Superficial Punctate Keratitis and Conjunctival Erosions Associated With Congenital Tufting Enteropathy




Purpose


To study the value of conjunctival biopsy in congenital tufting enteropathy diagnosis.


Design


Case-comparative study.


Methods


Between January 2000 and June 2007, all children seeking treatment with an early onset of intractable diarrhea were examined in the ophthalmology department of Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, France. Children underwent complete ophthalmologic examination with concurrent conjunctival and intestinal biopsies. Main outcome measures were age at diagnosis, associated disorders, parenteral nutrition, and ophthalmologic symptoms. Conjunctival biopsies support diagnosis in the presence of specific alteration.


Results


Twenty patients were included. The mean age of the population was 30.2 months. Congenital tufting enteropathy was diagnosed in 15 cases. In the congenital tufting enteropathy group, 10 children exhibited ophthalmic functional disorders since the first months of life, with superficial punctate keratitis and conjunctivitis and in addition alacrima and cataract in 1 case, respectively, whereas 5 children had asymptomatic conjunctival hyperemia at presentation. Conjunctival biopsies showed epithelial parakeratosis, hyperplasia, basal cells hyperplasia, and tufts. In some cases, the lamina propria contained inflammatory cells or fibrosis, and the density of goblet cells then was abnormal. In the comparison group of 5 children with early-onset intractable diarrhea but without congenital tufting enteropathy diagnosis, no tuft occurrence was observed.


Conclusions


In cases of intractable diarrhea in infancy, even without ocular symptoms, a systematic ophthalmologic examination should be performed. It also should be associated with the pathologic examination of both the conjunctival and the intestine mucosae, which helps to diagnose congenital tufting enteropathy (adhesion molecules disease). Specific conjunctival findings allow affirmation of congenital tufting enteropathy before the genetic confirmation of an EpCAM gene mutation.


Congenital tufting enteropathy, also known as intestinal epithelial dysplasia, is an autosomal recessive disease related to the essential role of adhesion molecules in the development of the gastrointestinal system. This congenital epithelial disease causes early-onset intestinal failure. Within the first days of life, severe watery diarrhea develops in infants and persists despite bowel rest and parenteral nutrition. It seems that mutations in the gene coding for EpCAM are responsible for congenital tufting enteropathy. Indeed, pathologic studies show that various degrees of villous atrophy are characterized by specific abnormalities involving the epithelium, with disorganization of surface enterocytes forming focal crowding and resembling tufts. Several associated specific features of pathologic analysis were described as choanal, rectal, or esophageal atresia. Nonspecific superficial punctate keratitis (SPK) and conjunctival erosion were reported in more than 60% of the patients.


Initially, we examined a patient with a typical clinical history and established a pathologic diagnosis of congenital tufting enteropathy at the Department of Ophthalmology of Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Université René Descartes–Paris V, France. The child had experienced very severe ophthalmologic symptoms, including photophobia, conjunctival hyperemia, and SPK. The clinical severity justified small bulbar conjunctival biopsies. The results revealed that the characteristic pathologic features were similar to those observed on intestinal biopsies. According to this finding, we then systematically examined in our ophthalmology department all children seeking treatment at the hospital with severe intractable diarrhea in infancy who were suspected of having congenital tufting enteropathy. Consequently, we report a series of patients with congenital tufting enteropathy, presenting ocular alterations, and similar histopathologic expression on both intestinal and conjunctival mucosa.


Methods


Between January 2000 and June 2007, all children admitted to the Necker-Enfants Malades Hospital with symptoms of early-onset intractable diarrhea were examined in our ophthalmology department. A complete digestive workup was performed together with the ophthalmologic examination and functional evaluation. Intestinal biopsies were performed during upper gastrointestinal endoscopy under general anesthesia. Informed consent for being included in the study was obtained from all the children’s parents.


As previously described, criteria for establishing the diagnosis of congenital tufting enteropathy were: early onset of severe watery diarrhea persisting at bowel rest and absence of clinical and biological manifestations of autoimmune disorders. On small bowel biopsy examination, criteria were mild to severe villous atrophy, normal periodic acid–Schiff and anti-CD10 staining, surface epithelial crowding forming tufts. Criteria for the comparison group were the presence of early-onset intractable diarrhea in infancy without a diagnosis of congenital tufting enteropathy.


During the procedure, directed small bulbar conjunctival biopsy samples were obtained from the bottom of the lower conjunctival bag using the classic technique. One or more symptoms or signs were investigated, such as photophobia, blepharospasm, hypolacrimia, conjunctival hyperemia, or SPK. All biopsy specimens were fixed in formalin buffer for histologic examination. Serial sections were stained with hematoxylin and eosin. Epithelium, lamina propria, and connective tissue were analyzed carefully.




Results


Twenty patients (9 females and 11 males) were examined over 6.5 years. The mean age was 30.2 months (range, 4 to 120 months). Year of birth, sex, geographic origin, consanguinity, family history, associated disorders, ophthalmologic symptoms and signs, age at diagnosis, and conjunctival biopsies results are presented in Tables 1 and 2 . Conjunctival biopsies were carried out in all children, including those who were receiving long-term parenteral nutrition. The congenital tufting enteropathy group comprised 15 patients (8 males and 7 females), including 2 pairs of siblings. Mean age was 38.2 months (range, 3.9 to 120 months). A second-degree parental consanguinity was noted in 6 (40%) children. The brother of one child died early in life of severe digestive disorders of unexplained origin. Three (20%) children had associated malformations, including 1 (7%) case of anorectal atresia and 2 (14%) cases of choanal atresia. Ten (67%) patients had functional disorders associated with SPK and conjunctival ulcerations with fibrosis ( Figure 1 ) that emerged in the first months of life. Alacrima was observed in 1 child. One boy and his sister had a severe form of ophthalmologic disease. Five (34%) children did not exhibit any symptoms, but had conjunctival hyperemia, with biopsy results showing histologic modifications. One (7%) child with photophobia and keratitis had a vacuolated anterior cortical lens without visual loss. The histologic examination of all biopsy specimens in this group showed abnormal results for all patients and some epithelial alterations characterized by epithelial cell crowding resembling tufts on conjunctival tissue in 9 (60%) patients (Patient 2; Figure 2 , Left), epithelial parakeratosis in 7 (47%) cases, and epithelial cells hyperplasia in 3 (20%) cases. Some metaplastic squamous cells were present. No increased mitotic activity was seen. Basal cell hyperplasia was observed in 14 (93%) patients. Inflammatory cells were present in the lamina propria in 12 (80%) cases that was associated with fibrosis of the lamina propria in connective tissue in 3 (20%) cases. Density of goblet cells was normal in 3 (19%) patients, was decreased in 10 (67%) patients, and was increased in 2 (13%) patients. One (7%) patient had lymphoid nodules and another had polynuclear cells infiltration, both in association with inflammation in the lamina propria. One (7%) patient had only lymphoid follicles in the lamina propria. Modifications of the conjunctival tissue were present in all the congenital tufting enteropathy cases.



TABLE 1

Main Clinical and Ophthalmologic Characteristics of Children with Congenital Tufting Enteropathy




































































































































































































Patient No. Year of Birth Country of Origin Sex Consanguinity Family Ratio of Affected Siblings to Normal Siblings Age at Diagnosis of CTE Associated Disorders Ophthalmologic Signs Age at Conjunctival Biopsy Status
1 1989 Italy M − 1:1 5 yrs − Keratitis 17 yrs Home PN
2 1991 France F − 2:1 3 yrs − Photophobia, keratitis 12 yrs LITx
3 1994 France F − 2:0 2 yrs − Photophobia, keratitis 9 yrs LITx
4 1995 Italy M − 1:0 3 yrs Anorectal atresia Photophobia, keratitis 9 yrs LITx
5 1996 France M − 2:0 6 mos − Photophobia, keratitis 7 yrs ITx
6 1997 Italy F + 2:1 1 yr − − 7 yrs ITx
7 1998 Kuwait F + 2:2 8 yrs PN-related bone disease Photophobia, keratitis, cataract 10 yrs Home PN
8 1999 Italy M − 1:1 2 yrs − − 5 yrs Home PN
9 2000 Algeria F + 1:1 2 yrs − Photophobia, keratitis 4 yrs Home PN
10 2001 Italy M − 1:0 1.5 yrs Choanal atresia Photophobia, keratitis alacrima 2 yrs Home PN
11 2004 Egypt M + 1:2 2 yrs − Photophobia, keratitis 1 yr Home PN
12 2004 France M − 1:0 6 mos − − 8 mos Home PN
13 1997 Qatar M + 2:4 10 yrs PN-related bone disease − 9 yrs Home PN
14 2000 Qatar F + 2:4 7 yrs PN-related bone disease − 6 yrs Home PN
15 2005 France F − 1:0 3 mos Choanal atresia Photophobia, keratitis 3 mos Home PN

− = not present; + = present; CTE = congenital tufting enteropathy; F = female; ITx = intestinal transplantation; LITx = liver–intestine transplantation; M = male; mos = months; PN = parenteral nutrition; yrs = years.


TABLE 2

Main Clinical and Ophthalmologic Characteristics of Children with Intractable Diarrhea in Infancy But without Congenital Tufting Enteropathy (Comparison Group)












































































Patient No. Year of Birth Country of Origin Sex Consanguinity Family Ratio of Affected Siblings to Normal Siblings Diagnosis Associated Disorders Ophthalmologic Signs Age at Conjunctival Biopsy Status
16 2003 France F − 1:0 NID − − 2 yrs Home PN
17 2005 Morocco M + 1:0 NID − Keratitis 5 mos Home PN
18 2006 Turkey M + 1:0 Microvillous atrophy − − 4 mos Hospital PN
19 2006 Turkey M + 1:0 Lymphangiectasia − − 6 mos Hospital PN
20 2006 France F − 1:1 NID − − 4 mos Home PN

− = not present; + = present; F = female; M = male; mos = months; NID = neonatal intractable diarrhea of unknown origin; PN = parenteral nutrition; yrs = years.



FIGURE 1


Photograph showing conjunctival ulcerations and fibrosis in a child with congenital tufting enteropathy (Patient 2).



FIGURE 2


Photomicrographs showing conjunctival biopsy specimens. (Left) Conjunctival biopsy results in a child (Patient 2) with congenital tufting enteropathy showing typical congenital tufting enteropathy findings: the conjunctival surface epithelium is abnormal, the surface cells are stratified, and the columnar cells are crowded on the surface, forming tufts. Some metaplastic squamous cells are present at the bottom of tuft (arrows). Inflammatory cells are present in the stroma and infiltrate the epithelium; the number of goblet cells is decreased (tissue fixed in formalin buffer, hematoxylin and eosin, ×200 magnification). (Right) Conjunctival biopsy results in a child (Patient 18) with intractable diarrhea in infancy but without congenital tufting enteropathy: normal conjunctival epithelium with a basal layer, a surface columnar layer and goblet cells (tissue fixed in formalin buffer, hematoxylin and eosin, ×200 magnification).

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Jan 17, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Superficial Punctate Keratitis and Conjunctival Erosions Associated With Congenital Tufting Enteropathy

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