Aplasia Of Lacrimal And Salivary Glands

A number sign (#) is used with this entry because autosomal dominant aplasia of lacrimal and salivary glands (ALSG) is caused by heterozygous mutation in the FGF10 gene (602115) on chromosome 5p12.

Lacrimoauriculodentodigital syndrome (LADD; 149730) is an allelic disorder with a more severe phenotype.

Description

Autosomal dominant aplasia of lacrimal and salivary glands is a rare condition characterized by irritable eyes, epiphora (constant tearing), and xerostomia (dryness of the mouth), which increases risk of dental erosion, dental caries, periodontal disease, and oral infections. ALSG has variable expressivity, and affected individuals may have aplasia or hypoplasia of the lacrimal, parotid, submandibular, and sublingual glands and absence of the lacrimal puncta. In affected individuals, the misdiagnosis is often made of the more prevalent disorder Sjogren syndrome (270150), an autoimmune condition characterized by keratoconjunctivitis sicca and xerostomia. Both sporadic and familial cases of ALSG have been described (summary by Entesarian et al., 2005).

Clinical Features

Smith and Smith (1977) observed absence of the right parotid and submandibular glands in a father and complete absence of all 4 major salivary glands in his son. Affected father and daughter were reported by Ramsey (1924). Fantasia (1978) observed parotid agenesis or hypoplasia in 3 generations. His probands were 2 brothers, aged 15 and 10 years, with rampant caries, dry mouth, and no evidence of parotid ducts or palpable parotid glands. Submaxillary glands and ducts were present and salivary flow seemed normal. A younger brother and sister were unaffected. The father was edentulous because of rampant caries in adolescence and complained of a dry mouth. Although parotid ducts were present, no salivary flow occurred, even after stimulation. His mother was said to have had a dry mouth. Hughes and Syrop (1959) reported a similar family, in which 9 persons were affected in 3 generations. In the 7 available for examination, absence of the orifice of Stenson's duct, impalpable parotid gland, dry mouth, and high caries index were found in all; no other defects were detected except for absence or 'dysfunction' of the lacrimal glands in 2.

Wiesenfeld et al. (1985) reported a 62-year-old male with bilateral parotid gland aplasia, confirmed by computerized tomography and (99m)Tc-pertechnetate scintiscan. He was asymptomatic, although the oral mucosa was dry and the parotid ducts absent. Submandibular and minor salivary glands were functional. The patient retained his teeth until age 47 when they were extracted for unknown reasons. A brother was similarly affected; he had early loss of teeth for reasons not specified. Twenty other relatives examined for the presence of parotid duct orifices secreting saliva were found to be normal.

Higashino et al. (1987) described a 7-year-old girl who had congenital absence of all major salivary glands in association with congenital absence of all 4 lacrimal puncta. There was bilateral lacrimal fistula inferior to the medial canthal area. No other members of the family were affected. The child had recurrent acute dacryocystitis.

Smith and Smith (1977) found defects of the lacrimal apparatus in 3 of 11 cases of congenital absence of all 4 salivary glands.

Blackmar (1925) reported the first case of congenital absence of the lacrimal puncta associated with aptyalism (absence of salivation) and decreased lacrimation. Severe caries were present in the 11-year-old boy whom he reported.

Caccamise and Townes (1980) studied a family in which absence of lacrimal puncta, congenital alacrima, and lack of salivation seemed to be inherited as an autosomal dominant trait with variable expressivity. He described a 9-year-old girl with no lacrimal puncta, and no tears or salivation, who had florid dental caries. The girl's father and paternal grandfather had a similar condition. Sucupira et al. (1983) and Vogel and Reichart (1978) reported 12- and 18-year-old boys, respectively, who had this combination of manifestations associated with severe dental caries. The evidence seems to indicate that the saliva normally has an effect in preventing rampant caries.

Milunsky et al. (1990) described a single case of absence of the parotid glands, hypoplasia of both lacrimal glands, and marked hypofunction of both submandibular glands, with left nasolacrimal duct atresia. They wrote: 'We suspect that the pleiotropic effect of a single autosomal dominant gene, in all likelihood, explains the findings, ranging from agenesis to hypoplasia to presence of some or all salivary glands, lacrimal glands, and nasolacrimal ducts or puncta.' Their patient was an isolated case; parental consanguinity and the age of the parents were not commented on. Wiedemann (1991) suggested that the patient of Milunsky et al. (1990) had LADD syndrome (149730).

Ferreira et al. (2000) described a Brazilian family in which members of 3 generations had congenital absence of lacrimal puncta and salivary glands in an autosomal dominant pedigree pattern. The submaxillary and sublingual glands were present. A 41-year-old affected man had lost all teeth before the age of 20 and others had multiple dental caries.

Klar et al. (2011) analyzed pulmonary function in 12 patients from 2 Swedish families with FGF10-associated ALSG, originally studied by Entesarian et al. (2005). Compared to 3 unaffected family members as well as to predicted reference values, the FGF10-haploinsufficient patients exhibited nonreversible airway obstruction, with a significantly reduced forced expiratory volume in 1 second (FEV1) and a lower than normal FEV1/inspiratory vital capacity (IVC) ratio. Their reduced pulmonary function was consistent with moderate or stage II chronic obstructive pulmonary disease (COPD; 606963). Klar et al. (2011) concluded that FGF10 haploinsufficiency affects lung function measures, and proposed that genetic variants affecting the FGF10 signaling pathway are important determinants of lung function that may contribute to COPD.

Inheritance

The transmission pattern of ALSG in the families reported by Caccamise and Townes (1980) and Ferreira et al. (2000) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of 2 Swedish families with ALSG, Entesarian et al. (2005) identified mutations in the FGF10 gene (602115.0001-602115.0002). Both mutations were consistent with the idea that haploinsufficiency for FGF10 underlies ALSG. On reexamination of Fgf10 +/- mice, Entesarian et al. (2005) demonstrated aplasia of lacrimal glands and hypoplasia of salivary glands.

In a mother with ALSG and her daughter with LADD syndrome, Milunsky et al. (2006) identified a heterozygous mutation in the FGF10 gene (602115.0005). The findings in this family indicated that ALSG and LADD syndrome are allelic disorders. The authors suggested that differences in modifier genes may explain the less severe ALSG phenotype in the mother versus the LADD syndrome phenotype in her daughter.

In 2 unrelated boys with ALSG, Entesarian et al. (2007) identified 2 different missense mutations in the FGF10 gene (602115.0006 and 602115.0007, respectively). The patients had no abnormalities of the digits, ears, or primary teeth, and their hearing was normal. One of the boys had coronal hypospadias but no other urogenital abnormalities, showing overlap between the ALSG and LADD syndrome phenotypes.