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

Abstract

Heterozygous loss-of-function (LOF) SMAD4 mutations are associated with juvenile polyposis syndrome (JP) and hereditary hemorrhagic telangiectasia (HHT). Some carriers exhibit symptoms of both conditions, leading to the name JP-HHT syndrome. Three families have been reported with connective tissue abnormalities. In order to better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n=3), aortic and mitral insufficiency (n=2), aortic dissection (n=1), retinal detachment (n=1), brain aneurysms (n=1), lax skin and joints (n=1). JP-specific findings were almost uniformly present but variable. Ninety-seven percent had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent (15/31) had extensive gastric polyposis. HHT features were documented in 76% including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (AVM) (6/16, 38%), brain AVM (1/26, 4%), pulmonary AVM (9/17, 53%), and intrapulmonary shunting (14/23, 61%). SMAD4 carriers should be managed for JP and HHT, since symptoms of both are likely yet unpredictable. Connective tissue abnormalities are an emerging component of JP-HHT syndrome, and larger studies are needed to understand these manifestations.

Juvenile polyposis syndrome

“…However, some pilot studies have shown ENG germ line mutations to be associated with early‐onset JPS . Patient with JPS can have different phenotypic variations with same gene mutation, one such variant being a combined syndrome of JPS and hereditary hemorrhagic telangiectasia (JPS/HHT) with SMAD4 pathogenic variant . Furthermore, variations in polyp burden are also known to exist with JPS as some patients develop 4 to 5 polyps over lifetime and others may have more than 100 at a very young age itself.…”

“…2 Patient with JPS can have different phenotypic variations with same gene mutation, one such variant being a combined syndrome of JPS and hereditary hemorrhagic telangiectasia (JPS/HHT) with SMAD4 pathogenic variant. 3,4 Furthermore, variations in polyp burden are also known to exist with JPS as some patients develop 4 to 5 polyps over lifetime and others may have more than 100 at a very young age itself. Therefore, it becomes important to identify family-specific pathogenic variant to offer appropriate molecular genetic testing on atrisk family members in decades of life.…”

“…However, in a selected proband of patients the diagnosis can be established with clinical features of either more than five juvenile polyps of the colon or rectum; multiple juvenile polyps of the upper and lower GI tract; any number of juvenile polyps and a family history of juvenile polyposis and identification of a heterozygous pathogenic variant in one of the SMAD4 or BMPRA1A genes. 1,3,4 The clinical presentation of polyposis of infancy can have a varied presentation with symptoms of GI bleeding, obstruction, hyponatremia, anasarca, and failure to thrive. Clinical management of patients with symptomatic polyposis depends primarily on the anatomy of the GI tract involved and polyp burden.…”

An update on the molecular pathology of the intestinal polyposis syndromes

“…SMAD4 mutations are associated with more severe upper gastrointestinal disease 17 and, in some families, with arterio-venous malformations that can result in hereditary haemorrhagic telangiectasia. 18 Both SMAD4 and BMPR1A act in the bone morphogenetic protein signalling (BMP) pathway, which is related to the TGF-beta pathway. BMP signalling is thought to be a pro-differentiation force in the normal intestinal crypt, and its attenuation by germline mutation may favour proliferation and/or a stem cell phenotype.…”

Hereditary Cancer Syndromes—A Primer on Diagnosis and Management, Part 2: Gastrointestinal Cancer Syndromes

“…They commonly bleed, and patients often have iron deficiency anemia. 109 The polyps in JPS are made up of mucin-filled cysts lined by a columnar epithelium with an inflammatory infiltrate ( Figure 5B). A clinical diagnosis of JPS can be made when 3 or more juvenile polyps are present.…”