Unique cases written by pediatric residents with a faculty
Diagnostic Evaluation in Children
With Developmental Delay: A
Cautionary Tale for Genetic Testing
© The Author(s) 2012
Reprints and permission:
Meghana Desale, BA1, Lila T. Worden, BS1, Julie S. Cohen, ScM2, Anna Maria Wilms Floet, MD1,2, and Alexander Holliday Hoon, Jr., MD, MPH1,2
A 20-month-old female was referred for outpatient diagnostic evaluation of motor and speech delay. She was born at 39 weeks by induced vaginal delivery to a
35-year-old mother who had an uncomplicated pregnancy and delivery. Prenatal ultrasounds were normal. In retrospect, her mother reported a perception of relatively decreased fetal movement compared with her first child. At birth she was appropriate size for gestational
age and had an unremarkable perinatal course. She had
a subsequent history of recurrent ear infections for
which tympanostomy tubes were placed, but was otherwise healthy. Gross motor and language milestones were delayed.
She crawled at 12 months and walked at 19 months,
and continued to have difficulty with balance. She
inconsistently followed commands and spoke recognizable 3 words. She had a 4-year-old brother who was developmentally normal. There was a maternal uncle with a mild learning disability. The family history was otherwise
negative for intellectual disability, autism spectrum disorders, recurrent miscarriages, or congenital malformations. There was no history of consanguinity. On physical exam at 20 months of age, she was 15th
percentile for weight, 11th percentile for height, and
24th percentile for head circumference. She had mild
synophrys with medial eyebrow flaring but no other
dysmorphic features. The remainder of her physical
exam was unremarkable. On neurological examination,
she had mild hypotonia but normal strength and reflexes.
The etiology of her developmental delay was felt to be
a nonspecific central nervous system disorder. After
discussion with her family, we sent Fragile X DNA testing and single-nucleotide polymorphism (SNP) chromosome microarray (CMA) following a referral for
genetic counseling. During genetic counseling, it was
specified that SNP array had the potential to reveal
unexpected or unrelated information, as well as variants
of unknown significance, which would require further
SNP CMA subsequently revealed a 17.2 Mb deletion
on the long arm of chromosome 5, from 5q21.1-q23.1.
Parental genetic testing showed the deletion to be de
novo. The large deletion encompassing more than 30
genes explained her global developmental delay as it is
consistent with reports of other patients with a similar
region of deletion who have intellectual disability or
This deletion included the APC gene, which is
mutated in familial adenomatous polyposis. There is an
associated >99% lifetime risk for developing colorectal
cancer, as well as increased risk for multiple other cancers. Even though still a toddler, she will now require biannual screening abdominal ultrasounds and blood
tests for alpha-fetoprotein, and will eventually need a
prophylactic colectomy in the future. She was referred
to appropriate subspecialists for ongoing follow-up.
These recommendations were discussed in detail with
1. Pathogenic 5q21.1-q23.1 de novo deletion
resulting in developmental delay.
2. Familial Adenomatous Polyposis due to deletion of APC gene.
Johns Hopkins University, Baltimore, MD, USA
Kennedy Krieger Institute, Baltimore, MD, USA
Alexander Holliday Hoon, Jr, Kennedy Krieger Institute, 801 North Broadway, Baltimore, MD 21205, USA
Desale et al
References: includes the APC gene. J Hum Genet. 2006;51:141-146.
and microduplication syndromes with cancer predisposition by aCGH. Genet Med. 2009;11:314-322.
what are the issues? J Med Genet. 2011;48:535-539.
Dev Med Child Neurol. 2011;53:994-999.
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