Clinical Description
The 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, schizophrenia, anxiety, and bipolar disorder).
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 (Table 2) using the following criteria:
Table 2.
17q12 Recurrent Deletion Syndrome: Frequency of Select Features
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Frequency | Features |
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Most common (>50%)
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Common (25%-50%)
| Maturity-onset diabetes of the young type 5 Female & male genital abnormalities Structural & functional liver abnormalities Eye abnormalities Structural &exocrine abnormalities of the pancreas Nonspecific structural brain findings Prematurity
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Less common (<25%)
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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]
Most Common Features (>50%)
Kidney disease. Structural kidney abnormalities and unspecified chronic kidney disease have been described in 257 individuals (Table 2). Cystic dysplastic kidneys and other structural kidney anomalies are reported in 130/148 (88%) individuals who were not ascertained through cohorts with kidney disease, making this feature the most commonly reported manifestation of the 17q12 recurrent deletion syndrome.
Cystic dysplasia is the most common kidney finding; other kidney and urinary tract abnormalities include poor cortico-medullary 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.
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].
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 36/81 (44%) 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]. Some studies suggest that hypomagnesemia may be underdiagnosed among children with HNF1B-related disorders, including 17q12 recurrent deletion [Kołbuc et al 2020]. 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, a HNF1B missense variant, or a 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]. 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 with those with HNF1B intragenic mutations (78%) [Dubois-Laforgue et al 2017b].
Neurodevelopmental/neuropsychiatric disorders. Several studies have identified an increased risk for neurodevelopmental and neuropsychiatric disorders, such as developmental delay, intellectual disability (mild to severe), autism spectrum disorder (ASD), and schizophrenia [Moreno-De-Luca et al 2010, Laliève et al 2020].
In a case-control study, Moreno-De-Luca et al [2010] identified the following number of individuals with the 17q12 recurrent deletion:
Eighteen of 15,749 individuals referred for developmental delay, intellectual disability, and/or ASD. Detailed phenotypic information for nine individuals revealed six with anxiety and/or phobias, one of whom was diagnosed with bipolar disorder. Because the 17q12
recurrent deletion was not detected in 4,519 controls, the authors concluded that the deletion confers a high risk for developmental brain disorders.
Four of 6,340 individuals from two large schizophrenia cohorts. Because the 17q12
recurrent deletion was not detected in 43,076 controls, the authors concluded that deletion also confers a high risk for schizophrenia.
Overall, about half (37/79) of individuals with the 17q12 recurrent deletion are reported to have some degree of learning disability, although phenotypic information about cognitive skills was limited in most studies. Speech and motor delay are common findings, reported in 78% and 68% of individuals, respectively. While not routinely assessed, autism or autistic features are described in 9% 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]. Learning difficulties, when noted, are most often described as mild. One study found that only 14/110 (12.7%) children with the 17q12 recurrent deletion required special school placement, which the researchers used as a proxy for severe neuropsychiatric disorder [Laliève et al 2020].
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, but 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]. While haploinsufficiency of HNF1B alone may not be sufficient to result in the cognitive and behavioral features associated with the 17q12 recurrent deletion, the role of HNF1B in neurologic impairment cannot be ruled out.
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, downslanting 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, 2-3 finger/toe syndactyly, and clinodactyly of the fifth finger are also frequently reported [Moreno-De-Luca et al 2010, Kasperavičiūtė et al 2011, Palumbo et al 2014].
Hyperparathyroidism. Nineteen of 36 (53%) individuals who had parathyroid hormone 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]. 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 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 who are post-transplant independent of genetics, the authors concluded that the weight of the evidence suggests that HNF1B haploinsufficiency causes hyperparathyroidism independent of associated kidney failure.
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 49/125 (39%) individuals with the 17q12 recurrent deletion 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 the 17q12 recurrent deletion is 50%.
While many individuals with 17q12 deletion 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 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].
In males, genital abnormalities include cryptorchidism, shawl scrotum, phimosis, urethral stenosis or obstruction, hypospadias, and epydidimary cysts [Nagamani et al 2010, Madariaga et al 2018, Lim et al 2020].
Structural and functional abnormalities of the liver. Elevated liver enzymes were reported in 64/133 (48%) 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 neonatal and 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, 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, and steatohepatitis [Roehlen et al 2018, Lim et al 2020]. 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 LFTs may be even more common (>50%).
Eye abnormalities. Fifteen of 37 (41%) reported individuals had eye findings that included strabismus [Vasileiou et al 2019], horizontal nystagmus [Cheroki et al 2008], posterior embryotoxon [Dixit et al 2012], hypermetropia [Moreno-De-Luca et al 2010], cataracts [Nagamani et al 2010], and coloboma [Raile et al 2009].
Structural and exocrine abnormalities of the pancreas. About one third (32/105) 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].
One retrospective cohort study involving both 17q12 deletions and HNF1B sequence variants found pancreatic exocrine insufficiency in 29/38 cases (76%) and structural pancreatic abnormalities in 62% of 95 individuals who had imaging [Dubois-Laforgue et al 2017b]. The study's authors did not differentiate between the groups of individuals, but reported no significant genotype/phenotype differences for this feature. Most other studies did not measure fecal elastase, but those that did reported a lower frequency of pancreatic exocrine insufficiency (2 of 8 cases) [Raile et al 2009, Quintero-Rivera et al 2014, Roehlen et al 2018].
Prematurity. Among 16 studies that reported premature birth (gestational age <37 weeks), 13 of 47 individuals (28%) were affected.
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 eight of 31 (26%) individuals. These abnormalities, which appeared to be nonspecific and to vary widely, included the following:
Less Common Features (<25%)
Congenital cardiac anomalies. Congenital heart defects are reported in nine of 45 (20%) 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, ventricular septal defect, transposition of the great arteries, pulmonary valve defect, tricuspid regurgitation, and patent ductus arteriosus [Hinkes et al 2012, Palumbo et al 2014, Roberts et al 2014, Vasileiou et al 2019, Du et al 2020].
Musculoskeletal. Nine of 39 (23%) individuals were reported to have short stature. Other musculoskeletal differences include joint laxity (5 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 three individuals [Moreno-De-Luca et al 2010, Goumy et al 2015, Rasmussen et al 2016]. One individual had duodenal atresia [Quintero-Rivera et al 2014] and two had esophageal abnormalities, including hiatus hernia caused by a short esophagus and dysphagia [Rasmussen et al 2016].
Seizures. Seven out of 50 cases (14%) reported seizure activity, including febrile seizures [Moreno-De-Luca et al 2010], partial complex seizures [Nagamani et al 2010], and mesial temporal lobe epilepsy requiring lobectomy [Kasperavičiūtė et al 2011].
Case Reports
Other reported physical findings include hypotonia (6 persons), prenatal oligohydramnios (4), macrocephaly (4), sensorineural hearing loss (3), deep vein thrombosis/vascular calcifications (2) and congenital diaphragmatic hernia (2).