Juvenile polyposis and hereditary haemorrhagic telangiectasia Q87.89

Tumor predisposition syndrome; Vascular malformation syndrome; 

A rare, autosomal dominant tumor predisposition and vascular malformation syndrome that combines the features of juvenile polyposis syndrome (JPS) with those of hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease). Characteristic features include multiple hamartomatous polyps of the gastrointestinal tract, as well as mucocutaneous telangiectasias and visceral arteriovenous malformations.

The overall prevalence of juvenile polyposis syndrome is estimated to be approximately 1 in 100,000 to 1 in 160,000 people. The SMAD4-associated JPS/HHT phenotype is significantly rarer; reliable prevalence figures are lacking.

Pathogenic SMAD4 variants are found in approximately 20–30% of JPS cases with a confirmed molecular genetic diagnosis. Penetrance is high, but the severity and age of onset vary.

The condition is caused by heterozygous pathogenic germline variants in the SMAD4 tumor suppressor gene on chromosome 18q21.2. The SMAD4 protein encoded by this gene is a key intracellular signaling mediator of the TGF-β/BMP signaling pathway and regulates cell proliferation, differentiation, and vascular development. The mode of inheritance is autosomal dominant; de novo mutations occur.

Pathogenic variants in BMPR1A can also cause juvenile polyposis syndrome but do not typically lead to the HHT overlap phenotype.

Gastrointestinal:

• Multiple juvenile, histologically hamartomatous polyps, particularly in the colon, rectum, and stomach
• rectal bleeding, iron-deficiency anemia, abdominal pain, diarrhea, and protein loss
• Polyp prolapse, intussusception, or intestinal obstruction
• Increased risk, particularly for colorectal and gastric carcinomas; SMAD4 variants are frequently associated with pronounced gastric polyposis

HHT manifestations:

• Recurrent spontaneous epistaxis
• Telangiectasias on the lips, oral mucosa, tongue, face, and fingers (differential diagnosis:Osler-Weber-Rendu disease)
• Arteriovenous malformations of the lungs, liver, and brain
• gastrointestinal vascular malformations with chronic bleeding
• Possible complications: hypoxemia, paradoxical embolisms, brain abscess, stroke, and heart failure

In addition, dilations and aneurysms of the thoracic aorta have been described in association with SMAD4 variants. HHT signs may appear as early as childhood but often do not become clinically apparent until later in life.

The diagnosis is based on the detection of juvenile gastrointestinal polyps, clinical HHT criteria, and, in particular, molecular genetic evidence of a pathogenic SMAD4 germline variant. Once the diagnosis has been established, predictive testing should be offered to first-degree relatives.

There is no causal treatment.

Interdisciplinary care is required:

• regular gastroscopies and colonoscopies, usually starting in adolescence or earlier if symptoms are present
• endoscopic removal of accessible polyps
• in cases of uncontrollable polyposis, bleeding, or neoplasms, colectomy or partial or total gastrectomy as indicated
• Regular monitoring of blood counts and iron status; iron supplementation or blood transfusions as needed
• Screening for pulmonary and cerebral arteriovenous malformations, as well as evaluation of hepatic vascular changes
• Treatment of pulmonary AV malformations, preferably by catheter embolization
• Local, pharmacological, or interventional treatment of epistaxis
• Consider echocardiographic or imaging monitoring of the thoracic aorta
• Lifelong gastroenterological, HHT-specific, and human genetic care

Since SMAD4 variants confer both a high risk of gastrointestinal neoplasia and potentially severe vascular complications, the monitoring program must always take both disease components into account.

As part of a retrospective, multicenter review of medical records, 28 patients with a pathogenic SMAD4 variant from 13 families were identified across all Scottish centers for clinical genetics.

• Colonic polyps (87% (23/28)
• gastric polyps (67%)  

Complication rates were high: 43% (10/23) of patients with polyps required a colectomy, and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients at a median age of 33 years. Pulmonary arteriovenous malformations were detected in 42% (8/19) of the patients examined. 88% (23/26) and 81% (17/21) of the patients exhibited features of JP and HHT, respectively, with 70% (14/20) exhibiting features of both conditions (Pearson M et al. 2024).

1. Gallione CJ et al. (2004) A combined syndrome of juvenile polyposis and hereditary hemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363:852–859.
2. Haidle JL et al. (2022) Juvenile Polyposis Syndrome. In: GeneReviews^®. University of Washington, Seattle; updated 2022.
3. McDonald J et al. (2021) Hereditary Hemorrhagic Telangiectasia. In: GeneReviews^®. University of Washington, Seattle; updated 2021.
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