Clinical Description
17q12 recurrent deletion syndrome is characterized by variable combinations of the following three most common findings: kidney abnormalities – including congenital abnormalities of the kidney and urinary tract (CAKUT) and tubulointerstitial disease – maturity-onset diabetes of the young (MODY), and neurodevelopmental/neuropsychiatric disorders (e.g., developmental delay, intellectual disability, autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], schizophrenia, anxiety, and bipolar disorder). In families with more than one affected individual, significant intrafamilial variability has been reported.
To calculate the frequency rates for these features reported in 17q12 recurrent deletion syndrome, the authors reviewed phenotypic information for 282 individuals on whom sufficiently detailed phenotypic information was reported in 42 studies (see Table 2) using the following criteria:
Table 2.
17q12 Recurrent Deletion Syndrome: Frequency of Select Features
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Frequency | Features |
---|
Most common
(>50%)
|
|
Common
(25%-50%)
| Maturity-onset diabetes of the young type 5 Female & male genital abnormalities Structural & functional liver abnormalities Hyperparathyroidism Eye abnormalities Structural & exocrine abnormalities of the pancreas Prematurity Nonspecific structural brain findings
|
Less common
(<25%)
|
|
Clinical data summarized from 42 studies, including 282 individuals in whom the 17q12 recurrent deletion was identified [Bellanné-Chantelot et al 2005, Faguer et al 2007, Mefford et al 2007, Cheroki et al 2008, Edghill et al 2008, Bernardini et al 2009, Raile et al 2009, Loirat et al 2010, Moreno-De-Luca et al 2010, Nagamani et al 2010, Oram et al 2010, Kasperavičiūtė et al 2011, Nik-Zainal et al 2011, Dixit et al 2012, George et al 2012, Grozeva et al 2012, Hendrix et al 2012, Hinkes et al 2012, Sanna-Cherchi et al 2012, Ferrè et al 2013, Palumbo et al 2014, Quintero-Rivera et al 2014, Roberts et al 2014, Stefansson et al 2014, Goumy et al 2015, Laffargue et al 2015, Verbitsky et al 2015, Rasmussen et al 2016, Dubois-Laforgue et al 2017a, Madariaga et al 2018, Roehlen et al 2018, Stiles et al 2018, Dotto et al 2019, Li et al 2019, Okorn et al 2019, Vasileiou et al 2019, Bustamante et al 2020, Du et al 2020, Kołbuc et al 2020, Lim et al 2020, Sztromwasser et al 2020, Berberich et al 2021, Cleper et al 2021, Milone et al 2021, Motyka et al 2021, Cheng et al 2022, Thewjitcharoen et al 2022, Kumar et al 2023, Oh et al 2023, Xin & Zhang 2023, Chen et al 2024, Hasegawa et al 2024, Kołbuc et al 2024, Lee et al 2024, Song et al 2024, Verscaj et al 2024]
Most Common Features (>50%)
Kidney disease. Structural kidney abnormalities and unspecified chronic kidney disease have been described in 294 individuals. Cystic dysplastic kidneys and other structural kidney anomalies are reported in 167/193 (87%) individuals who were not ascertained through cohorts with kidney disease, making this feature the most commonly reported manifestation of 17q12 recurrent deletion syndrome.
Cystic dysplasia is the most common kidney finding; other structural kidney and urinary tract abnormalities include poor corticomedullary differentiation, collecting system abnormalities (duplicated collecting system, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter), single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), and horseshoe kidney. Prenatal imaging most often shows kidney cysts or echogenic kidneys, but in many individuals (35%) findings may not develop until childhood or later [Verscaj et al 2024].
Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine-concentrating ability, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, hyperuricemia, hypomagnesemia, hypokalemia, and slowly progressive kidney disease; interstitial fibrosis and tubular atrophy are seen on biopsy (although biopsy is not routinely indicated) [Eckardt et al 2015, Verhave et al 2016]. Of note, autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by HNF1B haploinsufficiency (frequently due to 17q12 deletion) is designated ADTKD-HNF1B [Eckardt et al 2015].
Renal tubular wasting of magnesium resulting in hypomagnesemia is common and can be the initial and predominant manifestation of kidney disease in individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Clissold et al 2015, Raaijmakers et al 2015, van der Made et al 2015]. Hypomagnesemia is reported in 46/107 (43%) individuals with 17q12 recurrent deletion and can be severe [Ferrè et al 2013, Madariaga et al 2018, Dotto et al 2019, Li et al 2019, Okorn et al 2019, Berberich et al 2021, Cleper et al 2021, Motyka et al 2021, Cheng et al 2022, Thewjitcharoen et al 2022, Xin & Zhang 2023, Hasegawa et al 2024, Lee et al 2024, Verscaj et al 2024]. Some studies suggest that hypomagnesemia may be underdiagnosed among children with HNF1B-related disorders, including 17q12 recurrent deletion, and may be present in as many as 59% when using age-appropriate norms for children [Kołbuc et al 2024]. In adults, renal tubular magnesium wasting can be diagnosed through an elevated fractional excretion of magnesium (FEMg >2%) in individuals with normal kidney function.
The spectrum of severity and range in age of detection of HNF1B-associated kidney disease are broad, including prenatal severe kidney failure, slow progression to end-stage kidney disease (ESKD) in adulthood, and normal kidney function never requiring kidney replacement therapy [Madariaga et al 2013, Clissold et al 2015, Verhave et al 2016]. While initial evidence suggested that the cause of HNF1B haploinsufficiency – 17q12 deletion, an HNF1B missense variant, or an HNF1B truncating variant (nonsense, frameshift, or splice site) – did not predict the type and severity of kidney involvement [Raaijmakers et al 2015], more recent evidence indicates that intragenic HNF1B pathogenic variants may be associated with worse kidney function and higher risk of progression to ESKD compared to 17q12 deletions [Dubois-Laforgue et al 2017b, Clissold et al 2018, Buffin-Meyer et al 2024]. The reason for this finding is unknown, but the authors speculate a possible dominant-negative effect of certain HNF1B variants resulting in a more severe phenotype, or a protective effect conferred by the loss of one or more genes in the 17q12 recurrent deletion region.
Progression to ESKD in childhood appears to be uncommon among individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Bockenhauer & Jaureguiberry 2016]. In a large retrospective cohort study, progression to ESKD was less common among adults with 17q12 deletion at follow up (51%) compared to those with HNF1B intragenic pathogenic variants (78%) [Dubois-Laforgue et al 2017b].
Neurodevelopmental/neuropsychiatric disorders. Deletions in 17q12 increase the risk of developing diverse neurodevelopmental or neuropsychiatric conditions. The studies that support these observations have taken complementary approaches, including (1) studying the different genetic findings identified in people with the same clinical diagnoses (phenotype first), and (2) studying the clinical features that occur in people who all share the same genetic cause (genotype first).
A recent large phenotype-first population study has established that, out of all recurrent deletions studied, deletions in 17q12 have the strongest association with ASD (hazard ratio [HR] 7.79, 95% CI 2.71-22.43) and ADHD (HR 4.24, 95% CI 1.29-13.92), and show a very strong trend toward increasing the chances of developing schizophrenia spectrum disorders (HR 4.84, 95% CI 0.81-28.85) [Vaez et al 2024]. This study has multiple strengths, including estimating effect sizes from the general population rather than from participants who are already engaged in the health care system, which could result in a bias toward more severe clinical phenotypes; and including multiple other recurrent copy number variants that help put into context the magnitude of the associations with neuropsychiatric and neurodevelopmental conditions.
Genotype-first studies have shown that ASD and schizophrenia are among the clinical features most strongly associated with 17q12 deletions and can be observed more frequently in people with this deletion compared to the general population. While not routinely assessed, ASD or autistic features are described in 13% of individuals ascertained for other clinical findings [Raile et al 2009, Loirat et al 2010, Dixit et al 2012, Palumbo et al 2014, Roberts et al 2014, Goumy et al 2015, Laffargue et al 2015, Rasmussen et al 2016, Li et al 2019, Vasileiou et al 2019, Lim et al 2020, Cleper et al 2021, Verscaj et al 2024]. One study found that 14/110 (13%) children with 17q12 recurrent deletion syndrome required special school placement, which the researchers used as a proxy for severe neuropsychiatric disorder [Laliève et al 2020]. In addition, global developmental delay, intellectual disability, ADHD, and bipolar disorder have been described in individuals with 17q12 deletions [Moreno-De-Luca et al 2010, Laliève et al 2020].
Moreover, speech and motor delay are common findings, reported in 56% and 64% of individuals, respectively. Overall, about half (41/89) of individuals with 17q12 recurrent deletion syndrome are reported to have some degree of learning disability, although phenotypic information about cognitive skills was limited in most studies. Learning difficulties, when noted, are most often described as mild.
Some studies suggest that genes other than HNF1B in the 17q12 region could be responsible for neurodevelopmental and neuropsychiatric features, although evidence is mixed. One study found that individuals with the recurrent 17q12 deletion, not an HNF1B intragenic pathogenic variant, exhibited neurodevelopmental disorders, psychopathology, and autistic traits [Clissold et al 2016]; however, other studies have found that both groups of HNF1B-related disorders are associated with an increased risk of intellectual disability [Dubois-Laforgue et al 2017a, Laliève et al 2020]. These findings were summarized in a recent review, where neurodevelopmental disorders seem to occur in about 25% of individuals with a recurrent 17q12 deletion, and in 6.8% of those with an HNF1B intragenic variant [Nittel et al 2023]. While haploinsufficiency of HNF1B alone may not be sufficient to result in the cognitive and behavioral features associated with the 17q12 recurrent deletion, HNF1B appears to contribute in part to the risk for neurodevelopmental disorders conferred by 17q12 deletion.
Dysmorphic features. Subtle but highly variable dysmorphic features are described for most individuals for whom this information is available. The most commonly described features include high forehead, frontal bossing, depressed nasal bridge, deep-set eyes, full cheeks, downslanted palpebral fissures, high palate, and high-arched eyebrows [Moreno-De-Luca et al 2010, Laffargue et al 2015, Rasmussen et al 2016, Roehlen et al 2018, Vasileiou et al 2019].
Hypoplastic nails and 2-3 finger/toe syndactyly are also frequently reported [Moreno-De-Luca et al 2010, Kasperavičiūtė et al 2011, Palumbo et al 2014].
Common Features (25%-50%)
Maturity-onset diabetes of the young type 5 (MODY5) is most often diagnosed before age 25 years (range: 10-50 years) [Bellanné-Chantelot et al 2005].
Overt diabetes mellitus and abnormal blood glucose levels and/or insulin response are reported in 58/155 (37%) individuals with 17q12 recurrent deletion syndrome not ascertained from cohorts with diabetes mellitus; however, this is almost certainly an underestimate of the lifetime prevalence, since many individuals described in the literature are children and young adults who may not yet have developed manifestations of diabetes. When cohorts with diabetes mellitus are considered, prevalence of MODY5 among individuals with 17q12 recurrent deletion syndrome is 50%.
While many individuals with 17q12 recurrent deletion syndrome with MODY5 have some residual insulin secretion at the time of diagnosis, one study found that 79% required insulin therapy by ten-year follow up [Dubois-Laforgue et al 2017b].
Genital abnormalities. About one third of females and one quarter of males have genital abnormalities.
In females, the most commonly reported finding is partial or complete absence of the upper part of the vagina, cervix, and uterus, often referred to as müllerian aplasia or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [Bernardini et al 2009]. Other reported uterine abnormalities include bicornuate uterus, uterus didelphys, hypoplastic uterus, and ovarian cysts [Oram et al 2010, Stiles et al 2018, Vasileiou et al 2019, Kumar et al 2023, Lee et al 2024, Song et al 2024].
In males, genital abnormalities include cryptorchidism, shawl scrotum, phimosis, urethral stenosis or obstruction, hypospadias, epididymal cysts, prostate cyst, and enlarged scrotum [Nagamani et al 2010, Madariaga et al 2018, Lim et al 2020, Xin & Zhang 2023, Hasegawa et al 2024, Verscaj et al 2024].
Structural and functional abnormalities of the liver. Elevated liver enzymes and/or structural abnormalities were reported in 74/171 (43%) individuals in cohorts ascertained for kidney involvement, diabetes mellitus, and uterine malformations [Rasmussen et al 2016, Dubois-Laforgue et al 2017a, Okorn et al 2019]. Liver involvement ranges from asymptomatic elevation of hepatic transaminase enzyme levels to adult-onset cholestasis [Kotalova et al 2015, Pinon et al 2019]. Neonatal cholestasis with paucity of interlobular bile ducts and variable periportal fibrosis has also been reported in several infants with 17q12 recurrent deletion syndrome, including one who required portoenterostomy and one who developed hepatocellular carcinoma requiring liver transplantation [Pinon et al 2019]. Additional reported liver abnormalities include choledochal and common bile duct cysts, hepatomegaly, steatohepatitis, and hypoplasia with portal vein thrombosis [Roehlen et al 2018, Lim et al 2020, Lee et al 2024]. One study reported an even higher frequency of abnormal liver function tests (71%) in a large cohort that included both intragenic HNF1B variants and 17q12 deletions [Dubois-Laforgue et al 2017b]. While the study's authors did not differentiate between genotypes, no statistically significant genotype-phenotype correlations were reported, suggesting that elevated liver function tests may be even more common (>50%).
Hyperparathyroidism. Twenty of 45 (44%) individuals who had parathyroid hormone (PTH) plasma levels tested were found to have hyperparathyroidism [Ferrè et al 2013, Li et al 2019, Kołbuc et al 2020, Lim et al 2020, Berberich et al 2021, Cleper et al 2021]. Furthermore, one study reported transient neonatal hypercalcemia and hypophosphatemia, the combination of which is suggestive of hyperparathyroidism, although PTH levels were not specifically measured to confirm [Dixit et al 2012]. Another study demonstrated that HNF1B (hepatocyte nuclear factor 1-beta, encoded by HNF1B) is expressed in the parathyroid gland and acts as a transcriptional repressor of PTH [Ferrè et al 2013]. Additionally, this study found that PTH levels remained increased even after kidney transplantation and normalized magnesium levels in some individuals. Although hyperparathyroidism is persistent in 20%-50% of individuals following kidney transplant regardless of the cause of kidney disease, the authors concluded that the weight of the evidence suggests that HNF1B haploinsufficiency causes hyperparathyroidism independent of associated kidney failure.
Eye abnormalities. Twenty-four of 66 (36%) reported individuals had eye findings that included strabismus [Vasileiou et al 2019, Kumar et al 2023, Verscaj et al 2024], esotropia [Milone et al 2021, Verscaj et al 2024], nystagmus [Cheroki et al 2008, Milone et al 2021], posterior embryotoxon [Dixit et al 2012], hypermetropia [Moreno-De-Luca et al 2010, Verscaj et al 2024], high myopia [Milone et al 2021], cataracts [Nagamani et al 2010, Oh et al 2023, Verscaj et al 2024], coloboma [Raile et al 2009], parapapillary dystrophy [Milone et al 2021], Purtcher-like retinopathy [Oh et al 2023], diabetic retinopathy [Lee et al 2024], and keratoconus requiring corneal transplant [Hasegawa et al 2024].
Structural and exocrine abnormalities of the pancreas. About one third (39/113) of individuals with imaging results were found to have some morphologic abnormality of the pancreas, most often hypoplasia, atrophy, and/or agenesis of the body and tail [Madariaga et al 2018, Roehlen et al 2018, Dotto et al 2019, Kołbuc et al 2020, Motyka et al 2021, Kumar et al 2023, Thewjitcharoen et al 2022, Xin & Zhang 2023, Hasegawa et al 2024, Lee et al 2024, Song et al 2024]. Two studies identified exocrine pancreatic insufficiency (EPI), defined as fecal elastase-1 level <200 µg/g, in 37/67 (55%) of individuals with either 17q12 deletion or HNF1B pathogenic variant [Dubois-Laforgue et al 2017b, Clissold et al 2018]. These publications did not provide case-level data sufficient to allow calculation of the frequency of EPI among those with a deletion specifically, although Dubois-Laforgue et al [2017b] reported no significant genotype-phenotype correlations for this feature. Several small studies reported EPI in 2/9 (22%) individuals with the 17q12 deletion [Raile et al 2009, Quintero-Rivera et al 2014, Roehlen et al 2018]. Structural anomalies of the pancreas and EPI occur more commonly, but not exclusively, when diabetes mellitus is present.
Prematurity. Among 20 studies that reported gestational age in infants with 17q12 recurrent deletion syndrome, 16/55 individuals (29%) were born prematurely (<37 weeks).
Nonspecific structural brain findings. No systematic neuroimaging studies of cohorts with 17q12 recurrent deletion syndrome have been published. Among publications describing neuroimaging findings, structural brain anomalies were reported in 10/37 (27%) individuals. These abnormalities, which appeared to be nonspecific and to vary widely, include the following:
Less Common Features (<25%)
Congenital heart anomalies are reported in 10/52 (19%) individuals, ranging from mild to severe. Cardiac anomalies include right heart failure with tricuspid valve insufficiency, increased aortic root size, aortic insufficiency, coarctation of the aorta, bicuspid aortic valve, ventricular septal defect, transposition of the great arteries, pulmonary valve defect, tricuspid regurgitation, patent ductus arteriosus, patent foramen ovale, and mitral valve prolapse [Hinkes et al 2012, Palumbo et al 2014, Roberts et al 2014, Vasileiou et al 2019, Du et al 2020, Cleper et al 2021, Verscaj et al 2024].
Musculoskeletal. Eleven of 47 (23%) individuals were reported to have short stature. Other musculoskeletal differences include joint laxity (8 persons), long/slender hands and feet (4), pectus deformity (3), fifth finger clinodactyly (3), single transverse palmar crease (1), and hip dysplasia (1).
Other gastrointestinal features. Gastroesophageal reflux disease was reported in four individuals [Moreno-De-Luca et al 2010, Goumy et al 2015, Rasmussen et al 2016, Cheng et al 2022]. Congenital diaphragmatic hernia was reported in two individuals. Two individuals had duodenal atresia [Quintero-Rivera et al 2014, Verscaj et al 2024] and two had esophageal abnormalities, including hiatal hernia caused by a short esophagus and dysphagia [Rasmussen et al 2016]. There has been one report of gastroparesis [Xin & Zhang 2023].
Seizures. Ten of 84 individuals (12%) had seizure activity, including febrile seizures [Moreno-De-Luca et al 2010], partial complex seizures [Nagamani et al 2010], tonic-clonic seizures [Cleper et al 2021], and mesial temporal lobe epilepsy requiring lobectomy [Kasperavičiūtė et al 2011].
Other
Hypotonia (6 persons)
Macrocephaly (6)
Prenatal oligohydramnios (4)
Sensorineural hearing loss (4)
Deep vein thrombosis / vascular calcifications (2)
Ovarian carcinoma (1)
Dyslipidemia (1)