Table 1 List of gene studies, including title, sample size, study design, results, and limitations

Aretz et al. (2007) [4]

High proportion of large genomic deletions and a genotype–phenotype update in 80 unrelated families with juvenile polyposis syndrome

80 patients, 65 of which were confirmed JPS, 15 suspected

Retrospective gene study

To characterise the frequency of large genomic deletions in SMAD4 and BMPR1A genes

Via gene sequencing, point mutations were identified in 30 patients (46%; SMAD4 = 17, BMPR1A = 13). Of SMAD4 point mutations, 11 led to truncated proteins (5 nonsense, 6 frameshift). 4 missense mutations were located in highly conserved AA positions (2 de novo, 1 mosaic). Large genomic deletions were found in 14% of all patients with typical JPS (SMAD4 = 6, BMPR1A = 3). From SMAD4, 4 had heterozygous deletion of all SMAD probes, the other 2 deleted coding exons from 6–11. SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than BMPR1A carriers (8%). All 7 cases of gastric cancer occurred in families with SMAD4 mutations. In 22% of the SMAD4 carriers, HHT was also diagnosed clinically (n = 5, 22%).

Small patient numbers, thus limited statistical analysis

Aytac et al. (2014) [5]

Oncologic outcomes and survival in juvenile polyposis syndrome with BMPR1A or SMAD4 mutation

35 JPS patients (SMAD4 n = 27, BMPR1A n = 8)

Prospective study, ~ 12 year follow-up

To evaluate oncologic outcomes in JPS patients with SMAD4 or BMPR1A gene mutations

Colonic phenotype (including rectal polyps) was similar between patients with SMAD4 and BMPR1A mutations, though SMAD4 mutations were associated with high gastric polyp numbers. Small bowel polyps diagnosed in 5 patients. No cancer in BMPR1A group, but 4 men with SMAD4 mutations developed cancer, wth a GI cancer risk of 11% (3/27). 2 patients with SMAD4 died during follow-up, all suggesting SMAD4 genotype is associated with more aggressive upper GI manifestations of JPS.

N/A

Aytac et al. (2015) [6]

Genotype-defined cancer risk in juvenile polyposis syndrome

35 JPS patients with mutations in either BMPR1A (8) or SMAD (27)

Prospective study

To investigate the impact of genotype on cancer risk and oncological phenotype in patients with JPS with a SMAD4 or BMPR1A gene mutation

Colonic phenotype was similar between patients with SMAD4 and BMPR1A mutations, where SMAD4 mutations were associated with larger gastric polyp numbers (14 with > 50 polyps). Small bowel juvenile polyps were diagnosed in 14 patients with SMAD4, and 2 with BMPR1A. No patient was diagnosed with cancer in the BMPR1A group, whereas four men with SMAD4 mutation developed GI or extra-intestinal cancer. The GI cancer risk in patients with JPS and SMAD4 mutation was 11%.

Retrospective nature of study and small patient numbers

Barlas et al. (2012) [8]

Follow-up of juvenile polyposis syndrome patients with BMPR1A or SMAD4 mutation

20 JPS patients (SMAD4 n = 15, BMPR1A n = 5)

Prospective study

To report clinical and natural history differences in JPS patients based on their underlying mutation

Of the 15 SMAD + ve JPS patients, 9 had a family history of JPS (while none of the BMPR1A + ve patients did). 10 of the 15 patients with SMAD4 mutations also had HHT. 7/15 had gastric polyps, where there were none in the BMPR1A group.

N/A

Blatter et al. (2015) [11]

Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers

25 polyps from 3 patients

Clinicopathological analysis

To evaluate the frequency and nature of the 2nd-hit mutations in juvenile polyposis in a series of 25 polyps from SMAD4 and BMPR1A mutation carriers, assessing their compartmental localisation

25 polyps from 3 patients were screened carrying either a pathogenic SMAD4 variant (c.1244-1246delACAG) or BMPR1A variant. No somatic alterations could be identified in the 14 SMAD4-related polyps. SMAD4 protein expression, however, was lost in 8 of 14 (57%) juvenile polyps. LOH was gene copy number neutral and had occurred in the epithelial compartment.

Nil mentioned

Blatter et al. (2020) [10]

Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers

221 JPS patients from ten European centres from 126 kindreds 473 carriers of SMAD4/BMPR1A from the literature

Retrospective study Questionnaire-based data analysis

To gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases

Compared to BMPR1A carriers, SMAD4 carriers displayed anaemia twice as often (58% vs 26%), and exclusively showed overlap symptoms with HHT (32%) with an increased prevalence of gastric juvenile polyps (39% vs 13%). Cancer was reported in 15% of JPS patients, mainly in the colorectum (62%; SMAD4: 58%, BMPR1A: 88%) and the stomach (21%; SMAD4: 27%, BMPR1A: 0%). SMAD4 DCV carriers displayed a more severe gastric phenotype and HHT overlap phenotype. SMAD4 missense DCVs diplayed younger median age at diagnosis (10.5y) compared to frameshift (28.0y).

Possible ascertainment ± selection bias given retrospective study. Differences in patient data collection and medical record completeness may impact data quality and comparability. Potential underestimations of phenotypic features if not specifically searched for

Bonjean et al. (2013) [12]

Clinical expression of hereditary haemorrhagic telangiectasia and digestive lesion characteristics in patients with SMAD4 mutation

14 SMAD + ve HHT patients (out of 589 HHT patients)

Retrospective analysis

To define clinical expression of HHT and GI lesions in HHT patients with SMAD4 mutation

Of the 14 SMAD + ve HHT patients, symptoms included: epistaxis (13), telangiectasia (11), pulmonary venous malformations (9). More severe symptoms included diffuse/multiple PVMs causing hypoxemia (4) and severe hepatic AVM with high cardiac output (3/11). 11 had endoscopies, where 10 (91%) had digestive lesions, with 4 confirming a JP diagnosis—with 5 upper GI and 9 lower GI lesions.

Small cohort

Calva-Cerqueira et al. (2009) [20]

The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis

102 JPS patients

Retrospective gene study

To determine the overall prevalence of genetic changes of SMAD4 and BMPR1A by sequencing and by screening for larger deletions

Via gene sequencing, 20 JPS patients had point mutations of SMAD4, 22 of BMPR1A. By multiplex ligation-dependent sequencing, one proband had deletion of most of SMAD4, one of both BMPR1A & PTEN, one of the 5' end of BMPR1A & another at the 5' end of SMAD4. Overall prevalence of SMAD4/BMPR1A point mutations was 45%, with large deletions being less frequent, though can represent other heritable causes of JPS which should be screened for (e.g. promoter region, non-coding exons, introns, 3' untranslated region).

Nil mentioned

Duan et al. (2019) [29]

SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections

223 families with HTAD (heritable thoracic aortic disease)

Retrospective gene study

To characterise SMAD4 rare variants in patients with thoracic aortic aneurysm/dissection

A SMAD4 heterozygous variant, c.290G > T, p.(Arg97Leu) was identified in a family with thoracic aortic disease and no evidence of HHT or JPS. In addition, two rare variants were identified in individuals with early age of onset of thoracic aortic dissection. These results suggest that SMAD4 rare missense variants can lead to thoracic aortic disease in individuals who do not have JPS or HHT. It is hypothesised that the missense variant in MH1 domain of SMAD4 leads to unstable protein and segregates with thoracic aortic disease in absence of JPS/HHT.

Additional studies needed to validate and determine the frequency of SMAD4 variants leading to thoracic aortic disease in absence of features of JPS/HHT

Friedl et al. (1999) [33]

Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients

11 unrelated patients with familial JP

Retrospective gene study

To evaluate the proportion of SMAD4 mutations in familial juvenile polyposis (FJP)

Through gene sequencing, 3/11 patients had SMAD 4 mutations. A 4-bp deletion (1372-1375delACAG) in exon 9 was observed in two unrelated patients. A novel mutation was found also, 959-960delAC at codon 277, exon 6.

Nil mentioned

Friedl et al. (2002) [34]

Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers

29 JPS patients

Retrospective gene study

To assess possible genotype–phenotype correlations in JPS

Germline MADH4 mutations were found in 24% cases (7) and BMPR1A in 17% (5). Prevalence of massive gastric polyposis was observed in patients with MADH4 mutations (4/7), when compared to BMPR1A. Of the SMAD4 mutations, all but one mutation resulted in a truncated protein, where 6/7 were located within the highly conserved MH2-region.

Not mentioned

Gallione et al. (2004) [36]

A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)

7 unrelated families with JP-HHT (13 total patients)

Retrospective gene study

To investigate the underlying aetiology of JP-HHT syndrome, via characterising individuals with this phenotype clinically and molecularly

Mutations in MADH4 were identified in all affected individuals with the combined phenotype. Mutations included 4 missense, 1 nonsense, and 2 frameshift mutations in exons 8, 9, 11 of MADH4 (i.e. COOH terminus). 3 had de novo mutations in MADH4, also exhibiting the combined syndrome. Individuals with MADH4 mutation showed phenotypes of both disorders, phenotypes including: multiple juvenile polyps, plus telangiectases (9), epistaxis (9), pulmonary AVM (7), clubbing/osteoarthropathy (7)

Nil mentioned

Gallione et al. (2006) [37]

SMAD4 mutations found in unselected HHT patients

30 unrelated HHT patients without apparent history of JP

Retrospective gene study

To characterise the frequency of SMAD4 mutations in HHT patients without a history of JP

10% (n = 3) harboured mutations in SMAD4, similar to those found in other patients with JP-HHT syndrome—found in the COOH terminus of SMAD4, where all mutations in previously reported JP-HHT cases have been identified.

Nil mentioned

Gallione et al. (2010) [35]

Overlapping spectra of SMAD4 mutations in juvenile polyposis and JP-HHT syndrome

19 JP-HHT patients, 15 SMAD4 mutations

Retrospective gene study

To evaluate whether the originally observed genotype:phenotype correlation is valid (i.e. mutations clustered within MH2 domain)

Although SMAD4 mutations in JP-HHT have a tendency to cluster in the MH2 domain (13/15), mutations in other parts of the gene also cause the combined syndrome (2/15) i.e. any mutation in SMAD4 can cause JP-HHT. Thus, any patient who tests positive for any SMAD4 mutation should be considered at risk for the combined JP-HHT syndrome & be monitored accordingly.

Nil mentioned

Gonzalez et al. (2017) [40]

Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases

22 patients with abundant juvenile-type or hyperplastic-like polyps, 14 diagnosed with JPS

Clinicopathological analysis

To evaluate the clinicopathological features of 22 patients with gastric juvenile-type or hyperplastic-like polyps

SMAD4 immunohistochemical staining showed patchy loss in polyps from 19 of 20 cases tested. 5 of 6 patients tested had a germline SMAD4 mutation. Massive gastric juvenile-type polyposis can occur in patients with and without known JPS, where SMAD4 mutation appears to be the greatest risk factor for upper tract involvement.

Not mentioned

Handra-Luca et al. (2005) [41]

Vessels' morphology in SMAD4 and BMPR1A-related juvenile polyposis

42 JPS patients

Retrospective gene study

To identify specific gene defects in those with JPS, which may be useful in predictive genetic testing and subsequent preventive screening & treatment

Mutations found in 14 patients, 9 in SMAD4 (21.5%), 5 in BMPR1A (11.9%). All but one were truncating mutations, and the remaining were point mutations. Only patients with SMAD4 mutations harboured carcinoma lesions (5/9). Malformative vessels were present in all SMAD4-related polyps when the mutation involved codons prior to position 423. Lack of SMAD protein was observed in 13 cases of polyps, 6 of which harboured germline SMAD4 mutation. SMAD4 germline mutations are responsible for a more aggressive digestive phenotype in JPS patients—associated with low-grade adenoma, high-grade adenoma/adenocarcinoma, upper GI location, and presence of malformative vessels within the polyp stroma (in absence of obvious HHT).

Nil mentioned

Hattem et al. (2008) [104]

Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis

29 JPS patients

Retrospective gene study

To perform a comprehensive genetic analysis of SMAD4, BMPR1A, PTEN and ENG, to address whether large genomic deletions of any known JPS genes may cause JPS

Of the 27 patients, 6 had SMAD4 mutations (22%), 3 BMPR1A (11%). Of the SMAD4 mutations, there were 2 missense mutations (exon 8), one nonsense (exon 9), 1 bp deletion (exon 8), 25 bp deletion (exon 10), and a single base pair duplication (exon 11).

Not mentioned

Heald et al. (2015) [43]

Prevalence of thoracic aortopathy in patients with Juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4

26 HHT patients / carriers of pathogenic mutations including SMAD4 (n = 16)

Retrospective chart review

To determine the prevalence of thoracic aortopathy in a JPS-HHT cohort

All six patients had SMAD4 mutations and JPS, who had aortopathy ranging from mild dilatation to aortic dissection (6/16 with SMAD4 mutation, 38%). This suggests aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations.

Small numbers in cohort. Overrepresentation of patients with SMAD4 mutations given recruitment method

Howe et al. (1998) [47]

Mutations in the SMAD4/DPC4 Gene in Juvenile Polyposis

9 unrelated JP patients

Retrospective gene study

To evaluate the proportion and nature of SMAD4 mutations in patients with JPS

Of the 9 patients, 3 had a similar 4-bp deletion in exon 9 (codon 414–416, frameshift resulting in premature stop codon), one with 2-bp deletion in exon 8 (exon 348, premature stop codon), and one with 1-bp insertion resulting in frameshift and premature stop codon.

Howe et al. (1999) [46]

Direct genetic testing for SMAD4 mutations in patients at risk for juvenile polyposis

Two large JP families 55 members, 18 with JP

Retrospective gene study

To define the role of genetic testing in the clinical management of patients with juvenile polyposis

All 18 affected family members (18/55), had a 4-bp deletion in exon 9 of the SMAD4 gene, leading to frameshift and premature stop codon at codon 434. In 30 patients at risk for JP, 17 previously had -ve endoscopic screening, while 13 had never been screened. 5 had inherited germline SMAD4 mutations, 2 with hematochezia without having been screened, and the other 3 were asymptomatic. This illustrates poor compliance with screening measures.

Nil mentioned

Howe et al. (2004) [48]

The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B and ACVR1 mutations

77 JPS patients

Retrospective gene study

To determine the prevalence of mutations in MADH4 and BMPR1A in a large number of JP patients

Germline MADH4 mutations were found in 18.2% cases, 20.8% for BMPR1A (n = 77). No mutations found in BMPR1B, BMPR2 or ACVR1. Of the SMAD4 mutations, 8 were deletions (resulting in premature stop codons) and 6 were substitutions (nonsense, missense), all distributed across six of the 11 exons.

Not mentioned

Howe et al. (2007) [45]

ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis

31 patients with JPS without mutations in SMAD4 or BMPR1A

Retrospective gene study

To examine the prevalence of ENG mutations in patients meeting diagostic criteria of JP who did not have germline mutations of SMAD4 or BMPR1A

Via gene sequencing, 13/31 of the patients had mutations in ENG. They had no clinical manifestations, family history of HHT, upper GI polyps. Mean age of JP diagnosis was 7.4y (compared to 14.4y for those without ENG mutations).

Limited sample size

Jelsig et al. (2016) [55]

JP-HHT phenotype in Danish patients with SMAD4 mutations

14 patients with SMAD4 mutation

Retrospective study

To describe the clinical characteristics of 14 patients with SMAD4 mutations

11 of 14 patients fulfilled criteria for JPS. 8 patients were screened for HHT symptoms, and 7 fulfilled the criteria for diagnosis. Thus, SMAD4 mutation carriers have symptoms of both HHT and JPS, with the frequency of PAVM and gastric involvement with polyps being higher than in patients with HHT/JPS not caused by the mutation.

Retrospective study, small patient numbers

Jones et al. (2017) [56]

SMAD4 mutation hotspot analysis and concomitant key cancer-related gene mutation profile in a large cohort of colorectal adenocarcinoma using next generation sequencing approach

242 CRC patients

Retrospective gene study

To evaluate the role of SMAD4 in a cohort of patients with CRC, utilising next-generation sequencing and immunohistochemistry

Frequency of SMAD4 mutations was 10.3% (25/242). Hotspot analysis for SMAD4 shows 40% (10/25) harbor a genetic alteration at the common codon 361, 88% (22/25) have missense mutations, 8% (2/25) have frameshift mutations, and one has a nonsense mutation. One case shows two point mutations at codons 352 and 523. Among the SMAD4-mutant CRC concomitant mutations include KRAS 52% (13/25), BRAF 16% (4/25), NRAS 4% (1/25), p53 44% (11/25), and PIK3CA 12% (3/25). SMAD4-mutant CRC lost expression of one or more DNA mismatch repair proteins in 16% (4/25). These tumors localized with 36% (9/25) in the right colon, 60% (15/25) in the left colon. Morphologic analysis demonstrates 48% (12/25) were moderately to poorly differentiated (high-grade) with 68% (17/25) either stage III or IV at the time of diagnosis, and 36% (9/25) demonstrate mucinous features.

Nil mentioned

Kamil et al. (2012) [58]

Colonic dysplasia and malignancy in patients with SMAD4 mutation-associated juvenile polyposis-hereditary hemorrhagic telangiectasia

15 JP-HHT patients

Retrospective review

To review the rate and types of dysplastic and malignant lesions in the JP-HHT phenotype

Of the 15 JP-HHT patients, the majority of the patients had only few juvenile polyps detected (3–5 polyps), but one patient had multiple (> 100 polyps). 6/15 patients developed dysplastic and malignant colonic lesions; 26 dysplastic lesions and 2 adenocarcinomas were identified at a mean patient age of 27.5 years. Four patients had lesions developing within juvenile polyps, including low grade and high grade dysplasia and signet ring carcinoma, the remainder of the dysplastic lesions were tubular or villous adenomas. Two patients developed invasive adenocarcinoma one year after dysplastic lesions were identified on colonoscopy.

Small patient numbers, thus limited statistical analysis

Karlsson & Cherif (2018) [60]

Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia

21 patients with HHT

Retrospective. Single-centre study

To evaluate whether ENG, AVRL1, and SMAD4 genes were associated with different phenotypes in HHT

Of the 21 patients, 2 had mutations in SMAD4 and had the overlapping JPS-HHT syndrome. Both displayed a full range of HHT clinical features, as well as GI polyps, with one having colorectal cancer and the other having thyroid cancer.

Nil mentioned

Latchford et al. (2012) [65]

Juvenile polyposis syndrome: A study of genotype, phenotype, and long-term outcome

44 JPS patients

Retrospective review

To review clinical features, genetic mutations, and long-term outcome data in patients with juvenile polyposis syndrome

Out of the 31 JPS patients who underwent genetic testing, 19 had SMAD4 mutation (43.1%) and 9 had BMPR1A (20.5%). All patients with upper GI disease had SMAD4 mutations. Where germline mutation was known, all patients with telangiectasia had SMAD4 mutation, supporting JPS-HHT overlap, with a prevalence of 21% within the study cohort.

Retrospective review, cohort size (though good for a rare condition)

Lawless et al. (2017) [66]

Massive gastric juvenile polyposis: a clinical pathologic study using SMAD4 immunohistochemistry

9 cases of massive gastric juvenile polyposis

Clinicopathological analysis

To evaluate the clinicopathological features of 9 patients with gastric juvenile polyposis

6 out of 9 patients had loss of SMAD4 immunoreactivity, thus subject to severe bleeding and hypoproteinemia, as well as developing severe dysplasia or adenocarcinoma. Thus, SMAD4 immunohistochemistry is a helpful diagnostic test in suspected JPS involving the stomach.

No details of mutational testing available for comparison

MacFarland et al. (2019) [71]

Clinical presentation and disease progression in juvenile polyposis syndrome patients with and without a mutation in SMAD4 or BMPR1A

60 JPS patients

Cross-sectional analysis

To understand the potential differences in the clinical presentation and outcomes of patients with or without a known causative gene mutation

Of the 60 patients, in the pediatric cohort, 7 patients (17%) had a mutation in BMPR1A (n = 6) or SMAD4 (n = 1); in the adult cohort, 15 patients (79%) had a mutation in BMPR1A (n = 3) or SMAD4 (n = 12). Rate of SMAD4/BMPR1A mutation is lower in a paediatric cohort than adult. Presence of a mutation in SMAD4/BMPR1A is associated with a more severe course of disease, given all those requiring gastrectomy ± colectomy (n = 8), and all those who developed GI cancer (n = 3) had either mutation.

Small cohort

MacFarland et al. (2021) [72]

Phenotypic differences in Juvenile Polyposis Syndrome with or without a disease-causing SMAD4/BMPR1A variant

118 JPS patients

Retrospective study

To characterise the phenotype of DCV-negative JPS and compare it with DCV-positive JPS

Of the included JPS patients, 54 (46%) had mutations in SMAD4 (27) and BMPR1A (27). SMAD4 carriers were more likely to have a family history of JPS and required gastrectomy.

Data was collected from multiple different centres with differing levels of data granularity, limiting analysis of certain potential endpoints

McDonald et al. (2020) [75]

SMAD4 mutation and the combined juvenile polyposis and HHT syndrome: a single centre experience

22 patients with combined JP-HHT syndrome with SMAD4 mutation

Retrospective study, case series

To describe the phenotype and clinical outcomes of patients with genetically confirmed JP-HHT combined syndrome

All 22 patients had JPS-HHT combined phenotype with SMAD4 mutation. 77% had prior episode of epistaxis, 55% skin telangiectasia, 60% with visceral AV malformations. 82% had a family history (FHx) of HHT. Lower GI polyps found in 85% patients, upper GI in 68%, mainly in the stomach (10/15) and duodenum (5/15). FHx of polyps and CRC in 91% and 54% respectively.

Retrospective analysis, single centre experience

Ngeow et al. (2013) [77]

Prevalence of Germline PTEN, BMPR1A, SMAD4, STK11, and ENG Mutations in Patients With Moderate-Load Colorectal Polyps

603 patients with > 5 GI polyps with > 1 hamartomatous or hyperplastic polyp

Prospective, referral-based study

To determine prevalnce of hamartomatous polyposis-associated mutations in the susceptibility genes PTEN, BMPR1A, SMAD4, ENG and STK11

Of 603 patients, 21 had mutations in SMAD4 (3.5%) out of 77 who were mutation-positive. SMAD4 mutations were more commonly seen in patients with unexplained polyps if <40y and no FHx of CRC, and in patients with a positive FHx of GI polyps. Of 69 who met clinical criteria for JPS, 13 had germline SMAD4 mutations (18.8%).

Nil mentioned

O'Malley et al. (2011) [80]

The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome

46 patients with JP

Retrospective cohort study

To determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in JP SMAD4 + ve patients

SMAD4 mutations found in 21 patients—77% of mutations were in the MH2 domain of the gene between exons 8 and 11 (3'-located). 81% of SMAD + ve patients had HHT (17/21), with 14% suspected to have it (3/21). Epistaxis and asthma were the most common symptoms. 17 of the patients underwent HHT screening, with 16/17 meeting criteria for HHT diagnosis, and one suspected with 2 manifestations. 71% epistaxis, 57% telangiectasia, 86% visceral AVM, 81% pulmonary AVM (13/16).

Single, tertiary referral centre

Pyatt et al. (2006) [86]

Mutation screening in JPS

70 patients referred for JPS gene testing given family and medical history

Retrospective gene study

To describe experiences in laboratory after 3 years of molecular diagnostic screening for JPS

18.6% had mutations in MADH4, 11.5% in BMPR1A. Most MADH4 mutations were clustered towards 3' portion of the gene with 9 of 13 located in the MH2 domain of the protein. Small deletions were the most common type (> 50%).

Nil mentioned

Sayed et al. (2002) [91]

Germline SMAD4 or BMPR1A mutations and phenotypes of juvenile polyposis

54 patients with JP

Retrospective gene study

To determine the differences in phenotype of patients with SMAD4 or BMPR1A compared to those without these mutations

Of the 54 patients, 9 had germline SMAD4 mutations, 13 had BMPR1A mutations, and 32 had neither (59%). No significant differences were observed between SMAD4 & BMPR1A, apart from FHx of upper GI involvement. There was a higher prevalence of familial cases, > 10 lower GI polyps and frequency of GI cancer amongst mutation + ve patients compared with mutation -ve patients. Age of LGI polyposis diagnosis, FHx of upper GI polyps and FHx of cancer were significantly different between SMAD + ve and mutation -ve patients.

Nil mentioned

Schwenter et al. (2012) [94]

Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation

358 patients (HHT n = 332, JP n = 26)

Prospective study

To describe the phenotype of patients with JP-HHT and SMAD4 mutations, and to compare this phenotype with HHT or JP with mutations other than SMAD4

14 patients were identified with SMAD4 mutation, 10 met the criteria for both JP and HHT (71%). 57% presented with a haemorrhagic episode, 57% had abnormal echocardiography. Patients with SMAD4 mutations had 100% penetrance of the polyposis phenotype. All patients with JP and SMAD4 mutation had features of HHT. Three JP-HHT patients developed early onset CRC. JP-HHT patients with SMAD4 mutation had a significantly higher rate of anaemia than HHT patients with mutations other than SMAD4.

Not mentioned

Suppressa et al. (2018) [101]

Severe pulmonary involvement of SMAD4-mutated patients with juvenile polyposis/hereditary hemorrhagic telangiectasia combined syndrome

5 SMAD4 + ve patients

Cross-sectional prospective survey

To describe clinical pulmonary features of patients affected by JP/HHT and confirmed mutations in SMAD4, and compare lung AVM features with HHT1 + 2 patients

All 5 patients had pulmonary AVM and GI polyps. Silent hepatic involvement in 4/5. Clinically overt manifestations secondary to PAVMs was reported by 4/5 patients including hypoxaemia, digital clubbing, brain abscess/stroke. JP-HHT patients had significantly higher prevalence of complex PAVMs (compared to HHT1/2 patients).

N/A

Sweet et al. (2005) [102]

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis

49 unrelated patients with multiple hamartomatous or hyperplastic polyps

Prospective gene study

To classify patients with unexplained hamartomatous or hyperplastic/mixed polyps by extensive molecular analysis in context of histopathology results

Of the 49 patients, 11 (22%) had germline mutations. 14 of these patients had juvenile polyposis, 2 of which had mutations in ENG (associated with HHT) with early-onset disease. 1 had an SMAD4 mutation, and 1 had a hemizygous deletion involving PTEN and BMPR1A. Thus, more extensive analysis of the known susceptibility genes is indicated.

Limited sample size

van Hattem et al. (2011) [105]

Histologic variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis

39 JPS patients (90 polyps): 8 patients (21 polyps) with SMAD4 DCVs, 6 patients (44 polyps) with BMPR1A DCVs

Clinicopathological analysis

To compare the histologic phenotype of juvenile polyps with a SMAD4 or BMPR1A germline mutation and sporadic juvenile polyps

Juvenile polyps with a SMAD4 germline mutation were predominantly type B (crypt-stroma ratio >  = 1.00; epithelial), whereas type A (crypt-stroma ratio < 1.00; classic, stromal juvenile polyp) was more common among juvenile polyps with a BMPR1A germline mutation. Dysplasia was equally common in JPS polyps with either a SMAD4 or BMPR1A germline mutation, where the adenoma-carcinoma sequence does not seem to play a distinct role.

Limited polyp numbers

Wain et al. (2014) [106]

Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review

34 JPS patients of 20 families

Retrospective gene study

To understand the spectrum and extent of clinical findings in SMAD4 carriers

Of the 34 patients with SMAD4 mutations, 21% had features of a connective tissue defect, including enlarged aortic root (n = 3), aortic and mitral valve insufficiency (n = 2), aortic diseection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis specific findings were mostly uniformly present, where 30/31 (97%) patients had colonic polyps (pan-colonic) of variable histology and number. 11/28 had small bowel polyps (39%). 21/31 (68%) had gastric polyps, where 15/31 (48% patients) had extensive gastric polyposis. 9/34 had neoplasms, where 3/34 were CRC, 1/34 pancreatic cancer. HHT features were also prominent among the group, with 19/31 (61%) having epistaxis, 15/31 (48%) with telangiectases, 6/16 with liver AVMs, 1/26 with brain AVM, 9/17 with pulmonary AVM, and intrapulmonary shunting (14/23). SMAD4 carriers should be managed for JP & HHT, where connective tissue abnormalities are an emerging component.

Small sample size, young ages of some individuals, incomplete screening for all findings of interest in some individuals

Woodford-Richens et al. (2000) [108]

Analysis of genetic and phenotypic heterogeneity in juvenile polyposis

56 JPS patients where 47 were found from 15 families, and 9 were sporadic

Retrospective gene study

To describe the clinical features of JPS patients. To determine contribution of DPC4 mutations to JPS. Assess existence of any associations between germline mutations and clinical features. Determine proportion of JPS cases caused by as yet unidentified genes

5 germline DPC4 mutations were identified (n = 24). i.e. around 21%. Three of these were deletions ranging in size from two to 11 base pairs in exons 1, 4, and 11. One of the mutations was a single base substitution creating a stop codon in exon 10. The fifth mutation was a missense mutation in exon 8

Not mentioned