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SMAD4 variants and its genotype–phenotype correlations to juvenile polyposis syndrome

Hereditary Cancer in Clinical Practice volume 21, Article number: 27 (2023) Cite this article

Abstract

Background

Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 – 50%. Around 40–60% of JPS cases are caused by disease-causing variants (DCV) in SMAD4 or BMPR1A genes, of which SMAD4 accounts for 20–30%.

Objectives

To characterise genotype–phenotype correlations between sites and types of variants within SMAD4 to JPS phenotypes, to inform diagnosis, screening, and management of JPS.

Search methods

Online search databases utilised included Ovid MEDLINE, Embase Classic + Embase and PubMed, using search terms classified by MeSH on Demand. Adjacency operators, word truncation and Boolean operators were employed. 110 articles were included in the review, collating 291 variants from the literature.

Results

In SMAD4 + JPS patients, most variants are located around SMAD4’s MH2 domain (3’ end). Extracolonic involvement, massive gastric polyposis and a more aggressive phenotype have been associated with SMAD4 + JPS, predisposing to gastric cancer. This has contributed to an overall higher incidence of GI cancers compared to other genes causing JPS, with DCVs mostly all within the MH2 domain. Genetically related allelic disorders of SMAD4 also have variants in this region, including hereditary haemorrhagic telangiectasia (HHT) alongside SMAD4 + JPS, and Myhre syndrome, independent of JPS. Similarly, with DCVs in the MH2 domain, Ménétrier’s disease, hypertrophic osteoarthropathy and juvenile idiopathic arthritis have been seen in this population, whereas cardiac pathologies have occurred both alongside and independently of SMAD4 + JPS with DCVs in the MH1 domain.

Conclusion

Truncating and missense variants around the MH2 region of SMAD4 are most prevalent and pathogenic, thus should undergo careful surveillance. Given association with extracolonic polyposis and higher GI cancer risk, endoscopic screening should occur more frequently and at an earlier age in SMAD4 + JPS patients than in patients with other causative genes, with consideration of Ménétrier’s disease on upper GI endoscopy. In addition, HHT should be evaluated within 6 months of diagnosis, alongside targeted clinical examination for extraintestinal manifestations associated with SMAD4 + JPS. This review may help modify clinical diagnosis and management of SMAD4 + JPS patients, and aid pathogenicity classification for SMAD4 DCVs through a better understanding of the phenotypes.

Peer Review reports

Introduction

JPS is a rare autosomal dominant syndrome affecting one per 100 000 births, where 50 – 75% of affected patients have a positive family history [19, 26]. Hamartomatous polyps occur throughout the GIT, increasing cumulative lifetime risk of GI cancer by 9 – 50%, which is decreased through increased surveillance [65]. Such “juvenile” polyps (JP) are histologically described as having dense stroma with inflammatory infiltrate with mucus-filled cystic glands in the lamina propria (Figs. 1, 2, and 3).

Fig. 1
figure 1

Macroscopic appearance of JPs. A Multiple pedunculated polyps with smooth surfaces post-bowel resection in a JPS patient. B JP from a patient with JPS, noted for its smooth surface [14]

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Fig. 2
figure 2

Structure of the SMAD4 gene, involving MH1 domain, linker domain and MH2 domain (self-made)

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Fig. 3
figure 3

Illustration showing SMAD4’s (blue oval) involvement in the TGF-β and BMP pathways [39]

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Clinical diagnosis of JPS is confirmed if any one of the following 3 criteria are met, given there is absence of syndromic extra-intestinal features that define other hamartomatous polyposis syndromes:

  1. 1.

     > 5 colonic hamartomatous polyps at one time or recurrent

  2. 2.

    Any number of hamartomatous polyps in a patient with family history of JPS

  3. 3.

    Extracolonic hamartomatous polyps (e.g., stomach, small bowel)

It is estimated that 40–60% of JPS cases are caused by DCVs in SMAD4 or BMPR1A genes, mostly consisting of missense, nonsense, deletions, and small insertions, together with large genomic deletions [4]. Germline SMAD4 DCVs have been observed in 20–30% JPS cases [3], similarly to BMPR1A, located at chromosome 10q23.2. PTEN DCVs have been sequenced in approximately 5% of JPS patients, near BMPR1A at chromosome 10q23.3, though confounds with Cowden syndrome. Finally, ENG DCVs have recently been associated with JPS, located at chromosome 9q34.1 with known associations to HHT [48, 77]. For example, Howe and colleagues [45] found ENG DCVs in 13/31 JPS patients without DCVs in SMAD4 or BMPR1A, whereas 2/11 JPS patients were ENG+ in Sweet and colleagues’ study [102]. Currently, > 50% of JPS cases have had causative genes described, all involved in the TGF-β signalling pathway, modulating colonic epithelial growth [38, 47].

The SMAD4 gene is located on chromosome 18q21.1 with 55 000 base pairs encompassing 11 exons, encoding a 551-amino acid protein. Functional domains include the MH1 domain, involved in DNA binding, a domain linking the two MH domains, and the MH2 domain which is involved in homodimerisation, heterodimerisation, and transcriptional activation and nuclear location of SMAD4 [48, 75].

Its protein product acts as an intracellular mediator to TGF-β and downstream bone morphogenetic protein (BMP) signalling, having a major role in colonic epithelial growth [21, 48]. Following activation of TGF-β, members of the SMAD family form a complex with SMAD4 via its COOH terminus. Mutations disrupting this complex formation result in loss of TGF-β signalling, thus partially explaining why most germline mutations of SMAD4 map to this domain [92]. Physiologically, these complexes are then transported to the nucleus, signalling growth inhibition. It is hypothesised that heterozygous loss-of-function (LOF) SMAD4 mutations may prevent formation of these complexes, thus promoting growth, resulting in cellular proliferation and subsequently neoplasia [39]. Potentially, DCVs in the linker region are less prominent, given this region is often deleted during alternative splicing.

Bosman’s hamartoma-adenoma-carcinoma sequence theory [13] postulates a “landscaper” defect, where SMAD4 mutations disrupt epithelial architecture, differentiation, and proliferation via altering the microenvironment. This pathway begins with JP formation, adenomatous change, dysplasia, then finally carcinoma [54, 55].

Current knowledge of genotype–phenotype correlations between SMAD4 variants and JPS is that individuals are more inclined to have upper gastrointestinal (UGI) polyposis and higher gastric cancer risk, as compared to BMPR1A [91]. HHT is exclusively seen within SMAD4 + JPS patients [8]. Thus, current treatment involves regular surveillance via routine endoscopy with polypectomy, together with monitoring and treatment of HHT manifestations [65].

Further detailed genotype–phenotype correlations between SMAD4 DCVs and JPS subtypes are yet to be fully described in this field of research. Better characterisation of these associations will help modify clinical diagnosis, screening, surveillance, and management of SMAD4 + JPS patients. In addition, this research will also aid pathogenicity classification for SMAD4 variants where phenotypic manifestations are incorporated into modified American College of Medical Genetics (ACMG) criteria, allowing, for example, segregation analyses to assist in classification.

This narrative review’s overarching research question is thus, in SMAD4 variant carriers, what are existing genotype–phenotype correlations relating to sites and types of variants within the gene, particularly focusing on phenotypes of JPS? Further from this, what implications will these correlations have on clinical management and for gene specific modifications to ACMG criteria?

Methods

A literature search was performed on July 27, 2021, via three online search databases: Ovid MEDLINE, Embase Classic + Embase, and PubMed. Search strategy utilised key words surrounding the research question: SMAD4, JPS, and gene association studies, via MeSH on Demand.

Regarding JPS, key words included juvenile polyposis, intestinal polyposis, JPS and hamartomatous polyposis syndrome. Aliases of SMAD4 gene included SMAD family member 4, MADH4, DPC4, JIP, MYHRS, mothers against decapentaplegic homolog 4, deletion target in pancreatic carcinoma 4, MAD homolog 4, deleted in pancreatic carcinoma locus 4 and HSMAD4. To capture keywords related to genotype–phenotype association studies, words included genotype, gene, genome, phenotype, DNA, mutation, chromosome, variant, and variations of gene associated studies. Boolean operators including AND and OR were utilised, adjacency operators, as well as word truncation to enable different forms of words to be searched for simultaneously (Appendix A).

Specific inclusion criteria included English and human studies, retrospective and prospective gene studies, unique case reports and reviews which discuss JPS, SMAD4 DCVs and/or genotype–phenotype correlations. Exclusion criteria included any non-English and animal studies, non-significant case reports, and studies that did not mention juvenile polyposis syndrome nor SMAD4.

Results

From this search, 829 studies were identified from three databases (Ovid MEDLINE = 251, Embase Classic + Embase = 386, PubMed = 192). 396 of these were duplicates, 30 were animal studies not excluded from search strategy, and 82 were considered irrelevant as they did not involve SMAD4, JPS or its causative genes, amounting to 321 studies. Full text screening thus isolated 110 papers, including narrative reviews, retrospective and prospective gene studies, together with pertinent case reports relevant to this review, pertaining to SMAD4 and its genotype–phenotype correlations to JPS and relevant conditions (Fig. 4). Results are tabulated in Fig. 5, Tables 1 and 2, and are further elucidated in the discussion.

Fig. 4
figure 4

PRISMA Diagram presenting the review process for this narrative review (self-made)

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Fig. 5
figure 5

Sites and types of SMAD4 DCVs, protein change and phenotypes, self-made via Microsoft Visio. All 291 variants were collated from the literature. In the top section, SMAD4 gene structure is represented via its exons demarcated by nucleotide numbers. DCVs causing JPS phenotypes have been depicted with lines extending below the diagram in brown (JPS), green (massive gastric polyposis in JPS) and red (GI cancer in JPS). Above the illustrations represent extra-gastrointestinal phenotypes, including HHT (dark red), aortopathy (pink), IBD (purple), Myhre syndrome (dark blue), JIA (light blue), hypertrophic osteoarthropathy (yellow), Ménétrier’s disease (grey) and concurrent GI cancer boxed in bright red. In the bottom section, large deletions and chromosomal translocations are portrayed via solid lines, surrounding the SMAD4 gene, where JPS phenotypes are below, and extra-GI phenotypes are above. c.1245_1248delCAGA (p.Asp415Glufs*20), a highly prevalent DCV, is represented by asterisks (*). Variants of uncertain significance (VUS) are marked with adjacent stars, sourced from JPS registries and case reports, with pathogenicity reviewed by ClinVar

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Table 1 List of gene studies, including title, sample size, study design, results, and limitations
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Table 2 Tabulated form of SMAD4 variants and associated phenotypes, where families are bolded
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Discussion

Genotype–phenotype correlations to JPS

Variant hotspot

In SMAD4 + JPS patients, the majority of germline DCVs are in the MH2 domain. Up to 80% of DCVs are located between exon 8 and 11, allowing complex formation and translocation to the nucleus in the TGF-β pathway [74]. Small deletions in this location have caused serious cases of JPS with colonic and gastric juvenile polyposis, particularly c.1245_1248del [34, 48, 86, 91]. In another study, 40% (10/25) harboured a genetic alteration at codon 361 in exon 8 [56].

Variant types

Most common variant types among SMAD4 DCVs are missense, deletions and small deletions, resulting in frameshift and premature stop codons [27]. Less common are nonsense, insertions, duplications and intronic mutations [20, 23, 93]. In a study by Jones and colleagues [56], 22/25 patients had missense mutations, 2/25 had frameshift mutations and 1/25 had a nonsense mutation, whereas Aretz and colleagues [4] reported 5/17 nonsense, 6/17 frameshift and 6/17 missense mutations, all found to be pathogenic variants, apart from one VUS (missense mutation c.425_426A > G). Chromosomal translocations are rare causes of JPS, historically requiring chromosomal analysis, as described in a JPS-HHT patient [1] with exons 6–11 deleted. Another case report involved a balanced translocation causing loss of the entire SMAD4 gene in a JPS-HHT patient, with dysmorphic features, intellectual disability, developmental delay, and corpus callosum agenesis [79].

Histologic phenotype

JPs with SMAD4 DCVs tend to be more epithelial with high crypt-to-stroma ratio, as compared to BMPR1A, with a tendance to be more stromal with a lower ratio. Despite this, dysplasia was equally common in JPS polyps with either mutation [104]. Polyp phenotype is variable, ranging from sessile to pedunculated, with adenomatous, hyperplastic, and inflammatory polyps described in the literature, especially in BMPR1A + JPS [69, 77].

Extracolonic polyposis

Patients with SMAD4 DCVs, especially in the linker and MH2 domains, tend to develop and have a family history of UGI polyps, including the small bowel and stomach [34, 91]. SMAD4 DCVs are associated with higher gastric polyp numbers, massive gastric polyposis, and thus, partial or total gastrectomy and gastric cancer [4, 5, 10, 28, 72]. In most cases, SMAD4 DCVs have been detected in patients with both UGI and LGI polyps, whereas polyps are restricted to LGI and anal canal for BMPR1A [100].

Aggressive phenotype and variant correlation

Patients with SMAD4 DCVs can develop a more aggressive GI phenotype, with polyps associated with low-grade adenoma, high grade adenocarcinoma, upper GI location, and presence of malformed vessels within the stroma [41]. This is especially the case in patients with DCVs in exons 8–11, especially c.1245_1248del and c.1421delC, involving massive gastric polyposis and GI cancer [33, 34, 55, 80, 89].

Genotype–phenotype correlations to cancer

Lifetime risk for development of GI cancers in JPS families in different studies range from 9 to 50%, attenuated by improved surveillance and polypectomies over time. Overall, most SMAD4 + JPS patients with GI cancer had DCVs in the MH2 region [36, 77]. They have a higher incidence of GI cancer than those with BMPR1A. In a study by Aytac and colleagues [6], following regular surveillance and appropriate polypectomies, 4/27 individuals with SMAD4 DCVs developed cancer, in comparison to 0/8 of BMPR1A + JPS patients. In another study by Blatter and colleagues [10], incidence of cancer was also higher in SMAD4 carriers, with 20.5% of patients with GI cancer (26/127), compared to 8.4% (8/94) in BMPR1A carriers (p = 0.015).

Gastric cancer

As aforementioned, gastric polyposis is more common in SMAD4 carriers with JPS, with gastric cancer risk occurring up to 30% in those with SMAD4 DCVs. 7/17 JPS patients with SMAD4 variants had gastric cancer in a study by Aretz and colleagues [4], compared to 0/13 for BMPR1A carriers. In Blatter and colleagues’ study [10], 7/127 SMAD4 carriers had gastric cancer, and 0/94 in BMPR1A.

Colorectal cancer

Colorectal cancer occurs at a similar incidence in both causative genes of JPS, where 15/127 (11.8%) had CRC in SMAD4 carriers, compared to 7/94 (7.4%) in BMPR1A carriers [10]. In another study by Schwenter and colleagues [93], 3/14 (21.4%) SMAD4 + JP-HHT patients developed early onset CRC.

Somatic studies

From somatic studies, SMAD4 is not seen to be a driver gene for GI cancer, though 16% of primary colorectal tumours have alterations in SMAD4, and 6% in SMAD2. SMAD4 follows APC mutation and precedes TP53 in CRC development [25]. Loss of SMAD4 expression is associated with worse overall survival in patients with CRC, given associations with metastasis and advanced disease [73].

In 30% of pancreatic cancers, SMAD4 is deleted following inactivation of K-ras, increasing TGF-β expression and creating an environment for tumour progression [74]. It is postulated that SMAD4 mutations do not initiate tumour formation, as germline mutations are not associated with pancreatic tumours, but instead promote metastases via LOH and intragenic mutations [73].

Genotype–phenotype correlations to genetically related allelic disorders of SMAD4

HHT & JPS-HHT syndrome

HHT is an autosomal dominant disorder affecting 1 in 5000 to 10 000 individuals, leading to vascular dysplasia with facial and peripheral telangiectasias, together with arteriovenous malformations (AVM) of lung, central nervous system, and GIT. In JPS-HHT, patients share symptoms of JPS and the full range of HHT features [53].

80–85% HHT patients have DCVs in ENG, ACVRL1 or SMAD4, where the former two encode for endothelial receptors of the TGF-β family, necessary to maintain vascular integrity and angiogenesis [42, 93]. SMAD4 DCVs account for < 2% of HHT patients [50]. It is hypothesised that its genetic loss disrupts the balance regulating vascular remodelling and angiogenesis, as well as communication between TGF-β and BMP signalling pathways, as SMAD4 is common to both [35]. Frequency of pulmonary AVMs and gastric involvement were higher amongst SMAD4 + JPS-HHT patients, than those not due to SMAD4 +  [55, 101]. Such DCVs are mostly found in SMAD4’s MH2 region [38], where up to 80% of SMAD4 + JPS are accompanied by HHT. Particularly prevalent DCVs include c.1228_1229delCA, c.1245_1248del, and missense variants in exon 8 [74, 75, 80].

Myhre syndrome (MS)

SMAD4 DCVs are solely responsible for MS, a rare developmental disorder with < 100 cases reported. It is characterised by dysmorphic features, joint limitation, muscular pseudohypertrophy, intellectual disability and deafness. DCVs include de novo missense mutations around codon 496–500 in exon 11 (Figs. 6 and 7).

Fig. 6
figure 6

Diagram of variant location in the SMAD4 gene causing MS, mostly around the Ile500 residue in the MH2 domain [67]

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Fig. 7
figure 7

Diagram depicting SMAD4’s involvement in the TGF-β pathway, as shared with TGFB11/2 and FBN1, the signalling pathway to transcribe profibrotic genes [2]

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All reported MS cases have occurred independently of JPS [67], with associations to neoplasia. In a recent study, 6/61 MS patients exhibited neoplasia, including endometrial (3/6) and brain tumours (3/6). Given LOF mutations in SMAD4 cause JPS, it is hypothesised that gain-of-function mutations observed in MS may contribute to neoplasia [70].

Other conditions observed in carriers of SMAD4 variants

Cardiac pathologies

Cardiac pathologies have been reported in SMAD4 DCV carriers both independently and in conjunction with JPS-HHT. Manifestations include aortic root dilatation, aneurysm, aortic dissection, and mitral valve dysfunction, including regurgitation and prolapse.

This has been reported in SMAD4 + JPS-HHT patients with variants in the MH2 region, particularly c.1245_1248del and c.1333C > T [2, 16, 103, 106, 107]. Heald and colleagues [43] observed cardiac pathologies in 6/16 SMAD4 + JPS-HHT patients, while Wain and colleagues [106] reported 7/34 JPS patients had connective tissue defects including enlarged aortic root, aortic and mitral valve insufficiency and aortic dissection. Thus, these cardiac pathologies have been postulated to be part of SMAD4-induced HHT manifestations.

Notably, without JPS-HHT, hereditary thoracic aortic disease was described in patients with rare MH1 domain missense mutations. In Duan and colleagues’ case report [29], two family members exhibited different phenotypes, one with ascending aortic dissection, and the other with aortic aneurysm and bicuspid aortic valve. Two unrelated patients both had early onset type A aortic dissection. The proposed pathway is that SMAD4’s involvement in TGF-β signalling is shared with TGFBR1/2 and FBN1, genes involved in connective tissue disorders, where SMAD4 is a transcriptional regulator and tumour suppressor [2].

Juvenile idiopathic arthritis (JIA) & Hypertrophic osteoarthropathy (HOA)

In SMAD4 + JPS-HHT patients, JIA has been described in carriers of MH2 domain missense mutations, particularly c.1052A > T in exon 8. Along with colonic JPs with HHT features, patients had upper and lower limb joint swelling, erythema, and digital clubbing [9, 61].

HOA has also been observed in SMAD4 + JPS families, marked by digital clubbing and extensive new bone formation, in MH2 domain DCVs, particularly c.1236C > G [7, 64]. In addition, digital clubbing has been examined in many SMAD4 + JPS-HHT patients, potentially as a manifestation of pulmonary AVMs and right-to-left cardiac shunts [9, 35, 36, 50, 59, 61]. It is postulated that SMAD4 mediates intracellular signals of TGF-β and BMP, found at high levels in bone and cartilage, potentially having a role in bone formation, thus explaining HOA and JIA.

Ménétrier’s disease (MD)

MD has been diagnosed concurrently in SMAD4 + JPS patients with gastric polyposis, marked by giant mucosal folds in gastric fundus and body, with diminished acid secretory capacity and protein losing state causing hypoalbuminemia. All MD cases were caused by the SMAD4 variant, c.1245_1248del. In one family, there were 5 MD cases, 3 JPS cases and 1 case of JPS-MD, and two other studies reported familial JPS-MD cases [82, 83]. Mechanistically it is proposed that TGF-alpha overexpression leads to TGF-β pathway inactivation, promoting cell proliferation, where MD could be a manifestation of gastric polyposis in JPS, or be confounding given their similar pathology.

Diagnosis and genetic testing

SMAD4 + JPS patients mostly have generalised and colonic juvenile polyposis, together with JPS-HHT syndrome in some patients. JPS subtypes include:

  • 1. Infantile JP (< 2 years old): rare in SMAD4 + JPS patients, but more common in large deletions involving BMPR1A and PTEN, this is the most severe form of JPS with poor prognosis given aggressive polyp formation [49]

  • 2. Generalised JP: JPs throughout the GIT

  • 3. Colonic JP or JP coli: JPs exclusively in the colon, common to BMPR1A carriers.

  • The latter two phenotypes, generalised and colonic JP, are common to SMAD4, and are caused by DCVs throughout the gene. Malignancy mainly occurs in those with DCVs in the MH2 region, whereas non-malignant polyposis can occur anywhere.

  • 4. JPS-HHT syndrome: Exclusive to SMAD4 + patients, JPS-HHT patients have features of both JPS and HHT, caused by DCVs in MH2 region with few exceptions [35, 36].

Once diagnosed with JPS, genetic testing of SMAD4 and BMPR1A germline mutations for probands should occur, in combination with familial genetic counselling [106]. Molecular genetic testing approaches can include BMPR1A and SMAD4 concurrent testing, including multiplex-ligation dependent probe amplification for single or partial gene deletions. Also, serial-gene testing in patients with suspected JPS-HHT can occur, via sequence analysis and gene-targeted duplication or deletion analysis for SMAD4. Contemporarily, multigene panels with BMPR1A, SMAD4, PTEN and other genes, exome and genome sequencing, and chromosomal analysis for translocations are utilised [68, 88].

In addition, all SMAD4 DCV carriers should be screened following JP and HHT protocols, further elucidated in management.

Implications on management

Surveillance for asymptomatic SMAD4 or BMPR1A DCV carriers, or at-risk family members with no variant detected, are distinct between LGI and UGI tracts. In general, careful surveillance should occur for SMAD4 DCVs in the MH2 domain.

LGI management

Asymptomatic LGI surveillance follows conventional endoscopic monitoring, involving 3-yearly full blood examination and colonoscopy from 12–15 years old if no abnormalities are found, or commence screening earlier if symptomatic [24, 109]. Otherwise, if polyps are found, annual screening and endoscopic polyp resection would occur until polyp free [48]. Others suggest patients should be screened annually or biennially regardless, until 70 years old [30]. If colonic polyps are unable to be monitored, controlled or demonstrate malignant potential, this warrants consideration of total abdominal colectomy with ileo-rectal anastomosis or proctocolectomy with or without pouch reconstruction [32, 96]. There are no randomised controlled trials of surveillance to provide a strong evidence base for surveillance and its frequency.

UGI management

In terms of UGI surveillance, there are competing thoughts, but are tailored towards known genotype–phenotype correlations. Howe and colleagues [48] suggest UGI endoscopy should take place concomitantly with colonoscopy, in conjunction with biliary and/or pancreatic duct brushings in the context of abnormal liver function tests or elevated amylase. Dunlop [30] advises one or two-yearly UGI endoscopies with colonoscopy from 25 years old. Sayed and colleagues [91] differentiate screening between SMAD4 + JPS patients, who should receive it one to three-yearly, while BMPR1A + or DCV negative patients should be screened five-yearly. Similarly differentiating management based on causative genes, Monahan and colleagues [76] have suggested UGI endoscopic surveillance from 18 years old in SMAD4 + JPS patients, and from 25 years old for BMPR1A + patients, at a frequency of one to three-yearly. Nonetheless, given current data, no UGI surveillance for BMPR1A carriers could be justified due to lack of UGI pathology reported, especially cancer. Additionally, Ménétrier’s disease could be considered during UGI endoscopy. If polyps are detected, UGI endoscopy would be repeated annually with appropriate resection, though complete or partial gastrectomy may be warranted in cases of massive gastric polyposis, dysplasia and gastric cancer, as seen in SMAD4 + JPS patients [40, 66, 97, 98].

Extra-intestinal manifestations

SMAD4 + JPS patients should be evaluated for HHT within 6 months of diagnosis, examining for manifestations such as telangiectasia, AVM and digital clubbing. Together with complete blood count, annual targeted clinical examination should occur to monitor for HHT and cardiac pathologies, including full facial observation, peripheral examination to assess for clubbing and joint swelling as per JIA, and cardiorespiratory examination. If HHT is confirmed, screening would thus include 2 yearly bubble contrast echocardiography and pulse oximetry for pulmonary AVMs, followed by CT pulmonary angiogram if abnormal, and a single MRI brain to exclude brain AVMs [32, 35,36,37, 51].

Limitations

Overall, limitations of most studies were that they were retrospective, with limited patient numbers given JPS’ rarity, and had incomplete screening of all findings of interest. As a result, low numbers often precluded statistically significant observations. In some cases, there was overrepresentation of SMAD4 + patients given recruitment methods and did not compare phenotypes with other causative genes. As such, larger scale follow-up studies of JPS patients should occur both retrospectively and prospectively to assess genotype–phenotype correlations, with complete screening of all potentially associated syndromes and conditions.

Conclusion

In conclusion, truncating, missense and nonsense mutations around the MH2 region of SMAD4 are most prevalent and hence more likely to be pathogenic. In SMAD4 + JPS patients, given association with extracolonic polyposis and higher risks of GI cancers, endoscopic screening should occur from 12–15 years at a 3-yearly frequency, especially for patients with DCVs in the MH2 region. With associated genetically related allelic disorders like HHT, cardiac pathologies, HOA and potentially JIA, symptoms should be monitored for these via regular targeted clinical examination. Where HHT is suspected, further investigations should include 2-yearly bubble echocardiogram and a single brain MRI.

This review may help modify clinical diagnosis, screening, surveillance, and management of SMAD4 + JPS patients, as well as aid development of gene specific modifications to the ACMG/AMG criteria for pathogenicity assessment of SMAD4, thus supporting the work of the planned SMAD4 InSiGHT ClinGen Variant Curation Expert Panel.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

JPS:

Juvenile polyposis syndrome

DCV:

Disease-causing variant(s)

JP:

Juvenile polyp

HHT:

Hereditary haemorrhagic telangiectasia

AGMG:

American College of Medical Genetics and Genomics

GI:

Gastrointestinal

LGI:

Lower gastrointestinal

UGI:

Upper gastrointestinal

VUS:

Variants of uncertain significance

TGF-β:

Transforming growth factor β

BMP:

Bone morphogenetic protein

CRC:

Colorectal carcinoma

LOF:

Loss-of-function

LOH:

Loss-of-heterozygosity

AVM:

Arteriovenous malformation

MS:

Myhre syndrome

JIA:

Juvenile idiopathic arthritis

HOA:

Hypertrophic osteoarthropathy

MD:

Ménétrier’s disease

IBD:

Inflammatory bowel disease

References

  1. Aagaard KS, Brusgaard K, Miceikaite I, Larsen MJ, Kjeldsen AD, Lester EB, et al. Chromosomal translocation disrupting the SMAD4 gene resulting in the combined phenotype of Juvenile polyposis syndrome and Hereditary Hemorrhagic Telangiectasia. Mol Genet Genomic Med. 2020;8(11):e1498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Andrabi S, Bekheirnia MR, Robbins-Furman P, Lewis RA, Prior TW, Potocki L. SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am J Med Genet A. 2011;155A(5):1165–9.

    Article  PubMed  Google Scholar 

  3. Arber N, Moshkowitz M. Small bowel polyposis syndromes. Curr Gastroenterol Rep. 2011;13(5):435–41.

    Article  PubMed  Google Scholar 

  4. Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44(11):702–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Aytac E, Sulu B, Heald B, O’Malley M, LaGuardia L, Remzi F, et al. Oncologic outcomes and survival in juvenile polyposis syndrome patients with BMPR1A or SMAD4 mutation. Dis Colon Rectum. 2014;57(5):e136–7.

    Google Scholar 

  6. Aytac E, Sulu B, Heald B, O’Malley M, LaGuardia L, Remzi FH, et al. Genotype-defined cancer risk in juvenile polyposis syndrome. Br J Surg. 2015;102(1):114–8.

    Article  CAS  PubMed  Google Scholar 

  7. Baert AL, Casteels-Van Daele M, Broeckx J, Wijndaele L, Wilms G, Eggermont E. Generalized juvenile polyposis with pulmonary arteriovenous malformations and hypertrophic osteoarthropathy. AJR Am J Roentgenol. 1983;141(4):661–2.

    Article  CAS  PubMed  Google Scholar 

  8. Barlas S, Kalady M, Aytac E, Heald B, Church J, Remzi F. Follow-up of juvenile polyposis syndrome patients with BMPR1A or SMAD4 mutation. Dis Colon Rectum. 2012;55(5):e210–2.

    Google Scholar 

  9. Bishop JC, Britton JF, Murphy AM, Sule S, Mitchell S, Takemoto C, et al. Juvenile Idiopathic arthritis associated with combined jp-hht syndrome: a novel phenotype associated with a novel variant in SMAD4. J Pediatric Genet. 2018;7(2):78–82.

    Article  CAS  Google Scholar 

  10. Blatter R, Tschupp B, Aretz S, Bernstein I, Colas C, Evans DG, et al. 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. Genet Med. 2020;22(9):1524–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blatter RH, Plasilova M, Wenzel F, Gokaslan ST, Terracciano L, Ashfaq R, et al. Somatic alterations in juvenile polyps from BMPR1A and SMAD4 mutation carriers. Genes Chromosomes Cancer. 2015;54(9):575–82.

    Article  CAS  PubMed  Google Scholar 

  12. Bonjean M, Giraud S, Decullier E, Saurin JC, Edery P, Dupuis-Girod S. Clinical expression of hereditary haemorrhagic telangiectasia and digestive lesion characteristics in patients with SMAD4 mutation. Hematology Reports. 2013;1:11–2.

  13. Bosman FT. The hamartoma-adenoma-carcinoma sequence. J Pathol. 1999;188(1):1–2.

    Article  CAS  PubMed  Google Scholar 

  14. Brosens LA, Langeveld D, van Hattem WA, Giardiello FM, Offerhaus GJ. Juvenile polyposis syndrome. World J Gastroenterol. 2011;17(44):4839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brosens LAA, Offerhaus GJ, Canto MIF, Montgomery EA, Giardiello FM. Simultaneous juvenile polyposis syndrome and neurofibromatosis type 1. Histopathology. 2016;68(2):313–5.

    Article  PubMed  Google Scholar 

  16. Bruceta M, De Souza L, Carr Z, Bonavia A, Karamchandani K. Novel association of juvenile polyposis syndrome with atrial septal aneurysm and patent foramen ovale: a case report. A and A Practice. 2018;10(12):331–4.

    Article  PubMed  Google Scholar 

  17. Burger B, Uhlhaas S, Mangold E, Propping P, Friedl W, Jenne D, et al. Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis. Am J Med Genet. 2002;110(3):289–91.

  18. Burmester JK, Bell LN, Cross D, Meyer P, Yale SH. A SMAD4 mutation indicative of juvenile polyposis syndrome in a family previously diagnosed with Menetrier’s disease. Dig Liver Dis. 2016;48(10):1255–9.

    Article  CAS  PubMed  Google Scholar 

  19. Calva D, Howe JR. Hamartomatous Polyposis Syndromes. Surg Clin North Am. 2008;88(4):779–817.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe JR. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009;75(1):79–85.

    Article  CAS  PubMed  Google Scholar 

  21. Carr JC, Dahdaleh FS, Wang D, Howe JR. Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling. J Surg Res. 2012;174(2):211–4.

    Article  CAS  PubMed  Google Scholar 

  22. Chang W, Renaut P, Pretorius C. SMAD4 juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia presenting in a middle-aged man as a large fungating gastric mass, polyposis in both upper and lower GI tract and iron deficiency anaemia, with no known family history. BMJ Case Rep. 2020;13(12):22.

  23. Chen HM, Fang JY. Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 2009;24(8):865–74.

    Article  PubMed  Google Scholar 

  24. Chow E, Macrae F. Review of juvenile polyposis syndrome. J Gastroenterol Hepatol (Australia). 2005;20(11):1634–40.

    Article  CAS  Google Scholar 

  25. Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology. 2000;119(3):854–65.

    Article  CAS  PubMed  Google Scholar 

  26. Cichy W, Klincewicz B, Plawski A. Juvenile polyposis syndrome. Arch Med Sci. 2014;10(3):570–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dahdaleh FS, Carr JC, Calva D, Howe JR. Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet. 2012;81(2):110–6.

    Article  CAS  PubMed  Google Scholar 

  28. de Leon MP, Pedroni M, Viel A, Luppi C, Conigliaro R, Domati F, et al. Massive juvenile polyposis of the stomach in a family with SMAD4 gene mutation. Fam Cancer. 2019;18(2):165–72.

    Article  PubMed  Google Scholar 

  29. Duan XY, Guo DC, Regalado ES, Shen H, University of Washington Center for Mendelian G, Coselli JS, et al. SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections. Eur J Hum Genet. 2019;27(7):1054–60.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dunlop MG. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut. 2002;51(suppl 5):v21–7.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Faisal MS, Cruise M, Burke CA, Liska D, Leach B, O’Malley M, et al. Juvenile polyposis syndrome & inflammatory bowel disease: Balancing the risk of malignancy. Am J Gastroenterol. 2020;115(SUPPL):S1758.

    Article  Google Scholar 

  32. Ford MM. Hamartomatous polyposis syndromes: Diagnosis and management. Seminars Colon Rectal Surg. 2018;29(3):120–3.

    Article  Google Scholar 

  33. Friedl W, Kruse R, Uhlhaas S, Stolte M, Schartmann B, Keller KM, et al. Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients. Genes Chromosomes Cancer. 1999;25(4):403–6.

    Article  CAS  PubMed  Google Scholar 

  34. Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, et al. Juvenile polyposis: Massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet. 2002;111(1):108–11.

    Article  CAS  PubMed  Google Scholar 

  35. Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010;152A(2):333–9.

    Article  CAS  PubMed  Google Scholar 

  36. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852–9.

    Article  CAS  PubMed  Google Scholar 

  37. Gallione CJ, Richards JA, Letteboer TGW, Rushlow D, Prigoda NL, Leedom TP, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006;43(10):793–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gammon A, Jasperson K, Kohlmann W, Burt RW. Hamartomatous polyposis syndromes. Best Pract Res Clin Gastroenterol. 2009;23(2):219–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gomez-Puerto MC, Iyengar PV, Garcia de Vinuesa A, Ten Dijke P, Sanchez-Duffhues G. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol. 2019;247(1):9–20.

    Article  CAS  PubMed  Google Scholar 

  40. Gonzalez RS, Adsay V, Graham RP, Shroff SG, Feely MM, Drage MG, et al. Massive gastric juvenile-type polyposis: a clinicopathological analysis of 22 cases. Histopathology. 2017;70(6):918–28.

    Article  PubMed  Google Scholar 

  41. Handra-Luca A, Condroyer C, de Moncuit C, Tepper M, Flejou JF, Thomas G, et al. Vessels’ morphology in SMAD4 and BMPR1A-related juvenile polyposis. Am J Med Genet A. 2005;138A(2):113–7.

    Article  PubMed  Google Scholar 

  42. Hashimoto Y, Yokoyama K, Kumagai H, Okada Y, Yamagata T. Juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia associated with a SMAD4 mutation in a girl. Clin J Gastroenterol. 2020;13(6):1096–101.

    Article  PubMed  Google Scholar 

  43. Heald B, Rigelsky C, Moran R, LaGuardia L, O’Malley M, Burke CA, et al. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia due to SMAD4. Am J Med Genet A. 2015;167A(8):1758–62.

    Article  PubMed  Google Scholar 

  44. Honda Y, Sato Y, Yokoyama J, Kobayashi M, Narisawa R, Kawauchi Y, et al. Familial juvenile polyposis syndrome with a novel SMAD4 germline mutation. Clin J Gastroenterol. 2013;6(5):361–7.

    Article  PubMed  Google Scholar 

  45. Howe JR, Haidle JL, Lal G, Bair J, Song C, Pechman B, et al. ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis. Clin Genet. 2007;71(1):91–2.

    Article  CAS  PubMed  Google Scholar 

  46. Howe JR, Ringold JC, Hughes JH, Summers RW. Direct genetic testing for SMAD4 mutations in patients at risk for juvenile polyposis. Surgery. 1999;126(2):162–70.

  47. Howe JR, Roth S, Ringold JC, Summers RW, Jarvinen HJ, Sistonen P, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280(5366):1086–8.

    Article  CAS  PubMed  Google Scholar 

  48. Howe JR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A, et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet. 2004;41(7):484–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang SC, Erdman SH. Pediatric juvenile polyposis syndromes: an update. Curr Gastroenterol Rep. 2009;11(3):211–9.

    Article  PubMed  Google Scholar 

  50. Inoguchi Y, Kaku B, Kitagawa N, Katsuda S. Hereditary hemorrhagic telangiectasia with SMAD4 mutations is associated with fatty degeneration of the left ventricle, coronary artery aneurysm, and abdominal aortic aneurysm. Intern Med. 2019;58(3):387–93.

    Article  PubMed  Google Scholar 

  51. Iyer NK, Burke CA, Leach BH, Parambil JG. SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia. Thorax. 2010;65(8):745–6.

    Article  PubMed  Google Scholar 

  52. Jee MJ, Yoon SM, Kim EJ, Choi HJ, Kim JW, Sung RH, et al. A novel germline mutation in exon 10 of the SMAD4 gene in a familial juvenile polyposis. Gut and liver. 2013;7(6):747–51.

  53. Jelsig AM. Hamartomatous polyps - a clinical and molecular genetic study. Dan Med J. 2016;63(8).

  54. Jelsig AM, Qvist N, Brusgaard K, Nielsen CB, Hansen TP, Ousager LB. Hamartomatous polyposis syndromes: A review. Orphanet J Rare Dis. 2014;9(1).

  55. Jelsig AM, Tørring PM, Kjeldsen AD, Qvist N, Bojesen A, Jensen UB, et al. JP-HHT phenotype in Danish patients with SMAD4 mutations. Clin Genet. 2016;90(1):55–62.

    Article  CAS  PubMed  Google Scholar 

  56. Jones RD, Dittmann D, Beaubier NT, Gao J, Yang GY. SMAD4 mutation hotspot analysis and concomitant key cancer-related gene mutation profile in a large cohort of colorectal adenocarcinoma using next generation sequencing approach. Lab Invest. 2017;97(Supplement 1):458A.

    Google Scholar 

  57. Kadiyska T, Nossikoff A, Kratunkov P, Hachmerian M, Angelova L. Clinical and genetic challenges in a family with history of childhood polyp, aortopathy, and clinical diagnosis of hereditary hemorrhagic teleangiectasia (HHT). Ann Pediatr Cardiol. 2016;9(2):176–8.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kamil ZS, Schwenter F, Berk T, Pollett A, Grin A, Faughnan ME, et al. Colonic dysplasia and malignancy in patients with SMAD4 mutation-associated juvenile polyposis-hereditary hemorrhagic telangiectasia. Lab Invest. 2012;92:164A.

    Google Scholar 

  59. Kang B, Hwang SK, Choi S, Kim ES, Lee SY, Ki CS, et al. Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: First report in Korea with a novel mutation in the SMAD4 gene. Translatl Pediatr. 2021;10(5):1369–76.

    Article  Google Scholar 

  60. Karlsson T, Cherif H. Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler’s Disease, Uppsala University Hospital. Ups J Med Sci. 2018;123(3):153–7.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Karnsakul W, Cuffari C, Sule S, Collaco JM, Hwang M, Dietz E, et al. A novel SMAD 4 mutation in a child with probable emerging phenotypes of JP-HHT syndrome. Angiogenesis. 2018;21(1):152.

    Google Scholar 

  62. Kim IJ, Ku JL, Yoon KA, Heo SC, Jeong SY, Choi HS, et al. Germline mutations of the dpc4 gene in Korean juvenile polyposis patients. Int J Cancer. 2000;86(4):529–32.

    Article  CAS  PubMed  Google Scholar 

  63. Kopiec DK, Plawski A, Stronka MB, Teisseyre M, Dadalski M, Kuszyk JC, et al. Juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia caused by the SMAD4 gene mutation in a paediatric patient-A case report and a review of the literature. Pediatr Pol. 2021;96(1):71–6.

    Article  Google Scholar 

  64. Lamireau T, Olschwang S, Rooryck C, Le Bail B, Chateil JF, Lacombe D. SMAD4 germinal mosaicism in a family with juvenile polyposis and hypertrophic osteoarthropathy. J Pediatr Gastroenterol Nutr. 2005;41(1):117–20.

    Article  PubMed  Google Scholar 

  65. Latchford AR, Neale K, Phillips RK, Clark SK. Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum. 2012;55(10):1038–43.

    Article  PubMed  Google Scholar 

  66. Lawless ME, Toweill DL, Jewell KD, Jain D, Lamps L, Krasinskas AM, et al. Massive Gastric Juvenile Polyposis: a clinicopathologic study using SMAD4 immunohistochemistry. Am J Clin Pathol. 2017;147(4):390.

    Article  CAS  PubMed  Google Scholar 

  67. Le Goff C, Michot C, Cormier-Daire V. Myhre syndrome. Clin Genet. 2014;85(6):503–13.

    Article  PubMed  Google Scholar 

  68. Lee GH, Payne SJ, Melville A, Clark SK. Genetic testing in inherited polyposis syndromes - how and why? Colorectal Dis. 2014;16(8):595–602.

    Article  CAS  PubMed  Google Scholar 

  69. Lieberman S, Beeri R, Walsh T, Schechter M, Keret D, Half E, et al. Variable features of juvenile polyposis syndrome with gastric involvement among patients with a large genomic deletion of BMPR1A. Clin Transl Gastroenterol. 2019;10(7):e00054.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lin HC, Fiorino KN, Blick C, Anupindi SA. A rare presentation and diagnosis of juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia overlap syndrome. Clin Imaging. 2015;39(2):321–4.

    Article  PubMed  Google Scholar 

  71. MacFarland SP, Ebrahimzadeh J, Zelley K, Mamula P, Brodeur GM, Katona BW. Clinical presentation and disease progression in juvenile polyposis syndrome patients with and without a mutation in SMAD4 or BMPR1A. Fam Cancer. 2019;18(Supplement 1):S66.

    Google Scholar 

  72. MacFarland SP, Ebrahimzadeh JE, Zelley K, Begum L, Bass LM, Brand RE, et al. Phenotypic differences in Juvenile Polyposis Syndrome with or without a disease-causing SMAD4/BMPR1A variant. Cancer Prev Res. 2021;14(2):215–22.

    Article  CAS  Google Scholar 

  73. Malkoski SP, Wang XJ. Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett. 2012;586(14):1984–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. McCarthy AJ, Chetty R. Smad4/DPC4. J Clin Pathol. 2018;71(8):661–4.

    Article  PubMed  Google Scholar 

  75. McDonald NM, Ramos GP, Sweetser S. SMAD4 mutation and the combined juvenile polyposis and hereditary hemorrhage telangiectasia syndrome: a single center experience. Int J Colorectal Dis. 2020;35(10):1963–5.

    Article  PubMed  Google Scholar 

  76. Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, et al. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United KinFgdom Cancer Genetics Group (UKCGG). Gut. 2020;69(3):411–44.

    Article  CAS  PubMed  Google Scholar 

  77. Ngeow J, Heald B, Rybicki LA, Orloff MS, Chen JL, Liu X, et al. Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. Gastroenterology. 2013;144(7):1402–9, 9.e1-5.

    Article  CAS  PubMed  Google Scholar 

  78. Ngeow J, Yu W, Yehia L, Niazi F, Chen J, Tang X, et al. Exome sequencing reveals germline smad9 mutation that reduces phosphatase and tensin homolog expression and is associated with hamartomatous polyposis and gastrointestinal ganglioneuromas. Gastroenterology. 2015;149(4):886–9.e5.

    Article  CAS  PubMed  Google Scholar 

  79. Oliveira MM, Meloni VA, Canonaco RS, Takeno SS, Bortolai A, de Mello CB, et al. Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome in an adolescent with complex chromosomal rearrangement and intellectual disability. Am J Med Genet A. 2014;164(10):2685–8.

    Article  Google Scholar 

  80. O’Malley M, LaGuardia L, Kalady M, Parambil J, Leach B, Eng C, et al. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome patients with SMAD4 mutations. Hereditary Cancer Clin Pract. 2011;1:2–3.

    Google Scholar 

  81. O'Malley M, LaGuardia L, Leach B, Marquard J, Liska D, Cruise M, et al. Immature teratoma in juvenile polyposis - A case study. Fam Cancer. 2019;18(Supplement 1):S62.

  82. Piepoli A, Mazzoccoli G, Panza A, Tirino V, Biscaglia G, Gentile A, et al. A unifying working hypothesis for juvenile polyposis syndrome and Menetrier’s disease: Specific localization or concomitant occurrence of a separate entity? Dig Liver Dis. 2012;44(11):952–6.

    Article  PubMed  Google Scholar 

  83. Pintiliciuc OG, Heresbach D, de-Lajarte-Thirouard AS, Dugast C, Reignier A, Cottereau J, et al. Gastric involvement in juvenile polyposis associated with germline SMAD4 mutations: an entity characterized by a mixed hypertrophic and polypoid gastropathy. Gastroenterol Clin Biol. 2008;32(5 Pt 1):445–50.

    Article  CAS  PubMed  Google Scholar 

  84. Poaty H, Batamba Bouya L, Ondima IPL, Mongo-Onkouo A, Lumaka Zola A, Peko JF, et al. BMPR1A and SMAD4 mutations in juvenile polyposis syndrome: clinicopathological and genetic data from two congolese patients. Gene Reports. 2021;23 (no pagination).

  85. Poletto ED, Trinh AM, Levin TL, Loizides AM. Hereditary hemorrhagic telangiectasia and juvenile polyposis: An overlap of syndromes. Pediatr Radiol. 2010;40(7):1274–7.

  86. Pyatt RE, Pilarski R, Prior TW. Mutation screening in juvenile polyposis syndrome. J Mol Diagn. 2006;8(1):84–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ramos GP, Sharain K, Ravi K. Lightning strikes twice. Am J Gastroenterol. 2016;111(Supplement 1):S1029.

    Article  Google Scholar 

  88. Rohlin A, Rambech E, Kvist A, Törngren T, Eiengård F, Lundstam U, et al. Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. Fam Cancer. 2017;16(2):195–203.

    Article  CAS  PubMed  Google Scholar 

  89. Roth S, Sistonen P, Salovaara R, Hemminki A, Loukola A, Johansson M, et al. SMAD genes in juvenile polyposis. Genes Chromosom Cancer. 1999;26(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  90. Sakurai Y, Kikuchi S, Shigeyasu K, Kakiuchi Y, Tanaka T, Umeda H, et al. SMAD4 germline pathogenic variant-related gastric juvenile polyposis with adenocarcinoma treated with laparoscopic total gastrectomy: a case report. Am J Case Rep. 2021;22:e932241.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Sayed MG, Ahmed AF, Ringold JR, Anderson ME, Bair JL, Mitros FA, et al. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol. 2002;9(9):901–6.

    Article  CAS  PubMed  Google Scholar 

  92. Schreibman IR, Baker M, Amos C, McGarrity TJ. The hamartomatous polyposis syndromes: A clinical and molecular review. Am J Gastroenterol. 2005;100(2):476–90.

    Article  PubMed  Google Scholar 

  93. Schwenter F, Gradinger AB, Berk T, Gryfe R, Pollett A, Cohen Z, et al. Juvenile polyposis, Hereditary hemorrhagic telangiectasia and early onset colorectal cancer in patients with SMAD4 mutation. Fam Cancer. 2011;10(4):716.

    Google Scholar 

  94. Schwenter F, Ratjen F, Berk T, Gallinger S, Gryfe R, Gradinger AB, et al. Juvenile polyposis syndrome, SMAD4 mutations, and hereditary hemorrhagic telangiectasia. J Pediatr Gastroenterol Nutr. 2012;54(1):120–2.

  95. Schwetz V, Uhrig S, Spuller E, Deutschmann A, Hogenauer C. Manifestations of juvenile polyposis syndrome in SMAD4 mutation carriers of a kindred. Eur J Gastroenterol Hepatol. 2012;24(8):988–94.

    Article  PubMed  Google Scholar 

  96. Shah NB, Lindor NM. Lower gastrointestinal tract cancer predisposition syndromes. Hematol Oncol Clin North Am. 2010;24(6):1229–52.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Shikata K, Kukita Y, Matsumoto T, Esaki M, Yao T, Mochizuki Y, et al. Gastric juvenile polyposis associated with germline SMAD4 mutation. Am J Med Genet A. 2005;134(3):326–9.

    Article  PubMed  Google Scholar 

  98. Soer E, de Vos Tot Nederveen Cappel WH, Ligtenberg MJ, Moll F, Pierik RG, Vecht J, et al. Massive gastric polyposis associated with a germline gene mutation. Fam Cancer. 2015;14(4):569–73.

  99. Stadler ZK, Salo-Mullen E, Zhang L, Shia J, Bacares R, Power DG, et al. Juvenile polyposis syndrome presenting with familial gastric cancer and massive gastric polyposis. J Clin Oncol. 2012;30(25):e229–32.

    Article  PubMed  Google Scholar 

  100. Stojcev Z, Borun P, Hermann J, Krokowicz P, Cichy W, Kubaszewski L, et al. Hamartomatous polyposis syndromes. Hereditary Cancer Clin Pract. 2013;11(1):1–9.

    Google Scholar 

  101. Suppressa P, Lenato GM, Lastella P, Chiumarulo L, Marano G, Mastropierro V, et al. Severe pulmonary involvment of SMAD4-mutated patients with juvenile polyposis/hereditary hemorrhagic telangiectasia combined syndrome. Angiogenesis. 2018;21(1):143.

    Google Scholar 

  102. Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, et al. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA. 2005;294(19):2465–73.

    Article  CAS  PubMed  Google Scholar 

  103. Teekakirikul P, Milewicz DM, Miller DT, Lacro RV, Regalado ES, Rosales AM, et al. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. Am J Med Genet A. 2013;161(1):185–91.

    Article  CAS  Google Scholar 

  104. van Hattem WA, Brosens LA, de Leng WW, Morsink FH, Lens S, Carvalho R, et al. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008;57(5):623–7.

    Article  PubMed  Google Scholar 

  105. van Hattem WA, Langeveld D, De Leng WWJ, Morsink FH, Van Diest PJ, Iacobuzio-Donahue CA, et al. Histologic variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis. Am J Surg Pathol. 2011;35(4):530–6.

  106. Wain KE, Ellingson MS, McDonald J, Gammon A, Roberts M, Pichurin P, et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med. 2014;16(8):588–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wiener E, Martin P, Mehta S, Markus HS. Clinical/Scientific Notes: Cervical artery dissection and iliac artery aneurysm in an SMAD-4 mutation carrier. Neurology. 2017;3(5):e191.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Woodford-Richens K, Bevan S, Churchman M, Dowling B, Jones D, Norbury CG, et al. Analysis of genetic and phenotypic heterogeneity in juvenile polyposis. Gut. 2000;46(5):656–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zbuk KM, Eng C. Hamartomatous polyposis syndromes. Nat Clin Pract Gastroenterol Hepatol. 2007;4(9):492–502.

    Article  CAS  PubMed  Google Scholar 

  110. Zimmer V, Grobholz R, Lammert F, Raedle J. Endoscopic resection of a large duodenal hamartoma related to SMAD4-associated juvenile polyposis/hereditary hemorrhagic teleangiectasia syndrome. Am J Gastroenterol. 2011;106(11):2047–8.

    Article  PubMed  Google Scholar 

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Acknowledgements

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This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, Australia

    Kimberley Cao, John-Paul Plazzer & Finlay Macrae

  2. Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia

    Kimberley Cao & Finlay Macrae

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  1. Kimberley Cao
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Contributions

KC performed the literature search, provided substantial contributions to the conception and design of the work, acquired, analysed, and interpreted the data, and drafted the manuscript. JP was a supervisor for this work, who made substantial contributions to the conception and design of the work, aided with data analysis and manual variant curation, together with confirming their classification, and helped with final drafting and editing. FM was a supervisor for this work, who made substantial contributions to the conception and design of the work, aided with data interpretation, and substantively edited and revised it throughout its multiple drafts. All authors read and approved the final manuscript.

Authors’s information

KC is a junior doctor at the Royal Melbourne Hospital, and was previously a student of the University of Melbourne Medical School.

JP is a database curator at the Royal Melbourne Hospital and a member of the InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel.

FM AO MBBS MD FRACP FRCP AGAF MWGO is Head of Colorectal Medicine and Genetics at the Royal Melbourne Hospital, with public and private practices focusing on familial bowel cancer and inflammatory bowel disease. He has performed extensive research in the field of DNA variant interpretation of inherited GI cancers.

Corresponding author

Correspondence to Kimberley Cao.

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Ethics approval and consent to participate

This study was approved by institutional review board of the Melbourne Health Human Research Ethics Committee and Office for Research Ethics and Governance (QA2021082), who deemed the project did not require ethics committee review and was subject to quality assurance acknowledgement. This project was reviewed under the tenets of the National Statement on Ethical Conduct in Research 2007 (updated 2018) and the NHMRC Ethical Considerations in Quality Assurance and Evaluation Activities (March 2014).

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The authors declare no competing interests.

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Appendix A

Appendix A

Search strategy

  1. 1.

    SMAD4-related juvenile polyposis or juvenile polyposis* or infantile juvenile polyposis or juvenile intestinal polyposis or intestinal polyposis or JPS or hamartomatous polyposis syndrome* or retention polyp*

  2. 2.

    SMAD4* or SMAD family member 4 or MADH4 or DPC4 or human SMAD4 protein or JIP or MYHRS or mothers against decapentaplegic homolog 4 or deletion target in pancreatic carcinoma 4 or MAD homolog 4 or deleted in pancreatic carcinoma locus 4 or HSMAD4

  3. 3.

    gene analysis or gene association stud* or genetic association stud* or candidate gene identification or genotype–phenotype correlation* or genotype–phenotype association*

  4. 4.

    genotype* or gene* or genetic* or genom* or phenotype* or DNA* or mutat* or chromosom* or variant

  5. 5.

    1 AND 2

  6. 6.

    ((SMAD4-related juvenile polyposis or juvenile polyposis* or infantile juvenile polyposis or juvenile intestinal polyposis or intestinal polyposis or JPS or hamartomatous polyposis syndrome* or retention polyp*) adj5 (gene analysis or gene association stud* or genetic association stud* or candidate gene identification or genotype–phenotype correlation* or genotype–phenotype association*))

  7. 7.

    ((SMAD4-related juvenile polyposis or juvenile polyposis* or infantile juvenile polyposis or juvenile intestinal polyposis or intestinal polyposis or JPS or hamartomatous polyposis syndrome* or retention polyp*) adj5 (genotype* or gene* or genetic* or genom* or phenotype* or DNA* or mutat* or chromosom* or variant))

  8. 8.

    5 OR 6 OR 7

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Cao, K., Plazzer, JP. & Macrae, F. SMAD4 variants and its genotype–phenotype correlations to juvenile polyposis syndrome. Hered Cancer Clin Pract 21, 27 (2023). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13053-023-00267-z

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13053-023-00267-z

Keywords

Hereditary Cancer in Clinical Practice

ISSN: 1897-4287