Lacrimoauriculodentodigital Syndrome

A number sign (#) is used with this entry because LADD syndrome can be caused by heterozygous mutation in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 (FGFR2; 176943) and 3 (FGFR3; 134934). LADD syndrome can also be caused by heterozygous mutation in the FGF10 gene (602115), which encodes an FGFR ligand.

Mutations in the FGF10 gene also result in aplasia of the lacrimal and salivary glands (ALSG; 180920), an allelic disorder.

Description

Lacrimoauriculodentodigital syndrome is a multiple congenital anomaly disorder mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments (summary by Rohmann et al., 2006).

Clinical Features

Hollister et al. (1973) described a Mexican man and 5 of his 8 children (4 girls and 1 boy) with a similar syndrome, which the authors designated lacrimoauriculodentodigital (LADD) syndrome. The lacrimal feature was aplasia or hypoplasia of the puncta with obstruction of the nasal lacrimal ducts. The auricular features were cup-shaped pinnas with mixed hearing deficit. The dental features included small and peg-shaped lateral maxillary incisors and mild enamel dysplasia. The digital features were variable but included fifth finger clinodactyly, duplication of the distal phalanx of the thumb, triphalangeal thumb, and syndactyly.

Levy (1967) described a possible sporadic case of this syndrome. Hoyme and Kreutz (1985) described affected mother and daughter. The mother's father was 39 at the time of her birth. The daughter had bilateral lacrimal duct fistulae and the mother had unilateral radial aplasia in addition to the digital anomalies.

Thompson et al. (1985) described affected mother and son. They suggested that poor saliva and tear production be added to the phenotypic features. Both the mother and the son produced very little saliva and had to take a drink with dry food to swallow. As pointed out by Wiedemann and Drescher (1986), aplasia or hypoplasia of the salivary glands leads to dry mouth and early onset of severe dental caries.

Calabro et al. (1987) described affected mother and daughter. The 26-year-old mother had small dysplastic ears with downward-folded helix and agenesis of the upper lateral incisors. The thumbs were longer than normal with scars from surgical correction of a bifid terminal phalanx. At 17 months, the daughter showed bilaterally low-placed, cup-shaped, small ears, a bifid thumb with ulnar deviation on the right and clinodactyly V on the left. Tooth eruption was delayed.

Bamforth and Kaurah (1992) described this disorder in members of 3 generations of a family. In addition to the well-described abnormalities such as blocked nasal lacrimal duct, congenital renal disease causing death in the neonatal period was observed in 2, an uncle and niece.

Francannet et al. (1994) described LADD syndrome in 5 members of 3 generations of a family. The disorder was first recognized in this family when prenatal ultrasonography showed bilateral radial aplasia in a 17-week-old fetus. The pregnancy was terminated. Pathologic examination showed severe facial dysmorphism associated with broad anterior fontanel, high forehead, deep metopic fissure, bilateral hypoplasia of the auricles, and pronounced microretrognathia. There was bilateral aplasia of the thumbs and bilateral radial agenesis with club hands. Radiography also showed abnormalities of the chest wall with angulation of ribs and hypoplasia of the ischial bones. The mother had been operated on in early childhood for obstruction of the lacrimal ducts. At the age of 12, she had orthodontic treatment and removal of 12 'dysplastic' teeth. On examination, her ears were round and protruding and audiograms showed right conductive deafness. There was cutaneous syndactyly of the first and second right toes. A previously born son was delivered prematurely at 35 weeks of gestation and showed multiple malformations: hypoplasia of the right thumb (floating thumb), bilateral cutaneous syndactyly of the second and third toes, and bilateral clinodactyly of toes IV and V. Hypospadias was also noted. He was found to have a complex pulmonary malformation with right diaphragmatic palsy (which was present in asymptomatic form in the mother also); hypoplasia of the left lung vasculature without bronchial anomalies, mild hypoplasia of the left pulmonary artery, and, on echocardiography, aneurysm of the interventricular septum. He had chronic conjunctivitis with no tear production, small protruding ears without lobules, and hypoplasia of the alae nasi with protruding subseptum. The maternal grandmother, aged 54 years, had had an operation for obstruction of the lacrimal ducts at the age of 4 years. For several years she had suffered from deafness, and audiometric tests revealed a mixed sensorineural loss. The left forearm was hypoplastic and flexion of the thumb and index finger was not possible. Because of their poor quality, all her teeth had been extracted before the age of 40 years. Radiography showed left radial-ulnar synostosis. A brother of the mother had had obstruction of the tear ducts in infancy which required surgery. Further information was not available. The family illustrated the great variability of the expression of this syndrome and the need for caution in genetic counseling. Francannet et al. (1994) suggested that prenatal ultrasound should be offered to families at risk so that severe forms of the syndrome in which termination of pregnancy might be considered are detected early.

Cortes et al. (2005) stated that most of the 35 reported cases of LADD syndrome had 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. They described a mother and daughter with LADD syndrome who had limbal stem cell deficiency and corneal sensitivity impairment (hypesthesia). Both patients had partially reduced visual acuity.

Rohmann et al. (2006) examined 5 large LADD families and 1 sporadic case presenting a wide range of typical clinical symptoms with variable expression, even within a family. Hypoplasia, atresia, and aplasia of the nasolacrimal ducts and puncta led to frequent conjunctivitis in patients, and salivary gland abnormalities such as hypoplasia or aplasia of the parotid and submandibular glands caused xerostomia and early-onset caries. Hypodontia and microdontia were frequently observed. External ear anomalies included cup-shaped, small, and low-set ears, and in over 50% of the cases sensorineural, conductive, or mixed-type hearing loss was found. Limb defects most often involved the thumbs, ranging from total aplasia to hypoplastic, digitalized, triphalangeal, and duplicated thumbs. Mild syndactylies of fingers or toes and lower limb anomalies were less frequent. None of the affected individuals had short stature or craniosynostosis.

Talebi et al. (2017) described an affected mother and son in a consanguineous Iranian family with LADD syndrome. Aplasia, atresia, and hypoplasia of the nasolacrimal ducts and puncta resulted in conjunctivitis in both patients. The son also had hypodontia and microdontia. External ear anomalies included small, cup-shaped ears, and both patients had bilateral profound sensorineural hearing loss. Limb defects involved the thumbs, ranging from full aplasia to hypoplastic, digitalized, and duplicated thumbs. Mild syndactylies of toes or fingers and lower limb anomalies were also present. The mother's brother had been diagnosed with LADD syndrome but was not available for study.

Mapping

By linkage analysis using DNA from 12 affected and 10 unaffected members in 3 LADD families, Rohmann et al. (2006) obtained a combined maximum parametric lod score of 3.61 for a region on chromosome 10q26 that contains the FGFR2 gene (176943), in which causative mutations were found. The detection of mutations in the FGFR3 (134934) and FGF10 (602115) genes in affected individuals placed additional LADD loci on chromosomes 4p16.3 and 5p13-p12, respectively.

Molecular Genetics

Rohmann et al. (2006) sequenced the 24 coding and noncoding exons of the FGFR2 gene (176943), which maps within the critical region on 10q26 defined for LADD syndrome, and detected a heterozygous mutation in each affected family member of the 3 families studied. In a Dutch family they found heterozygosity for a missense mutation in exon 16 in all 5 affected members (A648T; 176943.0035). The same heterozygous mutation was found in an English LADD family. Rohmann et al. (2006) concluded that the A648T mutation probably arose independently in the 2 families since they did not share a common founder haplotype. In another family, a heterozygous 3-bp deletion in exon 16 of FGFR2 was found (176943.0036). In a de novo mutation case of LADD syndrome, they found heterozygosity for an A628T missense mutation (176943.0037). In a LADD family from Turkey, Rohmann et al. (2006) detected a mutation in the FGFR3 gene predicting a D513N amino acid substitution in the conserved TK1 domain (134934.0028). In a German family of Turkish origin, Rohmann et al. (2006) found that LADD syndrome was associated with heterozygosity for a missense mutation in the gene encoding fibroblast growth factor-10 (FGF10) (602115.0003).

Milunsky et al. (2006) identified a heterozygous mutation in the FGF10 gene (602115.0005) in a mother with aplasia of the lacrimal and salivary glands (ALSG) and her daughter with LADD syndrome. The findings in this family indicated that ALSG and LADD syndrome are allelic disorders and part of the same phenotypic spectrum. The authors suggested that differences in modifier genes, perhaps including FGFR2, may explain the less severe ALSG phenotype in the mother versus the LADD syndrome phenotype in her daughter. Another unrelated girl with LADD syndrome had a de novo heterozygous mutation in the FGF10 gene (602115.0004).

In an affected mother and son in a consanguineous Iranian family with LADD syndrome, Talebi et al. (2017) identified heterozygosity for a missense mutation (D628N; 134934.0038) in the FGFR3 gene.