CCPR: What portion of the population has an identifiable dysmorphological condition?

Dr. Jones: About 3%–4% of the global population has a birth defect or congenital anomaly. That’s a lot of kids, and up to 5% of kids have had significant exposure to alcohol prenatally, which is a huge neurodevelopmental risk (May PA et al, JAMA 2018;319(5):474–482).

CCPR: What are the most common conditions that you see?

Dr. Jones: The most common genetic disorder of which psychiatrists should be aware is 22q deletion syndrome, formerly known as DiGeorge syndrome or velocardiofacial syndrome. The disorder occurs in one out of 4,000 births. Roughly 20% of affected individuals have major psychiatric problems as they hit adolescence and adulthood, including schizophrenia, depression, and anxiety (Botto LD et al, Pediatrics 2003;112(1):101–107; Provenzani U et al, Int Rev Psychiatry 2022;34(7–8):676–688).

CCPR: So when we see a teen with schizophrenia, depression, or anxiety, we should have this in the differential diagnosis?

Dr. Jones: Many families already know about it because of associated congenital heart malformations. But not every child with 22q-related heart malformation has somebody to try to investigate the cause of that structural problem.

CCPR: What are we looking for in 22q deletion syndrome?

Dr. Jones: Some of the kids are on the small side relative to their family. Many have learning challenges; a lot of them have hypernasal speech, as if they have a cleft palate, even though the palate may be intact. A congenital heart malformation or cleft palate should make you think about this diagnosis. They have recognizable facial features, which are subtle, but the child doesn’t look like their parents. (Editor’s note: Visit www.thecarlatreport.com/dysmorphologyquickref for our “Concise Guide to Dysmorphology” table.)

CCPR: What other signs or symptoms should we be on the lookout for as tipoffs to a genetic condition?

Dr. Jones: Fragile X is an X-linked deficit of FRMP protein needed for brain development. In fragile X, many affected males have significant cognitive challenges. Females can have a subtle phenotype. But anxiety is a big piece of the neurobehavior of fragile X.

CCPR: Are there other common conditions mental health professionals should know more about?

Dr. Jones: After 22q and alcohol-related neurodevelopmental disorder (ARND), everything else is much less common. ARND tops my list because those kids have tremendous challenges with impulse control and frontal lobe issues that create challenges in school and at home. (Editor’s note: For more on ARND, see our interview with Dr. Ira Chasnoff in this issue.)

CCPR: Fragile X is further down?

Dr. Jones: Yes. Fragile X usually occurs in a family where there are other individuals at risk. It becomes a reproductive issue, particularly if a couple is interested in having more kids. The next conditions that you might see are sex chromosome aneuploidy conditions. Many of these individuals never have medical problems, but a subpopulation has learning challenges and behavioral issues that may end up with psychiatry. These are kids with XY plus another Y, children with XY plus another X, girls who have three X’s, etc. We’re picking them up on prenatal genetic screening using cell-free fetal DNA.

CCPR: How does early identification of 22q make a difference in the trajectory of the child’s development?

Dr. Jones: You may need to address immunodeficiency, cardiac defects, and learning challenges. A program or group might help with social interactions. Don’t let that fester unaddressed.

CCPR: For our readers who are not in the field, how widespread is fetal DNA testing and why is it important?

Dr. Jones: It’s the standard in California to offer it to all pregnant people. The state screens for trisomy 21 (T21), trisomy 18, and trisomy 13. You can add sex chromosomal aneuploidy for a fee, and there are companies that will do 22q deletion and some other microdeletion syndromes prenatally as well. Fetal DNA testing could lead you to do a diagnostic test, which would either be a chorionic villus sampling or an amniocentesis, to directly examine the genetic composition of fetal DNA. That might result in better planning for a new child or perhaps in a decision to terminate a pregnancy.

CCPR: Has this affected amniocentesis rates?

Dr. Jones: They’ve gone way down because there are fewer false positives with this type of screening. But there are ethical issues. For some practices, this just goes with your prenatal labs. Patients have no idea that they’ve just had genetic screening for T21.

CCPR: I work with people who would not do the testing since they do not plan to terminate a pregnancy based on genetic testing.

Dr. Jones: I think that’s the 25% who opt out. They do not want this information since they are not going to act on it, so they don’t need it—and that’s absolutely a fair approach.

CCPR: Are there guidelines for identifying children we might refer to a dysmorphologist?

Dr. Jones: Think of those kids who have been struggling all along. They have learning challenges, developmental challenges, and now behavioral challenges. Often there’s no history of birth injury or meningitis or something that you can relate to the challenges the child is having. Those are the kids who need a closer look.

CCPR: And is that next look a chromosomal microarray?

Dr. Jones: Yes. Microarray and fragile X are reasonable. But genetic testing is not always clear. It’s important to explore the cause of a child’s difficulties, including genetic reasons; however, that investigation might bring up more questions. You need to warn people ahead of time that there are three results you can get: positive, negative, and a variant of uncertain significance.

CCPR: That’s what SPARK is for, right?

Dr. Jones: SPARK is a multisite national effort in the United States where families of autistic kids can provide DNA samples from their child and family members. SPARK is gathering huge numbers of DNA samples hoping that the numbers will help identify new developmental conditions that include autism as part of their picture. However, they are finding many genetic variant that have no known ­significance.

CCPR: How do parents react to the news that a genetic variant may be related to their child’s difficulties?

Dr. Jones: From the perspective of the parent, their child has a behavioral problem, and you try to figure out why the child is having the problem. During your workup, you wonder about genetic components. If there is a genetic finding, how will the parents feel? Will they blame themselves or perhaps each other? Will they feel relieved that there is a cause and that their child is not misbehaving on purpose? There are many possibilities. Ask parents for their thoughts on the results and work with them so that you can support a better relationship between the parents and the child.

CCPR: How do you talk with kids and parents about these conditions?

Dr. Jones: Usually, I see the child when they’re young and I’m talking to the parents, although I do talk to adolescents as well. I take the perspective that all of us have genetic differences and they just have one that we know something about, and it helps us understand why they’re struggling and gives us a direction for helping them.

CCPR: Have you encountered issues with implicit bias that might limit the opportunities offered to kids based on low expectations?

Dr. Jones: There’s tremendous bias. Forty years ago, people were told to put their kids with T21 in institutions for the intellectually disabled. I remember in medical school taking a field trip out to one of those places and being overwhelmed with cottage after cottage of individuals who were not doing much because there was no expectation. They were sort of warehoused and it was just incredibly sad. I don’t see that anymore, but there tends to be a sense that there’s nothing we can do because you can’t fix the underlying genetic problem. We all need to advocate for these kids to have opportunities to learn and participate in society. It’s unfair to take away a family’s hope and limit a child’s future. Kids haven’t read the book about how it’s supposed to go, and most of them make liars out of the doctors who talk to their families early on. And then the family never trusts anything they hear from medical professionals. Stigma is a huge problem, especially with some conditions such as those related to alcohol exposure.

CCPR: What we can do about the stigma?

Dr. Jones: Women who drink during pregnancy are stigmatized, and their kids are horribly stigmatized. This makes disclosure of the information to get that history difficult, particularly because few kids have physical findings. Many have neurobehavioral challenges, and the only way you’re going to get at that is with a history of exposure, unless the psychologist who is testing them can recognize the pattern of neurobehavioral problems as pointing toward an alcohol-related injury. (Editor’s note: See our other Q&A in this issue for more on how to obtain a history of prenatal alcohol exposure.)

CCPR: Are there resources for reference or further learning that we could share with clinicians?

Dr. Jones: My book has summaries on hundreds of disorders (Jones KL, Jones MC, and del Campo M. Smith’s Recognizable Patterns of Human Malformation (8th ed.). Amsterdam: Elsevier; 2021). It can be used at the bedside for a quick once-over on a diagnosis and what you need to know about it. For more in-depth discussion, many genetic disorders have expert GeneReviews online (www.tinyurl.com/4zu4ray5). They’re written in an easy-to-use format. Parent support websites often have superb content and a positive take about the kinds of things that help. There is also a facial recognition app called Face2Gene (www.face2gene.com) where you can take a picture of an individual and upload it on their website and they’ll give you a differential diagnosis. Many of my colleagues find it helpful.

CCPR: Thank you for your time, Dr. Jones.