A Toddler's Unexpected Delay
A toddler's developmental speed, distorted speech and heart defect
help solve a genetic puzzle.
By Mark Cohen|Thursday, August 28, 2014
RELATED TAGS: GENES & HEALTH
“Hi, Carlos. What’s that you’re playing with?”
The 2½-year-old boy with curly dark-brown hair was sitting in my exam room, holding a
Spider-Man figure in his small hands. He looked up at me with a shy smile, but didn’t say
anything.
“He doesn’t talk much,” said his mother. “And when he does, it’s really hard to understand
him.”
“Yes, Dr. Connolly mentioned that when he referred Carlos to me,” I replied. “Is there
anything else you’re worried about?”
“Well, he just seems slow. He didn’t start walking until he was almost a year and a half, and
he still doesn’t say many words — probably less than 30 altogether. And he only says one
word at a time.”
“I see. Does he point to any body parts? You know, eyes, nose, mouth?”
“Just his nose. Mostly he just looks at us and smiles. He’s really friendly.”
“Yes, I can see that,” I said. Clearly something was off. At 30 months, Carlos should have
been saying more than 100 words, and ought to be putting them together in three- or fourword sentences. And he had not started walking until 18 months, while most children are
walking by a year. I asked about things he was and was not able to do, and then I watched
him play with blocks, do puzzles, draw with crayons — all part of the developmental
assessment. Carlos was functioning at about the 21-month level in his motor, cognitive,
language and social development. This gave him a “developmental quotient” of about 70,
which is in the mildly delayed range.
There are many reasons for a child to have a developmental delay, and in many cases we
never come up with a specific reason. I started going through the list in my mind, and then
noticed something: When Carlos did talk, his speech was even less clear than an 18-monthold’s, let alone a 2½-year-old’s. Many of his words were very distorted, which suggested
that he might not be able to move his tongue, pharynx and palate properly when he tried to
speak.
Also, when he made certain sounds, air seemed to come out of his nose. That meant he
could have velopharyngeal insufficiency — the soft palate wasn’t closing off the nasal cavity
during speech.
Then I remembered something I’d noted when reviewing Carlos’ medical history. He was
born with a large ventricular septal defect (VSD), a “hole in the heart” that required surgery
when he was 3 months old.
While a VSD would not have caused his developmental problems, that bit of medical history,
combined with the way his mouth and palate worked, led me to what might be causing
Carlos’ developmental delay. I just needed to do one blood test to be sure.
Carlos had three red flags in his medical history: congenital heart disease, developmental
delay and a likely problem with his soft palate. When I put these together, I suspected that
he might have a genetic disorder called velocardiofacial syndrome (VCF).
"I didn't think that Carlos had Down syndrome. Instead, I suspected that when his
genetic code was forming, a much more common type of error occurred."
VCF is also known as 22q11.2 deletion syndrome because it occurs when a small piece is
missing from a specific location on chromosome 22. Interestingly, there is another
condition, DiGeorge syndrome, that is caused by a deletion in the same location on the same
chromosome. I once cared for a 7-year-old boy with DiGeorge syndrome. David had
persistent hypocalcemia (low blood calcium levels) and frequent infections because of
inadequate levels of T cells in his immune system. He also had a small head, moderately
severe mental retardation and a large ventricular septal defect.
If I had seen David and Carlos in my office on the same day, I would never have thought
they had the same genetic disorder. But the field of genetics has undergone a revolutionary
change during my clinical career. When I was in training, we made genetic diagnoses largely
by recognizing patterns of abnormalities. Now we can detect very small changes in the
chromosomes that are the root causes of those patterns. Except for the heart defect, David
and Carlos had no abnormalities in common. Yet if Carlos had the chromosomal deletion I
suspected, it would mean that he and David had the same genetic condition.
Alison Mackey/Discover, after U.S. National Library of Medicine
An Error of Division
How can this be? To understand the solution to this puzzle, a brief review of basic genetics
may be helpful. Most of us remember from high school biology that the genetic material in
each of our cells is composed of long strands of DNA, which are arranged in thousands of
segments called genes. During most of the cell’s life, the strands are in relative disarray. But
at the time of cell division, they are packaged into elongated bundles called chromosomes.
Human cells have 46 chromosomes arranged in pairs — except for the germ cells, sperm
and egg, which each have 23 unpaired chromosomes. The process of meiosis, the delicate
dance of DNA twisting and untwisting with its supporting cast of proteins and other
molecules, neatly separates each pair of chromosomes and allocates them efficiently to the
nuclei of the primordial germ cells.
But the process is seldom that neat. Errors can occur, and even a small one can result in big
problems for a child like Carlos. Sometimes an entire chromosome is misdirected during the
formation of a germ cell. Then all the cells of the resultant embryo have a missing or added
chromosome, as in trisomy 21 (Down syndrome), where chromosome 21 has three
chromosomes instead of a pair.
I didn’t think that Carlos had Down syndrome. Instead, I suspected that when his genetic
code was forming, a much more common type of error occurred. A tiny piece of a
chromosome can get lost, or duplicated, or moved onto another chromosome where it
doesn’t belong. This happens more frequently than you might think. Most of the time, the
misplaced genetic material is not critical, and this natural error does no harm. But if enough
critical genes are lost or gained, a pattern of significant medical or developmental problems
can result.
The 22q11.2 deletion is an example of a contiguous gene syndrome: The deleted genetic
material includes a number of genes that are next to one another on the chromosome. This
particular syndrome, which occurs in about 1 in 4,000 births, has been associated with more
than 200 abnormalities. The most common problems include heart defects, unusual facial
features, problems with the palate (sometimes affecting speech), feeding problems,
gastrointestinal difficulties, frequent infections and other manifestations of immune system
problems, growth delay, kidney problems, hearing loss, low calcium in the newborn period,
cognitive difficulties including developmental delay and learning disorders, behavior
problems, and other developmental disorders, including autism.
Whether a particular person with 22q11.2 deletion has any or all of these conditions
depends on how large the deletion is — in other words, which genes are lost and which are
retained. David, the boy with DiGeorge syndrome, presumably lost a larger piece of the
chromosome than Carlos, who had heart disease but did not have many of the other
complications.
Teasing Out the Anomaly
The blood test I ordered for Carlos is a way of looking at an individual’s chromosomes in
very fine detail. When I was a medical student, if we wanted to look at a person’s
chromosomes, a technologist would literally take a photograph of a dividing cell, print the
photo, cut out the images of each chromosome and line them up in order on a sheet of
paper. We now use what’s called an aCGH study (array comparative genomic hybridization),
in which the patient’s DNA, broken into small pieces, is placed on a plastic chip that has
been impregnated with hundreds of snippets of DNA. If the patient’s chromosomes have
extra or missing genetic material at one location on a particular chromosome, then too
much or too little DNA will bind to the corresponding area of the chip, and the anomaly can
be detected.
A few days later, Carlos’ aCGH test came back positive for a deletion in the long arm of
chromosome 22, at location 22q11.2. I called his mother and told her the results.
“But what does it mean?” she asked.
“It means we now know why Carlos is developing and learning more slowly than other
children. And we also know that it isn’t your fault.” I have rarely known a patient with a
developmental disability whose parent did not wonder if they might have “caused” the
problem in some way, though that is almost never the case.
But there is no treatment for contiguous gene syndromes like 22q11.2 deletion; too many
genes and complex biological systems are affected. However, Carlos’ delays appeared to be
mild. With early intervention and special education programs, and with kind and loving
care at home, there was a good chance that Carlos would eventually be able to live on his
own and have a happy and productive life.
And that’s just what every parent hopes for.
[This article originally appeared in print as "Unexpected Delay."]