Clin Genet 2007: 71: 91–92
Printed in Singapore. All rights reserved
#2007 The Authors
Journal compilation #2007 Blackwell Munksgaard
Letter to the Editor
ENG mutations in MADH4/BMPR1A
mutation negative patients with
To the Editor:
Juvenile polyposis (JP, OMIM 174900) is an
autosomal dominant syndrome in which affected
individuals may develop colonic hamartomatous
polyps, upper gastrointestinal (GI) polyps, and
a pre-disposition to GI cancer (1–3). Two pre-
disposing genes for JP have been identified thus
far, with MADH4 and BMPR1A each account-
ing for approximately 20% of cases (4–6).
Some patients with JP also have hereditary
hemorrhagic telangiectasia (HHT) (7, 8). The
genes pre-disposing to HHT are ENG (HHT1,
OMIM 131195) (9) and ACVR1 (HHT2, OMIM
601284) (10, 11). Both genes are members of the
transforming growth factor beta (TGF-b) super-
family, like MADH4 and BMPR1A. Gallione
et al. found MADH4 germline mutations in seven
families with both JP and HHT but no mutations
of ENG or ACVR1 (12). We previously found no
ACVR1 mutations in 32 patients with JP without
HHT, MADH4 mutation, or BMPR1A mutation
(6). Sweet recently reported that 2 of 14 patients
with JP had germline ENG mutations and
suggested a role for this gene in the causation of
JP (13). The objective of this study was to examine
the prevalence of ENG mutations in patients
meeting the diagnostic criteria for JP who did not
have germline mutations of MADH4 or BMPR1A.
All exons and intron–exon boundaries of
MADH4 and BMPR1A were sequenced in
probands with JP and sporadic cases (6), and in
31 mutation-negative cases, all exons and intron–
exon boundaries of ENG were amplified and
sequenced. When sequence variants were found,
these exons were amplified from a panel of 132
randomly selected individuals and subjected to
restriction enzyme digestion, allowing detection
of the mutant or wild-type sequence.
The results of ENG sequencing are shown in
Table 1. One patient with multiple juvenile
polyps diagnosed at age of 8 was homozygous
for a 14C.T (T5M) substitution. Markers
D9S934 and D9S1825 were both heterozygous
(9 and 3 Mb centromeric to ENG, respectively)
and D9S2157 was homozygous in this patient
(5 Mb telomeric to ENG). A second patient
with multiple juvenile polyps diagnosed at the
age of 5 was heterozygous for the 14C.T (T5M)
mutation. Three of 132 controls digested with
SphI also manifested this change. A third patient
with multiple juvenile polyps diagnosed at age 9
had a 1096G.C mutation (D366H), which was
not found in control samples digested with HgaI.
The patients with JP with ENG mutations did
not have clinical manifestations, a family history
of HHT, or upper GI polyps and had a mean age
of 7.4 years (vs 14.4 years for those without ENG
The 14C.T(T5M) substitution has been
described in patients with HHT and is believed
to be a polymorphism rather than a disease-
causing mutation (14, 15), with an approximately
2% incidence in controls (16, 17). The
1096G.C(D366H) substitution has also been
described as a polymorphism in families with
HHT (18, 19), with an allele frequency of 0.3–1%
of controls (16, 17).
Sweet et al. found two ENG mutations in 14
patients with JP found to be negative for
MADH4,BMPR1A and PTEN mutations (13).
Both patients had an early onset of disease (at
ages 3 and 5 years) and no stigmata of HHT. One
patient with JP had the change 1538A.G
(K531R) and the other 1711C.T(R571C),
which were not found in 105 controls, and have
not been described in patients with HHT (15).
Sweet et al. concluded that these children had a
new, genetically defined form of JP. Gallione
et al. found that seven probands with both JP
and HHT had germline MADH4 mutations,
while none had ENG or ACVR1 mutations and
suggested that the overlap of JP and HHT
phenotypes could be because of the varied effects
of perturbing the TGF-bpathway in different
cell types (20). The findings of the current study
do not confirm the suggestion that ENG is
a pre-disposition gene for JP, and the absence of
disease-causing mutations in a larger subset of
patients with JP suggests that routine screening
for ENG mutations in genetic testing is pre-
mature. The finding of mutations in additional
patients with JP and the cosegregation of these
mutations with the disease phenotype in families
with JP would clearly help confirm the role of
ENG as a JP-causing gene.
This work was supported by a generous grant from the Carver
Charitable Trust and National Institutes of Health Grant
Department of Surgery, University of Iowa Roy J.
and Lucille A. Carver College of Medicine,
Iowa City, IA,
Genetic Counselor, Hubert H. Humphrey
Cancer Center, Minneapolis, MN, and
Department of Preventive Medicine,
Creighton University School of Medicine,
Omaha, NE, USA
1. Jarvinen HJ, Franssila KO. Familial juvenile polyposis coli:
increased risk of colorectal cancer. Gut 1984: 25: 792–800.
2. Jass JR, Williams CB, Bussey HJR et al. Juvenile polyposis –
a precancerous condition. Histopathology 1988: 13: 619–630.
3. Howe JR, Mitros FA, Summers RW. The risk of
gastrointestinal carcinoma in familial juvenile polyposis.
Ann Surg Oncol 1998: 5: 751–756.
4. Howe JR, Roth S, Ringold JC et al. Mutations in the
SMAD4/DPC4 gene in juvenile polyposis. Science 1998:
5. Howe JR, Bair JL, Sayed MG et al. Germline mutations of
the gene encoding bone morphogenetic protein receptor 1A
in juvenile polyposis. Nat Genet 2001: 28: 184–187.
6. Howe JR, Sayed MG, Ahmed AF et al. The prevalence of
MADH4 and BMPR1A mutations in juvenile polyposis
and absence of BMPR2, BMPR1B, and ACVR1 muta-
tions. J Med Genet 2004: 41 (7): 484–491.
7. Cox KL, Frates RC Jr, Wong A et al. Hereditary
generalized juvenile polyposis associated with pulmonary
arteriovenous malformation. Gastroenterology 1980: 78 (6):
8. Conte WJ, Rotter JI, Schwartz AG et al. Hereditary
generalized juvenile polyposis, arteriovenous malforma-
tions and colonic carcinoma. Clin Res 1982: 30: 93A.
9. McAllister KA, Grogg KM, Johnson DW et al. Endoglin,
a TGF-beta binding protein of endothelial cells, is the gene
for hereditary haemorrhagic telangiectasia type 1. Nat
Genet 1994: 8 (4): 345–351.
10. Johnson DW, Berg JN, Baldwin MA et al. Mutations in the
activin receptor-like kinase 1 gene in hereditary haemor-
rhagic telangiectasia type 2. Nat Genet 1996: 13 (2): 189–195.
11. Berg JN, Gallione CJ, Stenzel TT et al. The activin
receptor-like kinase 1 gene: genomic structure and muta-
tions in hereditary hemorrhagic telangiectasia type 2. Am J
Hum Genet 1997: 61 (1): 60–67.
12. Gallione CJ, Repetto GM, Legius E et al. Mutations in
SMAD4 cause a combined hereditary hemorrhagic telan-
giectasia – juvenile polyposis syndrome. Am J Hum Genet
2003: 73: A248.
13. Sweet K, Willis J, Zhou XP et al. Molecular classification of
patients with unexplained hamartomatous and hyperplastic
polyposis. J Am Med Assoc 2005: 294 (19): 2465–2473.
14. Shovlin CL, Hughes JM, Scott J et al. Characterization of
endoglin and identification of novel mutations in hereditary
hemorrhagic telangiectasia. Am J Hum Genet 1997: 61 (1):
15. Abdalla SA, Letarte M. Hereditary haemorrhagic telangi-
ectasia: current views on genetics and mechanisms of
disease. J Med Genet 2006: 43 (2): 97–110.
16. Abdalla SA, Cymerman U, Rushlow D et al. Novel mutations
and polymorphisms in genes causing hereditary hemorrhagic
telangiectasia. Hum Mutat 2005: 25 (3): 320–321.
17. Lastella P, Sabba C, Lenato GM et al. Endoglin gene
mutations and polymorphisms in Italian patients with
hereditary haemorrhagic telangiectasia. Clin Genet 2003:
63 (6): 536–540.
18. Lin WD, Tsai FJ, Lee CC et al. Identification of
a polymorphism (D366H) in the endoglin gene in Chinese.
Hum Mutat 2000: 15 (6): 583.
19. Lesca G, Plauchu H, Coulet F et al. Molecular screening of
ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic
telangiectasia in France. Hum Mutat 2004: 23 (4): 289–299.
20. Gallione CJ, Repetto GM, Legius E et al. A combined
syndrome of juvenile polyposis and hereditary haemor-
rhagic telangiectasia associated with mutations in MADH4
(SMAD4). Lancet 2004: 363 (9412): 852–859.
James R. Howe
Department of Surgery
200 Hawkins Drive
University of Iowa Hospitals and Clinics
Table 1. Nucleotide changes in ENG coding sequence
found in patients with juvenile polyposis
patients Exon Nucleotide
2/31 1 14C.T T5M 3/132
1/31 2 120C.T None (G40G) 1/134
4/31 2 207G.A None (L69L) 32/131
4/31 8 1029C.T None (T343T) Not done
1/31 8 1060C.T None (L354L) Not done
1/31 8 1096G.C D366H 0/132
No restriction endonuclease sites present.
Letter to the Editor