Juvenile Polyposis of Infancy Associated with Paracentric Inversion and Deletion of Chromosome 10 in a Hispanic Patient: A Case Report

Abstract

Juvenile polyposis of infancy is a rare genetic disorder, involving multiple hamartomatous polyps of the gastrointestinal tract, which usually has a very aggressive clinical course and is often fatal. It is characterized by early onset (during the 1st months of life) and by diffuse juvenile polyposis with anemia, recurrent gastrointestinal bleeding, diarrhea, rectal prolapse, intussusception, protein-losing enteropathy, starvation, and malnutrition. There is a hypothesis that mutation of the tumor-suppressor genes BMPR1A and PTEN, located on the long arm of chromosome 10, is associated with the development of this disease. Medical treatment for this disorder is challenging and should be conservative whenever possible. We present the case of a 3-year-old girl with juvenile polyposis of infancy who eventually died from mesenteric artery thrombosis during surgical colectomy. Karyotype of the patient showed a paracentric inversion in 10q and a deletion in 10p. We will briefly comment on some genetic considerations of this disease.

Keywords

infantile Cronkhite-Canada syndrome juvenile polyposis of infancy juvenile polyposis syndrome

INTRODUCTION

Juvenile polyposis syndrome (JPS) (OMIM 174900) is a clinically and genetically heterogeneous disorder, characterized by the presence of multiple juvenile hamartomatous polyps in the gastrointestinal tract. In 1964, McColl and colleagues [1] coined the term “juvenile polyposis” and, after careful analysis of the syndrome, concluded that JPS is a distinct entity of adenomatous polyposis coli. Juvenile polyposis syndrome affects 1 in 100 000 live births; there are sporadic and familial cases that follow a pattern of autosomal dominant inheritance with incomplete penetrance. There are 3 types of JPS: juvenile polyposis of infancy, juvenile polyposis coli, and generalized juvenile polyposis.

Juvenile polyposis of infancy, also called infantile Cronkhite-Canada syndrome, is the rarest and most severe form of JPS; reports of only sporadic cases appear in the literature [2 –8]. It is characterized by early onset in the 1st months of life and by generalized juvenile polyposis with a serious clinical course that is generally fatal as a result of recurrent gastrointestinal bleeding, diarrhea, protein-losing enteropathy, and malnutrition. We describe the case of a 3-year-old girl with juvenile polyposis of infancy who presented with diffuse, generalized condition spanning from the stomach to the rectum. We will discuss diagnostic criteria and briefly comment on genetic aspects of this disease.

CASE PRESENTATION

A 3-year-old girl with developmental delay presented with a history of recurrent rectal prolapse from 8 months of age, episodes of fresh blood in the stool, secondary anemic syndrome, and intestinal malabsorption syndrome. She had a normal birth history, having been delivered naturally without complications and weighing 2895 g. No congenital abnormalities or dysmorphic syndromes were identified. Her parents, both of whom were Mexican, were healthy, with no family history of consanguinity, inflammatory bowel syndrome, colon cancer, or gastrointestinal polyposis syndrome. Physical examination showed generalized hypotonia and complete rectal prolapse with multiple sessile polyps (Fig. 1A). We did not observe oral, ocular, or genital mucocutaneous hyperpigmentation. There was also no evidence of macrocephaly, lipomas, hemangiomas, musculoskeletal disorders, or mental retardation (Table 1). A barium enema revealed extensive polyposis from the cecum to the rectum (Fig. 1B). Subsequently, a colonoscopy was performed, in which we found multiple pedunculated and sessile polyps of different sizes throughout the colon and rectum. Endoscopic polypectomy was performed on several occasions (Fig. 2A). Histologically all polyps were well circumscribed, composed of dilated glands filled with mucus, coated with a layer of columnar cells without atypia, and consisted of a prominent stroma exhibiting a marked mixed inflammatory infiltrate. No dysplasia was identified (Fig. 2B,C). Upper gastrointestinal endoscopy revealed confluent pedunculated and sessile polyps spanning from the stomach to the 4th portion of the duodenum (Fig. 3A,B).

Table 1.

Patients with juvenile polyposis of infancy and a 10q aberration

Patient ID No.	M/F	U/L	D/E	Age at onset	Macr	Dysm	Retard	Others	Colectomy	Follow-up	Karyotype	Reference
1	M	–/+		3 years	–	+	+	Heart defect and clubbing			46,XY, del(10)(q22.3q24.1)	[14]
2	M	+/+		18 months	+	+	+	Lipoma	+	11 years	46,XY, del(10)(q23.2q24.1)	[15]
3	M				+	+	+		+		46,XY, del(10)(q23.2q24.1)	[16]
											1.0 cM D10S541-D10S1735
4	F							Heart defect and clubbing			46,XX, del(10)(q23.1q24.2)	[16]
											11.6 cM D10S1687-D10S1736
5	M	+/+	–	2 years	+	+	+	Digital clubbing and hyperpigmented penile macula		6 years	46,XY.ish del(10)(q23.2q23.3)	[17]
6	F	+/+	+	1 month	+	+	–	Lipoma and hemangioma	+10 months	Died at 3 years	46,XX.ish del(10)(q23.2q23.3)	[11]
7	F	+/+	+	2.5 months	+	+	–		+17 months	4 years	46,XX.ish del(10)(q23.2q23.3)	[11]
8	M	+/+		3 months	+	–	–	Hemangioma and speckled penis	+ 8 years	14 years	46,XY.ish del(10)(q23.2q23.3)	[11]
9	F	+/+		18 months	+	+	–	Heart defect	–	18 months	46,XX,t(2;10)(q31;pl5)	[11]
10	F	–/+	–	5 years	–	+	+	Heart defect	–	Favorable	46,XX, del(10)(q22.3q23.33)dn	[18]
											12.3 Mb loss (FISH)
11	M	+	–	2 years	+	+	+	Heart defect and hypotonia	–		46,XY.ish del(10)(q23.2q23.31)	[13]
											2.88 Mb loss (SNP array)
12	M	+	+	18 months	+	+	+	Hypotonia and hemangioma	+ 23 months		46,XY.ish del(10)(q23.2q24.31) 4.26 Mb loss (SNP array)	[13]
13	F	+/+	–	4 years	+	+	+	Cleft palate and heart defect	–		46,XX.ish del(10)(q23.2q23.31)	[13]
											3.55 Mb loss (SNP array)
14	M		–		+	+	+	Coarse facies and kyphosis		Died at 25 years	46,XY.ish del(10)(q23.2q23.31)	[13]
											4.01 Mb loss (SNP array)
15	F	+/+	+	8 months	–	–	+	Clubbing and hypotonia	+ 3 years	Died at 3 years	46,XX, inv(10q)/del(10p)	Present case

ID indicates identification; M, male; F, female; U/L, juvenile polyposis in upper/lower gastrointestinal tract; D/E, bloody diarrhea and/or protein-losing enteropathy; Macr, macrocephaly; Dysm, facial dysmorphism; Retard, psychomotor retardation; +, positive; –, negative; FISH, fluorescent in situ hybridization SNP, affymetrix 250k NspI array.

Figure 1.

Complete rectal prolapse with multiple polyps (A). Barium enema showed polypoid formations evident in transverse colon (B).

Figure 2.

Endoscopic polypectomy identified sessile polyps with a fine granular external surface (A). Colorectal glands with cystic dilatation (×4) (B), covered by a layer of columnar cells without dysplasia (×40) (C).

Figure 3.

Gastric (A) and duodenal (B) polyps (endoscopy). Specimen removed in total colectomy showing diffuse juvenile polyposis. Note the strawberry-like appearance of some polyps and the sparing of residual areas of normal colonic mucosa (C).

Cytogenetic study revealed the following karyotype: 46,XX, inv(10q)/del(10p). Clinical findings, including phenotype and histological characteristics of the polyps, led to the diagnosis of juvenile polyposis of infancy. The patient's disease progressed insidiously, requiring several exploratory laparotomies over an almost 3-year period as a result of intussusception, perforation, and intestinal subocclusion. During the evolution and management of the disease, the patient required frequent and increasingly long hospitalizations due to chronic malnutrition, intestinal malabsorption syndrome, protein-losing enteropathy, and systemic infections. The patient was started on a multidisciplinary management program consisting of total parenteral nutrition with the goal of achieving nutritional recovery. The hematology service initiated treatment for hypochromic microcytic anemia with iron, erythropoietin, and blood transfusion.

As a therapeutic measure, we attempted chemoprevention of the polyp growth with celecoxib (a selective COX-2 inhibitor) at a dosage of 5 mg/kg. Treatment was administered for 8 months, with strict adherence to the prescribed dosage. The initial response to therapy was favorable; the patient gained weight, experienced fewer episodes of rectal prolapse and intestinal obstruction, and exhibited improved mood and appetite with the decrease of parenteral nutritional support. During follow-up serial colonoscopies at 3, 6, and 9 months, we identified a decline in the number and size of polyps, especially at the gastric and duodenal levels. However, colonic polyps did not decrease in number or size, prompting the administration of rectal irrigations with celecoxib. The patient's improvement quickly plateaued, and we scheduled her for a total colectomy with ileal pouch–anal anastamosis. During surgery, the patient suffered acute mesenteric venous thrombosis with immediate intestinal ischemia, which did not respond to surgical attempts at mesenteric re-perfusion. The patient was admitted to the intensive care unit, where she died within 24 hours at the age of 3 years and 8 months. Gross examination of the colon showed >200 sessile and pedunculated polyps with a fine, reddish-white granular external surface (Fig. 3C) and sizes ranging from 2 mm to 4 cm. All polyps larger than 1 cm were submitted for histology. All polyps were consistent with classic juvenile polyposis histologically, except for 2 colonic polyps, which demonstrated reactive epithelial changes.

DISCUSSION

Juvenile polyposis syndrome is a rare autosomal dominant disorder characterized by multiple juvenile hamartomatous polyps, which may be limited to the colon and rectum or may involve the entire gastrointestinal tract in a generalized fashion. Classic symptoms include diarrhea, abdominal pain, prolapsed rectal polyps, anemia, and acute or chronic gastrointestinal bleeding. The number of polyps may vary from 5 to 200. Diagnostic criteria, as defined by Jass and colleagues [9], include the following: (1) more than 5 juvenile polyps in the colon and/or rectum or (2) juvenile polyps in other parts of the gastrointestinal tract or (3) any number of juvenile polyps and a positive family history.

In 1975, Sachatello and Griffen [10] divided JPS cases into 3 phenotypic categories based on clinical presentation and course of the disease: (1) juvenile polyposis of infancy, (2) juvenile polyposis coli (limited to the colon), and (3) generalized juvenile polyposis.

Juvenile polyposis of infancy, which affects the entire gastrointestinal tract, is the most severe form of the disease and confers the worse prognosis. As in our case, the onset of disease is early, during the 1st months of life, and the typical course includes gastrointestinal bleeding, intestinal intussusception, recurrent rectal prolapse, and protein-losing enteropathy. Some patients may present with macrocephaly, clubbing fingers, and hypotonia, but the presence of other extraintestinal abnormalities indicates the diagnosis of other gastrointestinal hamartomatous polyposis syndromes. Medical treatment should be conservative; however, loss of blood and protein in infants may necessitate blood transfusion and albumin administration. Malnutrition with protein loss may predispose children with central catheters to sepsis. There is not much that can be done surgically, unless the patient develops intestinal intussusception, obstruction, or irreducible prolapse. Intestinal transplantation is an option in specialized centers; however, the nutritional state of these patients makes them unsuitable candidates for this kind of surgery. The clinical course of patients with juvenile polyposis of infancy is always poor and leads to death during the 1st years of life.

The absence of family history in juvenile polyposis of infancy led some researchers to consider this disorder autosomal recessive. However, in 2006 Delnatte and colleagues [11] found that a contiguous deletion of the BMPR1A and PTEN genes within the long arm of chromosome 10 is associated with juvenile polyposis of infancy. Delnatte and colleagues [11] suggested that the severity of the disease reflects the cooperation between these 2 tumor suppressor genes. The main characteristic of diseases associated with the BMPR1A gene is the development of digestive polyposis; BMPR1A is located in chromosome 10q23, close to the PTEN gene. In a study using multiplex ligation-dependent probe amplification, Van Hattem and colleagues [12] identified 2 more cases of juvenile polyposis with deletion of the BMPR1A and PTEN genes, probably also a contiguous gene deletion at 10q22-23. They proposed multiplex ligation-dependent probe amplification as a valuable test for diagnosing JPS.

In our case, karyotype results showed a paracentric inversion of the long arm of chromosome 10. Furthermore, we assume that this case of juvenile polyposis of infancy was caused by this chromosomal aberration. Unfortunately, the patient died, and no fluorescent in situ hybridization or comparative genomic hybridization was performed to identify the precise breakpoints. In a study performed in 2008, Menko and colleagues [13] compared 8 cases of juvenile polyposis of infancy with 10q deletion. They concluded that patients with microdeletions in the PTEN and BMPR1A genes have variable phenotypes, which are independent of the size of the deletion. They later found that these phenotypes are not always restricted to juvenile polyposis of infancy but may also be related to cases of macrocephaly, mental retardation, mild gastrointestinal symptoms, and possibly early colorectal cancer. Several of the patients analyzed by Menko and colleagues [13] with 10q23 deletion showed heart defects. These defects were mainly atrial septal and/or ventricular but also included left superior vena cava defects, tricuspid insufficiency, pulmonary valve dysplasia, and portal vein atresia. These defects may be associated with complex genetic alterations involved in chromosome microdeletions and may not be attributable to a single gene defect.

At an endoscopic level, the polyps usually have a smooth surface and translucent appearance. Histologically, these polyps are indistinguishable from solitary juvenile polyps (ie, they are composed of dilated glands without atypia and full of mucus). The lamina propria appears edematous and is associated with an intense inflammatory infiltrate composed of neutrophils, lymphocytes, and plasma cells. There is no doubt that juvenile polyposis is a premalignant condition. However, in this variety of juvenile polyposis, patients usually die in the 1st years of life from nonneoplastic causes.

The main differential diagnoses are the PTEN hamartoma tumor syndromes and Peutz-Jeghers syndrome. Each of these syndromes has intestinal and distinctive extraintestinal findings, which help guide the diagnosis and choice of appropriate genetic tests. However, the clinical presentation of juvenile polyposis of infancy, as described by Sachatello in 1974 [2], is also quite distinctive. The PTEN hamartoma tumor syndromes represent a group of autosomal dominant syndromes caused by mutation of the PTEN gene; these syndromes are characterized by cell overgrowth and development of benign hamartomas in virtually any organ. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are two such PTEN hamartoma tumor syndromes that present with a gastrointestinal juvenile-type hamartomatous polyposis similar to juvenile polyposis of infancy.

References

McColl

IBH

Veale

Morson

. Juvenile polyposis coli. Proc R Soc Med 1964;57:896–897.

Sachatello

Hahn

Carrington

. Juvenile gastrointestinal polyposis in a female infant: report of a case and review of the literature of a recently recognized syndrome. Surgery 1974;75:107–114.

Scharf

Becker

Laage

. Juvenile gastrointestinal polyposis or the infantile Cronkhite-Canada syndrome. J Pediatr Surg 1986;21:953–954.

Ruymann

. Juvenile polyps with cachexia. Report of an infant and comparison with Cronkhite-Canada syndrome in adults. Gastroenterology 1969;57:431–438.

Arbeter

Courtney

Gaynor

Jr . Diffuse gastrointestinal polyposis associated with chronic blood loss, hypoproteinemia, and anasarca in an infant. J Pediatr 1970;76:609–611.

Soper

Kent

. Fatal juvenile polyposis in infancy. Surgery 1971;69:692–698.

Ray

Heald

. Growing up with juvenile gastrointestinal polyposis: report of a case. Dis Colon Rectum 1971;14:375–380.

Nicholls

Smith

Davies

. Diffuse juvenile non-adenomatous polyposis: a rare cause of severe hypoalbuminaemia in childhood. Acta Paediatr 1995;84:1447–1448.

Jass

Williams

Bussey

HJR

. Juvenile polyposis: a precancerous condition. Histopathology 1988;13:619–630.

10.

Sachatello

Griffen

Jr . Hereditary polypoid diseases of the gastrointestinal tract: a working classification. Am J Surg 1975;129:198–203.

11.

Delnatte

Sanlaville

Mougenot

. Contiguous gene deletion within chromosome arm 10q is associated with juvenile poliposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. Am J Hum Genet 2006;78:1066–1074.

12.

Van Hattem

Brosens

LAA

de Leng

WWJ

. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut 2008;57:623–627.

13.

Menko

Kneepkens

CMF

de Leeuw

. Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes. Clin Genet 2008;74:145–154.

14.

Jacoby

Schlack

Sekhon

. Del(10)(q22.3q24.1) associated with juvenile polyposis. Am J Med Genet 1997;70:361–364.

15.

Marsh

Kum

Lunetta

. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999;8:1461–1472.

16.

Zigman

Lavine

Jones

. Localization of the Bannayan-Riley-Ruvalcaba syndrome gene to chromosome 10q23. Gastroenterology 1997;113:1433–1437.

17.

Tsuchiya

Wiesner

Cassidy

. Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome. Genes Chromosomes Cancer 1998;21:113–118.

18.

Salviatti

Patricelli

Guariso

. Deletion of PTEN and BMPR1A on chromosome 10q23 is not always associated with juvenile polyposis of infancy. Am J Hum Genet 2006;79:593–596.