Alternative titles; symbols
SNOMEDCT: 1149069001; ORPHA: 2929, 329971, 79076; DO: 0111543;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q21.2 | Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome | 175050 | Autosomal dominant | 3 | SMAD4 | 600993 |
A number sign (#) is used with this entry because juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JPHT) is caused by heterozygous mutation in the MADH4 gene (SMAD4; 600993) on chromosome 18q21.
The JPHT syndrome includes the features of both the juvenile polyposis syndrome (JPS; 174900) and hereditary hemorrhagic telangiectasia (HHT; 187300) in a single individual. JPS is characterized by hamartomatous polyps occurring throughout the gastrointestinal tract, resulting in an increased risk of gastrointestinal cancer, and HHT is a vascular dysplasia characterized by telangiectases of the skin, and oral and nasal mucosa, epistaxis, and arteriovenous malformations (AVMs) of the lungs, liver, brain, and gastrointestinal tract (summary by Gallione et al., 2010).
Cox et al. (1980) described a 28-year-old woman and her 10-year-old daughter with this combination. Both showed severe digital clubbing. Polyps were discovered in the colon of the daughter at age 5 years. At the age of 8 years, a density was discovered in the left lower lobe on chest x-ray and shown by pulmonary arteriography to be an arteriovenous malformation (AVM). The mother had a pulmonary AVM resected at the age of 10 years, and at the age of 12, partial colectomy was performed for multiple polyposis, leading to severe rectal bleeding. At age 16 years, 16 cm of the distal ileum was resected.
Conte et al. (1982) described an autosomal dominant syndrome of juvenile gastrointestinal polyposis, cutaneous telangiectasia, and pulmonary arteriovenous malformations in a father and his son and daughter. The father died from colon cancer at the age of 36. The brother and sister presented with recurrent rectal bleeding at an early age. All 3 had radiologically demonstrated pulmonary AV malformations with clubbing of the digits and hypertrophic pulmonary osteoarthropathy prompting arthritis clinic care. The sister additionally had repeated episodes of subarachnoid hemorrhage from cerebral AV malformations. Juvenile polyps are characteristically smooth surfaced but cystic on section. Adenomatous polyps are lobulated without cystic dilatation of glands. Microscopically, juvenile polyps are hamartomas.
Baert et al. (1983) described a 15-year-old girl with juvenile polyps, mild digital clubbing, subperiosteal thickening of metacarpals, and AV malformations of the lung. Simpson and Dalinka (1985) noted a 14-year-old girl with juvenile polyps of the colon, clubbing of digits, and hypertrophic osteoarthropathy of long bones, but no AV malformations of the lungs.
Seven patients in the study of HHT/JPS by Gallione et al. (2004) had digital clubbing or osteoarthropathy. The latter feature had been attributed to the intrapulmonary shunting caused by untreated pulmonary AVMs. In some of the patients the clubbing resolved after embolization of the pulmonary lesions. Association of digital clubbing or osteoarthropathy with juvenile polyposis had been previously reported (Cox et al., 1980; Baert et al., 1983; Prieto et al., 1990; Burger et al., 2002; Simpson and Dalinka, 1985; Erkul et al., 1994).
Nine of the 14 patients in the study of Gallione et al. (2004) had mucocutaneous telangiectases, 9 epistaxis, and 7 pulmonary arteriovenous malformations, 1 patient being diagnosed at age 9 months. One patient had a cerebellar cavernous hemangioma, and 2 had episodes of intracranial bleeding, 1 resulting in right-sided hemiparesis and the other in vision loss in the upper right quadrant. Four patients had hepatic arteriovenous malformations, 1 of whom was only 9 years old when diagnosed. These early ages of onset in several of the patients with the combined syndrome contrasted with more typical later ages of diagnosis for hereditary hemorrhagic telangiectasia, especially for arteriovenous malformations.
Kumar et al. (2008) reported a 35-year-old man with HHT and polyposis, confirmed by genetic analysis, who presented with a frontoparietal lobe abscess resulting from pulmonary AVMs. He also had a history of epistaxis, gum bleeds, iron deficiency anemia, and lower gastrointestinal bleeding. Abdominal CT scan showed hepatic telangiectasia and evidence of arterial-portal shunting. Brain MRI showed increased T1-weighted signals from the globus pallidus to substantia nigra, suggestive of manganese deposition, and blood tests showed increased serum manganese. The patient reported occupational exposure and inadvertent manganese ingestion. Kumar et al. (2008) noted that since patients with iron deficiency have increased manganese absorption and that the liver usually excretes manganese, this man was predisposed to hypermanganesemia and may later develop signs of an extrapyramidal syndrome.
Clinical Variability
Andrabi et al. (2011) reported a family with juvenile polyposis, aortopathy, and mitral valve dysfunction associated with a heterozygous truncating mutation in the SMAD4 gene (R445X; 600993.0014). The proband was followed from early childhood because a parent had died suddenly of a presumed arrhythmia due to mitral valve prolapse, severe mitral regurgitation, left ventricular dilatation, and mild dilation of the aortic root. At autopsy, the parent was also found to have hyperextensible joints and multiple hamartomatous colonic polyps. The proband had mild hyperextensibility of the fingers, juvenile polyposis, and mitral valve prolapse with mitral valve regurgitation; the aorta was normal. Family history revealed a grandparent who had died at age 43 of colon cancer and 2 sibs of the deceased parent with colonic polyps, 1 of whom also had redundant mitral valve and mild dilatation of the aortic valve, root, and ascending aorta. Of 5 affected individuals with gastrointestinal hamartomatous polyps, 3 had aortic dilatation, 3 had mitral regurgitation, and 2 had mitral valve prolapse. Telangiectases were not noted in this family. Andrabi et al. (2011) noted the role of SMAD4 in the TGF-beta-1 signaling pathway, suggesting overlap with other connective tissue disorders such as Marfan syndrome (154700) and Loeys-Dietz syndrome (see, e.g., 609192). The findings indicated that haploinsufficiency of SMAD4 may cause an aortopathy and mitral valve dysfunction.
Heald et al. (2015) retrospectively reviewed the charts of 26 patients with HHT from 15 families, of which 13 had known mutations (SMAD4; ENG, 131195; ACVRL1, 601284). Aortopathy ranging from mild dilation to aortic dissection was detected in 6 (23%) of the 26 patients, and all 6, who came from 5 unrelated families, carried SMAD4 mutations. The authors suggested that aortopathy might be part of the spectrum of SMAD4-induced HHT manifestations.
The juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome maps to chromosome 18q21.1, the location of the SMAD4 gene (600993), which is mutant in this disorder.
Juvenile polyposis and hereditary hemorrhagic telangiectasia are autosomal dominant disorders with distinct and nonoverlapping clinical features. The former, a predisposition to gastrointestinal malignancy, is caused by mutations in MADH4 or BMPR1A (601299); the latter, a vascular malformation disorder, is caused by mutations in ENG (131195) or ALK1 (601284). All 4 genes encode proteins involved in the transforming growth factor-beta signaling pathway (see 190180). Furthermore, although both of these inherited disorders are uncommon, there are many reports of patients and families with both disorders, or of patients with juvenile polyposis who show some symptoms of hereditary hemorrhagic telangiectasia. These considerations prompted Gallione et al. (2004) to study the DNA from 6 unrelated families segregating both phenotypes and from an isolated case of association. No patient had mutation in the ENG or ALK1 genes; all had MADH4 mutations. Three cases of de novo MADH4 mutations were found; in each case the 2 phenotypes were present, arguing that they are pleiotropic manifestations of the 1 mutation. Furthermore, in 1 de novo case, the mutation was transmitted to an offspring.
Gallione et al. (2006) screened the SMAD4 gene in 30 unrelated patients diagnosed with HHT who were negative for mutations in the ENG and ALK1 genes, and identified 3 who had mutations in SMAD4 (see 600993.0008 and 600993.0013, respectively). None of the patients had a prior diagnosis of juvenile polyposis, but all 3 mutation-positive patients were found to have colonic polyps, and 1 of the 3 had a history of colorectal cancer. Gallione et al. (2006) proposed that the SMAD4 gene should routinely be screened in HHT patients in whom mutations in neither ENG nor ALK1 are identified, and that HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps.
Gallione et al. (2010) identified heterozygous mutations in the SMAD4 gene in 15 of 19 patients with JP/HHT. Thirteen patients had mutations affecting the MH2 domain of the protein, but 2 others had mutations in the linker and MH1 domains, respectively. At least 1 mutation (R361C; 600933.0008) had also been found in patients with isolated JPS. Combined with a review of the literature, the findings indicated that there are no clear genotype/phenotype correlations when comparing JP/HHT to JPS alone. In addition, the mechanism for both disorders is consistent with a loss of function of SMAD4. Gallione et al. (2010) emphasized that any JPS patient with a SMAD4 mutation is at risk for the visceral manifestations of HHT, and any HHT patient with SMAD4 mutation is at risk for early-onset gastrointestinal cancer.
Andrabi, S., Bekheirnia, M. R., Robbins-Furman, P., Lewis, R. A., Prior, T. W., Potocki, L. SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am. J. Med. Genet. 155A: 1165-1169, 2011. [PubMed: 21465659] [Full Text: https://doi.org/10.1002/ajmg.a.33968]
Baert, A. L., Casteels-Van Daele, M., Broeckx, J., Wijndaele, L., Wilms, G., Eggermont, E. Generalized juvenile polyposis with pulmonary arteriovenous malformations and hypertrophic osteoarthropathy. Am. J. Roentgen. 141: 661-662, 1983. [PubMed: 6604412] [Full Text: https://doi.org/10.2214/ajr.141.4.661]
Burger, B., Uhlhaas, S., Mangold, E., Propping, P., Friedl, W., Jenne, D., Dockter, G., Back, W. Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis. (Letter) Am. J. Med. Genet. 110: 289-291, 2002. [PubMed: 12116240] [Full Text: https://doi.org/10.1002/ajmg.10411]
Conte, W. J., Rotter, J. I., Schwartz, A. G., Congleton, J. E. Hereditary generalized juvenile polyposis, arteriovenous malformations and colonic carcinoma. (Abstract) Clin. Res. 30: 93A only, 1982.
Cox, K. L., Frates, R. C., Jr., Wong, A., Gandhi, G. Hereditary generalized juvenile polyposis associated with pulmonary arteriovenous malformation. Gastroenterology 78: 1566-1570, 1980. [PubMed: 7372073]
Erkul, P. E., Ariyurek, O. M., Altinok, D., Bakkaloglu, A., Kotiloglu, E. Colonic hamartomatous polyposis associated with hypertrophic osteoarthropathy. Pediat. Radiol. 24: 145-146, 1994. [PubMed: 8078721] [Full Text: https://doi.org/10.1007/BF02020177]
Gallione, C., Aylsworth, A. S., Beis, J., Berk, T., Bernhardt, B., Clark, R. D., Clericuzio, C., Danesino, C., Drautz, J., Fahl, J., Fan, Z., Faughnan, M. E., and 19 others. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am. J. Med. Genet. 152A: 333-339, 2010. [PubMed: 20101697] [Full Text: https://doi.org/10.1002/ajmg.a.33206]
Gallione, C. J., Repetto, G. M., Legius, E., Rustgi, A. K., Schelley, S. L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C. J. J., Marchuk, D. A. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363: 852-859, 2004. [PubMed: 15031030] [Full Text: https://doi.org/10.1016/S0140-6736(04)15732-2]
Gallione, C. J., Richards, J. A., Letteboer, T. G. W., Rushlow, D., Prigoda, N. L., Leedom, T. P., Ganguly, A., Castells, A., Ploos van Amstel, J. K., Westermann, C. J. J., Pyeritz, R. E., Marchuk, D. A. SMAD4 mutations found in unselected HHT patients. J. Med. Genet. 43: 793-797, 2006. [PubMed: 16613914] [Full Text: https://doi.org/10.1136/jmg.2006.041517]
Heald, B., Rigelsky, C., Moran, R., LaGuardia, L., O'Malley, M., Burke, C. A., Zahka, K. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhgic telangiectasia due to SMAD4. Am. J. Med. Genet. 167A: 1758-1762, 2015. [PubMed: 25931195] [Full Text: https://doi.org/10.1002/ajmg.a.37093]
Kumar, N., Boeve, B. F., Cowl, C. T., Ellison, J. W., Kamath, P. S., Swanson, K. L. Hypermanganesemia, hereditary hemorrhagic telangiectasia, brain abscess: the hepatic connection. Neurology 71: 1118-1119, 2008. [PubMed: 18824676] [Full Text: https://doi.org/10.1212/01.wnl.0000326959.44088.e0]
Prieto, G., Polanco, I., Sarria, J., Larrauri, J., Lassaletta, L. Association of juvenile and adenomatous polyposis with pulmonary arteriovenous malformation and hypertrophic osteoarthropathy. J. Pediat. Gastroent. Nutr. 11: 133-137, 1990. [PubMed: 2388124] [Full Text: https://doi.org/10.1097/00005176-199007000-00026]
Simpson, E. L., Dalinka, M. K. Association of hypertrophic osteoarthropathy with gastrointestinal polyposis. Am. J. Roentgen. 144: 983-984, 1985. [PubMed: 3872584] [Full Text: https://doi.org/10.2214/ajr.144.5.983]