient has deep-set eyes and large ears. He is highly active, banging a set of toy trains on the floor. The patient does not make eye contact or answer questions directly and mumbles 1- or 2-word phrases. Which of the following is most likely to establish an underlying diagnosis?

Question

A 4-year-old boy is brought to the office by his parents due to behavioral difficulties at preschool.  The patient's teacher has concerns that his speech is difficult to understand and that he hits other children for no clear reason.  His mother says, "He is generally a happy kid but gets easily upset sometimes.  It takes a long time to calm him down."  The patient was born at term with no complications and has no significant medical history.  Family history includes autism spectrum disorder in his older brother.  Vital signs are within normal limits, and his height and weight track at the 60th percentile.  On physical examination, the patient has deep-set eyes and large ears.  He is highly active, banging a set of toy trains on the floor.  The patient does not make eye contact or answer questions directly and mumbles 1- or 2-word phrases.  Which of the following is most likely to establish an underlying diagnosis?

Quizplus · Accepted Answer

Explanation: 11ec25c8_d78c_0f2a_bc81_4930b4942529_MD0003_00 This child's developmental delay and dysmorphic features are suggestive of fragile X syndrome (FXS). FXS is an X-linked dominant condition caused by an unstable trinucleotide repeat expansion (CGG) in the FMR1 gene. This loss-of-function mutation results in low or absent levels of fragile X mental retardation protein (FMRP) and characteristic features of FXS: FMR1 gene Physical features include a long, narrow face with a prominent jaw and forehead; large ears; and deep-set eyes. Macroorchidism is classic but typically not noted until preadolescence. Developmental delay particularly affects motor and speech skills, as seen in this 4-year-old patient who speaks in 1- or 2-word phrases instead of intelligible sentences. Intellectual disability of varying severity is usually present. Behavioral symptoms include aggression and self-injurious behavior (eg, hand biting). Features of autism spectrum disorder (ASD) (eg, poor eye contact, stereotypical hand movements, social deficits) and attention deficit hyperactivity disorder (eg, distractibility, impulsivity) are also common. The gold standard for diagnosing FXS is FMR1 DNA analysis with PCR followed by Southern blot analysis to measure the length of the CGG repeat. (Choice A) The Autism Diagnostic Observation Schedule is a tool used to evaluate for ASD. Although autistic behaviors are common with FXS, ASD alone would not explain this child's large ears and deep-set eyes. In addition, ASD in this patient's brother also suggests a genetic cause. (Choice C) Karyotyping can detect gross structural abnormalities in chromosomes, such as trisomy 21. Down syndrome is a common cause of intellectual disability, but this patient does not have characteristic clinical features (eg, up-slanting palpebral fissures, epicanthal folds, brachycephaly). Molecular testing (eg, PCR) is far more sensitive than karyotyping in the detection of smaller genetic defects, such as CGG repeats in FXS. clinical features (Choice D) MRI of the head is indicated for seizure activity, which can occur in some patients with FXS but is not seen in this boy. MRI is not part of the standard diagnostic workup for FXS, intellectual disability, or developmental delay. (Choice E) The serum concentration of phenylalanine is increased in phenylketonuria, which causes intellectual disability and behavioral difficulties. However, seizures, a musty odor, and fair skin would also be expected and present in early infancy. Educational objective: Fragile X syndrome is characterized by neuropsychiatric symptoms (eg, developmental delay, autism) and dysmorphic features (eg, elongated face, deep-set eyes, large ears). Diagnosis is with FMR1 DNA analysis. References: Fragile X syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/28960184) Molecular biomarkers in fragile X syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/31035599) Triplet-repeat primed PCR and capillary electrophoresis for characterizing the fragile X mental retardation 1 CGG repeat hyperexpansions. (http://www.ncbi.nlm.nih.gov/pubmed/30847793)

A 4-Year-Old Boy Is Brought to the Office by His