What is the Developmental Outcomes of Patients with 22q11 Deletion Sequence?

Patient Presentation
A 5-year-old male came to clinic for his health supervision visit. He was transferring from a developmental preschool to kindergarten in the fall. The past medical history was significant for having 22q11.2 deletion sequence (22q11) after being diagnosed in the neonatal period because of congenital heart disease and dysmorphic facial features including hypertelorism, a small chin and ear abnormalities. In addition to successful cardiac surgery, he has had speech delays and bilateral grade II hydronephrosis that is being monitored. The family history was non-contributory. The pertinent physical exam showed a happy boy who had a weight parameter of 10%, height of 50% but was tracking. He had some speech problems but would talk right along with examiner. He overall seemed slightly immature for his age, but very pleasant. He had minor hypertelorism, small chin, and cupped ears. Pressure equalizing tubes were in place. His lungs were clear. His heart had a murmur consistent with his cardiac shunt.

The diagnosis of a child with 22q11.2 deletion going to kindergarten was made. The pediatrician reviewed each of the ongoing medical problems the boy had and the appropriate followup care. She then turned to the school issues. “He’s also getting speech therapy at preschool so will that be continuing at the new school too?” she asked. “We’re meeting with the school to make all of his transition plans. They have never had a child with this problem before but they seem willing to help. They can do speech therapy at school but I think he is going to need more than they can do and I’ve already identified someone who can do it after school. The school nurse already has his medical care plan updated from preschool. We probably are going to do a regular classroom for most of the day with the other part with the special education teacher. He may need an aide in the future too but I think we want to wait and see how things go. Part of it will depend on the other children’s needs in both classrooms and the teachers and paraeducators they may already have, ” the mother said. “It sounds like you have already been talking with them and have thought out a lot of what he will need to be successful next year. His needs are probably going change over time as you say, depending a bit on the other children and the teachers and resources the school has and how he grows and develops over time. I’d just make sure that you are in contact with the school, so that if something isn’t going as well, you all can work on it together. I’m happy to provide medical or other information to them if you would like. I know that his cardiologist and the geneticist can also do that if you want. Sometimes the specialty nurses will also go to schools to provide training for the staff or to answer questions the kids have. Let the school know that I’m happy to try to help if they want some help,” the pediatrician offered.

22q11.2 deletion sequence (22q11) is the most common micro-deletion syndrome. Most deletions are de novo. It affects ~1 in 2000-4000 live births. As it is autosomal, it affects males and females equally. Childhood mortality is low and often associated with congenital heart defects. Its phenotypic expression is highly variable.

Some of the most common medical problems are:

  • Congenital heart defects especially conotruncal abnormalities
  • Palatal problems especially velopharyngeal incompetence and/or cleft lip/palate
  • Immunodeficiency especially T-cell lymphopenia, but also abnormalities of IgG production, autoimmune and humoral defects
  • Hypoparthyroidism resulting in hypocalcemia – may be evident also only at times of stress
  • Genitourinary abnormalities – renal agensis, hydronephrosis, absent uterus, cryptoorchidism, hypospadias
  • Feeding – gastroesophageal reflux, dysphagia, constipation
  • Dysmorphic features included hooded eyelids, hypertelorism, auricular or nasal abnormalities, small mouth and micrognathia. Cleft lip, cleft palate and Pierre Robin Sequence are also seen.

Learning Point
The cognitive and social phenotypes of patients with 22q11 has a wide variability in the overall development and trajectory of individual children because of genetics and the environment. In infancy and early childhood (0-4 years) studies show more gross motor and expressive language delays compared to siblings or other controls. In preschool to adolescence (4-18 years) learning difficulties and cognitive delays often occur.

The overall intelligence quotient (IQ) distribution for normally developing children is 85-115 with 100 being the mean. For children with 22q11 the distribution is still normal but is shifted with the mean falling in mid 70s (70-75). Most children (55%) have borderline intellectual disability (full score IQ 70-84), about 45% have mild to moderate intellectual disability (full score IQ 55-70) and a minority having severe intellectual disability. Children with 22q11 have better verbal reasoning than perceptual reasoning but again this varies with the individual. A large study of pooled cross-sectional data reported that “…between 8-24 years showed an average 7-point decline in [full score]IQ, driven by an average 9-point decline in [verbal]IQ and an average 5.1-point decline in [perceptual reasoning]IQ.” Again the trajectory for an individual is variable but potentially includes having a stable IQ trajectory, growing into a deficit as the patient falls behind peers, or an absolute decline.

Children are also at increased risk for developing psychiatric disorders over childhood, adolescence and adulthood including attention deficit hyperactivity disorder, autism spectrum disorder, anxiety, mood disorders and psychotic disorders particularly schizophrenia. Studies have found schizophrenia in up to 40% of patients with 22q11. Having 22q11 is one of the highest identifiable risk factors for schizophrenia; in comparison the general population’s life-time risk for schizophrenia is 1%.

Questions for Further Discussion
1. How are genetic disorders categorized? A review can be found here.
2. What does a child need to do to be ready for kindergarten? A review can be found here.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.
Information prescriptions for patients can be found at MedlinePlus for this topic: Developmental Disabilities

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, et.al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015 Nov 19;1:15071.

Swillen A, McDonald-McGinn D. Developmental trajectories in 22q11.2 deletion. Am J Med Genet C Semin Med Genet. 2015 Jun;169(2):172-81.

Swillen A. The importance of understanding cognitive trajectories: the case of 22q11.2 deletion syndrome. Curr Opin Psychiatry. 2016 Mar;29(2):133-7.

Norkett EM, Lincoln SH, Gonzalez-Heydrich J, D’Angelo EJ. Social cognitive impairment in 22q11 deletion syndrome: A review. Psychiatry Res. 2017 Jul;253:99-106.

Shi H, Wang Z. Atypical microdeletion in 22q11 deletion syndrome reveals new candidate causative genes: A case report and literature review. Medicine (Baltimore). 2018 Feb;97(8):e9936.

Norkett EM, Lincoln SH, Gonzalez-Heydrich J, D’Angelo EJ. Social cognitive impairment in 22q11 deletion syndrome: A review. Psychiatry Res. 2017 Jul;253:99-106.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa