SMAD4 or BMPR1A (Juvenile polyposis) – risk management

Juvenile polyposis syndrome (JPS) is an autosomal dominant condition. It can be due to a germline pathogenic variant in the SMAD4 or BMPR1A genes.

Juvenile polyposis syndrome is associated with a predisposition to multiple hamartomatous gastrointestinal polyps, often before the age of 20. SMAD4 pathogenic variants are associated with hereditary haemorrhagic telangiectasia (HHT).

• Individuals with a pathogenic variant in SMAD4 or BMPR1A
• Individuals with a clinical diagnosis of JPS with uninformative molecular testing:
  • A person with ≥1 juvenile polyp and a family history of juvenile polyps
  • A person with ≥1 juvenile polyp and clinical signs of hereditary haemorrhagic telangiectasia (HHT)
  • A person with ≥5 juvenile polyps in the colorectal tract
  • A person with juvenile polyps in both the upper and lower gastrointestinal tract at any age (regardless of number)
• Individuals at 50% risk for JPS

Exclusion criteria

• PTEN hamartoma syndrome
• 10q23 deletion syndrome and juvenile polyposis infantile
• Peutz-Jeghers syndrome
• Isolated juvenile polyp in the absence of a family history of juvenile polyposis
• Individual with a variant of uncertain significance

* These lifetime risks are based on a small number of cases and caution is recommended in their application.
** Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2017 data)
^ This data does not take into account the impact of surveillance. 
^^ Colorectal cancer occurs approximately 20 years after the onset of juvenile polyps; the lower age range reflects cases with a 10q23 deletion with onset of juvenile polyps in infancy. ^r
^^^ The lifetime risk for gastric cancer is higher in those with the large deletion referred to as the 'Bukharin mutation'^r

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Hereditary haemorrhagic telangiectasia

Always consider possible associated diagnosis of hereditary haemorrhagic telangiectasia (HHT). The majority of individuals with a SMAD4 pathogenic variant have some evidence of associated HHT-termed JP/HHT.^rr Surveillance and treatment of HHT complications is required in all SMAD4 pathogenic variant carriers. Consider baseline investigations for HHT in those individuals with a clinical diagnosis of JPS with uninformative molecular testing.

Gastrointestinal polyps

Individuals with JPS and a SMAD4 pathogenic variant are more likely to have a personal or family history of upper GI polyps than individuals with pathogenic variants in BMPR1A or those with no known pathogenic variants.^r Consider small bowel evaluation for individuals who develop unexplained anaemia. Lower GI juvenile polyps are reported in up to 97% of individuals.^rrAdenomas and hyperplastic polyps occur in 40-90% of individuals with JPS.^r Unexplained anaemia in children with JPS needs to be investigated.

See clinical findings in SMAD4 pathogenic variant carriers

There are few descriptive or comparative studies to confirm clinical benefit from this surveillance regime. However, these surveillance schedules are supported by published expert opinion.^rr

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Bibliography

Dunlop, M. G. 2002. "Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polypolis, juvenile polyposis, and Peutz-Jeghers syndrome." Gut 51 Suppl 5:V21-27.

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Abstract not available.

Friedl, W., S. Uhlhaas, K. Schulmann, et al. 2002. "Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers." Hum Genet 111(1):108-111.

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Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to multiple juvenile polyps in the gastrointestinal tract. Germline mutations in the MADH4 or BMPR1A genes have been found to be causative of the disease in a subset of JPS patients. So far, no genotype-phenotype correlation has been reported. We examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in seven (24%) and BMPR1A mutations in five patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This is the first genotype-phenotype correlation observed in JPS.

Gallione, C. J., G. M. Repetto, E. Legius, et al. 2004. "A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)." Lancet 363(9412):852-859.

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BACKGROUND: Juvenile polyposis and hereditary haemorrhagic telangiectasia are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in MADH4 (encoding SMAD4) or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG (endoglin) or ACVRL1 (ALK1). All four genes encode proteins involved in the transforming-growth-factor-beta signalling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic aetiology of this association is unknown. METHODS: Blood samples were collected from seven unrelated families segregating both phenotypes. DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes. Mutations were examined for familial cosegregation with phenotype and presence or absence in population controls. Findings No patient had mutations in the ENG or ACVRL1 genes; all had MADH4 mutations. Three cases of de-novo MADH4 mutations were found. In one, the mutation was passed on to a similarly affected child. Each mutation cosegregated with the syndromic phenotype in other affected family members. INTERPRETATION: Mutations in MADH4 can cause a syndrome consisting of both juvenile polyposis and hereditary haemorrhagic telangiectasia phenotypes. Since patients with these disorders are generally ascertained through distinct medical specialties, genetic testing is recommended for patients presenting with either phenotype to identify those at risk of this syndrome. Patients with juvenile polyposis who have an MADH4 mutation should be screened for the vascular lesions associated with hereditary haemorrhagic telangiectasia, especially occult arteriovenous malformations in visceral organs that may otherwise present suddenly with serious medical consequences.

Howe, J. R., S. Roth, J. C. Ringold, et al. 1998. "Mutations in the SMAD4/DPC4 gene in juvenile polyposis." Science 280(5366):1086-1088.

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Familial juvenile polyposis is an autosomal dominant disease characterized by a predisposition to hamartomatous polyps and gastrointestinal cancer. Here it is shown that a subset of juvenile polyposis families carry germ line mutations in the gene SMAD4 (also known as DPC4), located on chromosome 18q21.1, that encodes a critical cytoplasmic mediator in the transforming growth factor-beta signaling pathway. The mutant SMAD4 proteins are predicted to be truncated at the carboxyl-terminus and lack sequences required for normal function. These results confirm an important role for SMAD4 in the development of gastrointestinal tumors.

Howe, J. R., J. L. Bair, M. G. Sayed, et al. 2001. "Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis." Nat Genet 28(2):184-187.

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Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. Previous studies have demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline mutations in the homolog of the gene for mothers against decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP families. However, mutations in MADH4 are only present in a subset of JP cases, and although mutations in the gene for phosphatase and tensin homolog (PTEN) have been described in a few families, undefined genetic heterogeneity remains. Using a genome-wide screen in four JP kindreds without germline mutations in MADH4 or PTEN, we identified linkage with markers from chromosome 10q22-23 (maximum lod score of 4.74, straight theta=0.00). We found no recombinants using markers developed from the vicinity of the gene for bone morphogenetic protein receptor 1A (BMPR1A), a serine-threonine kinase type I receptor involved in bone morphogenetic protein (BMP) signaling. Genomic sequencing of BMPR1A in each of these JP kindreds disclosed germline nonsense mutations in all affected kindred members but not in normal control individuals. These findings indicate involvement of an additional gene in the transforming growth factor-beta (TGF-beta) superfamily in the genesis of JP, and document an unanticipated function for BMP in colonic epithelial growth control.

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