1 | INTRODUCTION

Pathogenic variants in genes involved in the transforming growth factor beta (TGF-β) signaling pathway are increasingly recognized as causes of familial thoracic aorta aneurysm and dissection (TAAD, OMIM no. 607086) and are often accompanied by abnormalities of connective tissue. These include pathogenic variants in the TGF-β receptors types I and II (TGFBR1 and TGFBR2, respectively) which cause Loeys–Dietz syndrome (OMIM no. 609192) and at least 10 additional genes associated with familial TAAD (Table 1, Chou & Lindsay, 2020). Two genes, endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) (Faughnan et al., 2020; Gallione et al., 2010) cause most cases of Hereditary Hemorrhagic Telangiectasia (HHT, OMIM no. 187300). The least common form of HHT (10%) is due to pathogenic variants in SMAD4 which cause a unique phenotype of juvenile polyposis (JP) and HHT (SMAD4-JP-HHT) (Gallione et al., 2010; Iyer et al., 2010). Aortic dilation and dissection, in addition to features similar to Marfan syndrome (MFS), have been documented in patients with SMAD4-JP-HHT (Andrabi et al., 2011; Heald et al., 2015; Teekakirikul et al., 2013; Wain et al., 2014).

Recurrent pathogenic variants in SMAD4 at isoleucine500 (amino acid change to valine, methionine, and threonine) and at arginine496 cause Myhre syndrome, which are postulated to be gain-of-function (Caputo et al., 2012; Caputo et al., 2014; Le Goff et al., 2012). Myhre syndrome is characterized by short stature, stiff joints and/or arthropathy, firm skin, thick scars, characteristic facial appearance, congenital heart defects, aortic hypoplasia, deafness, and variable neurodevelopmental/social disabilities (Starr et al., 2017). Somatic gain-of-function pathogenic variants in SMAD4 cause a large variety of cancers. Similarly, the germline pathogenic variants in Myhre syndrome are associated with endometrial cancer and brain tumors (Lin et al., 2020). These features contrast with SMAD4-JP-HHT which can resemble an inherited disorder of connective tissue (IDCT). We compare an additional patient with SMAD4-JP-HHT and IDCT abnormalities to other reported patients with SMAD4-JP-HHT and to those with Myhre syndrome in order to illustrate that contrasting molecular mechanisms result in opposing features.

2 | CASE REPORT

This 70-year-old man presented in 2012 to Mass General Brigham with a history of a large colonic adenoma, status post ileocecectomy, and gastrointestinal bleeding; additional endoscopies of stomach, small intestine, and colon-reported JP (due to the presence of more than five juvenile polyps in the colon/rectum). Based on the history of multiple juvenile polyps, he underwent JP gene sequencing analysis of BMPR1A and SMAD4 through Ambry Genetics laboratory, and was found to harbor a pathogenic variant in SMAD4, c.692dupG (p.S232Qfs*3). This frameshift variant causes a premature stop codon in the SMAD4 gene where loss-of-function is a known mechanism of disease; it has previously been reported in an individual with JP-HHT (Gallione et al., 2010), and is absent from gnomAD population database. Deletion and duplication analysis was not performed since a diagnostic result was identified. He met two of the four Curaçao diagnostic criteria for HHT, including JP and recurrent epistaxis since age 30. Subsequent positive contrast echocardiography (“bubble study”) without obvious arteriovenous malformations (AVMs) on chest imaging suggested that the patient had micro-pulmonary AVMs. Although he lacked mucocutaneous telangiectasias, the SMAD4 variant established the diagnosis of SMAD4-JP-HHT. Family history was unremarkable. Symptoms of HHT, polyps, and colon cancer were absent in his parents, three brothers, and four sisters; his two sons and a daughter had negative genetic testing.

Following the diagnosis of SMAD4-JP-HHT, the patient experienced recurrent gastrointestinal bleeding due to >50 gastric polyps and angioectasias, and resulting in anemia refractory to multiple therapies. Given the persistence of bleeding, the patient underwent laparoscopic total gastrectomy in 2015. He has not had overt intestinal bleeding nor required iron transfusions since his surgery; however, “dumping syndrome” has been problematic. Given his diagnosis of HHT, the patient underwent chest CT in 2012 to assess for pulmonary AVMs, which detected mild aortic dilatation (4.3 cm). Subsequent serial images with echocardiography and CT scans showed an initial slow trajectory of aortic aneurysmal dilatation which reached 4.7 cm in a CT scan in 2018. At the same time, note was made of progressive valvulopathy with thickening of the mitral valve and ultimately prolapse of the posterior leaflet with severe mitral regurgitation noted in 2015. Subsequently, dilatation of the right and left ventricles, right and left atria, inferior vena cava (IVC), aortic sinuses (42 mm enlarging to 47 mm over 6-year period), and ascending aorta (with an ejection fraction of 72%), led to cardiac surgery in 2018. He underwent mitral valve repair, tricuspid valve repair, patent foramen ovale closure, Florida sleeve reinforcement of aortic root, and ascending aortic replacement. Postoperative transesophageal echocardiogram showed no regurgitation of the aortic, mitral, or tricuspid valves, with normal sinus rhythm, and good left ventricular function. Because of recurrent postoperative symptomatic atrial fibrillation upon cessation of amiodarone, he had radiofrequency ablation with no recurrences.

In addition to typical JP-HHT features, the patient had joint laxity since childhood and mild pectus excavatum. He had normal stature (175 cm), but progressive scoliosis has led to a reduction in height. Over 20 months (2018–2019), the Cobb angle increased from 43 to 49 degrees. Radiographs showed straightening of the cervical lordosis and thoracic kyphosis with an exaggerated focal kyphosis at the thoracolumbar junction. He also has multilevel degenerative changes of the spine including prominent degenerative disc changes involving the upper lumbar spine at the apex of the scoliosis. Worsening knee pain and instability since his 20s necessitated bilateral total knee replacements at an outside hospital at ages 53 and 58 years. Bilateral foot and back pain were attributed to significant degenerative osteoarthritis, and vascular calcifications in his ankles were noted incidentally on radiographs. The mild pectus excavatum was “corrected” by the sternotomy performed for cardiac surgery. Ocular features include glaucoma, bilateral retinal detachment, rapid onset of bilateral cataracts requiring lensectomy, and the absence of lens dislocation. He had no telangiectases, striae, or excessive laxity.

Pulmonary function tests showed normal forced expiratory volume in the first second (FEV1) and forced vital capaticy (FVC), with reduced FEV1/FVC, and significant response to inhaled bronchodilator. These pulmonary function tests were consistent with dysynaptic lung growth with an element of mild reactive airways disease.

3 | LITERATURE REVIEW

A comprehensive PubMed (English language) search found 18 patients with SMAD4-JP-HHT (Table 1) reported as case reports or in small series from 2011 to 2019. Reviews consisting of aggregate data were excluded (Vorselaars et al., 2017; Wain et al., 2014).

4 | RESULTS

Of 19 (18 literature, 1 new) patients with SMAD4-JP-HHT, molecular genetic confirmation of a SMAD4 variant was reported in 16 (84%) patients (Table 1). Of the 19 informative cases, 8/16 (50%) variants were novel (Bishop et al., 2018; Gallione et al., 2010; Heald et al., 2015; Jelsig et al., 2016; Teekakirikul et al., 2013). Ages ranged from 6 to 70 years (mean 34 years). There were 10/14 (71%) males. Six (32%) patients, including our new patient, had both cardiovascular and IDCT features, 12 (63%) had mostly cardiovascular features, and 1 (5%) had mild IDCT. The most severely affected patient (Patient 2 in Teekakirikul et al., 2013) had SMAD4-JP-HHT, aortic dilatation, meeting clinical diagnostic criteria for MFS (arachnodactyly, scoliosis, pes planus, positive wrist and thumb sign, and cutaneous striae), as well as other connective tissue features including marked joint hypermobility and visible veins. FBN1 gene analysis had been declined by patient (Loeys et al., 2010). Our patient lacked striae, atrophic scars, and arachnodactyly. Aortic dilatation was noted in 17 (89%) patients, and 2 (11%) patients with aortic dissection and moderate–severe mitral regurgitation. Because SMAD4-JP-HHT shares multiple features with the well-described condition of MFS, we have included a description of MFS in Table 1.

5 | DISCUSSION

These 19 patients with SMAD4-JP-HHT provide support that SMAD4 loss-of-function pathogenic variants can be associated with IDCT features. The role of SMAD4 in the TGF-β signaling pathway and as a tumor suppressor gene is consistent with the clinical features observed including polyposis, vascular, and connective tissue involvement (Wain et al., 2014). No clear genotype–phenotype correlations have been demonstrated. Individuals with the same SMAD4 loss-of-function variant may have JP syndrome alone with varying polyp onset and burden, SMAD4-JP-HHT, or JP with some features of HHT but not meeting Curaçao criteria (Gallione et al., 2010; Wain et al., 2014). This suggests polygenic or environmental modifiers. SMAD4 is one of many genes in which a gain-of-function variant causes a different multiple anomaly phenotype (i.e., Myhre syndrome).

Diverse SMAD4 variants that cause SMAD4-JP-HHT include missense, nonsense, and frameshift variants, strongly implying that haploinsuffiency for SMAD4 protein is the mechanism driving pathology. In contrast, Myhre syndrome is caused by recurrent missense variants at only two positions (arginine 496 and isoleucine 500) suggesting a likely dominant gain-of-function mechanism. Biologically, SMAD4 plays a prominent role in both canonical TGF-β and bone morphogenic signaling; the systemic manifestations of SMAD4-JP-HHT and Myhre syndrome suggest dysregulation of these pathways. The systemic manifestations of these two disorders suggest opposing biologic effects, such as the finding of aortic aneurysm in SMAD4-JP-HHT versus the aortic hypoplasia seen in Myhre syndrome. Future investigation of the molecular signaling events in cellular and animal models of SMAD4-related disease will be needed to clarify these clinical impressions.

6 CONCLUSION

Despite the small number of patients in which the clinical descriptions were often brief or absent, this series expands the phenotype of SMAD4-JP-HHT as a disorder of connective tissue which has implications for surveillance and better treatment of co-morbidities.

CONFLICT OF INTEREST

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.