17q12 Recurrent Deletion Syndrome

Excerpt

Clinical characteristics: 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 [ASD], attention-deficit/hyperactivity disorder [ADHD], 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%-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-Mb heterozygous recurrent deletion at chromosome 17q12 by chromosomal microarray testing or other genomic methods.

Management: Treatment of manifestations: Treatment of kidney disease, neurodevelopmental and neuropsychiatric disorders, MODY5, genital tract abnormalities, liver abnormalities, hyperparathyroidism, eye abnormalities, exocrine pancreatic insufficiency, 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 two to three years in childhood/adolescence, then every three to five years in adulthood; presence of an abnormality may warrant more frequent monitoring. Monitor blood pressure, kidney function, serum concentration of magnesium, potassium, uric acid, urine magnesium, creatinine, and protein-to-creatinine ratio with frequency per nephrologist; more frequent monitoring may be advised in those with lab findings of kidney disease, those who are taking potentially nephrotoxic medications, and/or those with genitourinary structural abnormalities. Assess developmental progress and educational needs at each visit throughout childhood and adolescence; assess for features of ASD and ADHD at each visit in early childhood; full psychoeducational evaluation for children who experience difficulty with school or behavioral changes; assess for prodromal psychotic symptoms and bipolar disorder at each visit in adolescence. Annual hemoglobin A1c; educate individuals and their families for clinical signs and symptoms of diabetes mellitus. Consider reevaluation for uterine and vaginal abnormalities related to müllerian duct aplasia in pubertal females with primary amenorrhea. Hepatic function panel and GGT periodically; consider periodic lipid panel. Annual serum calcium and phosphorus to assess for hyperparathyroidism; annual ophthalmologic evaluation during early childhood. Fecal elastase-1 to test for exocrine pancreatic insufficiency in individuals with suggestive signs and symptoms. 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 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 (e.g., ASD, schizophrenia, or bipolar disorder), careful consideration of antipsychotic agents that may lead to weight gain, as this may lead to metabolic syndrome and diabetes mellitus, for which individuals with 17q12 recurrent deletion syndrome are at increased risk. 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 kidney abnormalities.

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: 17q12 recurrent deletion syndrome is inherited in an autosomal dominant manner, with approximately 75% of deletions occurring de novo and approximately 25% inherited from a parent. Each child of an individual with 17q12 recurrent deletion syndrome has a 50% chance of inheriting the deletion. Once the 17q12 recurrent deletion has been identified in an affected family member, prenatal and preimplantation genetic testing for 17q12 recurrent deletion syndrome are possible.