Published on in Children's Doctor
James is a 3-year-old male with developmental delay and rapid weight gain/obesity. Prenatal history was unremarkable. His birth weight was 50th percentile and length was 90th percentile at birth. Soon after birth, he started showing feeding difficulties, poor suck/coordination, and aspiration. James’ mother first noticed gross motor issues and called early intervention at 11 months, as he was not crawling. He was evaluated by a developmental pediatrician and was found to have expressive language delay and fine motor delay. His rapid weight gain started when he was 2 years old. He appears to always be hungry, and he eats snacks often. No food hoarding behaviors and no food seeking behaviors were observed. He was referred to the Genetics clinic for further evaluation.
His physical measurements at 3 years, 8 months were height: 99th percentile (Z score 2.3), weight: >99th percentile (Z score 4), head circumference: 59th percentile, and BMI: >99th percentile (Z score 4.37). His physical examination was remarkable for mild facial dysmorphisms such as synophrys (fusion of eyebrows above the bridge of nose) and upturned nose, hypotonia, and joint laxity. James had chromosomal microarray to screen microdeletion/ microduplication syndromes and was found to have distal 220kb 16p11.2 chromosome deletion.
While the major contribution of environmental factors such as consumption of high-energy/high-fat foods, and fast food consumption is well known in the pathogenesis of pediatric obesity, recent studies demonstrate the role of genetic variants in obesity pathogenesis. Indeed, genetic disorders associated with obesity are responsible for up to 7% of severe childhood obesity. Many genetic diagnoses have been associated with obesity/rapid weight gain. The majority are syndromic forms of obesity associated with neurodevelopmental issues, structural birth defects, and/or systemic manifestations as exemplified in James’ case.
Among the syndromic forms of obesity, the most common diagnosis in our outpatient clinic is 16p11.2 deletion syndrome. Both proximal and distal 16p11.2 deletion syndrome are associated with obesity and neurocognitive impairment. Distal 16p11.2 deletion syndrome is due to a 220-kb chromosomal microdeletion of 16p11.2. This deletion involves approximately 9 genes including the SH2B1 gene, which is considered to be main driver of the obesity phenotype in this syndrome, because SH2B1 mutant mice demonstrate increased food intake and obesity. This syndrome is also associated with autism, developmental delay, hypotonia, and seizures. The degree of neurological involvement is quite variable, and we occasionally see familial transmission of the 16p11.2 deletion in an autosomal dominant manner.
Other common genetic diagnoses causing syndromic obesity include Down syndrome and Prader-Willi syndrome. Down syndrome is due to an extra copy of chromosome 21, and children with Down syndrome are prone to develop obesity during childhood. Prader-Willi syndrome is due to chromosomal deletion or methylation defects within 15q11.2 region. Children with Prader-Willi syndrome start demonstrating rapid weight gain after 2 years old. While these syndromes need to be considered as differential diagnoses for children with obesity, since they tend to cause neonatal problems due to hypotonia and feeding difficulties, the diagnosis of these syndromes tend to be made soon after birth.
Other chromosomal disorders associated with obesity include 2q37 deletion syndrome and 17p11.2 deletion syndrome. Syndromic form obesity can be also seen as single gene disorders such as Bardet-Biedl syndrome, Prader- Willi-like syndrome due to SIM1 mutations, and pseudohypoparathyroidism.
While obese children with syndromic features tend to undergo genetic evaluation, those without syndromic features could have genetic mutations in genes encoding proteins regulating appetites and metabolism. These genes include MC4R, LEP, LEPR, PCSK1, and POMC, all belonging to the leptin- melanocortin pathway, which is involved in hunger and energy homeostasis regulation. Children with genetic mutations in the leptin-melanocortin pathway genes tend to show hyperphagia and obesity without other organ system involvement. In this class of genetic disorders, treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide improves hunger and obesity. In 2020, setmelanotide was approved for obesity treatment in children (>6 years old) with POMC, PCSK1, and LEPR mutations. Therefore, identification of pathogenic POMC, PCSK1, and LEPR mutations will have therapeutic implications.
When to consider genetic etiology
- Facial dysmorphisms: When facial features of children with obesity are different from his/her biological parents or siblings, syndromic obesity diagnosis should be considered.
- Other organ system involvement: The presence of developmental delay and structural birth defects suggests a syndromic obesity diagnosis.
- Hyperphagia: Excessive eating can be seen as part of many obesity genetic syndromes.
- Rapid weight gain out of proportion to his/her dietary history: When dietary history is unremarkable, abnormalities in resting energy expenditures may be involved in the pathogenesis of rapid weight gain. Some obesity genetic diagnoses such as pseudohypoparathyroidism type 1A are associated with reduced resting energy expenditure, contributing to excessive weight gain.
Genetic testing recommendations for children with obesity
To screen for genetic diagnoses discussed above, we usually recommend chromosome microarray and a monogenic obesity panel, which allows genetic screening of genes associated with syndromic and non-syndromic forms of obesity. One study put the utility of chromosome microarray in identifying pathogenic chromosomal abnormality at 22%. The diagnostic yield of a monogenic obesity panel was reported to be 7.3% in a pediatric population. In obese children who are strongly suspected of having an underlying genetic diagnosis, exome sequencing should also be considered.
References and further readings
Bochukova EG, Huang N, Keogh J, Henning E, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature. 2010;463(7281):666-670.
Bachmann-Gagescu R, Mefford HC, Cowan C, et al. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med. 2010;12(10):641-647.
Miller T, Chung W, Nasir R, etal. 16p11.2 Recurrent Microdeletion. NCBI website. https://www.ncbi.nlm.nih.gov/books/NBK11167/. Accessed October 1, 2021.
Ren D, Zhou Y, Morris D, et al. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest. 2007;117(2):397–406.
Kühnen P, Clément K, Wiegand S, et al. Proopiomelanocortin deﬁciency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375(3):240-246.
Clément K, van den Akker E, Argente J, et al. Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Eﬃcacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deﬁciency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960-970.
Roizen JD, Danzig J, Groleau V, et al. Resting energy expenditure is decreased in pseudohypoparathyroidism type 1A. J Clin Endocrinol Metab. 2016;101(3):880-888.
D’Angelo CS, Varela MC, de Castro CIE, et al. Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity. Mol Cytogenet. 2018;11:14.
Kleinendorst L, Massink MPG, Cooiman MI, et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet. 2018;55(9):578-586.