Schinzel–Giedion syndrome

Touge, Hiroshi; Fujinaga, Takuji; Okuda, Masumi; H, Aoshi

doi:10.1046/j.1442-2042.2001.00291.x

Cited by 16 publications

(14 citation statements)

References 10 publications

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“…Typically, SGS patients have large fontanelles (n = 37/41), a prominent forehead (n = 41/44), bitemporal narrowing (n = 32/36), shallow orbits or prominent eyes (n = 36/38), hypertelorism (n = 36/42) a retracted and shortened midface (n = 45/45) and full cheeks, leading to a facial frontal silhouette in the shape of a number eight [19]. Additionally, most patients have a deep groove under the eyes (n = 38/39), upslanting palpebral fissures (n = 21/26) and a short nose with a bulbous nasal tip (n = 43/44).…”

Section: Resultsmentioning

confidence: 99%

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

et al. 2017

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Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

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Section: Resultsmentioning

confidence: 99%

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

et al. 2017

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“…Prior to delivery, polyhydramnios was noted with Patient 1. Among nine SGS patients for whom prenatal findings were reported, polyhydramnios was observed in two and fetal hydronephrosis in six . Polyhydramnios is caused by excess production of amniotic fluid or poor swallowing of amniotic fluid by the fetus.…”

Section: Discussionmentioning

confidence: 99%

“…Prenatal ultrasonography thus predicted hydronephrosis in six of the nine fetuses for which findings have been reported. Touge et al reported that many SGS patients displayed several types of urinary tract anomalies, such as pyeloureteral junction stenosis, ureterovesical junction stenosis, and vesicoureteral reflux. These anomalies caused hydronephrosis with or without hydroureter.…”

Section: Discussionmentioning

confidence: 99%

Genetic and prenatal findings in two Japanese patients with Schinzel–Giedion syndrome

Hishimura

Watari

Ohata

et al. 2016

Clinical Case Reports

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“…Only 36 cases have been reported to date [37][38][39]. Common features include normal intrauterine growth and gestation with severe intellectual disability and low physical growth after birth, coarse facial appearance with midfacial hypoplasia, abnormal auricles and deep groves under eyes.…”

Section: Vesicoureteral Refluxmentioning

confidence: 96%

“…Common features include normal intrauterine growth and gestation with severe intellectual disability and low physical growth after birth, coarse facial appearance with midfacial hypoplasia, abnormal auricles and deep groves under eyes. Epilepsy, spasms, hydronephrosis and genital anomalies are also frequent findings [38]. About half of patients die before 2 years of age due to respiratory failure, epilepsy and infection.…”

Section: Vesicoureteral Refluxmentioning

confidence: 99%

Prenatally detected ureteropelvic junction obstruction: clinical features and associated urologic abnormalities

et al. 2008

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Urologic congenital anomalies associated with ureteropelvic obstruction (UPJO) have been previously characterized; however, less data are available regarding these associations in a prenatally diagnosed population. A retrospective study was conducted to evaluate significant clinical features and urological anomalies associated with prenatally diagnosed UPJO. The records of 143 children with prenatally diagnosed hydronephrosis secondary to UPJO were retrospectively reviewed. The gender, side of obstruction, degree of hydronephrosis, associated clinical features, and urological anomalies were noted. Hundred and forty-three children (M/F = 2.7) with a total of 198 affected renal units (RU) presenting with unilateral (61%) or bilateral (39%) UPJO were enrolled. In cases of unilateral obstruction, the left side was affected in 60 children (68%). The grade of hydronephrosis was Grade 1 in 56 RU (28%), Grade 2 in 51 RU (26%), Grade 3 in 50 RU (25%) and Grade 4 in 41 RU (21%). Associated clinical features included prematurity (n = 7, 4.9%), twinning (n = 5, 3.5%) and presentation with renal failure (RF) (n = 2). Excluding contralateral UPJO, other urologic anomalies were encountered in 29 patients (20.3%). Associated vesicoureteral reflux (VUR) was encountered in 11 patients (7.7%, M/F = 2.7). Pyeloplasty was required more often in children with associated VUR (54.5 vs. 18.2%) (P = 0.01). Contralateral multicystic dysplastic kidney (MCDK) was encountered in six patients (M/F = 2), one of whom presented with RF. One child carried the diagnosis of Schinzel-Giedion syndrome (SGS), demonstrating severe developmental and neurological disorders and bilateral hydronephrosis. The more frequent occurrence of UPJO in males with predominantly left-sided location, association with VUR and MCDK, and increased frequency of bilaterality in our prenatally diagnosed patients were similar to historical reports. In addition, prematurity and twinning were independently associated with UPJO. The higher rate of pyeloplasty in patients with associated reflux warrants further investigation.

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Schinzel–Giedion syndrome

Cited by 16 publications

References 10 publications

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Genetic and prenatal findings in two Japanese patients with Schinzel–Giedion syndrome

Prenatally detected ureteropelvic junction obstruction: clinical features and associated urologic abnormalities

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