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

Introduction

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are 2 distinct autosomal diseases. However, in patients with mutations in the SMAD4 gene (Mothers against decapentaplegic homologue 4 gene), they can be present as a combined syndrome. The coexistence of these diseases was first described early in the 1980s. Nevertheless, the association between this combined syndrome and mutation in the SMAD4 gene was first reported in 2004 by Gallione et al. [1]. Empirical evidence indicates that patients with JPS-HHT are at risk of an early onset of colorectal cancer (mean age 28 years) [2].
Juvenile polyposis syndrome is an autosomal dominant disorder, characterized by the predisposition to hamartomatous (juvenile) polyps in the gastrointestinal tract, especially in the stomach, small intestine, colon, and rectum. The term “juvenile” refers to the histopathology of the polyp and not to the age of the onset of polyps. The prevalence rate of the JPS ranges from 1 in 160,000 to 1 in 100,000 people [3]. Rectal bleeding is often its primary manifestation and may appear in early childhood. It is worth mentioning that this condition is associated with an increased risk of gastrointestinal tract cancer, with a lifetime risk of 38% to 68% [3]. The most likely cancer is that of the colon, but cancers of the stomach, upper gastrointestinal tract, and pancreas have been reported.
Hereditary haemorrhagic telangiectasia is also an autosomal dominant disorder characterized by vascular dysplasia with mucocutaneus telangiectasia and organ arteriovenous malformations (AVMs) mainly affecting the lungs, liver, and brain. It was originally known as Osler-Weber-Rendu syndrome after the 3 scientists who described it at the turn of the 20th century. The aim of the study is to present the medical case of a teenage boy with combined juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia.

CASE REPORT

An 11-year-old boy was referred to the regional Gastroenterology Department in 2014 because of rectal bleeding. The rectal bleeding had been noticed for the first time 7 years earlier and was most frequent after defecation. The patient also complained of recurrent nasal bleeding. The boy’s mother underwent a colectomy in adulthood because of polyposis syndrome. She suffers from arteriovenous malformations in the lungs. During the physical examination on admission, asthenic body type, protruding shoulder blades, and skin discoloration on his left forearm were noticed. Laboratory tests revealed elevated inflammation parameters (CRP 14.2 mg/dl, normal range: 0.1–10.0 mg/l) and reduced capillary blood saturation (83.1%). The abdominal ultrasound examination was normal. During hospitalization, an endoscopy was performed and showed oesophageal erosions, a sentinel polyp in the stomach, a 1-cm polyp in the duodenum, a 1-cm polyp in the ascending colon, and six 2–4-cm polyps in the sigmoid colon and rectum. Histology revealed hyperplastic polyps. The patient was directed to our Department.
A clinical interview revealed periodical stools with a small amount of blood (3–4 times a month). In the physical examination small telangiectasias on the lower lip, a funnel-shaped chest, hypermobility of interphalangeal joints in the hands, arachnodactyly, and cyanosis of the lips and nails were noticed (Fig. 1). Endoscopy revealed over a dozen polyps in the large intestine, the biggest aggregation in the rectum. Eight polyps were removed, the biggest being 1.5 cm in diameter. Histopathology described juvenile polyposis with a strong inflammation infiltrate.
A control colonoscopy was carried out 2 months later. During the examination 18 polyps were removed. Because of the desaturation during anaesthesia, the patient was directed to the Department of Pulmonology. CT angiography of chest was carried out and revealed arteriovenous malformations in the lungs. Home oxygen therapy was recommended and caused a rise in the oxygen saturation from 85% to 92%. The patient was subsequently admitted to the Cardiology Department. Echocardiography showed a dilatation of the pulmonary artery to 2 cm and small tricuspid valve regurgitation. Diagnostic cardiac catheterization was carried out and showed numerous arteriovenous malformations, but their seclusion was infeasible because of the anatomy. Lung transplantation was considered. Sildenafil therapy, among other things, was introduced to the pharmacological treatment, and an improvement in effort tolerance was achieved. The patient could abstain from home oxygen therapy.
The patient underwent a gastroscopy and colonoscopy once a year (on average). Due to the diagnosis of the JPS, molecular genetic tests were conducted to exclude mutations in the BMRP1A (bone morphogenetic protein receptor type 1 A), SMAD4, and PTEN (phosphatase and tensin homologue) genes. Sanger sequencing of the SMAD4 gene identified a pathogenic substitution c.1082G>A (p. Arg361His, Fig. 2). The last endoscopy showed esophagitis LA B and numerous sitting and pedunculated polyps in the colon (mostly in the proximal colon, with a diameter of 4 to 10 mm, displayed in Fig. 3). The histopathology revealed juvenile polyps (presented in Fig. 4). Magnetic resonance imaging (MRI) of the brain was carried out and did not show any malformations. An ultrasound examination also did not reveal any arteriovenous malformations in the liver.
Because of the SMAD4 mutation and higher risk of colorectal cancer and the fact that the burden of polyps is not manageable by the polypectomy alone, a colectomy should be considered in future. The patient’s younger brother also had a gastroscopy and colonoscopy. The first examination showed only a small, creating polyp in rectum. The histopathology revealed inflammation changes. An examination, which took place 3 years later, did not show any changes. Molecular genetic tests were also conducted, but they did not identify mutations in the BMRP1A, SMAD4, and PTEN genes; notably, the mutation c.1082G>A was not found.

DISCUSSION

The mutation in the SMAD4 gene causes a combined syndrome of juvenile polyps of the gastrointestinal tract and HHT, also known as JP-HHT. It is a very rare condition, and it can have various clinical presentations. Juvenile polyposis (JP) can be present in infancy and in adulthood with abdominal pain, anaemia, acute or chronic gastrointestinal bleeding, prolapsed rectal polyps, bowel obstruction, or intussusception [2]. Patients may also be asymptomatic [2]. The diagnostic criteria of JPS proposed by Jass et al. [4] contain 5 or more juvenile polyps of the colon or rectum, or juvenile polyps in other parts of the gastrointestinal tract, or any number of juvenile polyps and a positive family history. In 40% to 60% of patients with JPS a mutation in SMAD4 (18q21.1) or BMPR1A (10q23.2) genes is reported [3]. It is worth remembering that many patients with JPS due to SMAD4 mutation have features of HHT (epistaxis, telangiectasia, clubbing, and AVM) [5]. The most common feature of HHT is epistaxis. The arteriovenous malformations can lead to a life-threatening haemorrhage, circulatory insufficiency, brain abscesses, and stroke. Eighty per cent of families suffering from HHT have a mutation in the endoglin (ENG) or activin receptor-like kinase 1 (ALK1) genes. Twenty per cent of patients have a mutation in the SMAD4 gene or in the new loci mapped to chromosome 5 and chromosome 7. It is known that HHT patients with SMAD4 mutations have anaemia more frequently than do patients with alterations of the ENG and ALK1 gene [2].
Clinical features of HHT in patients with SMAD4 mutations [6] are epistaxis, mucocutaneus telangiectasias, AVM (visceral, hepatic, intracranial), aortopathy, and intrapulmonary shunting on echocardiogram. The Curacao criteria for HHT [7] is definite if 3 criteria are present, possible or suspected if 2 criteria are present, and unlikely if fewer than 2 criteria are present (Table 1). The first symptom, as in the case of our patient, can be hypoxia. Children with HHT are at risk of life-threatening complications. In JPS patients with mutations within the SMAD4 gene the risk of colorectal cancer is higher (in a cohort of 14 SMAD4 Danish patients 3 colorectal cancers occurred at a mean age of 34 years) [3]; the risk of severe gastric polyposis and gastric cancer appears to be increased [3]. Thoracic aortic disease and mitral dysfunction have also been reported [6]. That is why systematic HHT screening is recommended for JPS patients with proven SMAD4 mutation.
A Position Paper From the ESPGHAN Polyposis Working Group recommends also that a colectomy should only be discussed in patients in whom the burden of polyps is not manageable by polypectomy alone, and/or leading to uncontrollable anaemia or hypoalbuminaemia from colonic polyposis [3]. The question is, however, whether the recommendation for polypectomy should not be expanded for patients with JPS and SMAD4 mutations and JPS-HHT overlap syndrome in which the risk of colorectal cancer is higher. Jelsig et al. [8] described the clinical characteristics of 14 Danish patients with SMAD4 mutations. They found that probands with SMAD4 mutation have symptoms of both HHT and JPS and that the frequency of PAVM and of gastric involvement with polyps in this group is higher than in patients with HHT or JPS not caused by mutations in the SMAD4 gene. Furthermore, the authors detected 4 occurrences of GI – cancer at a young age. Similar results were presented in the work of Schwenter et al., in which 10 patients met the clinical diagnostic criteria for both JP and HHT [2]. Three JPS-HHT patients developed early-onset colorectal cancer [2]. In a study of 80 unrelated families with juvenile polyposis syndrome, Aretz et al. found that 35 of the cases of JPS were caused by the SMAD4 mutations, of which 22% exhibited features of the HHT [9]. All the described cases of gastric cancer in that publication (i.e. 7 cases) were reported in families with mutations in the SMAD4 gene. In addition to those studies, there are also case presentations in the literature. Teekakirikul et al. reported 2 patients with JPS-HHT and with SMAD4 mutations associated with thoracic aortic disease [10]. This report confirmed the fact that SMAD4 mutations predispose to thoracic aortic aneurysms and aortic dissections. Their work emphasized that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent death from dissection [10]. Iyer et al. reported a patient with the JPS-HHT syndrome and SMAD4 mutations [11]. The patient suffered from asymptomatic cerebral and pulmonary arteriovenous malformations. The only study that reports multiple arteriovenous malformations involving the liver was that of Chung et al. [12].
We found only one paper by Pantaleoni et al. describing a patient with severe hypoxaemia secondary to an inoperable pulmonary arteriovenous malformations treated by long-term management with sildenafil [13]. In Table 2 we summarize data from the literature concerning JPS-HHT syndrome. We present the case because of the rarity of the JPS-HHT syndrome in the literature, particularly in paediatric patients, and the need for multidisciplinary care of these patients to avoid life-threatening complications. We highlight a positive influence of sildenafil on the respiratory function of our patient.

CONCLUSIONS

1. Patients with features of both JP and HHT should be screened for mutations in the SMAD4 gene.
2. Paediatric patients with JPS-HHT syndrome and arteriovenous malformations of the lungs may profit from sildenafil treatment.

DISCLOSURE

The authors declare no conflict of interest.

REFERENCES