Clinical characteristics: The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: structural or functional abnormalities of the kidney and urinary tract, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental or neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder, schizophrenia, anxiety, and bipolar disorder). Using a method of data analysis that avoids ascertainment bias, the authors determined that multicystic kidneys and other structural and functional kidney anomalies occur in 85% to 90% of affected individuals, MODY5 in approximately 40%, and some degree of developmental delay or learning disability in approximately 50%. MODY5 is most often diagnosed before age 25 years (range: age 10-50 years).
Diagnosis/testing: The diagnosis is established in a proband by detection of the 1.4-megabase (Mb) heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods.
Management: Treatment of manifestations: Treatment of kidney anomalies, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, eye abnormalities, congenital heart defects, seizures and sensorineural hearing loss should follow standard practice.
Surveillance: Kidneys and urinary tract: In the absence of known structural abnormalities, kidney and bladder ultrasound examination 12 months after establishing the diagnosis, then every 2-3 years in childhood/adolescence, then every 3-5 years in adulthood; presence of an abnormality may warrant more frequent monitoring. Annual monitoring of kidney function in individuals with abnormalities detected on kidney ultrasound examination; more frequent monitoring may be advised in those taking potentially nephrotoxic medications and/or known to have impaired kidney function. Routine monitoring of neurodevelopment through early childhood; full neuropsychological evaluation for children who experience difficulty with school. HbA1C annually to monitor for MODY5; self-monitoring by individuals and their families for clinical signs and symptoms of diabetes mellitus, such as polydipsia and polyuria. Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea. Consider annual hepatic function panel (or comprehensive metabolic panel), GGT, and lipid panel. Annual ophthalmologic evaluation during early childhood. Monitor those with seizures as clinically indicated. Hearing screening throughout childhood.
Agents/circumstances to avoid: Because kidney transplantation increases the risk for post-transplant diabetes mellitus, an immunosuppressive regimen that avoids tacrolimus and mammalian target of rapamycin (mTOR) inhibitors and reduces corticosteroid exposure may benefit those without preexisting diabetes mellitus. Nephrotoxic and hepatotoxic drugs should be avoided by individuals with kidney or liver abnormalities. For individuals with mental health conditions such as autism, schizophrenia, or bipolar disorder, careful consideration of antipsychotic agents that may lead to weight gain is recommended, as this potential increase has been associated with metabolic syndrome and the later development of diabetes mellitus, for which people with 17q12 deletions are at baseline increased risk. Likewise, the use of mood stabilizers that affect kidney function in the long term, such as lithium, should be carefully considered in the setting of potential underlying anatomic and functional abnormalities in people with 17q12 deletions.
Evaluation of relatives at risk: If one of the proband's parents has the 17q12 recurrent deletion, it is appropriate to test older and younger sibs of the proband and other relatives at risk in order to identify those who would benefit from close assessment/monitoring for evidence of genitourinary structural or functional defects, MODY5, and developmental delays / intellectual disability.
Genetic counseling: The 17q12 recurrent deletion is inherited in an autosomal dominant manner, with approximately 75% of deletions occurring de novo and approximately 25% inherited from a parent. If the 17q12 recurrent deletion identified in the proband is not found in one of the parents, the risk to sibs is presumed to be lower than 1% (but slightly greater than that of the general population because of the theoretic possibility of parental germline mosaicism for the deletion). Offspring of an individual with the 17q12 recurrent deletion have a 50% chance of inheriting the deletion. Prenatal testing and preimplantation genetic testing using genomic testing that will detect the 17q12 recurrent deletion are possible.
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