Familial Occurrence of an Association of
Multiple Intestinal Atresia and Choanal Atresia:
A New Syndrome?
Alessandra Ferrarini,1Maria-Chiara Osterheld,2Yvan Vial,3Pierre A. de Viragh,4Jacques Cotting,5
Danielle Martinet,1Jacques S. Beckmann,1,6and Florence Fellmann1*
1Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
2University Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
3Department of Gynaecology and Obstetric, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
4Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
5Department of Paedriatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
6Department of Medical Genetics, Universit? e de Lausanne, Lausanne, Switzerland
Received 6 January 2009; Accepted 29 August 2009
We report on two familial cases from a non-consanguineous
marriage, presenting multiple intestinal and choanal atresia.
Massive hydramnios and dilatation of the bowel were observed
at 29 weeks of gestation during routine ultrasound scan of a
healthy mother. The fetal karyotype was normal and cystic
fibrosis screening was negative. Regular scans were performed
throughout the pregnancy. The child was born at 34 weeks
bowel and the colon. Further interventions were necessary
because of recurrent obstructions. During the following preg-
nancy, a dilatation of the fetal intestinal tract was detected by
ultrasonography at 27 weeks of gestation. Pregnancy was inter-
rupted. Post-mortem examination of the fetus confirmed the
stenosis of long segments of the small intestine associated with
were consistent with those reported in hereditary multiple
intestinal atresia (HMIA). An association between multiple
intestinal and choanal atresia has never been reported.
We suggest it could correspond to a new autosomal recessive
entity for which cytogenetic investigations and high-resolution
array CGH revealed no visible anomalies. ? 2009 Wiley-Liss, Inc.
Key words: choanal atresia; multiple intestinal atresia; progres-
sive fibro-inflammatory process; ectodermal dysplasia
2,000 live births. The proportion of patients with multiple atresias
varies from 6% to 32%. Hereditary multiple intestinal atresia
(HMIA) is the rarest form of multiple intestinal atresia, variously
extending from the antrum to the rectum [Bilodeau et al., 2004].
Choanal atresia has an incidence of 1/7,000 to 1/8,000 live births;
the cases, its association with intestinal atresia is rare, as demon-
Here we report on the case of two siblings, a female child and a
male fetus, focusing on the histo-pathological aspects of intestinal
atresia. We consider the differential diagnosis and suggest that this
condition is a previously unreported autosomal recessive entity.
The propositus was the first child of non-consanguineous, healthy
parents. Paternal and maternal families originated from distinct
parts of Switzerland. Anamnestic data reported a previous medical
Florence Fellmann, Service of Medical Genetics, CHUV, 1011 Lausanne,
Switzerland. E-mail: firstname.lastname@example.org
Published online 23 November 2009 in Wiley InterScience
How to Cite this Article:
PA, Cotting J, Martinet D, Beckmann JS,
Fellmann F. 2009. Familial occurrence of an
association of multiple intestinal atresia and
choanal atresia: A new syndrome?
Am J Med Genet Part A 149A:2661–2665.
? 2009 Wiley-Liss, Inc.
termination of pregnancy for anencephaly. Maternal TORCH
serologies were unremarkable. A massive hydramnios was discov-
ered at 29 weeks of gestation. Ultrasounds and MRI of the fetus
detected a dilatation of the stomach and of the small intestine.
Conventional chromosomal analysis of amniotic cell cultures
showed a normal 46,XX karyotype. Due to hyperechogenic bowel,
molecular analysis of the 12 most frequent CFTR gene mutations
of gestation. At birth, weight was 2,250g (10–50th centile),
height 44.5cm (10–50th centile), and head circumference 33cm
(50–90th centile). Apgar scores were 9 and 10. During the first
minutes of life bradycardia and desaturations required the aspira-
tion of more than 100ml of amniotic fluid from the stomach.
Nasotracheal intubation was not possible, suggesting the existence
of choanal atresia. Abdomen X-ray showed pneumatization of the
tomography and ultrasounds showed a hyperechogenic mass
into the small pelvis. A double pyelocaliceal system on the left
side was suspected from cystoureteroscopy, while vaginoscopy
was normal. No anomalies were detected at cardiac, cerebral, or
Abdominal laparoscopic exploration was performed on day 2,
ofTreitzto ileocecalvalvewith only 55cm left andan atresia of the
colon with <10cm of residual patency of the transverse colon.
Colostomy and ileostomy were performed and parenteral and
enteral alimentation introduced. A second laparotomy 1 month
later showed an atresia 3cm upstream of the ileostomy. A new
ileostomy permitted to re-establish the intestinal transit.
Six months after the first surgical treatment, a new resection of
the ileal and colonic atretic tracts was necessary and ileo-colic and
colo-colic anastomoses were done. Starting from first days of life,
lasertreatment andmultiples cyclesofendoscopicdilatationofthe
proposita is now 6 years old and an intestinal graft is planned.
Genetic clinical reevaluation was performed when the patient was
5 years old: weight was at 3rd centile, length at ?3rd centile,
apparent hypertelorism, downslanting palpebral fissures, epi-
canthic folds, and well-marked philtrum. High arched palate and
well as dysplastic nails were also noticed. Regarding the particular
aspect of hair, complementary analysis was performed. Scanning
electron microscopy showed anisotrichosis, pili torti et canaliculi
the long hospitalization. Genetic investigations were performed:
CGH (Agilent Human Genome CGH Microarray Kit 244K) was
normal. Completeanalysis of the CFTR gene including sequencing
of all coding regions and Multiplex Ligation-dependent probe
Amplification (MLPA) was normal.
tant structural modifications with an alternation of stenosed and
dilated segments associated with a thin intestinal wall. External
diameters ranged from 0.6 to 1.5cm whereas internal diameters
ranged from absent lumen to 1.3cm. A rectal atresia was also
observed. Microscopic examination revealed severe histological
changes (Fig. 2). The mucosa showed marked reorganization. The
villi were enlarged and flattened and contained numerous inflam-
with irregular areas of ulcerations, suggesting a still evolving
inflammatory process. Periodic acid Schiff (PAS) staining revealed
the presence of eosinophilic material in the remaining intestinal
glands. Muscularis mucosae thickness was irregular, ranging from
normal to thin and fragmented. The submucosa was thick and
showed fibrotic and inflammatory modifications with numerous
eosinophilic elements. Acetylcholinesterase staining revealed the
presence of hypertrophic nerve fibers in both mucosa and submu-
consistentwith a chronicfibro-inflammatory process. The muscu-
lar layer was conserved while serosa was enlarged and showed
inflammation with fibrin deposition. Hepatic involvement was
characterized by signs of acute and chronic inflammation and
fibrosis of the portal tracts without biliary ducts neoproliferation.
Some foci of acute intralobular hepatitis with cholestasis were also
observed. Histology of the skin was unremarkable.
During the following pregnancy of the same parents, ultrasound
gravity of the disease was not predictable, but regarding the sister’s
serious clinical history, the parents opted for a termination of
pregnancy, that was performed at the 29th week of gestation.
Standard karyotype was normal, 46,XY.
FIG. 1. Scanning electron microscopy showing anisotrichosis
2662 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Necropsy of the fetus showed normal mensurations according to
gestational age. There were no dysmorphic features. Macroscopic
stenosis, reducing the diameter of the intestine to 0.2cm, started
stenosed with a maximal diameter of the lumen of 0.3cm (Fig. 3).
FIG. 3. Intestine from the 29-week-old fetus. Gross appearance of multiple segments from small and large bowel, corresponding to enlarged and
FIG. 2. A,B:Microscopicappearanceoftheresectedcolonicspecimenfromthefirstchild.A:Completefibroticocclusionofthecoloniclumina,4?,HE.
B: Great enlargement of the lumina with overlying irregular epithelium and inflammatory reaction in the submucosa, 4?, HE. C–E: Three different
aspects of the GI from the fetus (microscopic examination, 4?, HE). C. Intraluminal stenosing fibrosis, (D) luminal dilatation with inflammatory
reaction, (E) intraluminal meconium plug. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
FERRARINI ET AL.
Microscopically, dilated segments showed desquamation of the
surface epithelium cells while muscularis mucosa was preserved
(Fig. 2). In stenosed segments, particularly in the colon, mucosa,
still present, erosive inflammation was noted. Muscularis propria
was occupied by fibrosis with many neutrophils and eosinophils.
of the pancreas and submaxillary gland revealed the presence
of some PAS positive material in the excretory ducts. Bilateral
choanal atresia was suspected as it was impossible to insert a
nasal catheter. Heart, macroscopically normal, revealed a slight
endocardial fibroelastosis of both ventricles. No other visceral
anomalies were observed.
by a rare association of choanal and multiple intestinal atresia,
which we believe has not been described before.
An association among intestinal disease and choanal atresia has
been previously reported, most cases corresponding to intestinal
epithelial dysplasia [Davidson et al., 1978; Bird et al., 2007]. This
condition, also known as tufting enteropathy, has a specific histo-
logical hallmark consisting of surface epithelial tufts, composed by
disorganized, closely packed surface enterocytes with rounding of
the plasma membrane, and decreased numbers of intraepithelial T
lymphocytes [Goulet et al., 2007]. Specificity of these findings rule
out that tufting enteropathy and the inflammatory and fibrotic
process reported here are the same entity.
The co-occurrence of ileal atresia and bilateral choanal atresia
was described twice. In the first case, reported by Yoskovitch et al.
intestinal atresia was shown to occur secondary to an ileal volvulus
and the post-operative evolution was uneventful. Uchida et al.
 presented a female patient in which congenital jejunal and
bilateral choanal atresias wereassociatedwith posteriorpalatecleft
and bilateral athelia. Surgical treatment of jejunal atresia and post-
operative course were uneventful. At 3 years old, this patient
presented mild mental and growth retardation [Uchida et al.,
2006]. In both cases chromosome analyses were performed, show-
ing normal karyotypes. Unfortunately, histological aspects of the
intestinal atresias were not detailed. Nevertheless, the fact that
atresia was limited to the jejunal region in both cases and their
favorable post-operative evolutions, make it unlikely that these
entities are the same for lack of a progressive fibro-inflammatory
process as observed in our familial case.
In the present cases pathologic examinations revealed the pres-
ence of elements of acute and chronic inflammation. The patho-
physiological mechanism of inflammation remains unclear: it
could be either a primary or a secondary phenomenon, such as
disrupted apoptosis leading to failure of canalization of gut and
a secondary inflammation. We speculate that this inflammatory
process—of unknown origin—started from the mucosa and sub-
mucosa and subsequently involved the entire intestinal wall, pro-
ducing a stenosis. This phenomenon reminds one of the so-called
neonates [Smyth et al., 1994; Lee et al., 1997; Serban et al., 2002;
Taylor, 2002].Furthermore,histologyshowed abnormalglandular
parental haplotypes at the CFTR locus, a complete CFTR gene
analysis was performed, and no mutations were identified.
et al. . It is characterized by the presence of multiple atresias
from the antrum to the rectum. HMIA is generally an isolated
multiple intestinal atresia, and newborns could present symptoms
examination of the resected sections reveals the presence of
multiple lumina with a common muscularis propria and sub-
mucosa, intraluminal, and intramural calcifications and a diffuse
acute and chronic inflammation of the mucosa and submucosa
[Lambrecht and Kluth, 1998]. Shorter et al.  reported a new
case of multiple intestinal atresia and reviewed the literature
Among these, class 3 includes atresias which can occur anywhere
along the length of the gastrointestinal tract, from the stomach to
sieve-like multiple intestinal lumina. Cystic dilatation of the bile
ducts could coexist. The completely obstructed areas were com-
posed by fibrous tissue septa and surrounded by thick muscularis
mucosae. These aspects look like those we found in both our cases.
Of the 16 patients reported by Bilodeau et al. , 4 underwent
further surgical intervention because of recurrent obstruction.
While the modality of transmission has not been definitively
established, cases of siblings with a HMIA have been reported,
supporting an autosomal recessive transmission mode.
In addition to intestinal and choanal atresia, the first child
Hair abnormalities, especially anisotrichosis, have been described
no evidence of nutritional deficiency. Moreover pili canaliculi are
not usually observed in cases of nutritional deficiency nor malab-
dysplasia (ED). The EDs comprise a large, heterogeneous group of
inherited disorders that are defined by primary defects in the
development of two or more tissues derived from embryonic
ectoderm. While an association with choanal atresia has been
occasionally reported, we found no data reporting an association
with multiple intestinal atresia.
Our cases present an intestinal involvement resembling HMIA.
Theassociation ofHMIAandchoanal atresiahave, however, never
of unaffected and non-consanguineous parents, without evidence
a common genetic basis, compatible with an autosomal recessive
2664 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
transmission mode. It should be noted that cytogenetic and array Download full-text
the causal gene(s) remains unidentified, a detailed histological
description is provided, in the hopes of elucidating the underlying
physiopathological mechanism of a really rare malformative pro-
cess taking place early in intrauterine life.
We express our gratitude to the family who participated in this
Bilodeau A, Prasil P, Cloutier R, Laframboise R, Meguerditchian AN, Roy
G, Leclerc S, P? eloquin J. 2004. Hereditary multiple intestinal atresia:
Thirty years later. J Pediatr Surg 39:726–730.
Bird LM, Sivagnanam M, Taylor S, Newbury RO. 2007. A new syndrome
of tufting enteropathy and choanal atresia, with ophthalmologic,
hematologic and hair abnormalities. Clin Dysmorphol 16:211–221.
Boyd PA, Chamberlain P, Gould S, Ives NK, Manning N, Tsang T. 1994.
Hereditary multiple intestinal atresia- ultrasound findings and outcome
of pregnancy in an affected case. Prenat Diagn 14:61–64.
Davidson GP, Cutz E, Hamilton JR, Gall DG. 1978. Familial enteropathy:
A syndrome of protracted diarrhea from birth, failure to thrive and
hypoplastic villus atrophy. Gastroenterol 75:783–790.
Goulet O, Salomon J, Ruemmele F, de Serres NP, Brousse N. 2007.
Intestinal ephitelial dysplasia (tufting enteropathy). Orphanet J Rare
Guttman FM, Braun P, Garance PH, Blanchard H, Collin PP, Dallaire L,
hereditary multiple atresias involving the gastrointestinal tract from
stomach to rectum. J Pediatr Surg 8:633–640.
Lambrecht W,Kluth D. 1998.Hereditary multiple atresias of the gastroin-
testinal tract: Report of a case and review of the literature. J Pediatr Surg
Lee J, Ip W, Durie P. 1997. Is fibrosing colonopathy an immune mediated
disease? Arch Dis Child 77:66–70.
Moreno LA, Gottrand F, Turck D, Manouvrier-Hanu S, Mazingue F,
MorisotC,LeDeist F,RicourC,Nihoul-Feket? eC,DebeugnyP, Griscelli
C, Farriaux J-P. 1990. Severe combined immunodeficiency syndrome
associated with autosomal recessive familial multiple gastrointestinal
atresias: Study of a family. Am J Med Genet 37:143–146.
fibrosis in a neonate before any pancreatic enzyme supplementation.
J Pediatr Gastroenterol Nutr 35:356–359.
Shorter NA, Georges A, Perenyi A, Garrow E. 2006. A proposed classifica-
tion system for familial intestinal atresia and its relevance to the under-
standing of the etiology of jejunoileal atresia. J Pediatr Surg 41:
Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of
ascending colon in cystic fibrosis and high-strength pancreatic enzymes.
Lancet 1994. 343:85–86.
Stevenson RE, Hall JG. 2006. Human malformations and related anoma-
lies. 2nd edition. New York: Oxford University Press, Inc. 1495 p.
Taylor CJ. 2002. Fibrosing colonopathy unrelated to pancreatic enzyme
supplementation. J Pediatr Gastroenterol Nutr 35:268–269.
Uchida K, Konishi N, Inoue M, Otake K, Kusunoki M. 2006. A case of
congenital jejunal atresia associated with bilateral athelia and choanal
atresia: New syndrome spectrum. Clin Dysmorphol 15:37–38.
FERRARINI ET AL.