Clinical Description
The 17q12 recurrent deletion syndrome is characterized by variable combinations of the three following findings: renal 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 164 individuals on whom sufficiently detailed phenotypic information was reported in 28 studies () using the following criteria:
Table 2.
Clinical Features of the 17q12 Recurrent Deletion Syndrome
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| Frequency | Features |
|---|
| Most Common (>50%) |
|
| Common (25%-50%) |
|
| Less Common (<25%) | Other endocrine Cardiac Musculoskeletal Gastrointestinal Seizures Macrocephaly Congenital diaphragmatic hernia Hypotonia Sensorineural hearing loss Hypoplastic, thick nails / onychodystrophy Prenatal oligohydramnios
|
Clinical data summarized from 27 studies, including 152 individuals with the 17q12 recurrent deletion 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, Haeri et al 2010, 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, 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]
Most Common Features (>50%)
Renal disease. Structural kidney abnormalities and unspecified chronic kidney disease have been described in 125 individuals (). Cystic dysplastic kidneys and other structural renal anomalies are reported in 73/88 (83%) 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 renal dysplasia is the most common renal finding; other renal and urinary tract abnormalities include poor cortico-medullary differentiation, prenatal hyperechogenicity, hydronephrosis, pyelectasis, vesicoureteral reflux, dilated ureter, single kidney (due to unilateral agenesis or involution of a cystic dysplastic kidney), duplex kidney, and horseshoe kidney.
Individuals may also present with tubulointerstitial disease, which is characterized by reduced urine-concentrating ability, hyperuricemia, hypomagnesemia, hypokalemia, bland urinary sediment, absent-to-minimal albuminuria/proteinuria, and slowly progressive renal 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 renal disease in individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Adalat et al 2009, Faguer et al 2011, Clissold et al 2015, Raaijmakers et al 2015, van der Made et al 2015].
The spectrum of severity and the age of detection of HNF1B-associated renal disease are broad, including prenatal severe renal failure, slow progression to end-stage renal disease (ESRD) in adulthood, and normal renal function never requiring renal replacement therapy [Edghill et al 2008, Haeri et al 2010, Heidet et al 2010, Faguer et al 2011, Madariaga et al 2013, Clissold et al 2015, Verhave et al 2016]. Available evidence suggests that the cause of HNF1B haploinsufficiency – 17q12 deletion, a HNF1B missense variant, or a HNF1B truncating variant (nonsense, frameshift, or splice site) – does not predict the type and severity of renal involvement [Heidet et al 2010, Faguer et al 2011, Raaijmakers et al 2015].
Progression to ESRD in childhood appears to be uncommon among individuals with HNF1B haploinsufficiency, including those with the 17q12 recurrent deletion [Heidet et al 2010, Bockenhauer & Jaureguiberry 2016]. While small studies of selected cohorts of adults have suggested that 12%-15% of individuals may progress to ESRD, the true risk is largely unknown [Chen et al 2010, Faguer et al 2011].
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 [Loirat et al 2010, Moreno-De-Luca et al 2010, Nagamani et al 2010].
In a case-control study, Moreno-De-Luca et al [2010] identified the following number of individuals with the 17q12 recurrent deletion:
18 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, 28/53 (53%) individuals with the 17q12 recurrent deletion are reported to have some degree of learning disability, although limited phenotypic information about cognitive skills was collected in most studies. Researchers report a diagnosis of intellectual disability in about 16% of individuals, while autistic features are described in 8% of individuals who were ascertained for other clinical findings.
Recent evidence suggests that genes other than HNF1B in the 17q12 region could be responsible for neurodevelopmental and neuropsychiatric features.
For instance, 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].The authors concluded that haploinsufficiency of HNF1B alone is not sufficient to result in the cognitive and behavioral features associated with the 17q12 recurrent 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, downslanting palpebral fissures, and high-arched eyebrows [Moreno-De-Luca et al 2010, Dixit et al 2012, Quintero-Rivera et al 2014, Goumy et al 2015, Laffargue et al 2015, Rasmussen et al 2016].
Hypoplastic nails, 2-3 finger/toe syndactyly, and clinodactyly of the 5th finger 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 28/70 (40%) 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 well over 50%.
Genital abnormalities. About one third of females and 25% 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, and hypoplastic uterus [Oram et al 2010].
In males, genital abnormalities include cryptorchidism [Mefford et al 2007, Raile et al 2009, Haeri et al 2010], shawl scrotum [Nagamani et al 2010], phimosis [Edghill et al 2008], urethral stenosis [Moreno-De-Luca et al 2010], and coronal hypospadias [Dixit et al 2012].
Liver. Elevated liver enzymes were reported in 29/73 (40%) individuals in cohorts ascertained for renal involvement, diabetes mellitus, and uterine malformations [Bellanné-Chantelot et al 2005, Mefford et al 2007, Edghill et al 2008, Oram et al 2010, Quintero-Rivera et al 2014, Rasmussen et al 2016]. Additional reported liver abnormalities included cysts, hepatomegaly, cholestasis, and steatohepatitis [Raile et al 2009, Rasmussen et al 2016].
Eye abnormalities. Twelve of 33 (36%) reported individuals had eye findings that included strabismus [Rasmussen et al 2016], 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].
Nonspecific structural brain findings. Structural brain anomalies were reported in seven of 28 (25%) individuals. These abnormalities, which appeared to be nonspecific and to vary widely, included the following:
Less Common Features (<25%)
Other endocrine. Pancreatic abnormalities (most often atrophy or small size) were reported in 10/50 (20%) individuals [Mefford et al 2007, Edghill et al 2008].
In one study three infants had neonatal hypercalcemia [Dixit et al 2012]. In another study two of 17 individuals had hypothyroidism [Edghill et al 2008].
Cardiac. Congenital heart defects, reported in seven of 31 individuals, ranged from mild (soft systolic murmur [Dixit et al 2012]) to more severe (right heart failure with tricuspid valve insufficiency [Hinkes et al 2012]). Other reported cardiac anomalies included increased aortic root size, transposition of the great arteries, pulmonary valve defect, and patent ductus arteriosus.
Musculoskeletal. Seven of 25 (28%) individuals were reported to have short stature. Other musculoskeletal differences include joint laxity (4 persons), long/slender hands and feet (4), pectus deformity (3), long fingers (2), and hip dysplasia (1).
Gastrointestinal. Gastroesophageal reflux disease (GERD) 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].
Other reported physical findings include hypotonia (6 persons), seizures (4), prenatal oligohydramnios (4), macrocephaly (4), sensorineural hearing loss (3), and congenital diaphragmatic hernia (2).
