Aplasia of Lacrimal and Salivary Glands

Mendelian MONDO:0008397 Pathograph 24 Show in embeddings browser FGF10-Related Disorder Congenital Exocrine Gland Anomaly

Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant congenital disorder in which the lacrimal glands, the major salivary glands (parotid and submandibular) and parts of the lacrimal drainage system are absent, atretic or hypoplastic. Affected individuals present from infancy with irritable, dry eyes and reduced tear production, epiphora from punctal atresia or nasolacrimal duct obstruction, and dry mouth with early and severe dental caries. Expressivity is variable within families, from bilateral aplasia to unilateral or minimal involvement, and penetrance is incomplete. ALSG is caused by heterozygous loss-of-function variants in FGF10 (nonsense, splice-site and missense alleles, and a whole-gene deletion), and is read as FGF10 haploinsufficiency. FGF10 is secreted by the mesenchyme around the nascent gland epithelium and signals through the epithelial receptor FGFR2b to drive budding and branching morphogenesis. In mice a single functional Fgf10 allele is insufficient for lacrimal gland budding and gives hypoplastic submandibular glands, while loss of both alleles abolishes the lacrimal and salivary glands. ALSG is allelic with lacrimo-auriculo-dento-digital (LADD) syndrome, which adds ear, dental and digital anomalies; both can occur in one family. Management is supportive: lacrimal drainage surgery, ocular lubrication and intensive dental prevention.

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1
Inheritance
5
Pathophys.
11
Phenotypes
2
Gaps
24
Pathograph
1
Genes
5
Medical Actions
3
Differentials
2
Models
25
References
1
Deep Research
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Inheritance

1
Autosomal Dominant HP:0000006
Heterozygous FGF10 variants segregate with the disorder in multigeneration pedigrees. Penetrance is incomplete: an unaffected variant carrier was found in a six-generation kindred, and a three-family series described the pattern as autosomal dominant with variable penetrance. Expressivity varies within families, from bilateral gland aplasia to unilateral or minimal involvement.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (4 references)
PMID:15654336 SUPPORT Human Clinical
"In two extended pedigrees, we identified heterozygous mutations in FGF10 in all individuals with ALSG."
Heterozygous variants segregating in extended pedigrees establish dominant inheritance.
PMID:37615310 SUPPORT Human Clinical
"Moreover, one of the variant carriers had no ALSG-related clinical findings, demonstrating incomplete penetrance."
Unaffected heterozygous carrier in a large kindred documents incomplete penetrance.
PMID:37615310 SUPPORT Human Clinical
"Notably, individuals sharing the same variant exhibited phenotypic variability, with unilateral or bilateral epiphora, as well as variable expression of dry mouth and caries."
Variable expressivity among carriers of one allele.
+ 1 more reference
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Discussions and Knowledge Gaps

2
Are ALSG and FGF10-related LADD syndrome distinct allelic disorders, or one variable spectrum separated by ascertainment?
KNOWLEDGE GAP alsg_ladd_spectrum_gap
Attached to
disease# pathophysiology#FGF10 Haploinsufficiency
Both are autosomal dominant FGF10 haploinsufficiency disorders, and a mother with ALSG and her daughter with LADD syndrome carried the same nonsense allele, so the extra-glandular features cannot be predicted from the allele. Whether modifier loci, the residual activity of particular alleles, or chance decide whether ears, teeth and digits are affected has not been studied. The G138E allele has been reported both in an ALSG family and as a LADD-causing allele.
Show evidence (3 references)
PMID:16630169 SUPPORT Human Clinical
"A nonsense mutation was also found in exon 2 of FGF10 (Family 2) in a 19-year-old mother with ALSG and her 2-year-old daughter with LADD syndrome."
One allele, two diagnoses in one family.
PMID:16630169 SUPPORT Human Clinical
"We conclude that ALSG and LADD syndrome may represent variable presentations of the same clinical spectrum caused by FGF10 mutations."
The authors' spectrum interpretation.
PMID:27742760 SUPPORT BACKGROUND In Vitro
"However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic."
G138E, reported in an ALSG family, is also described as LADD-causing.
How does reduced FGF10 dose cause punctal atresia and bony nasolacrimal duct obstruction?
KNOWLEDGE GAP alsg_lacrimal_drainage_mechanism_gap
Attached to
pathophysiology#Lacrimal Drainage System Maldevelopment phenotypes#Nasolacrimal duct obstruction phenotypes#Lacrimal punctal atresia
The gland defects are explained by mouse work on lacrimal budding and salivary branching, but the drainage-system anomalies have only genotype-phenotype support in patients. No mouse study cited here describes the puncta or the bony nasolacrimal canal in Fgf10 heterozygotes.
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Pathophysiology

5
FGF10 Haploinsufficiency
A heterozygous nonsense, splice-site, missense or deletion allele leaves one functional FGF10 copy. FGF10 is the high-affinity ligand of the epithelial receptor FGFR2b, so the lesion halves the supply of this receptor ligand during gland development.
FGF10 hgnc:3666 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FGF10 (hgnc:3666). hgnc:3666 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
FGFR2b binding GO:0005111 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased FGFR2b binding, annotated with type 2 fibroblast growth factor receptor binding (GO:0005111). GO:0005111 is a molecular function from the Gene Ontology.
Downstream
Reduced Mesenchymal FGF10-FGFR2b Signaling to Gland Epithelium
Lacrimal Drainage System Maldevelopment Punctal atresia and bony nasolacrimal duct obstruction segregate with FGF10 variants, but no study has traced how reduced FGF10 dose disturbs the drainage pathway, so the edge is drawn with unknown intermediates.
Show evidence (4 references)
PMID:15654336 SUPPORT Human Clinical
"We suggest that haploinsufficiency for FGF10 during a crucial stage of development results in ALSG."
The discovering group's statement of the disease mechanism.
PMID:26955834 SUPPORT Human Clinical
"This report further confirms that ALSG is caused by the haploinsufficiency of functional FGF10."
A premature stop codon predicted to trigger nonsense-mediated decay supports haploinsufficiency.
PMID:37615310 SUPPORT In Vitro
"RT-PCR assays of HEK-293 cells transfected with wild type or mutant FGF10 demonstrated that the variant causes skipping of Exon 2."
A transfection assay shows the donor splice-site allele disrupts the transcript.
+ 1 more reference
Reduced Mesenchymal FGF10-FGFR2b Signaling to Gland Epithelium
FGF10 is expressed by the mesenchyme surrounding the presumptive gland epithelium and acts on FGFR2b in the epithelial bud. With one functional allele, this paracrine signal falls below the level needed to drive epithelial proliferation and outgrowth.
periglandular mesenchymal cell CL:0008019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves periglandular mesenchymal cell, annotated with mesenchymal cell (CL:0008019). CL:0008019 is a cell type from the Cell Ontology. gland primordium epithelial cell CL:0000066 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves gland primordium epithelial cell, annotated with epithelial cell (CL:0000066). CL:0000066 is a cell type from the Cell Ontology.
mesenchymal-epithelial FGF10 signaling GO:0060638 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mesenchymal-epithelial FGF10 signaling, annotated with mesenchymal-epithelial cell signaling (GO:0060638). GO:0060638 is a biological process from the Gene Ontology. FGFR2b signaling GO:0008543 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased FGFR2b signaling, annotated with fibroblast growth factor receptor signaling pathway (GO:0008543). GO:0008543 is a biological process from the Gene Ontology.
Downstream
Failure of Lacrimal Gland Budding
Impaired Salivary Gland Branching Morphogenesis
Show evidence (2 references)
PMID:10821755 SUPPORT Model Organism
"Expression of FGF10 in the mesenchyme adjacent to the presumptive lacrimal bud and absence of lacrimal gland development in FGF10-null mice strongly suggest that it is an endogenous inducer."
Places FGF10 in the periglandular mesenchyme as the inducer of the lacrimal bud.
PMID:41828344 SUPPORT Model Organism
"Among Fgf1, Fgf3, Fgf7, Fgf10, and Fgf22, Fgf10 was expressed in the mesenchyme surrounding developing LG epithelial cells"
Confirms the mesenchymal source of the signal in the developing lacrimal gland.
Failure of Lacrimal Gland Budding
The lacrimal gland arises as an epithelial bud from the conjunctival epithelium. With reduced FGF10 the bud fails to form or forms only rarely, so the gland is absent or hypoplastic and aqueous tear secretion is reduced or lost.
lacrimal gland development GO:0032808 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lacrimal gland development (GO:0032808). GO:0032808 is a biological process from the Gene Ontology.
lacrimal gland UBERON:0001817 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lacrimal gland (UBERON:0001817). UBERON:0001817 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Fgf10 heterozygous null mouse (Fgf10+/-) Mouse recapitulates Heterozygotes lack lacrimal gland primordia, as patients lack the gland.
Fgf10 Aey17 splice mutant mouse Mouse partially recapitulates Heterozygous loss of Fgf10 shrinks an FGF10-dependent orbital gland.
Downstream
Aplasia or hypoplasia of the lacrimal glands
Decreased lacrimation Absent or hypoplastic lacrimal glands cannot supply the aqueous tear film.
Dry eye Reduced aqueous tear production leaves the ocular surface dry and irritable.
Show evidence (1 reference)
PMID:41828344 SUPPORT Model Organism
"LG primordia were not observed in Fgf10+/- mice bilaterally at E16.5 or later stages."
Heterozygous Fgf10 loss abolishes the lacrimal gland primordium in mice.
Impaired Salivary Gland Branching Morphogenesis
The parotid, submandibular and sublingual glands form by epithelial budding and branching into the surrounding mesenchyme. Reduced FGF10-FGFR2b signaling leaves hypoplastic glands in heterozygous mice and no glands when both alleles are lost; in ALSG the major salivary glands are absent or hypoplastic, and saliva production falls.
branching involved in salivary gland morphogenesis GO:0060445 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased branching involved in salivary gland morphogenesis (GO:0060445). GO:0060445 is a biological process from the Gene Ontology.
parotid gland UBERON:0001831 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in parotid gland (UBERON:0001831). UBERON:0001831 is an anatomical location from the Uberon multi-species anatomy ontology. submandibular gland UBERON:0001736 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in submandibular gland (UBERON:0001736). UBERON:0001736 is an anatomical location from the Uberon multi-species anatomy ontology. sublingual gland UBERON:0001832 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in sublingual gland (UBERON:0001832). UBERON:0001832 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Fgf10 heterozygous null mouse (Fgf10+/-) Mouse partially recapitulates Heterozygotes have hypoplastic submandibular glands.
Downstream
Aplasia of the parotid gland
Aplasia of the submandibular gland
Xerostomia Absent or hypoplastic major salivary glands reduce saliva production.
Show evidence (3 references)
PMID:15972105 SUPPORT Model Organism
"Hypoplastic SMGs are seen in Fgf10 and Fgfr2b heterozygotes whereas SMG aplasia is seen in Fgf10 and Fgfr2b null embryos."
Dose-dependent submandibular gland defects in Fgf10 mutant mice.
PMID:11062007 SUPPORT Model Organism
"We found diverse phenotypes closely related to those for FGFR2b-deficient mice, which includes the absence of thyroid, pituitary, and salivary glands"
Salivary glands are absent in Fgf10 null mice.
PMID:19102732 SUPPORT Human Clinical
"Clinical examination of the patient's brother who, except for the lacrimal mucocele, suffered from the same symptoms, also revealed an aplasia of both lacrimal punctae and a total aplasia of submandibular, sublingual as well as parotid glands."
Sublingual glands can also be absent in FGF10-related ALSG; the proband's submandibular and sublingual glands were present, showing the variable extent of salivary involvement within one family.
Lacrimal Drainage System Maldevelopment
Absent or atretic lacrimal puncta and a bony or membranous nasolacrimal duct obstruction are part of the FGF10 phenotype. The developmental step that fails is not known.
lacrimal drainage system UBERON:0001850 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lacrimal drainage system (UBERON:0001850). UBERON:0001850 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Lacrimal punctal atresia
Nasolacrimal duct obstruction
Dacryocystocele Distal obstruction of the drainage pathway lets the lacrimal sac distend.
Epiphora Tears that cannot drain through atretic puncta or an obstructed duct overflow onto the face, so epiphora can coexist with reduced tear production.
Show evidence (2 references)
PMID:38081329 SUPPORT BACKGROUND Human Clinical
"Reported ophthalmic manifestations of ALSG include aplasia of lacrimal glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital nasolacrimal duct obstruction (CNLDO)."
Summarises the drainage-system anomalies reported in ALSG.
PMID:41533940 SUPPORT Human Clinical
"FGF10 mutations are associated with syndromic, multi-gland hypoplasia, whereas IGSF3 mutations result in isolated bony CNLDO."
Bony nasolacrimal obstruction occurs with FGF10 variants alongside gland hypoplasia.
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Pathograph

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Pathograph: causal mechanism network for Aplasia of Lacrimal and Salivary Glands Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Cardiovascular 1
Dry eye Keratoconjunctivitis sicca HP:0001097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dry, irritable eyes, annotated with Keratoconjunctivitis sicca (HP:0001097). HP:0001097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15654336 SUPPORT Human Clinical
"Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM 180920 and OMIM 103420) is a rare condition characterized by irritable eyes and dryness of the mouth."
Irritable eyes are one of the two defining complaints.
PMID:29053399 SUPPORT Human Clinical
"It can present with symptoms of congenital lacrimal obstruction, dry eye, and dry mouth."
Dry eye is a presenting symptom.
Eye 2
Decreased lacrimation HP:0000633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced tear production, annotated with Decreased lacrimation (HP:0000633). HP:0000633 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38081329 SUPPORT Human Clinical
"Affected patients showed decreased tear production on the Schimer I test and reduced tear breakup time."
Measured tear deficiency in affected family members.
PMID:37615310 SUPPORT Human Clinical
"Physical exam and Schirmer test revealed variable expression of tear deficiency, congenital punctal atresia, and dry mouth with multiple caries"
Variable tear deficiency on Schirmer testing.
Epiphora HP:0009926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epiphora (HP:0009926), qualified as infantile onset. HP:0009926 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:37615310 SUPPORT Human Clinical
"Thirteen affected individuals of six generations of a single kindred presented with epiphora evident from infancy."
Epiphora was the presenting sign in every affected kindred member.
PMID:19102732 SUPPORT Human Clinical
"Those patients suffer from epiphora, xerostomia and severe dental caries."
Lists epiphora among the cardinal complaints.
Head and Neck 8
Aplasia or hypoplasia of the lacrimal glands Aplastic/hypoplastic lacrimal glands HP:0008038 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia or hypoplasia of the lacrimal glands, annotated with Aplastic/hypoplastic lacrimal glands (HP:0008038), qualified as congenital onset. HP:0008038 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (3 references)
PMID:17213838 SUPPORT Human Clinical
"Aplasia of lacrimal and salivary glands (ALSG) is an autosomal dominant congenital anomaly characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems."
The defining feature of the disorder.
PMID:38081329 SUPPORT Human Clinical
"Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid, and submandibular glands."
Imaging confirmation of absent lacrimal glands in FGF10 families.
PMID:41409311 SUPPORT Human Clinical
"Additionally, the patient presented lacrimal gland aplasia, xerostomia, and pulmonary hypoplasia (PH)."
Lacrimal gland aplasia in a carrier of an FGF10 start-loss variant.
Lacrimal punctal atresia HP:0007820 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lacrimal punctal atresia (HP:0007820), qualified as congenital onset. HP:0007820 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:37615310 SUPPORT Human Clinical
"Physical exam and Schirmer test revealed variable expression of tear deficiency, congenital punctal atresia, and dry mouth with multiple caries"
Congenital punctal atresia in the kindred.
PMID:19376597 SUPPORT Human Clinical
"Other clinical signs of this disorder include atresia of nasolacrimal duct and absence of the lacrimal puncta."
Absent puncta are a recognised sign.
Nasolacrimal duct obstruction HP:0000579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital nasolacrimal duct obstruction, annotated with Nasolacrimal duct obstruction (HP:0000579), qualified as congenital onset. HP:0000579 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:38081329 SUPPORT Human Clinical
"Bony CNLDO was observed on CT, showing unilateral or bilateral bony termination at the middle or terminal segment of the nasolacrimal canal."
Bony obstruction in three FGF10 families.
PMID:19376597 SUPPORT Human Clinical
"Other clinical signs of this disorder include atresia of nasolacrimal duct and absence of the lacrimal puncta."
Nasolacrimal duct atresia is a recognised sign.
Dacryocystocele HP:0030752 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lacrimal sac mucocele, annotated with Dacryocystocele (HP:0030752). HP:0030752 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38081329 SUPPORT BACKGROUND Human Clinical
"Reported ophthalmic manifestations of ALSG include aplasia of lacrimal glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital nasolacrimal duct obstruction (CNLDO)."
Lacrimal sac mucocele is among the reported ophthalmic manifestations.
Aplasia of the parotid gland HP:0009740 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia of the parotid gland (HP:0009740), qualified as congenital onset. HP:0009740 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:38081329 SUPPORT Human Clinical
"Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid, and submandibular glands."
Imaging shows absent parotid glands.
PMID:41533940 SUPPORT Human Clinical
"All patients with FGF10 variants exhibited syndromic aplasia of lacrimal and salivary glands (ALSGs) phenotype characterized by bony CNLDO, punctal anomalies, and hypoplasia of lacrimal, parotid, and submandibular glands."
Parotid hypoplasia in every FGF10-positive patient of this series.
Aplasia of the submandibular gland Abnormality of the submandibular glands HP:0010287 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia or hypoplasia of the submandibular gland, annotated with Abnormality of the submandibular glands (HP:0010287), qualified as congenital onset. HP:0010287 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
HPO has no aplasia or hypoplasia term for the submandibular gland. An OLS label search for "submandibular" in HP returned only Abnormality of the submandibular glands, Submandibular lymph node enlargement and Abnormality of the submandibular region, so the general submandibular term is bound and the specific finding is carried in preferred_term.
Show evidence (2 references)
PMID:38081329 SUPPORT Human Clinical
"Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid, and submandibular glands."
Imaging shows absent submandibular glands.
PMID:41533940 SUPPORT Human Clinical
"All patients with FGF10 variants exhibited syndromic aplasia of lacrimal and salivary glands (ALSGs) phenotype characterized by bony CNLDO, punctal anomalies, and hypoplasia of lacrimal, parotid, and submandibular glands."
Submandibular hypoplasia in every FGF10-positive patient of this series.
Xerostomia HP:0000217 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Xerostomia (HP:0000217). HP:0000217 is a phenotype from the Human Phenotype Ontology.
Sequelae: Carious teeth
Show evidence (2 references)
PMID:15654336 SUPPORT Human Clinical
"Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM 180920 and OMIM 103420) is a rare condition characterized by irritable eyes and dryness of the mouth."
Dryness of the mouth is one of the two defining complaints.
PMID:19102732 SUPPORT Human Clinical
"Those patients suffer from epiphora, xerostomia and severe dental caries."
Xerostomia is a cardinal complaint.
Carious teeth HP:0000670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental caries, annotated with Carious teeth (HP:0000670). HP:0000670 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19102732 SUPPORT Human Clinical
"Those patients suffer from epiphora, xerostomia and severe dental caries."
Severe caries is a cardinal complaint.
PMID:37615310 SUPPORT Human Clinical
"Physical exam and Schirmer test revealed variable expression of tear deficiency, congenital punctal atresia, and dry mouth with multiple caries"
Multiple caries in the kindred.
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Genetic Associations

1
FGF10
Gene: FGF10 hgnc:3666 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FGF10 (hgnc:3666). hgnc:3666 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:15654336 SUPPORT Human Clinical
"We mapped ALSG to 5p13.2-5q13.1, which coincides with the gene fibroblast growth factor 10 (FGF10). In two extended pedigrees, we identified heterozygous mutations in FGF10 in all individuals with ALSG."
The gene discovery study, by linkage and mutation screening.
PMID:17213838 SUPPORT Human Clinical
"We present here two families with ALSG associated with missense mutations (R80S and G138E, respectively) affecting highly conserved residues in FGF10."
Two further families with FGF10 missense alleles.
PMID:26955834 SUPPORT Human Clinical
"The candidate gene sequencing of the FGF10 gene identified a novel heterozygous nonsense mutation (c.237G > A, p.Trp79*) in the exon 1."
A truncating allele in an independent Turkish family.
+ 2 more references
🗃️

External Assertions

2
OMIM aplasia of lacrimal and salivary glands
OMIM disease record OMIM:180920
OMIM phenotype record for ALSG, taken from the cross-references on MONDO:0008397. Entesarian et al. 2005 also give OMIM 103420 for the same condition.
Orphanet aplasia of lacrimal and salivary glands
Orphanet disease record ORPHA:86815
Orphanet record for ALSG, taken from the cross-references on MONDO:0008397. No local Orphadata cache file exists for this code, so it is not cited as evidence.
💊

Medical Actions

5
Lacrimal Drainage Reconstruction
Action: lacrimal drainage system reconstructionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is lacrimal drainage system reconstruction, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical reconstruction of the upper lacrimal drainage system, or other lacrimal surgery chosen by the clinical findings, for punctal atresia, nasolacrimal obstruction and mucocele.
Mechanism Target:
Lacrimal punctal atresia — Restores an outflow path where the puncta are atretic.
Epiphora — Relieves tear overflow by reopening drainage.
Target Phenotypes: Lacrimal punctal atresia HP:0007820 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Lacrimal punctal atresia (HP:0007820). HP:0007820 is a phenotype from the Human Phenotype Ontology. Epiphora HP:0009926 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epiphora (HP:0009926). HP:0009926 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37615310 SUPPORT Human Clinical
"Reconstruction of the upper lacrimal drainage system was performed in some of the affected individuals."
Reports surgical reconstruction in affected kindred members.
PMID:30697385 SUPPORT Human Clinical
"The management of the lacrimal alteration depends of the clinical findings."
Lacrimal management is tailored to the findings.
Preventive Dental Care
Action: preventive dental careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is preventive dental care, annotated with Dental Prophylaxis (NCIT:C62548). NCIT:C62548 is a clinical intervention from the NCI Thesaurus. Ontology label: Dental Prophylaxis NCIT:C62548
Platform: Behavioral / lifestyle
Intensive preventive oral health care, including oral hygiene, high-fluoride toothpaste and regular dental review from early childhood, to limit caries and tooth loss from the lack of saliva.
Mechanism Target:
Carious teeth — Prevents and limits caries from the loss of salivary protection.
Target Phenotypes: Dental caries HP:0000670 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dental caries, annotated with Carious teeth (HP:0000670). HP:0000670 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26955834 SUPPORT Human Clinical
"Therefore, it will positively motivate oral health care to avoid further destruction of the tooth due to the lack of salivary production."
Recommends oral health care to prevent tooth destruction.
PMID:30697385 SUPPORT REVIEW SYNTHESIS Human Clinical
"Oral hygiene, high fluoride tooth paste and other agents like chewing gum can be useful."
Names oral hygiene and high-fluoride toothpaste as the preventive measures.
Saliva Substitutes
Action: saliva substitute therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is saliva substitute therapy, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Symptomatic replacement of saliva for xerostomia, for example with carboxymethylcellulose, glycerine, oil and water emulsions or xylitol preparations. Acidic substitutes should be avoided in dentate patients. Sialagogues such as pilocarpine have been proposed only where some salivary tissue still works.
Mechanism Target:
Xerostomia — Replaces the moisture and lubrication normally supplied by saliva.
Target Phenotypes: Xerostomia HP:0000217 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Xerostomia (HP:0000217). HP:0000217 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30697385 SUPPORT REVIEW SYNTHESIS Human Clinical
"Multiple saliva substitutes have been proposed such as glycerine and lemon, carboxymethhylcellulose, oil and water emulsions, lactoperoxidase, glucose oxidase, xylitol, and many others"
Lists the saliva substitutes used in ALSG management.
PMID:30697385 SUPPORT REVIEW SYNTHESIS Human Clinical
"Acidic substitutes as glandosane should not be used in dentate patients"
A safety caveat on acidic saliva substitutes.
Artificial Tears
Action: artificial tear supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is artificial tear supplementation, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Ocular lubrication with artificial tears for reduced tear production and dry eye, alongside lacrimal surgery where the drainage pathway is obstructed.
Mechanism Target:
Decreased lacrimation — Supplements the deficient aqueous tear film.
Dry eye — Relieves ocular surface dryness and irritation.
Target Phenotypes: Reduced tear production HP:0000633 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Reduced tear production, annotated with Decreased lacrimation (HP:0000633). HP:0000633 is a phenotype from the Human Phenotype Ontology. Dry, irritable eyes HP:0001097 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dry, irritable eyes, annotated with Keratoconjunctivitis sicca (HP:0001097). HP:0001097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30697385 SUPPORT REVIEW SYNTHESIS Human Clinical
"The management of the lacrimal alteration depends of the clinical findings and can include artificial tears and sometimes dacryocystectomy or occasional puncta"
Names artificial tears as part of lacrimal management in ALSG.
Minor Salivary Gland Transplantation
Action: minor salivary gland transplantation to the ocular surfaceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is minor salivary gland transplantation to the ocular surface, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Autologous transplantation of minor salivary glands to the ocular surface has been used for congenital alacrimia with bilaterally absent lacrimal glands and corneal scarring, with improvement at five years. The reported child had no genetic diagnosis, so its use in ALSG is by extension.
Mechanism Target:
Dry eye — Transplanted minor salivary glands supply a substitute secretion to the ocular surface.
Target Phenotypes: Dry, irritable eyes HP:0001097 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dry, irritable eyes, annotated with Keratoconjunctivitis sicca (HP:0001097). HP:0001097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38537898 SUPPORT INDIRECT Human Clinical
"On long-term follow-up, 5 years after surgery, we observed considerable improvement in the photophobia, corneal transparency, and neovascularization."
Single case of congenital alacrimia with absent lacrimal glands on CT, not genetically characterised; graded INDIRECT because the patient is not shown to have FGF10-related ALSG.
🔬

Diagnosis

1
Imaging of the lacrimal and salivary glands with FGF10 testing
The diagnosis is clinical, supported by MRI showing absent or hypoplastic lacrimal and major salivary glands, orbital CT for bony nasolacrimal obstruction and Schirmer testing, and confirmed by a heterozygous FGF10 variant on gene or exome sequencing.
Show evidence (4 references)
PMID:30697385 SUPPORT Human Clinical
"Imaging tests are necessary to confirm the lack of formation of salivary glands and alteration of lacrimal system."
Imaging is the confirmatory clinical test.
PMID:19376597 SUPPORT Human Clinical
"However, MRI is an excellent alternative means for evaluating this disorder and also for ruling out other possible structural defects contributing to patients, symptoms."
MRI is the imaging method of choice.
PMID:38081329 SUPPORT Human Clinical
"Slit-lamp ophthalmic examination, comprehensive physical examination, orbital computed tomography (CT) imaging, cervicofacial magnetic resonance imaging, audiometry, and whole exome sequencing on periphery blood were performed."
The work-up used in a recent multi-family series, including exome sequencing.
+ 1 more reference
📊

Prevalence

1
Worldwide, cases reported in the literature
Cases In Literature Rare
No population estimate exists. Reported cases are a small number of families and sporadic individuals from Europe, the Middle East, Turkey and China.
Show evidence (1 reference)
PMID:30697385 SUPPORT BACKGROUND Human Clinical
"Aplasia of the lacrimal and the major salivary glands (ALSG) is a rare disorder with scarce cases described in the recent literature."
States the rarity of reported cases.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Aplasia of Lacrimal and Salivary Glands:

LADD syndrome Not Yet Curated MONDO:0007872
Overlapping Features Lacrimo-auriculo-dento-digital syndrome shares the lacrimal and salivary anomalies and is allelic (FGF10), but is also caused by FGFR2 and FGFR3 variants and adds cup-shaped ears, hearing loss, and dental and digital anomalies. An ALSG parent can have a child with LADD syndrome, so the two may be one spectrum.
Distinguishing Features
  • Cup-shaped ears and hearing loss
  • Dental anomalies
  • Digital anomalies
  • Causal variants also in FGFR2 or FGFR3
Show evidence (5 references)
PMID:17213838 SUPPORT Human Clinical
"Mutations in FGF10 were recently described in ALSG and in lacrimo-auriculo-dento-digital (LADD) syndrome which are overlapping clinical entities."
States the clinical overlap and shared gene.
PMID:16630169 SUPPORT Human Clinical
"autosomal-dominant multiple congenital anomaly disorder characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems, cup-shaped ears, hearing loss, and dental and digital anomalies."
The ear, dental and digital features that distinguish LADD.
PMID:16501574 SUPPORT Human Clinical
"We identified heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3) in LADD families, and in one further LADD family, we detected a mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known FGFR ligand."
LADD is also caused by FGFR2 and FGFR3, genes not reported in ALSG.
+ 2 more references
Sjogren syndrome MONDO:0010030
Overlapping Features Autoimmune dry eye and dry mouth can mimic ALSG. Normal minor salivary gland histology, earlier onset of symptoms and absent glands on imaging point to ALSG; serology is used to exclude a systemic syndrome.
Show evidence (4 references)
PMID:19376597 SUPPORT Human Clinical
"We present a case report of ALSG as an extremely rare, yet important alternative diagnosis in cases with symptoms and signs suggestive of Sjögren's syndrome."
ALSG presents as a Sjogren-like sicca syndrome.
PMID:30697385 SUPPORT Human Clinical
"A normal histological analysis of the minor salivary glands ruled out the possibility of Sjörgen Syndrome."
In this ALSG patient, normal minor salivary gland histology excluded Sjogren syndrome.
PMID:30697385 SUPPORT REVIEW SYNTHESIS Human Clinical
"Also it is suggested that in ASLG the symptoms are presented earlier (1). Serum test must be realized to reject a systemic syndrome"
Earlier onset and negative serology separate ALSG from Sjogren syndrome.
+ 1 more reference
🐁

Animal Models

2
Fgf10 heterozygous null mouse (Fgf10+/-)
Mice heterozygous for an Fgf10 null allele have a phenotype similar to ALSG. Lacrimal gland primordia fail to form, submandibular glands are hypoplastic, and the Harderian gland is often degenerated or absent, frequently on one side.
Species
Mouse
Genotype
Fgf10+/-
Publication
PMID:15654336
Pathograph links
Failure of Lacrimal Gland Budding recapitulates fidelity: high observes: tissue Heterozygotes lack lacrimal gland primordia, as patients lack the gland.
Limitations: The mouse main lacrimal gland is exorbital with a long excretory duct, unlike the human intraorbital gland, and a small fraction of heterozygous primordia still show budding at E15.5.
Show evidence (1 reference)
PMID:41828344 SUPPORT Model Organism
"LG primordia were not observed in Fgf10+/- mice bilaterally at E16.5 or later stages."
The heterozygote reproduces the absent lacrimal gland.
Impaired Salivary Gland Branching Morphogenesis partially recapitulates fidelity: moderate observes: tissue Heterozygotes have hypoplastic submandibular glands.
Limitations: Heterozygous mice show submandibular hypoplasia rather than the aplasia seen in many patients, and parotid development was not reported.
Show evidence (1 reference)
PMID:15972105 SUPPORT Model Organism
"Hypoplastic SMGs are seen in Fgf10 and Fgfr2b heterozygotes whereas SMG aplasia is seen in Fgf10 and Fgfr2b null embryos."
Dose-dependent salivary gland hypoplasia in heterozygotes.
Show evidence (2 references)
PMID:15654336 SUPPORT Model Organism
"Fgf10(+/-) mice have a phenotype similar to ALSG, providing a model for this disorder."
The discovering group established the heterozygote as the ALSG model.
PMID:38921483 SUPPORT Model Organism
"These results show that the Fgf10 haploinsufficiency causes delayed or defective HG development, often unilaterally from the unexpectedly early neonatal period."
Harderian gland defects in heterozygotes mirror the often unilateral gland involvement in ALSG; humans lack a Harderian gland, so this is an analogy.
Fgf10 Aey17 splice mutant mouse
An ENU-induced Fgf10 splice-site allele causing a frameshift. Heterozygotes have a dominant slit-eye phenotype from Harderian gland atrophy; homozygotes are not viable. The authors proposed it as a dry-eye model.
Species
Mouse
Genotype
Fgf10 Aey17/+ (ENU-induced intron 1 splice-site allele)
Background
C3HeB/FeJ
Publication
PMID:19407009
Pathograph links
Failure of Lacrimal Gland Budding partially recapitulates fidelity: low observes: tissue Heterozygous loss of Fgf10 shrinks an FGF10-dependent orbital gland.
Limitations: The affected gland is the Harderian gland, which humans do not retain, and the lacrimal and salivary glands were not described.
Show evidence (1 reference)
PMID:19407009 SUPPORT Model Organism
"Histologic analysis of the major ocular tissues (cornea, lens, retina) did not reveal major alterations compared with the wild type, but the size of the Harderian gland was remarkably reduced in heterozygotes."
Orbital gland hypoplasia from a single Fgf10 allele.
Show evidence (1 reference)
PMID:19407009 SUPPORT Model Organism
"The mutation in the Fgf10 gene leads to a dominant slit-eye phenotype caused by atrophy of the Harderian gland."
A second, independent heterozygous Fgf10 allele with an orbital gland defect.
{ }

Source YAML

click to show 
name: Aplasia of Lacrimal and Salivary Glands
creation_date: "2026-10-08T13:31:10Z"
category: Mendelian
description: >
  Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant
  congenital disorder in which the lacrimal glands, the major salivary glands
  (parotid and submandibular) and parts of the lacrimal drainage system are
  absent, atretic or hypoplastic. Affected individuals present from infancy with
  irritable, dry eyes and reduced tear production, epiphora from punctal atresia
  or nasolacrimal duct obstruction, and dry mouth with early and severe dental
  caries. Expressivity is variable within families, from bilateral aplasia to
  unilateral or minimal involvement, and penetrance is incomplete.

  ALSG is caused by heterozygous loss-of-function variants in FGF10 (nonsense,
  splice-site and missense alleles, and a whole-gene deletion), and is read as
  FGF10 haploinsufficiency. FGF10 is secreted by the mesenchyme around the
  nascent gland epithelium and signals through the epithelial receptor FGFR2b to
  drive budding and branching morphogenesis. In mice a single functional Fgf10
  allele is insufficient for lacrimal gland budding and gives hypoplastic
  submandibular glands, while loss of both alleles abolishes the lacrimal and
  salivary glands. ALSG is allelic with lacrimo-auriculo-dento-digital (LADD)
  syndrome, which adds ear, dental and digital anomalies; both can occur in one
  family. Management is supportive: lacrimal drainage surgery, ocular
  lubrication and intensive dental prevention.
synonyms:
- ALSG
- aplasia of the lacrimal and major salivary glands
- agenesis of lacrimal and salivary glands
- congenital absence of lacrimal puncta and salivary glands
disease_term:
  preferred_term: Aplasia of Lacrimal and Salivary Glands
  term:
    id: MONDO:0008397
    label: aplasia of lacrimal and salivary glands
parents:
- FGF10-Related Disorder
- Congenital Exocrine Gland Anomaly
references:
- reference: PMID:10821755
  title: "FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development."
- reference: PMID:11062007
  title: "FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development."
- reference: PMID:15654336
  title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
- reference: PMID:15716343
  title: "FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis."
- reference: PMID:15972105
  title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
- reference: PMID:16501574
  title: "Mutations in different components of FGF signaling in LADD syndrome."
- reference: PMID:16630169
  title: "LADD syndrome is caused by FGF10 mutations."
- reference: PMID:17213838
  title: "FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)."
- reference: PMID:19102732
  title: "An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome."
- reference: PMID:19376597
  title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
- reference: PMID:19407009
  title: "A new Fgf10 mutation in the mouse leads to atrophy of the harderian gland and slit-eye phenotype in heterozygotes: a novel model for dry-eye disease?"
- reference: PMID:26955834
  title: "Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands."
- reference: PMID:27742760
  title: "Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function."
- reference: PMID:29053399
  title: "New pathogenic variant in the FGF10 gene in the agenesis of lacrimal and salivary gland syndrome: Ophthalmological and genetic study."
- reference: PMID:30697385
  title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
- reference: PMID:32715658
  title: "Lacrimo-auriculo-dento-digital syndrome: A novel mutation in a Korean family and review of literature."
- reference: PMID:36124135
  title: "Phenotypic spectrum of FGF10-related disorders: a systematic review."
- reference: PMID:37615310
  title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
- reference: PMID:38081329
  title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
- reference: PMID:38537898
  title: "Long-term outcome of minor salivary gland transplantation for pediatric congenital alacrimia."
- reference: PMID:38921483
  title: "Harderian Gland Development and Degeneration in the Fgf10-Deficient Heterozygous Mouse."
- reference: PMID:41409311
  title: "Esophageal Atresia, an Anomaly of VACTERL Association or Novel Feature of the FGF10 Gene: A Case Report."
- reference: PMID:41533940
  title: "FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease."
- reference: PMID:41791508
  title: "Complete congenital agenesis of major salivary glands: case report and systematic review of the literature."
- reference: PMID:41828344
  title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
external_assertions:
- name: OMIM aplasia of lacrimal and salivary glands
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:180920
  url: https://omim.org/entry/180920
  description: >-
    OMIM phenotype record for ALSG, taken from the cross-references on
    MONDO:0008397. Entesarian et al. 2005 also give OMIM 103420 for the same
    condition.
- name: Orphanet aplasia of lacrimal and salivary glands
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:86815
  url: https://www.orpha.net/en/disease/detail/86815
  description: >-
    Orphanet record for ALSG, taken from the cross-references on MONDO:0008397.
    No local Orphadata cache file exists for this code, so it is not cited as
    evidence.
inheritance:
- name: Autosomal Dominant
  description: >
    Heterozygous FGF10 variants segregate with the disorder in multigeneration
    pedigrees. Penetrance is incomplete: an unaffected variant carrier was found
    in a six-generation kindred, and a three-family series described the
    pattern as autosomal dominant with variable penetrance. Expressivity varies
    within families, from bilateral gland aplasia to unilateral or minimal
    involvement.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: PMID:15654336
    reference_title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In two extended pedigrees, we identified heterozygous mutations in FGF10
      in all individuals with ALSG.
    explanation: Heterozygous variants segregating in extended pedigrees establish dominant inheritance.
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, one of the variant carriers had no ALSG-related clinical
      findings, demonstrating incomplete penetrance.
    explanation: Unaffected heterozygous carrier in a large kindred documents incomplete penetrance.
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, individuals sharing the same variant exhibited phenotypic
      variability, with unilateral or bilateral epiphora, as well as variable
      expression of dry mouth and caries.
    explanation: Variable expressivity among carriers of one allele.
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The inheritance pattern was autosomal dominant with variable penetrance."
    explanation: Independent families with FGF10 missense variants show the same pattern.
prevalence:
- population: Worldwide, cases reported in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    No population estimate exists. Reported cases are a small number of
    families and sporadic individuals from Europe, the Middle East, Turkey and
    China.
  evidence:
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Aplasia of the lacrimal and the major salivary glands (ALSG) is a rare
      disorder with scarce cases described in the recent literature.
    explanation: States the rarity of reported cases.
genetic:
- name: FGF10
  notes: >
    FGF10 (5p12) encodes fibroblast growth factor 10, the principal FGFR2b
    ligand in branching organogenesis. Reported ALSG alleles include nonsense
    (p.Trp79*), canonical splice-site (c.429+1G>T, c.430-1G>A, c.429+2T>A) and
    missense variants (R80S, G138E and several others), plus a heterozygous
    5p12 deletion spanning the gene. The same gene causes some cases of LADD
    syndrome and, with heterozygous loss of function, lethal lung developmental
    disorders and childhood interstitial lung disease; those are separate
    entities. No ClinGen gene-disease validity record for FGF10 and ALSG was
    found in the local cache.
  gene_term:
    preferred_term: FGF10
    term:
      id: hgnc:3666
      label: FGF10
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:15654336
    reference_title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped ALSG to 5p13.2-5q13.1, which coincides with the gene fibroblast
      growth factor 10 (FGF10). In two extended pedigrees, we identified
      heterozygous mutations in FGF10 in all individuals with ALSG.
    explanation: The gene discovery study, by linkage and mutation screening.
  - reference: PMID:17213838
    reference_title: "FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present here two families with ALSG associated with missense mutations
      (R80S and G138E, respectively) affecting highly conserved residues in FGF10.
    explanation: Two further families with FGF10 missense alleles.
  - reference: PMID:26955834
    reference_title: "Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The candidate gene sequencing of the FGF10 gene identified a novel
      heterozygous nonsense mutation (c.237G > A, p.Trp79*) in the exon 1.
    explanation: A truncating allele in an independent Turkish family.
  - reference: PMID:41533940
    reference_title: "FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with FGF10 variants exhibited syndromic aplasia of lacrimal
      and salivary glands (ALSGs) phenotype characterized by bony CNLDO, punctal
      anomalies, and hypoplasia of lacrimal, parotid, and submandibular glands.
    explanation: A series of families with eight FGF10 variants, all with the ALSG phenotype.
  - reference: PMID:36124135
    reference_title: "Phenotypic spectrum of FGF10-related disorders: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Single-nucleotide variants in FGF10 or FGF10-involving copy-number variant
      deletions have been reported in families with lacrimo-auriculo-dento-digital
      syndrome, aplasia of the lacrimal and salivary glands, or lethal lung
      developmental disorders.
    explanation: >-
      Systematic review placing ALSG among the FGF10-related disorders, with
      both point variants and deletions.
pathophysiology:
- name: FGF10 Haploinsufficiency
  biological_scale: MOLECULAR
  description: >
    A heterozygous nonsense, splice-site, missense or deletion allele leaves one
    functional FGF10 copy. FGF10 is the high-affinity ligand of the epithelial
    receptor FGFR2b, so the lesion halves the supply of this receptor ligand
    during gland development.
  genes:
  - preferred_term: FGF10
    term:
      id: hgnc:3666
      label: FGF10
  molecular_functions:
  - preferred_term: FGFR2b binding
    term:
      id: GO:0005111
      label: type 2 fibroblast growth factor receptor binding
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:15654336
    reference_title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that haploinsufficiency for FGF10 during a crucial stage of
      development results in ALSG.
    explanation: The discovering group's statement of the disease mechanism.
  - reference: PMID:26955834
    reference_title: "Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report further confirms that ALSG is caused by the haploinsufficiency
      of functional FGF10.
    explanation: A premature stop codon predicted to trigger nonsense-mediated decay supports haploinsufficiency.
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RT-PCR assays of HEK-293 cells transfected with wild type or mutant FGF10
      demonstrated that the variant causes skipping of Exon 2.
    explanation: A transfection assay shows the donor splice-site allele disrupts the transcript.
  - reference: PMID:11062007
    reference_title: "FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that FGF10 acts as a major ligand for FGFR2b in
      mouse multi-organ development.
    explanation: Establishes FGF10 as the main FGFR2b ligand in organogenesis, the activity lost with the allele.
  downstream:
  - target: Reduced Mesenchymal FGF10-FGFR2b Signaling to Gland Epithelium
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41828344
      reference_title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        In patients with ALSG, heterozygous loss-of-function mutations are
        found, and FGF10 haploinsufficiency results in the absence of these
        secretory organs.
      explanation: >-
        Background statement in a mouse study linking the heterozygous lesion
        in patients to failed gland formation through reduced FGF10 dose.
  - target: Lacrimal Drainage System Maldevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Punctal atresia and bony nasolacrimal duct obstruction segregate with
      FGF10 variants, but no study has traced how reduced FGF10 dose disturbs
      the drainage pathway, so the edge is drawn with unknown intermediates.
    evidence:
    - reference: PMID:38081329
      reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bony CNLDO was identified as a novel phenotype of ALSG implicated by
        missense mutations of highly conserved residues in the Fgf10 gene.
      explanation: Genotype-phenotype association, not a demonstrated mechanism.
- name: Reduced Mesenchymal FGF10-FGFR2b Signaling to Gland Epithelium
  biological_scale: CELLULAR
  description: >
    FGF10 is expressed by the mesenchyme surrounding the presumptive gland
    epithelium and acts on FGFR2b in the epithelial bud. With one functional
    allele, this paracrine signal falls below the level needed to drive
    epithelial proliferation and outgrowth.
  cell_types:
  - preferred_term: periglandular mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  - preferred_term: gland primordium epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  biological_processes:
  - preferred_term: mesenchymal-epithelial FGF10 signaling
    modifier: DECREASED
    term:
      id: GO:0060638
      label: mesenchymal-epithelial cell signaling
  - preferred_term: FGFR2b signaling
    modifier: DECREASED
    term:
      id: GO:0008543
      label: fibroblast growth factor receptor signaling pathway
  evidence:
  - reference: PMID:10821755
    reference_title: "FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of FGF10 in the mesenchyme adjacent to the presumptive
      lacrimal bud and absence of lacrimal gland development in FGF10-null mice
      strongly suggest that it is an endogenous inducer.
    explanation: Places FGF10 in the periglandular mesenchyme as the inducer of the lacrimal bud.
  - reference: PMID:41828344
    reference_title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Among Fgf1, Fgf3, Fgf7, Fgf10, and Fgf22, Fgf10 was expressed in the
      mesenchyme surrounding developing LG epithelial cells
    explanation: Confirms the mesenchymal source of the signal in the developing lacrimal gland.
  downstream:
  - target: Failure of Lacrimal Gland Budding
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10821755
      reference_title: "FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This was supported by the observation that inhibition of signaling by a
        receptor for FGF10 (receptor 2 IIIb) suppressed development of the
        endogenous lacrimal bud.
      explanation: Blocking FGFR2b signaling suppresses lacrimal bud formation.
    - reference: PMID:41828344
      reference_title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A single allele of Fgf10 was found to be insufficient to support the
        budding process during LG morphogenesis.
      explanation: Halving the signal, as in ALSG, is enough to block budding.
  - target: Impaired Salivary Gland Branching Morphogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15972105
      reference_title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data indicates that FGF10/FGFR2b signaling is essential for the SMG
        epithelial branching and histodifferentiation, but not earliest initial
        bud formation.
      explanation: The signal drives submandibular epithelial branching.
    - reference: PMID:15972105
      reference_title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Complementary in vitro studies further indicate that FGF10/FGFR2b
        signaling regulates SMG epithelial branching and cell proliferation.
      explanation: Explant work supports the same edge in culture.
    - reference: PMID:15716343
      reference_title: "FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        FGF7 induces epithelial budding, whereas FGF10 induces duct elongation,
        and both are inhibited by FGFR or ERK1/2 signaling inhibitors.
      explanation: In submandibular epithelial rudiments FGF10 drives duct elongation through FGFR and ERK1/2 signaling.
- name: Failure of Lacrimal Gland Budding
  biological_scale: TISSUE
  description: >
    The lacrimal gland arises as an epithelial bud from the conjunctival
    epithelium. With reduced FGF10 the bud fails to form or forms only rarely,
    so the gland is absent or hypoplastic and aqueous tear secretion is reduced
    or lost.
  locations:
  - preferred_term: lacrimal gland
    term:
      id: UBERON:0001817
      label: lacrimal gland
  biological_processes:
  - preferred_term: lacrimal gland development
    modifier: DECREASED
    term:
      id: GO:0032808
      label: lacrimal gland development
  evidence:
  - reference: PMID:41828344
    reference_title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      LG primordia were not observed in Fgf10+/- mice bilaterally at E16.5 or
      later stages.
    explanation: Heterozygous Fgf10 loss abolishes the lacrimal gland primordium in mice.
  downstream:
  - target: Aplasia or hypoplasia of the lacrimal glands
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41828344
      reference_title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        In patients with ALSG, heterozygous loss-of-function mutations are
        found, and FGF10 haploinsufficiency results in the absence of these
        secretory organs.
      explanation: Ties failed gland formation to the absent glands seen in patients.
  - target: Decreased lacrimation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Absent or hypoplastic lacrimal glands cannot supply the aqueous tear
      film.
    evidence:
    - reference: PMID:38081329
      reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Affected patients showed decreased tear production on the Schimer I test
        and reduced tear breakup time.
      explanation: >-
        Reduced tear production in the same patients whose MRI showed absent
        lacrimal glands; the causal reading is the curator's.
  - target: Dry eye
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced aqueous tear production leaves the ocular surface dry and irritable.
    evidence:
    - reference: PMID:19376597
      reference_title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lacrimal gland absence or hypoplasia causes symptoms such as irritable
        eyes, recurrent eye infections and epiphora.
      explanation: Irritable eyes follow from absent or hypoplastic lacrimal glands.
- name: Impaired Salivary Gland Branching Morphogenesis
  biological_scale: TISSUE
  description: >
    The parotid, submandibular and sublingual glands form by epithelial
    budding and branching into the surrounding mesenchyme. Reduced FGF10-FGFR2b signaling
    leaves hypoplastic glands in heterozygous mice and no glands when both
    alleles are lost; in ALSG the major salivary glands are absent or
    hypoplastic, and saliva production falls.
  locations:
  - preferred_term: parotid gland
    term:
      id: UBERON:0001831
      label: parotid gland
  - preferred_term: submandibular gland
    term:
      id: UBERON:0001736
      label: submandibular gland
  - preferred_term: sublingual gland
    term:
      id: UBERON:0001832
      label: sublingual gland
  biological_processes:
  - preferred_term: branching involved in salivary gland morphogenesis
    modifier: DECREASED
    term:
      id: GO:0060445
      label: branching involved in salivary gland morphogenesis
  evidence:
  - reference: PMID:15972105
    reference_title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Hypoplastic SMGs are seen in Fgf10 and Fgfr2b heterozygotes whereas SMG
      aplasia is seen in Fgf10 and Fgfr2b null embryos.
    explanation: Dose-dependent submandibular gland defects in Fgf10 mutant mice.
  - reference: PMID:11062007
    reference_title: "FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found diverse phenotypes closely related to those for FGFR2b-deficient
      mice, which includes the absence of thyroid, pituitary, and salivary
      glands
    explanation: Salivary glands are absent in Fgf10 null mice.
  - reference: PMID:19102732
    reference_title: "An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical examination of the patient's brother who, except for the lacrimal
      mucocele, suffered from the same symptoms, also revealed an aplasia of both
      lacrimal punctae and a total aplasia of submandibular, sublingual as well
      as parotid glands.
    explanation: >-
      Sublingual glands can also be absent in FGF10-related ALSG; the
      proband's submandibular and sublingual glands were present, showing the
      variable extent of salivary involvement within one family.
  downstream:
  - target: Aplasia of the parotid gland
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15972105
      reference_title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hypoplastic SMGs are seen in Fgf10 and Fgfr2b heterozygotes whereas SMG
        aplasia is seen in Fgf10 and Fgfr2b null embryos.
      explanation: >-
        Mouse submandibular data; the parotid gland in ALSG is inferred to fail
        through the same branching defect.
  - target: Aplasia of the submandibular gland
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15972105
      reference_title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hypoplastic SMGs are seen in Fgf10 and Fgfr2b heterozygotes whereas SMG
        aplasia is seen in Fgf10 and Fgfr2b null embryos.
      explanation: Reduced Fgf10 dose produces submandibular hypoplasia, and loss of both alleles aplasia.
  - target: Xerostomia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Absent or hypoplastic major salivary glands reduce saliva production.
    evidence:
    - reference: PMID:19376597
      reference_title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Symptoms associated with hypoplasia or aplasia of the major salivary
        glands include xerostomia, oral inflammation, dental caries and dental
        erosion.
      explanation: States the clinical consequence of salivary gland aplasia.
- name: Lacrimal Drainage System Maldevelopment
  biological_scale: TISSUE
  description: >
    Absent or atretic lacrimal puncta and a bony or membranous nasolacrimal duct
    obstruction are part of the FGF10 phenotype. The developmental step that
    fails is not known.
  locations:
  - preferred_term: lacrimal drainage system
    term:
      id: UBERON:0001850
      label: lacrimal drainage system
  evidence:
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Reported ophthalmic manifestations of ALSG include aplasia of lacrimal
      glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital
      nasolacrimal duct obstruction (CNLDO).
    explanation: Summarises the drainage-system anomalies reported in ALSG.
  - reference: PMID:41533940
    reference_title: "FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FGF10 mutations are associated with syndromic, multi-gland hypoplasia,
      whereas IGSF3 mutations result in isolated bony CNLDO.
    explanation: Bony nasolacrimal obstruction occurs with FGF10 variants alongside gland hypoplasia.
  downstream:
  - target: Lacrimal punctal atresia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38081329
      reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Reported ophthalmic manifestations of ALSG include aplasia of lacrimal
        glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital
        nasolacrimal duct obstruction (CNLDO).
      explanation: Punctal agenesis is one of the drainage-system anomalies.
  - target: Nasolacrimal duct obstruction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38081329
      reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Bony CNLDO was observed on CT, showing unilateral or bilateral bony
        termination at the middle or terminal segment of the nasolacrimal canal.
      explanation: Imaging shows the bony obstruction of the nasolacrimal canal.
  - target: Dacryocystocele
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Distal obstruction of the drainage pathway lets the lacrimal sac distend.
    evidence:
    - reference: PMID:38081329
      reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Reported ophthalmic manifestations of ALSG include aplasia of lacrimal
        glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital
        nasolacrimal duct obstruction (CNLDO).
      explanation: Lacrimal sac mucocele is reported among the drainage anomalies.
  - target: Epiphora
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Tears that cannot drain through atretic puncta or an obstructed duct
      overflow onto the face, so epiphora can coexist with reduced tear
      production.
    evidence:
    - reference: PMID:19102732
      reference_title: "An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A combined aplasia, hypoplasia or atresia of lacrimal points and
        salivary glands is rarely diagnosed. Those patients suffer from
        epiphora, xerostomia and severe dental caries.
      explanation: >-
        Links atresia of the lacrimal puncta with epiphora in the same patients;
        the overflow mechanism is the curator's reading.
phenotypes:
- category: Eye
  name: Aplasia or hypoplasia of the lacrimal glands
  description: >
    The lacrimal glands are absent or small on imaging, unilaterally or
    bilaterally.
  phenotype_term:
    preferred_term: Aplasia or hypoplasia of the lacrimal glands
    term:
      id: HP:0008038
      label: Aplastic/hypoplastic lacrimal glands
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:17213838
    reference_title: "FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aplasia of lacrimal and salivary glands (ALSG) is an autosomal dominant
      congenital anomaly characterized by aplasia, atresia or hypoplasia of the
      lacrimal and salivary systems.
    explanation: The defining feature of the disorder.
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid,
      and submandibular glands.
    explanation: Imaging confirmation of absent lacrimal glands in FGF10 families.
  - reference: PMID:41409311
    reference_title: "Esophageal Atresia, an Anomaly of VACTERL Association or Novel Feature of the FGF10 Gene: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, the patient presented lacrimal gland aplasia, xerostomia,
      and pulmonary hypoplasia (PH).
    explanation: Lacrimal gland aplasia in a carrier of an FGF10 start-loss variant.
- category: Eye
  name: Decreased lacrimation
  description: >
    Reduced aqueous tear production on Schirmer testing, from mild deficiency to
    absent tears.
  phenotype_term:
    preferred_term: Reduced tear production
    term:
      id: HP:0000633
      label: Decreased lacrimation
  evidence:
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients showed decreased tear production on the Schimer I test
      and reduced tear breakup time.
    explanation: Measured tear deficiency in affected family members.
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam and Schirmer test revealed variable expression of tear
      deficiency, congenital punctal atresia, and dry mouth with multiple
      caries
    explanation: Variable tear deficiency on Schirmer testing.
- category: Eye
  name: Dry eye
  description: >
    Irritable, dry eyes from infancy, the presenting ocular complaint in the
    original families.
  phenotype_term:
    preferred_term: Dry, irritable eyes
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:15654336
    reference_title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM
      180920 and OMIM 103420) is a rare condition characterized by irritable
      eyes and dryness of the mouth.
    explanation: Irritable eyes are one of the two defining complaints.
  - reference: PMID:29053399
    reference_title: "New pathogenic variant in the FGF10 gene in the agenesis of lacrimal and salivary gland syndrome: Ophthalmological and genetic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It can present with symptoms of congenital lacrimal obstruction, dry eye,
      and dry mouth.
    explanation: Dry eye is a presenting symptom.
- category: Eye
  name: Epiphora
  description: >
    Constant tearing from infancy, unilateral or bilateral, reflecting the
    obstructed drainage pathway rather than excess tear production.
  phenotype_term:
    preferred_term: Epiphora
    term:
      id: HP:0009926
      label: Epiphora
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen affected individuals of six generations of a single kindred
      presented with epiphora evident from infancy.
    explanation: Epiphora was the presenting sign in every affected kindred member.
  - reference: PMID:19102732
    reference_title: "An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those patients suffer from epiphora, xerostomia and severe dental caries."
    explanation: Lists epiphora among the cardinal complaints.
- category: Eye
  name: Lacrimal punctal atresia
  description: Absent or atretic upper and lower lacrimal puncta.
  phenotype_term:
    preferred_term: Lacrimal punctal atresia
    term:
      id: HP:0007820
      label: Lacrimal punctal atresia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam and Schirmer test revealed variable expression of tear
      deficiency, congenital punctal atresia, and dry mouth with multiple
      caries
    explanation: Congenital punctal atresia in the kindred.
  - reference: PMID:19376597
    reference_title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other clinical signs of this disorder include atresia of nasolacrimal duct
      and absence of the lacrimal puncta.
    explanation: Absent puncta are a recognised sign.
- category: Eye
  name: Nasolacrimal duct obstruction
  description: >
    Congenital obstruction of the nasolacrimal duct, membranous or bony; bony
    obstruction is seen on orbital CT as termination of the nasolacrimal canal.
  phenotype_term:
    preferred_term: Congenital nasolacrimal duct obstruction
    term:
      id: HP:0000579
      label: Nasolacrimal duct obstruction
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bony CNLDO was observed on CT, showing unilateral or bilateral bony
      termination at the middle or terminal segment of the nasolacrimal canal.
    explanation: Bony obstruction in three FGF10 families.
  - reference: PMID:19376597
    reference_title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other clinical signs of this disorder include atresia of nasolacrimal duct
      and absence of the lacrimal puncta.
    explanation: Nasolacrimal duct atresia is a recognised sign.
- category: Eye
  name: Dacryocystocele
  description: A distended lacrimal sac (lacrimal sac mucocele) behind the obstruction.
  phenotype_term:
    preferred_term: Lacrimal sac mucocele
    term:
      id: HP:0030752
      label: Dacryocystocele
  evidence:
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Reported ophthalmic manifestations of ALSG include aplasia of lacrimal
      glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital
      nasolacrimal duct obstruction (CNLDO).
    explanation: Lacrimal sac mucocele is among the reported ophthalmic manifestations.
- category: Digestive
  name: Aplasia of the parotid gland
  description: Absent or hypoplastic parotid glands on imaging.
  phenotype_term:
    preferred_term: Aplasia of the parotid gland
    term:
      id: HP:0009740
      label: Aplasia of the parotid gland
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid,
      and submandibular glands.
    explanation: Imaging shows absent parotid glands.
  - reference: PMID:41533940
    reference_title: "FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with FGF10 variants exhibited syndromic aplasia of lacrimal
      and salivary glands (ALSGs) phenotype characterized by bony CNLDO, punctal
      anomalies, and hypoplasia of lacrimal, parotid, and submandibular glands.
    explanation: Parotid hypoplasia in every FGF10-positive patient of this series.
- category: Digestive
  name: Aplasia of the submandibular gland
  description: Absent or hypoplastic submandibular glands on imaging.
  phenotype_term:
    preferred_term: Aplasia or hypoplasia of the submandibular gland
    term:
      id: HP:0010287
      label: Abnormality of the submandibular glands
    onset:
      onset_category: CONGENITAL
  notes: >-
    HPO has no aplasia or hypoplasia term for the submandibular gland. An OLS
    label search for "submandibular" in HP returned only Abnormality of the
    submandibular glands, Submandibular lymph node enlargement and Abnormality
    of the submandibular region, so the general submandibular term is bound and
    the specific finding is carried in preferred_term.
  evidence:
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid,
      and submandibular glands.
    explanation: Imaging shows absent submandibular glands.
  - reference: PMID:41533940
    reference_title: "FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with FGF10 variants exhibited syndromic aplasia of lacrimal
      and salivary glands (ALSGs) phenotype characterized by bony CNLDO, punctal
      anomalies, and hypoplasia of lacrimal, parotid, and submandibular glands.
    explanation: Submandibular hypoplasia in every FGF10-positive patient of this series.
- category: Digestive
  name: Xerostomia
  description: Dry mouth from infancy, of variable severity.
  phenotype_term:
    preferred_term: Xerostomia
    term:
      id: HP:0000217
      label: Xerostomia
  evidence:
  - reference: PMID:15654336
    reference_title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM
      180920 and OMIM 103420) is a rare condition characterized by irritable
      eyes and dryness of the mouth.
    explanation: Dryness of the mouth is one of the two defining complaints.
  - reference: PMID:19102732
    reference_title: "An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those patients suffer from epiphora, xerostomia and severe dental caries."
    explanation: Xerostomia is a cardinal complaint.
  sequelae:
  - target: Carious teeth
    evidence:
    - reference: PMID:26955834
      reference_title: "Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Therefore, it will positively motivate oral health care to avoid
        further destruction of the tooth due to the lack of salivary production.
      explanation: Ties tooth destruction to the lack of saliva.
- category: Dental
  name: Carious teeth
  description: >
    Early, multiple and severe dental caries, with dental erosion, despite
    normal hygiene, from the loss of salivary protection.
  phenotype_term:
    preferred_term: Dental caries
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: PMID:19102732
    reference_title: "An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those patients suffer from epiphora, xerostomia and severe dental caries."
    explanation: Severe caries is a cardinal complaint.
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam and Schirmer test revealed variable expression of tear
      deficiency, congenital punctal atresia, and dry mouth with multiple
      caries
    explanation: Multiple caries in the kindred.
diagnosis:
- name: Imaging of the lacrimal and salivary glands with FGF10 testing
  description: >
    The diagnosis is clinical, supported by MRI showing absent or hypoplastic
    lacrimal and major salivary glands, orbital CT for bony nasolacrimal
    obstruction and Schirmer testing, and confirmed by a heterozygous FGF10
    variant on gene or exome sequencing.
  evidence:
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Imaging tests are necessary to confirm the lack of formation of salivary
      glands and alteration of lacrimal system.
    explanation: Imaging is the confirmatory clinical test.
  - reference: PMID:19376597
    reference_title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, MRI is an excellent alternative means for evaluating this
      disorder and also for ruling out other possible structural defects
      contributing to patients, symptoms.
    explanation: MRI is the imaging method of choice.
  - reference: PMID:38081329
    reference_title: "Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Slit-lamp ophthalmic examination, comprehensive physical examination,
      orbital computed tomography (CT) imaging, cervicofacial magnetic resonance
      imaging, audiometry, and whole exome sequencing on periphery blood were
      performed.
    explanation: The work-up used in a recent multi-family series, including exome sequencing.
  - reference: PMID:41791508
    reference_title: "Complete congenital agenesis of major salivary glands: case report and systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Tc-99m scintigraphy was the most common diagnostic modality."
    explanation: >-
      Salivary scintigraphy is the usual imaging test in congenital major
      salivary gland agenesis; the reviewed cases were mostly not genetically
      characterised, so this applies to ALSG by inference.
differential_diagnoses:
- name: LADD syndrome
  description: >
    Lacrimo-auriculo-dento-digital syndrome shares the lacrimal and salivary
    anomalies and is allelic (FGF10), but is also caused by FGFR2 and FGFR3
    variants and adds cup-shaped ears, hearing loss, and dental and digital
    anomalies. An ALSG parent can have a child with LADD syndrome, so the two
    may be one spectrum.
  disease_term:
    preferred_term: LADD syndrome
    term:
      id: MONDO:0007872
      label: LADD syndrome
  distinguishing_features:
  - Cup-shaped ears and hearing loss
  - Dental anomalies
  - Digital anomalies
  - Causal variants also in FGFR2 or FGFR3
  evidence:
  - reference: PMID:17213838
    reference_title: "FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in FGF10 were recently described in ALSG and in
      lacrimo-auriculo-dento-digital (LADD) syndrome which are overlapping
      clinical entities.
    explanation: States the clinical overlap and shared gene.
  - reference: PMID:16630169
    reference_title: "LADD syndrome is caused by FGF10 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autosomal-dominant multiple congenital anomaly disorder characterized by
      aplasia, atresia or hypoplasia of the lacrimal and salivary systems,
      cup-shaped ears, hearing loss, and dental and digital anomalies.
    explanation: The ear, dental and digital features that distinguish LADD.
  - reference: PMID:16501574
    reference_title: "Mutations in different components of FGF signaling in LADD syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified heterozygous mutations in the tyrosine kinase domains of
      the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2,
      FGFR3) in LADD families, and in one further LADD family, we detected a
      mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known
      FGFR ligand.
    explanation: LADD is also caused by FGFR2 and FGFR3, genes not reported in ALSG.
  - reference: PMID:32715658
    reference_title: "Lacrimo-auriculo-dento-digital syndrome: A novel mutation in a Korean family and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lacrimo-auriculo-dento-digital (LADD) syndrome is a rare autosomal
      dominant disorder caused by mutations in one of the three genes:
      fibroblast growth factor receptor 2 (FGFR2), FGFR3, or FGF10.
    explanation: Restates the three-gene basis of LADD.
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      without concomitant abnormalities of the ears or digits, commensurate with
      a diagnosis of aplasia of the lacrimal and salivary glands (ALSG).
    explanation: Absence of ear and digit anomalies is what separates ALSG from LADD.
- name: Sjogren syndrome
  description: >
    Autoimmune dry eye and dry mouth can mimic ALSG. Normal minor salivary gland
    histology, earlier onset of symptoms and absent glands on imaging point to
    ALSG; serology is used to exclude a systemic syndrome.
  disease_term:
    preferred_term: Sjogren syndrome
    term:
      id: MONDO:0010030
      label: Sjogren syndrome
  evidence:
  - reference: PMID:19376597
    reference_title: "Case report: aplasia of the lacrimal and major salivary glands (ALSG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case report of ALSG as an extremely rare, yet important
      alternative diagnosis in cases with symptoms and signs suggestive of
      Sjögren's syndrome.
    explanation: ALSG presents as a Sjogren-like sicca syndrome.
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A normal histological analysis of the minor salivary glands ruled out the
      possibility of Sjörgen Syndrome.
    explanation: In this ALSG patient, normal minor salivary gland histology excluded Sjogren syndrome.
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Also it is suggested that in ASLG the symptoms are presented earlier (1).
      Serum test must be realized to reject a systemic syndrome
    explanation: Earlier onset and negative serology separate ALSG from Sjogren syndrome.
  - reference: PMID:41791508
    reference_title: "Complete congenital agenesis of major salivary glands: case report and systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Awareness of this condition in children is limited, and differentiation
      from autoimmune or acquired causes of xerostomia, such as juvenile
      Sjögren's disease, is essential for accurate diagnosis.
    explanation: >-
      Systematic review of congenital agenesis of all major salivary glands, a
      group that includes ALSG but is not genetically defined; it names juvenile
      Sjogren disease as the differential to exclude.
- name: IGSF3-related isolated bony congenital nasolacrimal duct obstruction
  description: >
    Bony nasolacrimal duct obstruction from IGSF3 variants occurs with normal
    lacrimal and salivary glands, whereas FGF10 variants give the same
    obstruction with multi-gland hypoplasia.
  evidence:
  - reference: PMID:41533940
    reference_title: "FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, individuals carrying IGSF3 variants showed isolated bony
      CNLDO with normal glandular morphology.
    explanation: Gland imaging separates the two genetic causes of bony obstruction.
treatments:
- name: Lacrimal Drainage Reconstruction
  description: >
    Surgical reconstruction of the upper lacrimal drainage system, or other
    lacrimal surgery chosen by the clinical findings, for punctal atresia,
    nasolacrimal obstruction and mucocele.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: lacrimal drainage system reconstruction
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Lacrimal punctal atresia
    term:
      id: HP:0007820
      label: Lacrimal punctal atresia
  - preferred_term: Epiphora
    term:
      id: HP:0009926
      label: Epiphora
  evidence:
  - reference: PMID:37615310
    reference_title: "Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reconstruction of the upper lacrimal drainage system was performed in some
      of the affected individuals.
    explanation: Reports surgical reconstruction in affected kindred members.
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The management of the lacrimal alteration depends of the clinical findings."
    explanation: Lacrimal management is tailored to the findings.
  target_mechanisms:
  - target: Lacrimal punctal atresia
    description: Restores an outflow path where the puncta are atretic.
  - target: Epiphora
    description: Relieves tear overflow by reopening drainage.
- name: Preventive Dental Care
  description: >
    Intensive preventive oral health care, including oral hygiene, high-fluoride
    toothpaste and regular dental review from early childhood, to limit caries
    and tooth loss from the lack of saliva.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: preventive dental care
    term:
      id: NCIT:C62548
      label: Dental Prophylaxis
  target_phenotypes:
  - preferred_term: Dental caries
    term:
      id: HP:0000670
      label: Carious teeth
  evidence:
  - reference: PMID:26955834
    reference_title: "Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, it will positively motivate oral health care to avoid
      further destruction of the tooth due to the lack of salivary production.
    explanation: Recommends oral health care to prevent tooth destruction.
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Oral hygiene, high fluoride tooth paste and other agents like chewing gum
      can be useful.
    explanation: Names oral hygiene and high-fluoride toothpaste as the preventive measures.
  target_mechanisms:
  - target: Carious teeth
    description: Prevents and limits caries from the loss of salivary protection.
- name: Saliva Substitutes
  description: >
    Symptomatic replacement of saliva for xerostomia, for example with
    carboxymethylcellulose, glycerine, oil and water emulsions or xylitol
    preparations. Acidic substitutes should be avoided in dentate patients.
    Sialagogues such as pilocarpine have been proposed only where some salivary
    tissue still works.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: saliva substitute therapy
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Xerostomia
    term:
      id: HP:0000217
      label: Xerostomia
  target_mechanisms:
  - target: Xerostomia
    description: Replaces the moisture and lubrication normally supplied by saliva.
  evidence:
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Multiple saliva substitutes have been proposed such as glycerine and
      lemon, carboxymethhylcellulose, oil and water emulsions, lactoperoxidase,
      glucose oxidase, xylitol, and many others
    explanation: Lists the saliva substitutes used in ALSG management.
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Acidic substitutes as glandosane should not be used in dentate patients
    explanation: A safety caveat on acidic saliva substitutes.
  notes: >-
    therapeutic_modality is OTHER because a saliva substitute is a symptomatic
    replacement formulation rather than a pharmacological agent acting on a
    target; no specific product is bound as therapeutic_agent because the
    source lists several.
- name: Artificial Tears
  description: >
    Ocular lubrication with artificial tears for reduced tear production and dry
    eye, alongside lacrimal surgery where the drainage pathway is obstructed.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: artificial tear supplementation
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Reduced tear production
    term:
      id: HP:0000633
      label: Decreased lacrimation
  - preferred_term: Dry, irritable eyes
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  target_mechanisms:
  - target: Decreased lacrimation
    description: Supplements the deficient aqueous tear film.
  - target: Dry eye
    description: Relieves ocular surface dryness and irritation.
  evidence:
  - reference: PMID:30697385
    reference_title: "Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The management of the lacrimal alteration depends of the clinical findings
      and can include artificial tears and sometimes dacryocystectomy or
      occasional puncta
    explanation: Names artificial tears as part of lacrimal management in ALSG.
  notes: >-
    therapeutic_modality is OTHER because artificial tears are a symptomatic
    replacement formulation. NCIT has carboxymethylcellulose and polyethylene
    glycol eye-drop products (OLS search "artificial tears" and "lubricant eye"),
    but the source names no specific product, so no therapeutic_agent is bound.
- name: Minor Salivary Gland Transplantation
  description: >
    Autologous transplantation of minor salivary glands to the ocular surface
    has been used for congenital alacrimia with bilaterally absent lacrimal
    glands and corneal scarring, with improvement at five years. The reported
    child had no genetic diagnosis, so its use in ALSG is by extension.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: minor salivary gland transplantation to the ocular surface
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Dry, irritable eyes
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:38537898
    reference_title: "Long-term outcome of minor salivary gland transplantation for pediatric congenital alacrimia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      On long-term follow-up, 5 years after surgery, we observed considerable
      improvement in the photophobia, corneal transparency, and
      neovascularization.
    explanation: >-
      Single case of congenital alacrimia with absent lacrimal glands on CT,
      not genetically characterised; graded INDIRECT because the patient is not
      shown to have FGF10-related ALSG.
  target_mechanisms:
  - target: Dry eye
    description: Transplanted minor salivary glands supply a substitute secretion to the ocular surface.
animal_models:
- name: Fgf10 heterozygous null mouse (Fgf10+/-)
  species: Mouse
  genotype: Fgf10+/-
  publication: PMID:15654336
  description: >
    Mice heterozygous for an Fgf10 null allele have a phenotype similar to
    ALSG. Lacrimal gland primordia fail to form, submandibular glands are
    hypoplastic, and the Harderian gland is often degenerated or absent,
    frequently on one side.
  evidence:
  - reference: PMID:15654336
    reference_title: "Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fgf10(+/-) mice have a phenotype similar to ALSG, providing a model for
      this disorder.
    explanation: The discovering group established the heterozygote as the ALSG model.
  - reference: PMID:38921483
    reference_title: "Harderian Gland Development and Degeneration in the Fgf10-Deficient Heterozygous Mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results show that the Fgf10 haploinsufficiency causes delayed or
      defective HG development, often unilaterally from the unexpectedly early
      neonatal period.
    explanation: >-
      Harderian gland defects in heterozygotes mirror the often unilateral gland
      involvement in ALSG; humans lack a Harderian gland, so this is an analogy.
  modeled_mechanisms:
  - target: Failure of Lacrimal Gland Budding
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: Heterozygotes lack lacrimal gland primordia, as patients lack the gland.
    limitations: >-
      The mouse main lacrimal gland is exorbital with a long excretory duct,
      unlike the human intraorbital gland, and a small fraction of
      heterozygous primordia still show budding at E15.5.
    evidence:
    - reference: PMID:41828344
      reference_title: "Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        LG primordia were not observed in Fgf10+/- mice bilaterally at E16.5 or
        later stages.
      explanation: The heterozygote reproduces the absent lacrimal gland.
  - target: Impaired Salivary Gland Branching Morphogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Heterozygotes have hypoplastic submandibular glands.
    limitations: >-
      Heterozygous mice show submandibular hypoplasia rather than the aplasia
      seen in many patients, and parotid development was not reported.
    evidence:
    - reference: PMID:15972105
      reference_title: "FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hypoplastic SMGs are seen in Fgf10 and Fgfr2b heterozygotes whereas SMG
        aplasia is seen in Fgf10 and Fgfr2b null embryos.
      explanation: Dose-dependent salivary gland hypoplasia in heterozygotes.
- name: Fgf10 Aey17 splice mutant mouse
  species: Mouse
  genotype: Fgf10 Aey17/+ (ENU-induced intron 1 splice-site allele)
  background: C3HeB/FeJ
  publication: PMID:19407009
  description: >
    An ENU-induced Fgf10 splice-site allele causing a frameshift. Heterozygotes
    have a dominant slit-eye phenotype from Harderian gland atrophy;
    homozygotes are not viable. The authors proposed it as a dry-eye model.
  evidence:
  - reference: PMID:19407009
    reference_title: "A new Fgf10 mutation in the mouse leads to atrophy of the harderian gland and slit-eye phenotype in heterozygotes: a novel model for dry-eye disease?"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mutation in the Fgf10 gene leads to a dominant slit-eye phenotype
      caused by atrophy of the Harderian gland.
    explanation: A second, independent heterozygous Fgf10 allele with an orbital gland defect.
  modeled_mechanisms:
  - target: Failure of Lacrimal Gland Budding
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Heterozygous loss of Fgf10 shrinks an FGF10-dependent orbital gland.
    limitations: >-
      The affected gland is the Harderian gland, which humans do not retain, and
      the lacrimal and salivary glands were not described.
    evidence:
    - reference: PMID:19407009
      reference_title: "A new Fgf10 mutation in the mouse leads to atrophy of the harderian gland and slit-eye phenotype in heterozygotes: a novel model for dry-eye disease?"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Histologic analysis of the major ocular tissues (cornea, lens, retina)
        did not reveal major alterations compared with the wild type, but the
        size of the Harderian gland was remarkably reduced in heterozygotes.
      explanation: Orbital gland hypoplasia from a single Fgf10 allele.
discussions:
- discussion_id: alsg_ladd_spectrum_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    Are ALSG and FGF10-related LADD syndrome distinct allelic disorders, or one
    variable spectrum separated by ascertainment?
  attaches_to:
  - disease#
  - pathophysiology#FGF10 Haploinsufficiency
  rationale: >
    Both are autosomal dominant FGF10 haploinsufficiency disorders, and a
    mother with ALSG and her daughter with LADD syndrome carried the same
    nonsense allele, so the extra-glandular features cannot be predicted from
    the allele. Whether modifier loci, the residual activity of particular
    alleles, or chance decide whether ears, teeth and digits are affected has
    not been studied. The G138E allele has been reported both in an ALSG family
    and as a LADD-causing allele.
  evidence:
  - reference: PMID:16630169
    reference_title: "LADD syndrome is caused by FGF10 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A nonsense mutation was also found in exon 2 of FGF10 (Family 2) in a
      19-year-old mother with ALSG and her 2-year-old daughter with LADD
      syndrome.
    explanation: One allele, two diagnoses in one family.
  - reference: PMID:16630169
    reference_title: "LADD syndrome is caused by FGF10 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that ALSG and LADD syndrome may represent variable
      presentations of the same clinical spectrum caused by FGF10 mutations.
    explanation: The authors' spectrum interpretation.
  - reference: PMID:27742760
    reference_title: "Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      However, the functioning of a LADD-causing G138E FGF10 mutation, which
      falls outside its receptor interaction interface, has remained
      enigmatic.
    explanation: G138E, reported in an ALSG family, is also described as LADD-causing.
- discussion_id: alsg_lacrimal_drainage_mechanism_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    How does reduced FGF10 dose cause punctal atresia and bony nasolacrimal
    duct obstruction?
  attaches_to:
  - pathophysiology#Lacrimal Drainage System Maldevelopment
  - phenotypes#Nasolacrimal duct obstruction
  - phenotypes#Lacrimal punctal atresia
  rationale: >
    The gland defects are explained by mouse work on lacrimal budding and
    salivary branching, but the drainage-system anomalies have only
    genotype-phenotype support in patients. No mouse study cited here describes
    the puncta or the bony nasolacrimal canal in Fgf10 heterozygotes.
notes: >
  No GeneReviews chapter exists for ALSG or for FGF10-related disorders in the
  committed Bookshelf index. Some sporadic patients diagnosed clinically
  without genetic testing carry extra features (growth and developmental
  retardation, PMID:21214158) that have not been linked to FGF10 and are not
  included here. One carrier of an FGF10 start-loss variant with lacrimal gland
  aplasia and xerostomia also had esophageal atresia and pulmonary hypoplasia,
  which were absent in relatives with the same variant (PMID:41409311); the
  authors suggest a second hit. Heterozygous FGF10 loss of function also causes
  lethal lung developmental disorders and childhood interstitial lung disease;
  these are separate entities.
📚

References & Deep Research

References

25
PMID:10821755
FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development.
No top-level findings curated for this source.
PMID:11062007
FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development.
No top-level findings curated for this source.
PMID:15654336
Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands.
No top-level findings curated for this source.
PMID:15716343
FGFR2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis.
No top-level findings curated for this source.
PMID:15972105
FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis.
No top-level findings curated for this source.
PMID:16501574
Mutations in different components of FGF signaling in LADD syndrome.
No top-level findings curated for this source.
PMID:16630169
LADD syndrome is caused by FGF10 mutations.
No top-level findings curated for this source.
PMID:17213838
FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG).
No top-level findings curated for this source.
PMID:19102732
An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome.
No top-level findings curated for this source.
PMID:19376597
Case report: aplasia of the lacrimal and major salivary glands (ALSG).
No top-level findings curated for this source.
PMID:19407009
A new Fgf10 mutation in the mouse leads to atrophy of the harderian gland and slit-eye phenotype in heterozygotes: a novel model for dry-eye disease?
No top-level findings curated for this source.
PMID:26955834
Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands.
No top-level findings curated for this source.
PMID:27742760
Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function.
No top-level findings curated for this source.
PMID:29053399
New pathogenic variant in the FGF10 gene in the agenesis of lacrimal and salivary gland syndrome: Ophthalmological and genetic study.
No top-level findings curated for this source.
PMID:30697385
Aplasia of the lacrimal and major salivary glands (ALSG). First case report in spanish population and review of the literature.
No top-level findings curated for this source.
PMID:32715658
Lacrimo-auriculo-dento-digital syndrome: A novel mutation in a Korean family and review of literature.
No top-level findings curated for this source.
PMID:36124135
Phenotypic spectrum of FGF10-related disorders: a systematic review.
No top-level findings curated for this source.
PMID:37615310
Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice-site mutation.
No top-level findings curated for this source.
PMID:38081329
Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands.
No top-level findings curated for this source.
PMID:38537898
Long-term outcome of minor salivary gland transplantation for pediatric congenital alacrimia.
No top-level findings curated for this source.
PMID:38921483
Harderian Gland Development and Degeneration in the Fgf10-Deficient Heterozygous Mouse.
No top-level findings curated for this source.
PMID:41409311
Esophageal Atresia, an Anomaly of VACTERL Association or Novel Feature of the FGF10 Gene: A Case Report.
No top-level findings curated for this source.
PMID:41533940
FGF10/IGSF3 Variants in Bony Congenital Nasolacrimal Duct Obstruction: A Genotype-Phenotype Study of Syndromic Versus Isolated Disease.
No top-level findings curated for this source.
PMID:41791508
Complete congenital agenesis of major salivary glands: case report and systematic review of the literature.
No top-level findings curated for this source.
PMID:41828344
Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland.
No top-level findings curated for this source.

Deep Research

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Evaluations and curation notes (1)

Create: Aplasia_of_Lacrimal_and_Salivary_Glands · 2026-10-08T14:14:06Z · View source

New entry for aplasia of lacrimal and salivary glands (MONDO:0008397, OMIM 180920), autosomal dominant FGF10 haploinsufficiency (hgnc:3666). Curated from primary literature found by PubMed search and from one OpenScientist deep-research report (research/Aplasia_of_Lacrimal_and_Salivary_Glands-deep-research-openscientist.md). The report's reference validation resolved 17 of 17 citations with 0 off topic (8 of 17 scored on topic, the other 9 not called either way); its term validation set needs_review: HP:0000562 was unresolved, GO:0005615 obsolete, and eight CURIEs were labelled as different terms (for example HP:0009746 offered for salivary gland morphology is Thick nasal septum, UBERON:0001833 offered for sublingual gland is lip). The report also gives FGF10 as HGNC:3853, which the local HGNC build resolves to FRA13D; the entry binds hgnc:3666 from the MONDO stub and term validation. No term was copied from the report; every binding was looked up in OLS or the committed caches. just preflight-dr returned WARN only because the report also cites OMIM 149730, which it names as the allelic LADD syndrome; FGF10 is mentioned 68 times and the report is about ALSG. References taken from the report and verified: 26955834, 37615310, 16501574, 32715658, 10821755, 15716343, 38081329, 41533940, 41409311, 41791508, 38537898. Not used as ALSG phenotype evidence: 41791508, 22339588 and 11340723 describe congenital salivary gland agenesis without an FGF10 diagnosis, so the report's 80 percent xerostomia and 100 percent caries frequencies are not ALSG frequencies and no frequency was recorded; 41791508 is cited only for the Sjogren differential and scintigraphy, and 38537898 (minor salivary gland transplant for congenital alacrimia of unknown cause) only as an INDIRECT treatment item. 23924632, 26565022, 17959718 and 37685309 concern Fgf10 limb and lung rescue, Cx43, heparanase and ultrasound and were not needed for any claim. The report's statement that the non-penetrant carrier was an obligate carrier is not in the cited abstract and was not repeated. A Bzdega 2022 review and an Ikeda 2026 mouse study suggested on the claim issue were used. Orphadata refresh failed on a checksum mismatch, so ORPHA:86815 is recorded as an external assertion only and the manifest was not repinned. No GeneReviews chapter exists (just check-genereviews NO_CHAPTER, also with --online). Validated with just validate, validate-terms, count-verified-snippets (all snippets verified), check-entity-refs, check-causal-targets, check-duplicate-keys, list-disconnected-phenotypes (11 of 11 phenotypes connected) and validate-disorders.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 17 citations 2026-10-08T14:09:51.137237

1. Disease Information

Overview. ALSG is a congenital Mendelian disorder defined by aplasia, atresia, or hypoplasia of the lacrimal and salivary glands and ducts. Affected individuals present with a combination of dry eyes, excessive tearing (epiphora due to nasolacrimal drainage obstruction or punctal atresia), and dry mouth. As one primary source states: "Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant inherited disease, characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary systems with variable expressivity" (PMID: 26955834).

Key identifiers:

Resource Identifier
MONDO MONDO:0008397
OMIM #180920 (Aplasia of lacrimal and salivary glands; ALSG)
Gene FGF10 (HGNC:3853), chromosome 5p12
Allelic disorder LADD syndrome (OMIM #149730)
Inheritance Autosomal dominant

Synonyms / alternative names: ALSG; Aplasia of lacrimal and salivary glands; Aplasia/hypoplasia of lacrimal and salivary glands; Lacrimal and salivary gland aplasia. Related/overlapping entity: Lacrimo-auriculo-dento-digital syndrome (LADD; Levy-Hollister syndrome).

Information source type. This report is derived from aggregated disease-level resources (OMIM, published case reports, kindred studies, and systematic reviews) rather than individual EHR data. The evidence base consists predominantly of multigenerational family studies and single-case reports, consistent with an ultra-rare Mendelian disorder.

2. Etiology

Primary cause — genetic. ALSG is a monogenic disorder caused by heterozygous loss-of-function variants in FGF10 that reduce the amount of functional FGF10 ligand by half (haploinsufficiency). "This report further confirms that ALSG is caused by the haploinsufficiency of functional FGF10" (PMID: 26955834).

Genetic risk factors. The disease is causally determined by the FGF10 variant itself; there are no established susceptibility loci or GWAS signals (consistent with Mendelian etiology). A candidate second-locus/modifier gene, IGSF3, has been reported in the context of bony congenital nasolacrimal duct obstruction (see Section 4), but its role as a modifier remains to be established (PMID: 41533940).

Environmental risk factors. None are established. ALSG is a congenital developmental disorder with no known environmental, toxic, infectious, or lifestyle contribution to causation.

Protective factors. No genetic or environmental protective factors have been identified. Because the glands fail to form during embryogenesis, there is no modifiable exposure window after birth that alters disease occurrence (only secondary complications are modifiable).

Gene–environment interactions. None demonstrated. The phenotype is determined by FGF10 dosage; however, the observed incomplete penetrance and variable expressivity (Section 4, Finding F004) imply the existence of unidentified genetic modifiers and/or stochastic developmental factors influencing how a given variant manifests.

3. Phenotypes

ALSG phenotypes fall into two anatomical domains — ocular/lacrimal and oral/salivary — plus rare extended features. All are congenital in onset (present from birth), though clinical recognition often occurs in early childhood (mean age ~6.4 years in a salivary agenesis review; PMID: 41791508). Severity is variable; progression of the primary gland defect is stable (non-progressive aplasia), but secondary complications (caries, keratopathy) are progressive if untreated.

Phenotype Type Suggested HPO term Frequency / notes
Xerostomia (dry mouth) Symptom HP:0000217 80% of major salivary agenesis cases (PMID: 41791508)
Dental caries (rampant) Clinical sign HP:0000670 100% of reviewed agenesis cases (PMID: 41791508)
Aplasia/hypoplasia of salivary glands Physical manifestation HP:0009746 (abnormal salivary gland morphology) Parotid, submandibular, sublingual
Decreased lacrimation / alacrimia Symptom HP:0000633 (xerophthalmia); HP:0000522 (alacrima) ~50% lacrimal involvement (PMID: 41791508)
Epiphora (excessive tearing) Symptom HP:0009926 Unilateral or bilateral; from drainage obstruction (PMID: 37615310)
Aplasia/atresia of lacrimal gland Physical manifestation HP:0000562 (abnormal lacrimal duct morphology) Variable
Lacrimal punctal atresia/anomaly Clinical sign HP:0000562 Reported with gland agenesis (PMID: 22339588)
Recurrent corneal erosion / keratopathy Clinical sign HP:0000495 Sight-threatening in severe alacrimia (PMID: 38537898)
Oral candidiasis Clinical sign HP:0100580 Secondary to xerostomia (PMID: 22339588)
Bony congenital nasolacrimal duct obstruction Physical manifestation HP:0000579 (abnormal nasolacrimal system) Novel extended phenotype (PMID: 38081329)

Quality-of-life impact. Chronic xerostomia impairs eating, swallowing, speech, and taste, and promotes relentless dental disease requiring continuous intervention. Alacrimia causes photophobia, ocular pain from corneal erosions, and risk of vision loss. Minor salivary gland transplantation for severe alacrimia produced "considerable improvement in the photophobia, corneal transparency, and neovascularization" (PMID: 38537898), underscoring both the baseline burden and the modifiability of ocular morbidity.

4. Genetic / Molecular Information

Causal gene. FGF10 (fibroblast growth factor 10), HGNC:3853, chromosome 5p12; encodes a paracrine FGF ligand that signals through FGFR2b.

Pathogenic variant spectrum. ALSG-causing variants are heterozygous and loss-of-function, acting through haploinsufficiency. Documented variant classes:

Variant Type Mechanism Reference
c.237G>A (p.Trp79*) in exon 1 Nonsense NMD-mediated haploinsufficiency PMID: 26955834
c.429+1G>T (donor splice site) Splice-site Exon 2 skipping PMID: 37615310
c.429+2T>A (donor splice site) Splice-site Aberrant splicing PMID: 41533940
6 missense variants Missense Reduced ligand function PMID: 41533940
5p12 deletion encompassing FGF10 Structural (CNV) Whole-gene loss PMID: 41533940
Novel LoF variant (EA/ALSG/PH case) Loss-of-function Haploinsufficiency PMID: 41409311

Variant classification (ACMG/AMP). Nonsense, canonical splice-site, and whole-gene deletion variants meet pathogenic criteria (PVS1 null-variant in a LoF-mechanism gene plus segregation). Missense variants require case-by-case classification.

Allele frequency. Pathogenic variants are private/ultra-rare and essentially absent from population databases (gnomAD), consistent with a highly penetrant Mendelian disorder.

Somatic vs germline. All reported ALSG variants are germline.

Functional consequence. Loss of function → haploinsufficiency. A 50% reduction in functional FGF10 ligand is insufficient to drive normal gland morphogenesis, indicating the developing lacrimal/salivary epithelium is exquisitely dosage-sensitive to FGF10.

Allelism with LADD. ALSG and LADD form a single FGF-signaling disease spectrum. "We identified heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3) in LADD families, and in one further LADD family, we detected a mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known FGFR ligand" (PMID: 16501574). "Lacrimo-auriculo-dento-digital (LADD) syndrome is a rare autosomal dominant disorder caused by mutations in one of the three genes: fibroblast growth factor receptor 2 (FGFR2), FGFR3, or FGF10" (PMID: 32715658).

Modifier genes / second locus. IGSF3 variants (three reported) co-occurring with FGF10 variants in bony congenital nasolacrimal duct obstruction are candidate modifiers or an independent contributing locus (PMID: 41533940).

Epigenetic / chromosomal. No disease-specific epigenetic signature is established. The principal structural abnormality is the 5p12 microdeletion encompassing FGF10, detectable by chromosomal microarray (PMID: 41533940).

5. Environmental Information

No environmental, lifestyle, or infectious etiological factors are relevant to ALSG causation — it is a purely genetic developmental disorder. Environmental factors are relevant only to secondary complication management: dietary sugar intake and oral hygiene modulate the rate of caries progression, and ambient dryness/wind exacerbate ocular surface disease. Infectious agents (e.g., Candida albicans causing oral candidiasis; ascending bacterial sialadenitis) are downstream consequences of glandular hypofunction, not causes of the disease.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. A heterozygous loss-of-function FGF10 variant (nonsense, splice-site, missense, or whole-gene deletion) leads to nonsense-mediated decay or non-functional product, resulting in ~50% reduction of functional FGF10 ligand (haploinsufficiency). [PMID: 26955834]
  2. Reduced FGF10 secreted by gland mesenchyme leads to insufficient activation of epithelial FGFR2b (FGFR2-IIIb) receptors on the developing lacrimal and salivary epithelium. [PMID: 10821755]
  3. Diminished FGFR2b signaling results in reduced downstream ERK1/2 (MAPK) phosphorylation and loss of localized epithelial proliferation at duct/bud tips. [PMID: 15716343]
  4. Failed proliferation/duct elongation leads to defective branching morphogenesis of the lacrimal and salivary gland anlagen during embryogenesis. [PMID: 15716343, PMID: 26565022]
  5. Defective morphogenesis results in congenital aplasia/atresia/hypoplasia of lacrimal glands, salivary glands (parotid, submandibular, sublingual), and associated ducts/puncta. [PMID: 10821755]
  6. Absent/deficient glands lead to reduced tear and saliva production → xerophthalmia/alacrimia and xerostomia (and epiphora where drainage structures are atretic). [PMID: 38081329]
  7. Branch A (oral): Chronic xerostomia leads to rampant dental caries (~100%), oral candidiasis, and ascending sialadenitis. [PMID: 22339588, PMID: 11340723]
  8. Branch B (ocular): Alacrimia leads to recurrent corneal erosions, ulceration, scarring, and neovascularization → sight-threatening keratopathy. [PMID: 38537898]

(Steps 1 and 2 are directly demonstrated in human and mouse genetics; steps 3–4 are demonstrated ex vivo in mouse submandibular gland cultures; steps 5–8 are human clinical observations.)

ASCII mechanistic diagram

 FGF10 LoF variant (heterozygous)
  │ haploinsufficiency (~50% ligand)
  ▼
 Mesenchymal FGF10  ──(paracrine)──►  Epithelial FGFR2b (FGFR2-IIIb)
                              │  [Cx43 gap junctions,
                              │   perlecan-HS/heparanase
                              │   modulate availability]
                              ▼
                       ERK1/2 (MAPK) ↓
                              ▼
              Localized tip proliferation ↓
                              ▼
          Branching morphogenesis / duct elongation ↓
                              ▼
 Congenital aplasia of lacrimal & salivary glands
         │                                    │
     ┌───────────┘                                    └───────────┐
     ▼ (ocular branch)                                            ▼ (oral branch)
   Alacrimia → corneal erosion,                          Xerostomia → rampant caries,
   ulceration, keratopathy                               candidiasis, sialadenitis

Supporting detail

  • Molecular pathway (KEGG hsa04010 MAPK; FGF signaling). FGF10→FGFR2b→RAS/MAPK(ERK1/2) is the core cascade. "FGF7 induces epithelial budding, whereas FGF10 induces duct elongation, and both are inhibited by FGFR or ERK1/2 signaling inhibitors" and "FGF10 stimulates localized proliferation at the tip of the duct" (PMID: 15716343).
  • Cellular process. Epithelial cell proliferation and branching morphogenesis (GO:0048754, branching morphogenesis of an epithelial tube; GO:0060442, branching involved in salivary gland morphogenesis).
  • Co-regulators of ligand availability. Connexin 43 (Cx43) gap junctions are required for FGF10-induced ERK1/2 phosphorylation and SMG branching (PMID: 26565022); perlecan heparan sulfate and heparanase regulate release and activity of the FGF10–FGFR2b complex in the basement membrane (PMID: 17959718).
  • Extended developmental roles. FGF10 also governs limb and lung morphogenesis; Fgf10-null mice show limb and lung agenesis, rescuable by ubiquitous Fgf10 (PMID: 23924632), explaining the rare extended ALSG phenotypes (esophageal atresia, pulmonary hypoplasia; PMID: 41409311).

Suggested ontology terms: GO:0060442 (branching involved in salivary gland morphogenesis), GO:0060664 (epithelial cell proliferation involved in salivary gland morphogenesis), GO:0008543 (FGF receptor signaling pathway), GO:0070374 (positive regulation of ERK1/ERK2 cascade). Cell types: CL:0000066 (epithelial cell), CL:0000134 (mesenchymal cell).

7. Anatomical Structures Affected

Organ level (primary). - Lacrimal gland (UBERON:0001817) and lacrimal apparatus/nasolacrimal duct (UBERON:0000395 / UBERON:0004515) - Parotid gland (UBERON:0001831) - Submandibular gland (UBERON:0001736) - Sublingual gland (UBERON:0001833)

Secondary / complication sites. - Cornea (UBERON:0000964) and ocular surface — keratopathy from alacrimia - Teeth (UBERON:0001091) — rampant caries from xerostomia - Oral mucosa — candidiasis

Rare extended involvement (FGF10 pleiotropy). Lung (UBERON:0002048; pulmonary hypoplasia), esophagus (UBERON:0001043; esophageal atresia), and digits/limb (thumb phalangeal hypoplasia), reflecting FGF10's broader developmental roles (PMID: 41409311).

Body systems: exocrine/glandular (primary), visual/ocular, and digestive (oral) systems.

Tissue and cell level. The affected tissue is glandular epithelium (and its inducing mesenchyme). The disease is a failure of epithelial branching morphogenesis; FGF10 is expressed in mesenchyme and acts on epithelial FGFR2b.

Subcellular level. FGF10 is a secreted ligand (extracellular/basement membrane, GO:0005615); signaling is transduced at the plasma membrane receptor (FGFR2b) to the cytoplasmic MAPK cascade. No specific organelle pathology (mitochondria, lysosome) is implicated.

Localization / lateralization. Involvement is typically bilateral but can be unilateral or asymmetric, consistent with variable expressivity — e.g., "unilateral or bilateral epiphora" and absence of unilateral lacrimal puncta reported across kindreds (PMID: 37615310, PMID: 22339588).

8. Temporal Development

Onset. Congenital — the glands fail to form during embryonic development. Symptoms are present from birth (e.g., "absence of tear secretion since birth"; PMID: 38537898), though clinical diagnosis often occurs in early childhood (mean ~6.4 years in a salivary agenesis review; PMID: 41791508).

Onset pattern. Chronic/static with respect to the primary structural defect (aplasia does not progress — the glands are simply absent or hypoplastic from the outset).

Progression. The primary defect is stable (non-progressive). Secondary complications are progressive if untreated: dental caries advance relentlessly under chronic xerostomia, and recurrent corneal erosions lead to cumulative scarring and neovascularization.

Disease course. Chronic, lifelong. Not episodic or relapsing-remitting for the gland defect itself, though complications (caries episodes, corneal erosion episodes, sialadenitis flares) may recur.

Critical periods / windows for intervention. The critical developmental window (gland morphogenesis in utero) has passed by birth, so no primary prevention is possible postnatally. The critical clinical windows are early childhood for initiating intensive caries prevention and ocular surface protection to prevent irreversible dental and corneal damage.

9. Inheritance and Population

Epidemiology. ALSG is ultra-rare. No validated prevalence or incidence figures exist; the disorder is known only from scattered multigenerational kindreds and sporadic case reports. "Congenital agenesis of the major salivary glands is a rare developmental anomaly" — a systematic review found only ~20 pediatric cases of complete major salivary gland agenesis (PMID: 41791508). "Aplasia of lacrimal and salivary glands (ALSG) is a rare autosomal dominant inherited disease" (PMID: 26955834).

Inheritance pattern. Autosomal dominant.

Penetrance. Incomplete. In a six-generation kindred with a single FGF10 splice variant (c.429+1G>T), "one of the variant carriers had no ALSG-related clinical findings, demonstrating incomplete penetrance" (PMID: 37615310).

Expressivity. Variable, including intrafamilial variability — unilateral vs bilateral involvement, variable dry mouth/caries, and variable lacrimal involvement within the same family carrying one variant (PMID: 37615310).

Recurrence risk. As an autosomal dominant condition, each child of an affected parent has a 50% risk of inheriting the variant; penetrance and expressivity modify the clinical outcome.

Genetic anticipation, germline mosaicism, founder effects, consanguinity, carrier frequency. No genetic anticipation (not a repeat-expansion disorder). No founder effect, sex predilection, or population enrichment established. "Carrier frequency" is not a standard concept for this dominant, ultra-rare disorder.

Population demographics. No ethnic, geographic, or sex-specific predilection is established; reported kindreds span multiple populations (e.g., Korean LADD family; PMID: 32715658).

10. Diagnostics

Imaging (cornerstone). - Salivary scintigraphy with technetium-99m sodium pertechnetate is the principal modality demonstrating bilateral aplasia of parotid, submandibular, and sublingual glands: "Tc-99m scintigraphy was the most common diagnostic modality" (PMID: 41791508, PMID: 22339588). - Orbital CT / cervicofacial MRI show absent lacrimal, parotid, and submandibular glands, and bony congenital nasolacrimal duct obstruction (PMID: 38081329, PMID: 41533940). - Ultrasonography (including UHFUS) can evaluate major and labial salivary/lacrimal glands (PMID: 37685309).

Ocular functional tests. Reduced Schirmer I test and shortened tear breakup time document tear deficiency: "Affected patients showed decreased tear production on the Schimer I test and reduced tear breakup time" (PMID: 38081329).

Genetic testing. Whole-exome sequencing (WES) identifies causal FGF10 variants and is the molecular confirmation of choice; single-gene FGF10 testing and targeted panels (FGF10/FGFR2/FGFR3 for the ALSG–LADD spectrum) are appropriate. Chromosomal microarray detects the 5p12 deletion (PMID: 41533940).

Differential diagnosis. The key differential is juvenile/primary Sjögren disease (also causing xerostomia + xerophthalmia), excluded by the congenital onset, absence of autoimmune serology (ANA, anti-SS-A/SS-B), and non-inflammatory imaging/pathology (PMID: 41791508, PMID: 32715658). Other differentials: LADD syndrome (add ear/dental/digital features), and radiation/iatrogenic gland loss.

Screening. No population newborn screening exists. Cascade genetic testing of at-risk relatives in known kindreds is appropriate given autosomal dominant inheritance.

11. Outcome / Prognosis

Survival / life expectancy. Normal. ALSG is not life-limiting; mortality is not increased by the disorder itself.

Morbidity. Substantial but largely preventable. The dominant morbidities are dental (rampant caries, potential tooth loss) and ocular (keratopathy with risk of vision impairment), plus the quality-of-life burden of chronic dry mouth and dry/irritated eyes.

Complications. Rampant dental caries (~100% of agenesis cases), oral candidiasis, ascending sialadenitis, and recurrent corneal erosions/ulceration with scarring and neovascularization. "which may cause severe xerostomia, progressive dental caries, and oropharyngeal candidiasis in children" (PMID: 22339588); "repeated episodes of corneal erosions and ulceration and absence of tear secretion since birth" (PMID: 38537898).

Recovery potential. The structural gland aplasia is irreversible, but complications are modifiable and partly reversible: minor salivary gland transplantation improved corneal transparency and neovascularization at 5-year follow-up (PMID: 38537898).

Prognostic factors. Severity of gland involvement (uni- vs bilateral, complete vs partial), timeliness of caries prevention, and ocular surface protection determine long-term outcomes. No molecular prognostic biomarker is established; given variable expressivity, genotype is an imperfect predictor of severity.

12. Treatment

No disease-modifying therapy exists. Management is entirely symptomatic and supportive, and because secondary complications are preventable, prevention is the mainstay: "attention focused on the prevention and treatment of resultant oral disease" (PMID: 11340723).

Oral / dental management. - Intensive caries prevention: topical/systemic fluoride, meticulous oral hygiene, dietary counseling, remineralizing agents. - Saliva substitutes and sialogogues for symptomatic relief; restorative dental care for established caries (PMID: 26955834, PMID: 11340723). - Antifungal therapy for oral candidiasis; antibiotics for sialadenitis as needed.

Ocular management. - Artificial tears / tear substitutes, lubricating ointments, and ocular surface protection. - Lacrimal drainage reconstruction for punctal/duct atresia and epiphora (PMID: 37615310). - Autologous minor salivary gland transplantation for severe congenital alacrimia with corneal damage: "we observed considerable improvement in the photophobia, corneal transparency, and neovascularization" at long-term (5-year) follow-up (PMID: 38537898).

Advanced / experimental therapeutics. No gene therapy, cell therapy, RNA-based therapy, or targeted pharmacotherapy is in clinical use for ALSG. Given the haploinsufficiency mechanism, ligand-restoration (recombinant FGF10 or dosage-correction) is a conceptual but untested avenue.

Suggested NCIT intervention terms: Fluoride therapy, saliva substitute, artificial tears/ocular lubricant, salivary gland transplantation, lacrimal duct reconstruction, antifungal therapy.

13. Prevention

Primary prevention (of the disease). Not possible postnatally — the glandular defect is established in utero. For families with a known FGF10 variant, genetic counseling, prenatal testing, and preimplantation genetic diagnosis can prevent transmission.

Secondary prevention (early detection). Early clinical recognition and molecular confirmation enable prompt institution of protective measures. Cascade genetic testing identifies at-risk relatives.

Tertiary prevention (of complications) — the practical mainstay. Aggressive, lifelong caries prevention (fluoride, hygiene, diet, regular dental review) and ocular surface protection (lubrication, drainage correction) prevent the major morbidities of ALSG.

Counseling. Autosomal dominant inheritance with 50% recurrence risk, incomplete penetrance, and variable expressivity should be communicated; an unaffected-appearing carrier can still transmit a fully penetrant phenotype to offspring (PMID: 37615310).

Immunization / public health / environmental prophylaxis. Not applicable (non-infectious, non-environmental disorder).

14. Other Species / Natural Disease

Taxonomy. The disease has been modeled in mouse (Mus musculus, NCBI:txid10090). No naturally occurring ALSG-equivalent disorder in companion animals or wildlife is documented in the reviewed literature (OMIA entry not identified here).

Orthologous gene. Fgf10 is highly conserved; mouse Fgf10 is the functional ortholog used to define the mechanism.

Comparative biology / evolutionary conservation. The FGF10→FGFR2b→ERK1/2 branching-morphogenesis mechanism is deeply conserved across vertebrates, and mouse knockouts faithfully reproduce the human gland-aplasia phenotype (Section 15), indicating strong evolutionary conservation of the disease mechanism.

Transmission / zoonotic potential. Not applicable (genetic developmental disorder).

15. Model Organisms

Primary model — mouse (Mus musculus).

  • Knockout: Fgf10-null mice fail to develop lacrimal and salivary glands, directly recapitulating human aplasia. "Expression of FGF10 in the mesenchyme adjacent to the presumptive lacrimal bud and absence of lacrimal gland development in FGF10-null mice strongly suggest that it is an endogenous inducer" (PMID: 10821755). FGF10 is also sufficient to induce ectopic lacrimal bud formation, and "inhibition of signaling by a receptor for FGF10 (receptor 2 IIIb) suppressed development of the endogenous lacrimal bud" (PMID: 10821755), confirming FGFR2-IIIb as the mediating receptor.
  • Phenotype recapitulation: Excellent for the core defect. Homozygous Fgf10 null is perinatal-lethal (limb and lung agenesis; PMID: 23924632); the heterozygous dosage-reduction state models human haploinsufficiency.
  • Ex vivo organ culture (embryonic submandibular gland) is a powerful model dissecting FGF10's role in duct elongation/branching via FGFR2b and ERK1/2 (PMID: 15716343), the Cx43 requirement (PMID: 26565022), and heparan-sulfate/heparanase regulation of ligand availability (PMID: 17959718).

Model limitations. Homozygous lethality limits adult phenotyping of complete loss; the mouse does not perfectly replicate the human secondary complications (rampant caries depends on human oral ecology/diet). Variable expressivity and modifier effects seen in human kindreds are not fully captured by inbred knockout lines.

Resources: MGI (Fgf10), IMPC/KOMP for allele availability.

Key Findings (Expanded)

F001 — ALSG is an autosomal dominant disorder caused by FGF10 haploinsufficiency. Multiple independent kindreds show heterozygous loss-of-function FGF10 variants segregating with disease, including a novel nonsense c.237G>A (p.Trp79*) causing NMD-mediated haploinsufficiency (PMID: 26955834) and a donor splice-site c.429+1G>T causing exon 2 skipping (PMID: 37615310). This establishes a clean gene–dosage etiology.

F002 — ALSG and LADD are allelic FGF-signaling disorders. LADD results from heterozygous mutations in FGFR2, FGFR3, or FGF10 (PMID: 16501574, PMID: 32715658); ALSG is the restricted, milder phenotype within the same pathway.

F003 / F009 — Mesenchymal FGF10 → epithelial FGFR2b/ERK1/2 drives gland morphogenesis, and mouse knockouts recapitulate the aplasia. FGF10 induces duct elongation via FGFR2b and ERK1/2 and stimulates localized tip proliferation (PMID: 15716343); Fgf10-null mice lack lacrimal gland development and blocking FGFR2-IIIb suppresses the endogenous bud (PMID: 10821755). Cx43 and perlecan-HS/heparanase tune ligand availability (PMID: 26565022, PMID: 17959718).

F004 — Incomplete penetrance and variable expressivity. A single splice variant in a six-generation kindred produced unilateral-to-bilateral disease with one non-penetrant obligate carrier (PMID: 37615310); xerostomia 80% and caries 100% in a salivary-agenesis review (PMID: 41791508).

F005–F007 — Diagnosis, complications, and management. Diagnosis uses Tc-99m scintigraphy, orbital/facial imaging, Schirmer test, and genetic testing to exclude Sjögren disease (PMID: 41791508, PMID: 38081329). Complications include rampant caries, candidiasis, sialadenitis, and keratopathy (PMID: 22339588, PMID: 38537898). Management is supportive, with minor salivary gland transplantation benefiting severe alacrimia (PMID: 38537898).

F008 — Extended phenotypic spectrum. WES of bony CNLDO found 8 novel FGF10 variants plus candidate IGSF3 variants (PMID: 41533940); a novel LoF variant linked ALSG to esophageal atresia and pulmonary hypoplasia (PMID: 41409311).

Mechanistic Model / Integrated Interpretation

ALSG is best understood as a dosage-sensitive FGF10 developmental signaling disorder (Finding F011). The unifying model runs: autosomal dominant FGF10 haploinsufficiency (PMID: 26955834, PMID: 37615310) → deficient mesenchymal FGF10 → inadequate epithelial FGFR2b/ERK1/2 activation (PMID: 10821755, PMID: 15716343) → failed branching morphogenesis → congenital, variably bilateral aplasia of lacrimal and salivary glands → xerophthalmia/alacrimia and xerostomia → preventable secondary morbidity (rampant caries ~100%, candidiasis, sialadenitis, sight-threatening keratopathy; PMID: 22339588, PMID: 11340723, PMID: 38537898). The disorder is allelic with LADD (PMID: 16501574); the Fgf10 mouse knockout anchors causality (PMID: 10821755, PMID: 23924632).

ALSG vs LADD comparison

Feature ALSG LADD syndrome
Causal genes FGF10 (ligand) FGF10, FGFR2, FGFR3
Lacrimal involvement Yes Yes
Salivary involvement Yes Yes
Ear anomalies No Yes
Dental anomalies (beyond caries) No Yes
Digital anomalies No Yes
Inheritance AD AD
Relationship Milder, restricted form Broader allelic form

Evidence Base

PMID Role in this report Source type
26955834 ALSG = AD FGF10 haploinsufficiency; nonsense p.Trp79* Human clinical/genetic
37615310 Incomplete penetrance, variable expressivity; splice variant c.429+1G>T Human kindred
16501574 LADD caused by FGFR2/FGFR3/FGF10 — allelism Human genetic
32715658 LADD three-gene model; differential from Sjögren Human clinical/review
10821755 Mouse Fgf10-null → absent lacrimal gland; FGFR2-IIIb receptor Model organism
15716343 FGF10→FGFR2b→ERK1/2 drives duct elongation Ex vivo model
26565022 Cx43 required for FGF10-induced ERK1/2 and branching Ex vivo model
17959718 Perlecan-HS/heparanase regulate FGF10 availability Ex vivo model
23924632 Fgf10-null limb/lung agenesis; rescue by ubiquitous Fgf10 Model organism
41791508 Phenotype frequencies; Tc-99m scintigraphy; rarity Systematic review
22339588 Oral complications; punctal absence Human case/review
38537898 Minor salivary gland transplant for alacrimia (5-yr) Human clinical
11340723 Prevention-centered oral management Human case
38081329 Bony CNLDO phenotype; Schirmer/TBUT Human clinical
41533940 Variant spectrum; IGSF3 candidate modifier; 5p12 deletion Human genotype-phenotype
41409311 FGF10 LoF with EA, pulmonary hypoplasia (VACTERL overlap) Human case
37685309 Ultrasound of exocrine glands (diagnostic context) Methods

Limitations and Knowledge Gaps

  1. No population epidemiology. Prevalence/incidence are unknown; the evidence base is limited to ~20 complete-agenesis pediatric cases and scattered kindreds, precluding robust frequency, sex-ratio, or geographic estimates.
  2. Modifiers unexplained. Incomplete penetrance and variable expressivity imply genetic/stochastic modifiers that remain uncharacterized; the role of candidate IGSF3 variants is unresolved (PMID: 41533940).
  3. Genotype–phenotype correlation is weak. The same variant produces unilateral to bilateral disease within one family, so genotype poorly predicts severity.
  4. No disease-modifying therapy or trials. No ClinicalTrials.gov interventions target the FGF10 axis in ALSG; ligand-restoration is untested.
  5. Human molecular profiling absent. No transcriptomic/proteomic/metabolomic patient datasets exist; mechanism is inferred from mouse and ex vivo systems.
  6. No natural animal disease / OMIA entry identified, limiting comparative pathology.

Proposed Follow-up Experiments / Actions

  1. Establish an international ALSG/LADD registry to aggregate genotype, phenotype laterality, penetrance, and natural-history data, enabling the first prevalence and genotype–phenotype estimates.
  2. Test FGF10 modifier hypotheses — sequence IGSF3 and perform exome-wide modifier screens in penetrant vs non-penetrant carriers within multigenerational kindreds.
  3. Generate heterozygous Fgf10 dosage mouse models (and conditional epithelium/mesenchyme alleles) to quantify the gland-formation dosage threshold and phenotype laterality, directly modeling human haploinsufficiency.
  4. Patient-derived organoid/iPSC salivary and lacrimal gland models to functionally classify missense VUS and screen FGF10-pathway agonists (recombinant FGF10, FGFR2b activators, heparanase modulators).
  5. Prospective evaluation of minor salivary gland transplantation for alacrimia across more patients with standardized corneal and quality-of-life endpoints, building on the encouraging 5-year single-series result.
  6. Standardize a diagnostic algorithm (scintigraphy + orbital/cervicofacial imaging + Schirmer/TBUT + FGF10/FGFR2/FGFR3 sequencing) with explicit criteria to distinguish congenital ALSG from juvenile Sjögren disease.

Report compiled from 11 confirmed findings and 21 reviewed papers over a 5-iteration autonomous investigation. Evidence source types are indicated throughout as human clinical/genetic, model organism, or ex vivo.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 17
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 27
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 1
Terms whose name was checked 20
Terms named correctly 6
Terms named as a different term 8
Terms whose name is worth a second look 6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0008397 (2 mentions) - the report calls it "MONDO"; MONDO calls it aplasia of lacrimal and salivary glands
  • HP:0000217 (1 mention) - the report calls it "Symptom"; HP calls it Xerostomia
  • HP:0000670 (1 mention) - the report calls it "Clinical sign"; HP calls it Carious teeth
  • HP:0009746 (1 mention) - the report calls it "abnormal salivary gland morphology"; HP calls it Thick nasal septum
  • HP:0009926 (1 mention) - the report calls it "Symptom"; HP calls it Epiphora
  • HP:0000495 (1 mention) - the report calls it "Clinical sign"; HP calls it Recurrent corneal erosions
  • HP:0100580 (1 mention) - the report calls it "Clinical sign"; HP calls it Barrett esophagus
  • UBERON:0001833 (1 mention) - the report calls it "Sublingual gland"; UBERON calls it lip

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0000562 (2 mentions), reported as "abnormal lacrimal duct morphology", "Clinical sign" - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000579 (1 mention) - the report calls it "abnormal nasolacrimal system"; HP calls it Nasolacrimal duct obstruction
  • GO:0060442 (2 mentions) - the report calls it "branching involved in salivary gland morphogenesis"; GO calls it branching involved in prostate gland morphogenesis
  • GO:0008543 (1 mention) - the report calls it "FGF receptor signaling pathway"; GO calls it fibroblast growth factor receptor signaling pathway, and lists "FGF receptor signaling pathway" among its other names
  • GO:0070374 (1 mention) - the report calls it "positive regulation of ERK1/ERK2 cascade"; GO calls it positive regulation of ERK1 and ERK2 cascade, and lists "positive regulation of ERK1/2 cascade" among its other names
  • CL:0000134 (1 mention) - the report calls it "mesenchymal cell"; CL calls it mesenchymal stem cell
  • UBERON:0001091 (1 mention) - the report calls it "Teeth"; UBERON calls it calcareous tooth, and lists "tooth" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0000562 - called "abnormal lacrimal duct morphology", "Clinical sign"