A 5-year-old boy is brought to the office by his parents due to behavioral difficulties. The patient just started kindergarten and has had difficulty staying focused on tasks and switching between activities. The teachers say that he is disruptive and often flaps and waves his hands. He was previously in a small preschool classroom with one-on-one teaching and was able to complete most activities with help. The patient's developmental history is notable for speaking his first word at age 19 months and walking at age 20 months. His mother also had learning difficulties, but she was able to graduate from high school with tutoring. Height and weight are at the 50th percentile, and head circumference is at the 90th percentile. Examination shows a prominent forehead and chin. Mild hypotonia and joint hypermobility are present in bilateral lower extremities. Which of the following is the most likely prognosis for this patient's condition?
Fragile X syndrome | |
Pathogenesis |
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Neuropsychiatric |
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Examination |
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Diagnosis |
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| FMR = fragile X messenger ribonucleoprotein. | |
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is caused by a trinucleotide (CGG) repeat expansion in the FMR1 gene. Because it is X-linked dominant, girls can be affected but typically have less severe symptoms, as seen by this patient's maternal history of learning difficulties, due to variable inactivation of the affected X chromosome.
Affected boys classically have a long face, prominent chin and forehead, protruding ears, and macroorchidism; however, some or all of these dysmorphic features may not be present until late childhood or adolescence. In contrast, infants and young children are more likely to have hypotonia and macrocephaly, as seen in this patient, and joint hypermobility can also occur. In addition to classic physical features, FXS causes speech and motor delays (eg, walking and talking around age 20 months instead of age 12 months). Attention deficit hyperactivity disorder (eg, difficulty focusing, task-switching) and autistic features (eg, hand flapping) are also common.
Patients with FXS have a normal life expectancy; however, prompt diagnosis with genetic testing allows for early implementation of developmental and behavioral therapies.
(Choice A) Early death from respiratory muscle weakness occurs with Duchenne muscular dystrophy, which often presents with gross motor delay in early childhood. Patients can have comorbid cognitive dysfunction and behavioral difficulties, but proximal muscle weakness would be expected, and dysmorphic facies and macrocephaly are not seen.
(Choice B) Marfan syndrome is a connective tissue disorder associated with joint hypermobility and an increased risk of aortic root disease. However, neuropsychiatric features (eg, developmental delay, inattention, stereotypic hand movements) are not associated with Marfan syndrome.
(Choice C) Down syndrome is a common genetic cause of intellectual and developmental disabilities and is associated with an increased risk of early-onset dementia and decreased life expectancy. However, the diagnosis is usually made in infancy due to characteristic dysmorphic features (eg, epicanthal folds, upslanting palpebral fissures), none of which are seen in this patient.
(Choice E) Rett syndrome is characterized by progressive brain deterioration that leads to deceleration of head growth (eg, microcephaly) and developmental regression. The disorder is seen almost exclusively in girls because the MECP2 mutation is generally fatal in boys.
Educational objective:
Physical features of fragile X syndrome can include a long face, prominent chin and forehead, protruding ears, joint hypermobility, and macrocephaly. Associated developmental delays and attention deficit hyperactivity disorder are common, but life expectancy is normal.