Case report: presentation of lacrimo-auriculodento-digital (LADD) syndrome in a young female patient.
Lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM #149730) is a very rare autosomal-dominant congenital multiple anomaly disorder characterized by aplasia (developmental absence of all or part of an organ), atresia (closure or blockage of a body passage), or hypoplasia (underdevelopment or incomplete development) of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental anomalies [Milunsky et al., 2006]. Furthermore, variable anomalies of the hands and feet, such as duplicated terminal phalanx of the thumb, triphalangeal thumb (long finger-like thumb with three phalanges instead of two), preaxial polydactyly (thumb duplication), syndactyly (fusion) of the second and third digits, and fifth finger clinodactyly (curving of the fifth finger towards the fourth) have also be seen in cases with LADD [Guven et al., 2008]. Additional features of the syndrome may include renal abnormalities such as agenesis (failure of an organ to develop during embryonic growth) or nephrosclerosis (sclerosis of the kidney), hiatus hernia (protrusion of the upper part of the stomach into the thorax through a tear or weakness in the diaphragm), and coronal hypospadias (ventral and proximal malposition of meatus in the coronal sulcus) [Jones and Smith, 2005; Bamforth and Kaurah, 1992]. Intracranial manifestations, such as calcifications of the basal ganglia have also been reported in patients with LADD syndrome [Haktanir et al, 2005].
The degree to which the different organs are involved varies considerably with dental anomalies regularly reported. Such abnormalities may include peg-shaped incisors, long thin-rooted teeth, malformed molars, microdontia, enamel hypoplasia, shallow cusps, taurodontism and partial anodontia [Levy, 1967]. This report details the first reported presentation of LADD syndrome in the Republic of Ireland with a 12-year-old girl who exhibited a range of dental and digital abnormalities.
Within the medical literature there are less than 50 reported cases of LADD syndrome, also known as the Levy-Hollister syndrome. In 1967 Levy first reported on a 'new combination of anomalies'. He described a patient with aplasia of the nasolacrimal duct, malformation of the auricles, a dry mouth, pronounced dental anomalies (unerupted and dysplastic teeth), and digital anomalies [Levy, 1967]. Hollister et al.  independently described a family with similar symptoms and signs of an autosomal-dominant transmission. It was this workgroup that coined the term lacrimo-auriculodento-digital (LADD) syndrome.
In addition to the clinical signs initially observed by Levy and by Hollister et al., other authors assigned further clinical findings to this syndrome (Table 1). These included varyingly expressed dysplasia of the auditory apparatus (e.g. auricular dysplasia, congenital hearing loss), renal abnormalities, e.g. agenesis or nephrosclerosis, hiatus hernia, facial dysmorphia, and epiglottic hypoplasia. A number of reports have detailed anomalies of the hands and feet, such as duplicated terminal phalanx of the thumb, triphalangeal thumb, preaxial polydactyly, syndactyly of the second and third digits, and fifth finger clinodactyly [Poznanski et al., 1972; Murdoch-Kinch and Miles, 1996].
Mixed sensorineural and conductive hearing loss, either unilateral or bilateral, is frequently found in patients with LADD syndrome. Although this hearing loss is usually mild to moderate, severe hearing loss has been reported. Improvements in hearing loss have been detailed after surgical intervention for middle ear abnormalities. Although the hearing loss at birth may be profound there can be a progressive component with reduced auditory acuity being detected for the first time in adults. Performing periodic hearing tests on all persons with LADD syndrome has been recommended [Wiedemann and Drescher 1986].
Reported lacrimal apparatus malformations have included nasolacrimal duct obstruction and hypoplasia or aplasia of the lacrimal puncta. It has been suggested that the basis for the decreased lacrimation in patients with LADD syndrome may be acinar aplasia or hypoplasia. It is thought that the basal secretion from the accessory lacrimal glands may provide sufficient tears to maintain the integrity of the corneal epithelium [Inan et al., 2006]. Another reported feature of this syndrome is congenital ptosis that in some cases may be associated with hypertelorism and telecanthus [Bamforth and Kaurah, 1992].
Salivary gland pathologies are commonly reported with LADD syndrome. Congenital absence of the major salivary glands has been described and affected patients may suffer from xerostomia. Even in the presence of submandibular and parotid glands with patent ductal systems, markedly reduced secretions have been found in some patients. Shiang and Holmes  described absence of the parotid glands and Stensen's ducts in one of two patients with the Levy-Hollister syndrome. However, Kreutz and Hoyme  surmised that the defects of salivary glands might not represent an associated feature of LADD syndrome because of absence of this defect in other affected individuals. The congenital absence of major salivary glands resulting in xerostomia has been reported without evidence of the LADD syndrome [Smith and Smith, 1977; Whyte and Hayward, 1989].
Another syndrome named the branchio-otorenal (BOR) syndrome may share a number of features of LADD syndrome and may necessitate differential diagnosis with LADD syndrome. The BOR syndrome can be distinguished from LADD syndrome by the presence of auricular pits and branchial fistulae and absence of dental and digital anomalies.
Ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome is distinguished by the presence of split hand/foot, by hair and skin anomalies and by cleft lip with or without cleft palate. Propping and Zerres  reported a family with close resemblance to the LADD and EEC syndromes and related disorders. The main manifestations were hypodontia and/ or early loss of permanent teeth, ectrodactyly, obstruction of lacrimal ducts, onychodysplasia, and excessive freckling. They proposed the acronym ADULT (acro-dermato-ungual-lacrimal-tooth)-syndrome for this condition.
Previously pathogenetically unclarified, the genetic cause of LADD syndrome has been identified as heterozygous mutations in the encoding of fibroblast growth factor receptors FGFR2 and FGFR3. It has also been found that LADD is associated with the mutations in the FGF10 gene, which has been shown to result in agenesis of the lacrimal and salivary glands [Milunsky et al, 2006; Shams et al., 2007; De Coster et al., 2009].
The Community Dental Service referred a 12-year-old girl to Cork University Dental Hospital. The patient was born in the Republic of Ireland to Moldovan parents. She had previously been diagnosed with LADD syndrome in a regional hospital within Ireland. The patient was under the medical care of her family medical practitioner who revealed that genetic testing in combination with clinical signs had been used to give a diagnosis of LADD. Questioning of the patient and her mother revealed no known previous family history of LADD syndrome and her younger siblings were unaffected. Genetic counselling had not been carried out for family members.
The patient's primary dental complaint was the appearance of her maxillary anterior teeth that she felt were small and spaced. The patient was taking no medications, had no known allergies and was otherwise medically well. No history of neonatal or perinatal complications was noted. The patient gave no history of renal symptoms or involvement of other major organs.
[FIGURE 1 OMITTED]
Extra oral examination. This revealed a prominent chin with a notable deviation to the right. The patient had cup shaped ears and mild ptosis but no further otolaryngologic abnormalities. The patient exhibited no evidence of deafness or hearing loss and reported no dryness of her eyes. (Figure 1)
Intra-oral examination: There was a mixed dentition with evidence of previous caries and untreated lesions present. Despite the evidence of caries there was no evidence of hypoplasia or other anomalies of the dental hard tissues. There was little clinical evidence of xerostomia and a normal salivary flow test was recorded, however the patient's mother reported she frequently sipped bottled water. The maxillary and mandibular permanent incisors were present and clearly spaced (Figure 2). The maxillary central incisors, particularly 11, were diminutive and an orthopantomogram revealed that 25, 35 and 45 were absent (Figure 3) in addition to all second permanent molars (17, 27, 37 and 47).
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
An examination of the patient's feet revealed no obvious abnormalities but her hands exhibited a number of anomalies (Figure 4). On her right hand there was evidence of fifth finger clinodactyly and preaxial polydactyly of the thumb. Her left hand also exhibited fifth finger clinodactyly and a triphalangeal thumb. The patient reported no functional difficulties with her hands but found gripping objects difficult with her left hand.
The dental treatment for this patient necessitated a multidisciplinary approach encompassing restorative and orthodontic elements. The initial treatment strategy involved preventative elements including fissure sealing unrestored first permanent molars, extensive oral hygiene instruction and the use a high fluoride mouthwash and dentifrice. Teeth with cavities present were restored.
As an interim measure, impressions of the patient's dentition were taken and a diagnostic wax up completed to illustrate the improvements that could be made to the shape of the anterior teeth. Wax was added to increase the width of the incisors and canines but not the length of the teeth, in order to maintain the existing occlusion. After a discussion with the patient, a number of minor adjustments were made to the contour of the teeth on the wax up. The exact shape of the teeth achieved with the diagnostic wax up was transferred to the teeth in the mouth after fabrication of maxillary and mandibular putty matrices. Composite resin was applied to the maxillary and mandibular incisors and canines to provide definite restorations (Figure 5).
[FIGURE 5 OMITTED]
The patient has been reviewed after provision of her composite build-ups. The resin composite was polished and a small repair made to the palatal surface of the right maxillary lateral incisor. The patient was very pleased with the outcome of the restorative treatment and she is now maintaining a good standard of oral hygiene.
The patient now requires orthodontic treatment that will be designed to provide appropriately sized spaces for the missing premolars which can then be restored with fixed prostheses. The composite resin restorations on the anterior teeth will be maintained until gingival maturity is reached, when extra coronal restorations could be considered. Her medical management will continue to be managed by her family practitioner.
Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal-dominant congenital multiple anomaly disorder. There are less than 50 reported cases of LADD syndrome in the medical literature with a variety of manifestations reported. This report details the presentation of a young girl with a sporadic case of LADD syndrome who presented with notable dental and digital abnormalities. The condition had not affected her auditory, lacrymal or renal systems as in other reported cases but this serves to illustrate the variable systemic expression of LADD syndrome.
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G. J. McKenna, F. M. Burke, K Mellan.
Dept of Restorative Dentistry, School of Dentistry, University College Cork, Cork, Ireland.
Postal address: Dr G. J. McKenna, Dept. Restorative Dentistry, School of Dentistry, University College Cork, Cork, Ireland.
Table 1. Reported manifestations of oral and other anomalies for subjects with LADD syndrome. Manifestations Reported Cases Peg shaped incisors Shiang and Holmes, ; Thompson et al, ; Hennekam, ; Calabro et al., ; Kreutz and Hoyme, ; Bamforth and Kaurah, ; Heinz et al., ; Francannet et al., ; Toumba and Gutteridge, ; Murdoch-Kinch and Miles, 1996. Hypodontia Levy, ; Thompson et al, ; Hennekam, ; Bamforth and Kaurah, ; Toumba and Gutteridge,  Murdoch-Kinch and Miles, ; Meuschel-Wehner et al, ; Lehotay et al, ; Hak-tanir et al, ; Inan et al, . Enamel hypoplasia Hollister et. al.,  ; Horn and Witkowski, . Unerupted teeth Levy, . Molars with single Toumba and Gutteridge,; Lehotay et al., conical roots ; Guven et al, . Taurodontism Guven et al., . Root dilacerations Lehotay et al., ; Guven et al., . Skeletal Class III Wiedemann and Drescher, ; Kreutz and Hoyme, ; Toumba and Gutteridge,; Lehotay et al., ; Guven et al., . Salivary gland Levy, ; Roodhooft et al., ; Shiang abnormalities, and Holmes, ; Thompson et al., ; xerostomia Wiedemann and Drescher, . Auricular anomalies Hollister et al., ; Levy, ; Thompson et al., . Lacrimal anomalies Hollister et al., ; Levy, ; Shiang and Holmes, ; Thompson et al., ; Wie-demann and Drescher . Digital anomalies Bamforth and Kaurah, ; Heinz at al., ; Hollister et al.,  ; Levy,  ; Thompson et al.,  ; Wiedemann and Drescher, . Renal abnormalities Roodhooft et al., ; Shiang and Holmes, 
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|Author:||McKenna, G.J.; Burke, F.M.; Mellan, K.|
|Publication:||European Archives of Paediatric Dentistry|
|Date:||Dec 1, 2009|
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