Lacrimo-auriculo-dento-digital (LADD) syndrome is a genetic disorder that mainly affects the eyes, ears, mouth, and hands. LADD syndrome is characterized by defects in the tear-producing lacrimal system (lacrimo-), ear problems (auriculo-), dental abnormalities (dento-), and deformities of the fingers (digital).
The lacrimal system consists of structures in the eye that produce and secrete tears. Lacrimal system malformations that can occur with LADD syndrome include an underdeveloped or absent opening to the tear duct at the edge of the eyelid (lacrimal puncta) and blockage of the channel (nasolacrimal duct) that connects the inside corner of the eye where tears gather (tear sac) to the nasal cavity. These malformations of the lacrimal system can lead to chronic tearing (epiphora), inflammation of the tear sac (dacryocystitis), inflammation of the front surface of the eye (keratoconjunctivitis), or an inability to produce tears.
Ears that are low-set and described as cup-shaped, often accompanied by hearing loss, are a common feature of LADD syndrome. The hearing loss may be mild to severe and can be caused by changes in the inner ear (sensorineural deafness), changes in the middle ear (conductive hearing loss), or both (mixed hearing loss).
People with LADD syndrome may have underdeveloped or absent salivary glands, which impairs saliva production. A decrease in saliva leads to dry mouth (xerostomia) and a greater susceptibility to cavities. Individuals with LADD syndrome often have small, underdeveloped teeth with thin enamel and peg-shaped front teeth (incisors).
Hand deformities are also a frequent feature of LADD syndrome. Affected individuals may have abnormally small or missing thumbs. Alternatively, the thumb might be duplicated, fused with the index finger (syndactyly), abnormally placed, or have three bones instead of the normal two and resemble a finger. Abnormalities of the fingers include syndactyly of the second and third fingers, extra or missing fingers, and curved pinky fingers (fifth finger clinodactyly). Sometimes, the forearm is also affected. It can be shorter than normal with abnormal wrist and elbow joint development that limits movement.
People with LADD syndrome may also experience other signs and symptoms. They can have kidney problems that include hardening of the kidneys (nephrosclerosis) and urine accumulation in the kidneys (hydronephrosis), which can impair kidney function. Recurrent urinary tract infections and abnormalities of the genitourinary system can also occur. Some people with LADD syndrome have an opening in the roof of the mouth (cleft palate) with or without a split in the upper lip (cleft lip). The signs and symptoms of this condition vary widely, even among affected family members.
LADD syndrome appears to be a rare condition; at least 60 cases have been described in the scientific literature.
Mutations in the FGFR2, FGFR3, or FGF10 gene can cause LADD syndrome.
The FGFR2 and FGFR3 genes provide instructions for making proteins that are part of a family called fibroblast growth factor receptors. The FGF10 gene provides instructions for making a protein called a fibroblast growth factor, which is a family of proteins that attaches (binds) to fibroblast growth factor receptors. The receptors are located within the membranes of cells, where they receive signals that control growth and development from growth factors outside the cell. The signals triggered by the FGFR2, FGFR3, and FGF10 genes appear to stimulate cells to form the structures that make up the lacrimal glands, salivary glands, ears, skeleton, and many other organs.
Mutations in the FGFR2, FGFR3, or FGF10 gene alter the proteins produced from these genes and disrupt the signaling within cells. As a result, cell maturation and development is impaired and the formation of many tissues is affected, leading to the signs and symptoms of LADD syndrome.
This condition is inherited in an autosomal dominant pattern, which means a mutation in one copy of the FGFR2, FGFR3, or FGF10 gene in each cell is sufficient to cause the disorder.
In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.
5. Other Names for This Condition
- Guven Y, Rosti RO, Tuna EB, Kayserili H, Aktoren O. Orodental findings of afamily with lacrimo-auriculo-dento digital (LADD) syndrome. Oral Surg Oral MedOral Pathol Oral Radiol Endod. 2008 Dec;106(6):e33-44. doi:10.1016/j.tripleo.2008.07.019.
- Inan UU, Yilmaz MD, Demir Y, Degirmenci B, Ermis SS, Ozturk F. Characteristicsof lacrimo-auriculo-dento-digital (LADD) syndrome: case report of a family andliterature review. Int J Pediatr Otorhinolaryngol. 2006 Jul;70(7):1307-14.
- Lew ED, Bae JH, Rohmann E, Wollnik B, Schlessinger J. Structural basis forreduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition andactivation. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19802-7.
- Lim LT, Blum R, Chia SN, Ting DS, Lavy TE, Dutton GN.Lacrimal-auricular-dental-digital (LADD) syndrome with diffuse ophthalmoplegia--anew finding. Semin Ophthalmol. 2012 May-Jul;27(3-4):59-60. doi:10.3109/08820538.2012.680639.
- Milunsky JM, Zhao G, Maher TA, Colby R, Everman DB. LADD syndrome is caused byFGF10 mutations. Clin Genet. 2006 Apr;69(4):349-54.
- Ramirez D, Lammer EJ. Lacrimoauriculodentodigital syndrome with cleftlip/palate and renal manifestations. Cleft Palate Craniofac J. 2004Sep;41(5):501-6.
- Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nürnberg G, Lew ED, Dobbie A,Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, LehnerdtK, Cremers CW, Yüksel-Apak M, Nürnberg P, Kubisch C, Schlessinger J, van BokhovenH, Wollnik B. Mutations in different components of FGF signaling in LADDsyndrome. Nat Genet. 2006 Apr;38(4):414-7.Genet. 2006 Apr;38(4):495. Kubisch, Chriütian [corrected to Kubisch, Christian].