16p11.2 deletion syndrome
Symptomsmotor speech and developmental coordination disorders, language disorder, psychiatric conditions, autism spectrum features[1]
ComplicationsObesity and related comorbidities
CausesGenetic (typically de novo)
Diagnostic methodGenetic testing
Differential diagnosisGlobal developmental delay, autism spectrum disorder, any chromosome abnormality associated with intellectual disability[1]
ManagementDepends on symptoms
Frequency~1 in 2,000[2]

16p11.2 deletion syndrome is a rare genetic condition caused by microdeletion on the short arm of chromosome 16. Most affected individuals experience global developmental delay and intellectual disability, as well as childhood-onset obesity.[1] 16p11.2 deletion is estimated to account for approximately 1% of autism spectrum disorder cases.[3][4]

Signs and symptoms

Developmental and behavioral

The most commonly observed features of 16p11.2 deletion syndrome are global developmental delay and psychiatric or behavioral issues, though severity varies significantly. Most affected individuals do not have intellectual disability defined as IQ below 70, but many have learning disabilities. The average IQ of individuals with 16p11.2 deletion syndrome is approximately 2 standard deviations below that of family members without the deletion.[4] Many have language disorders and motor speech disorders including dysarthria and apraxia.[1]

Half of affected individuals have at least one psychiatric or behavioral diagnosis. Approximately 30% of individuals are diagnosed with attention deficit hyperactivity disorder. Approximately 20-25% of individuals are diagnosed with autism spectrum disorder (ASD), and nearly all share some behavioral traits with ASD.[1][4]

Neurologic

Up to 25% of affected individuals experience seizures.[1] The most common type is tonic-clonic seizure; complex focal seizures and absence seizures are also reported.[5] Many individuals may exhibit EEG, CT, or MRI abnormalities. Hyporeflexia, gait abnormalities, and truncal or symmetric limb hypotonia were observed in at least 15% of individuals in a cohort of 136 16p11.2 deletion carriers.[5] Sensorineural or conductive hearing loss and paroxysmal kinesigenic choreoathetosis are observed in some individuals.

Obesity

16p11.2 deletion syndrome strongly predisposes individuals to increased body mass index (BMI) and obesity beginning in childhood. BMI in individuals with the syndrome is significantly higher than that in the general population by age 5, and 50% of carriers are obese by age 7.[6] By adulthood, 75% of individuals are obese.[1] Affected individuals report hyperphagia due to sensory and social cues or boredom.[7] Obesity and related comorbidities such as insulin resistance or type 2 diabetes comprise the majority of medical challenges for adults with 16p11.2 deletion syndrome.[1]

Other

Macrocephaly is slightly more prevalent in 16p11.2 deletion syndrome compared to the general population. Approximately one-third of individuals have a sacral dimple or café au lait spots.[5] Vertebral anomalies associated with scoliosis are also observed.[1] 16p11.2 deletion has been associated with a 13.9-fold increased risk of neuroblastoma.[8]

Genetics

16p11.2 deletion syndrome is caused by a heterozygous microdeletion of ~600 kilobases between the recurrent breakpoint regions BP4 and BP5 on the short arm of chromosome 16. Genes in the BP4-BP5 region include the following:[2]

Nearby regions on chromosome 16 may also be affected. Notably, deletion of SH2B1 is associated with obesity and may be involved in the pathogenesis of obesity observed in the syndrome.[9]

16p11.2 deletion typically occurs by de novo mutation. Approximately 7% of affected individuals inherit the mutation from a parent in an autosomal dominant fashion. Parents carrying the deletion often have no history of intellectual disability or autism spectrum disorder.[1][2][10] Prevalence of 16p11.2 deletion syndrome was initially estimated to be 3 in 10,000 in the general population,[3][11] though more recent estimates have increased to 1 in 2,000.[2]

Management

Management of 16p11.2 deletion syndrome is highly variable and based on an individual's specific symptoms or deficits. Interventions may include special education, psychiatric treatment, standard epilepsy treatment, audiology assessment, physical and occupational therapy for gross/fine motor skills, and regular monitoring of congenital anomalies or defects. Due to increased risk of obesity associated with the syndrome, psychiatric medications associated with weight gain are not recommended. Social work involvement and community support can also benefit affected individuals and caregivers.[1]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Taylor, Cora M.; Smith, Rebecca; et al. (1993). "16p11.2 Recurrent Deletion". GeneReviews. University of Washington, Seattle. PMID 20301775.
  2. 1 2 3 4 Chung, Wendy K; Roberts, Timothy PL; et al. (1 June 2021). "16p11.2 deletion syndrome". Current Opinion in Genetics & Development. 68: 49–56. doi:10.1016/j.gde.2021.01.011. ISSN 0959-437X. PMC 10256135. PMID 33667823.
  3. 1 2 Weiss, Lauren A.; Shen, Yiping; et al. (14 February 2008). "Association between Microdeletion and Microduplication at 16p11.2 and Autism". New England Journal of Medicine. 358 (7): 667–675. doi:10.1056/NEJMoa075974. PMID 18184952.
  4. 1 2 3 Fetit, Rana; Price, David J.; et al. (October 2020). "Understanding the clinical manifestations of 16p11.2 deletion syndrome: a series of developmental case reports in children". Psychiatric Genetics. 30 (5): 136–140. doi:10.1097/YPG.0000000000000259. ISSN 0955-8829. PMC 7497286. PMID 32732550.
  5. 1 2 3 Steinman, Kyle J.; Spence, Sarah J.; et al. (November 2016). "16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort". American Journal of Medical Genetics Part A. 170 (11): 2943–2955. doi:10.1002/ajmg.a.37820. PMID 27410714. S2CID 2469192.
  6. ↑ Zufferey, Flore; Sherr, Elliott H; et al. (October 2012). "A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders". Journal of Medical Genetics. 49 (10): 660–668. doi:10.1136/jmedgenet-2012-101203. PMC 3494011. PMID 23054248.
  7. ↑ Gill, Richard; Chen, Qixuan; et al. (December 2014). "Eating in the absence of hunger but not loss of control behaviors are associated with 16p11.2 deletions: 16p11.2 Deletion and Disinhibited Eating". Obesity. 22 (12): 2625–2631. doi:10.1002/oby.20892. PMID 25234362.
  8. ↑ Egolf, Laura E.; Vaksman, Zalman; et al. (September 2019). "Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma". The American Journal of Human Genetics. 105 (3): 658–668. doi:10.1016/j.ajhg.2019.07.020. PMC 6731370. PMID 31474320.
  9. ↑ Chung, Wendy K. (12 October 2011). "An Overview of Monogenic and Syndromic Obesities in Humans". Pediatr Blood Cancer. 58 (1): 122–128. doi:10.1002/pbc.23372. ISSN 1545-5009. PMC 3215910. PMID 21994130.
  10. ↑ Kleinendorst, Lotte; van den Heuvel, Lieke M.; et al. (September 2020). "Who ever heard of 16p11.2 deletion syndrome? Parents' perspectives on a susceptibility copy number variation syndrome". European Journal of Human Genetics. 28 (9): 1196–1204. doi:10.1038/s41431-020-0644-6. ISSN 1476-5438. PMC 7608422. PMID 32415274.
  11. ↑ Szelest, Monika; Stefaniak, Martyna; et al. (10 March 2021). "Three case reports of patients indicating the diversity of molecular and clinical features of 16p11.2 microdeletion anomaly". BMC Medical Genomics. 14 (1): 76. doi:10.1186/s12920-021-00929-8. ISSN 1755-8794. PMC 7945342. PMID 33691695.
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