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Clinicopathologic Reports, Case Reports, and Small Case Series
May 01, 2005

Limbal Stem Cell Deficiency Associated With LADD Syndrome

Arch Ophthalmol. 2005;123(5):691-694. doi:10.1001/archopht.123.5.691

The lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant hereditary disease with variable expression. It was first described in 1967 by Levy1 as an isolated case of bilateral absence of the tear system, cup-shaped ears, dry mouth, and dental, arm, and digital abnormalities. Subsequently, new clinical findings such as renal anomalies, absent salivary glands, congenital hip dislocation, congenital hiatal and diaphragmatic hernias, sensory and conductive deafness, hypodontia, limb anomalies, xerostomia, and xerophthalmia were described associated with this syndrome.

Thirty-five cases of LADD syndrome are described in the literature and most of them include ocular involvement. In particular, 71% showed hypoplasia or aplasia of the tear glands, hypoplasia or aplasia of the lacrimal puncta or canaliculi, and 64% showed tear deficiency, recurrent or chronic conjunctivitis, keratoconjunctivitis sicca, and corneal ulcerations related to the underlying tear gland aplasia.2,3

We describe, for the first time, limbal stem cell deficiency and corneal hypoanesthesia in 2 patients (mother and child) with LADD syndrome.

Report of a Case

In February 2002, a 30-year-old woman and her 9-year-old daughter were referred to our cornea and external disease center at the University of Rome “Campus Bio-Medical,” Rome, Italy. They both came with a clinical diagnosis of LADD syndrome, on the basis of genetic counseling and radiographic and ultrasonographic examinations.

On physical examination, the patients had several digital abnormalities: syndactyly of the thumb and second finger and absence of the left third finger, as well as the left second toe. In addition, the mother showed agenesis of the central mandibular incisors and a history of extensive dental caries. Her nostrils appeared flared and both ears were small and cup-shaped. Moreover, signs of salivary insufficiency were present, such as fissures and ulcers of the tongue, oral mucosa, and lips.

On their ocular history, both described episodes of corneal ulceration with a more severe clinical evolution in the mother's eyes (3 perforations, ocular dryness, and tear deficiency since the age of 10 years). The daughter had no symptoms of dry eye.

At slitlamp examination, they both showed haziness of the corneal epithelium with an irregular, gray appearance and superficial neovascularization of the corneal surface (Figure 1A and Figure 2A). The central cornea was thinned, and small epithelial defects were present. Their visual acuities were partially reduced. In addition, the mother showed marked conjunctival hyperemia and evident anatomical changes of the ocular surface in both eyes with fornix shortening and more pronounced corneal epithelial defects.

Figure 1.
Clinical evaluation of the mother's right eye showed corneal epithelial dystrophy and superficial neovascularization (A). A corneal impression cytology test showed the presence of goblet cells (periodic acid–Schiff) (B), cytokeratin K3 negative cells (immunohistochemistry) (C), and cytokeratin K19 positive cells (immunohistochemistry) (D) (original magnification ×20; digitally processed images).

Clinical evaluation of the mother's right eye showed corneal epithelial dystrophy and superficial neovascularization (A). A corneal impression cytology test showed the presence of goblet cells (periodic acid–Schiff) (B), cytokeratin K3 negative cells (immunohistochemistry) (C), and cytokeratin K19 positive cells (immunohistochemistry) (D) (original magnification ×20; digitally processed images).

Figure 2.
Clinical evaluation of the daughter's right eye showed corneal epithelial haziness and neovascularization on the inferior corneal sector (A). Goblet cells (periodic acid–Schiff) (B) and cytokeratin K19 positive cells (immunohistochemistry) (D) were present on the inferior sector. Cytokeratin K3 positive cells (immunohistochemistry) (C) were present on the other sectors (original magnification ×20; digitally processed images).

Clinical evaluation of the daughter's right eye showed corneal epithelial haziness and neovascularization on the inferior corneal sector (A). Goblet cells (periodic acid–Schiff) (B) and cytokeratin K19 positive cells (immunohistochemistry) (D) were present on the inferior sector. Cytokeratin K3 positive cells (immunohistochemistry) (C) were present on the other sectors (original magnification ×20; digitally processed images).

Corneal sensitivity, as tested by Cochet-Bonnet esthesiometer (Luneau Ophtalmologie, Chartres-Cedex, France) for each of the 5 corneal sectors (temporal, inferior, nasal, superior, and central), resulted in mild to marked corneal hypoesthesia. Reduced Schirmer tests, types 1 and 2, and break-up time, as well as squamous metaplasia and low density of conjunctival goblet cells, were present in the mother but not in the daughter (Table).

Table. 
Corneal Esthesiometry and Tear Function Tests
Corneal Esthesiometry and Tear Function Tests

Two corneal swabs and routine hematological tests, including antinuclear antibody, extractible nuclear antibody, immunocomplex, and rheumatoid factor, were performed to exclude any infection or autoimmune disease. A conjunctival biopsy was also performed in the left inferior conjunctival fornix of the mother's eye to exclude ocular cicatricial pemphigoid. The biopsy specimen showed a nonspecific monocytic infiltration and epithelial squamous metaplasia. Direct immunofluorescence results were negative for IgG, IgM, IgA, and complement factors (C3 and C4).

As expected, magnetic resonance imaging showed marked hypoplasia or agenesia of the lacrimal glands in the mother. A corneal impression cytology test was performed in both patients and periodic acid–Schiff staining (Sigma Diagnostics, St Louis, Mo) showed the presence of epithelial squamous metaplasia and goblet cells on their corneal surfaces. (Figure 1B) Immunohistochemistry demonstrated the absence of cytokeratin K3 positive cells and the presence of cytokeratin K19 positive cells in their corneas (Figure 1C and D).4

Comment

In this report, we describe 2 cases of LADD syndrome associated with limbal stem cell deficiency5 and corneal hypoanesthesia. Limbal stem cell deficiency was diagnosed on the basis of clinical features (corneal epithelial erosions and neovascularization) and cytological findings (presence of goblet cells and specific cytokeratins of the corneal epithelium). Clinical ocular features of LADD syndrome, described as corneal erosions, neovascularization, and ulceration, were thought by authors to be clinical manifestations of the underlying dry eye condition.2,3 Based on the literature, we hypothesized that dry eye may also induce the development of limbal deficiency as well as corneal anesthesia. This hypothesis was at first confirmed by the mother's condition. However, the daughter showed an initial partial limbal deficiency and a history of corneal ulceration with no deficiency of tear production and without the anatomical changes related to dry eye. Therefore, it is possible that limbal deficiency could represent a genetically determined, clinical characteristic of LADD syndrome, adding this syndrome to the ever-increasing list of conditions associated with limbal stem cell deficiency. The impairment of corneal sensitivity is a new characteristic of LADD syndrome and the pathogenetic mechanism is unclear. Indeed, corneal hypoesthesia was also present in the child, with no presence of dry eye. It is possible that limbal stem cell deficiency and corneal hypoesthesia could both be contributing factors toward corneal changes found in this syndrome.

Our study suggests 2 additional clinical features of LADD syndrome, other than dry eye. Indeed, we found the presence of limbal stem cell deficiency and corneal sensitivity impairment in the absence of dry eye. These results have important therapeutic implications. In fact, to date, the therapeutic approach for the ocular manifestations of LADD syndrome was the treatment of the dry eye condition, based on tear substitutes and lacrimal punctum occlusion. These novel observations of LADD syndrome may introduce new therapeutic options; it would be interesting to evaluate if a limbal transplantation could be effective in improving the clinical manifestations of the disease, such as corneal anesthesia.

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Article Information

Correspondence: Dr Bonini, G. B. Bietti Eye Foundation, Via Livenza 3, 00196 Rome, Italy (s.bonini@unicampus.it).

Financial Disclosure: None.

References
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