Information on the following diseases can be found in the Related Disorders section of this report:

• Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome
• Split-Hand Deformity
• Ectodermal Dysplasias

The symptoms of LADD syndrome may greatly vary from case to case. Abnormalities may potentially affect multiple organ systems of the body including the eyes, ears, teeth, and limbs.

Malformations in the network of structures of the eye that secrete tears and drain them from the eyes are often found with LADD syndrome. These malformations may include an underdeveloped (hypoplastic) or missing (aplastic) opening in the edge of each eyelid that is linked to the tear duct (lacrimal puncta) and/or an obstruction of the channel that carries tears from the tear sac to the nasal opening (nasolacrimal duct). Absence of the lacrimal puncta is associated with excessive tearing (epiphora), inflammation of the tear sac (dacryocystitis), and keratoconjuntivitis, a condition marked by dryness and inflammation of the cornea and the membrane lining the eyes (conjunctiva). In some cases, underdevelopment or absence of the tear sacs may occur resulting in an absence of tears (alacrima) and dry eyes (xerophthalmia). Less often, an abnormal passage (fistula) from the tear sac to the nasal opening may develop.

Underdevelopment or absence of the salivary glands including the parotid and submandibular glands may occur. The parotid glands are located in front and below the ears and secrete saliva into the mouth. The submandibular glands are located underneath the tongue and also secrete saliva into the mouth. Salivary gland abnormalities may result in dry mouth (xerostomia) and a susceptibility to severe tooth cavities (caries). Affected individuals may also have small, underdeveloped (hypoplastic) teeth with thin enamel, peg-shaped incisors, and delayed eruption of primary teeth.

Individuals with LADD syndrome may have cup-shaped, low-set ears. Hearing loss, which has ranged from mild to severe, has also been reported. Hearing loss may due to blockage of sound waves (conductive), nerve impairment (sensorineural) or both (mixed).

Abnormalities affecting the forearms and hands occur in most individuals with LADD syndrome. The tip of the thumb may be clefted or split in two (bifid thumb) and three bones (phalanges) may be found in the thumb instead of two (triphalangeal thumb). In some cases, the thumb may be underdeveloped or absent. Additional abnormalities may occur including shortening of the forearm bones (radius and ulna), webbing of the index and middle fingers, and abnormal curving of the pinky toward the ring finger (clinodactyly). In some cases, toe abnormalities have also been reported.

Additional findings have been reported in some individuals with LADD syndrome including widely-spaced eyes (hypertelorism), abnormally increased distance between the inner corners of the eyes (telecanthus), downward slanting eyelid folds (palpebral fissures), and a broad forehead. Split-hand deformity has been reported in some cases. Abnormalities of genitourinary system may also occur including the abnormal location of the urethral opening on the underside of the penis (hypospadias), hardening of the kidneys (neprhosclerosis), abnormal accumulation of urine in the kidneys (hydronephrosis) or absence (agenesis) of a kidney.

LADD syndrome may occur randomly as the result of a spontaneous genetic change (i.e., new mutation). The mutation is inherited in an autosomal dominant fashion. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that LADD syndrome occurs due to disruption or changes (mutations) in one of at least three genes-the fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4 (4p13) and fibroblast growth factor 10 (FGF10) gene located on chromosome 5 (5p13-p12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 5p13-p12" refers to bands 13-12 on the short arm of chromosome 5. The numbered bands specify the location on each chromosome.

LADD syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature since the disorders first description in 1967.

Symptoms of the following disorders can be similar to those of LADD syndrome. Comparisons may be useful for a differential diagnosis.

Aplasia of the lacrimal and salivary glands (ALSG) is a rare genetic disorder characterized by absence (aplasia) or underdevelopment (hypoplasia) of the glands that secrete tears (lacrimal glands) and secrete saliva (salivary glands). Affected individuals may develop dry eyes (xerophthalmia) or dry mouth (xerostomia). These conditions may cause affected individuals to develop scarring of the membrane lining the eye (conjunctiva), dental erosion, gum (periodontal) disease and may make individuals extremely susceptible to developing cavities (dental caries). Inflammation of the tear sac (dacryocystitis) may also occur. Researchers believe that ALSG and some cases of LADD syndrome are allelic disorders meaning that they are caused by different mutations of the same gene (FGF10). ALSG is inherited as an autosomal dominant disorder.

EEC syndrome, also known as ectrodactyly-ectodermal dysplasia-cleft lip/palate, is a rare genetic disorder that may be characterized by absence of all or a portion of one or more fingers and/or toes (ectrodactyly) or other digital malformations; incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip); and/or other characteristic abnormalities. Additional symptoms and findings often include fine, sparse, abnormally light (hypopigmented) scalp hair and eyebrows; absent eyelashes; and/or abnormalities of the tear (lacrimal) ducts that may cause abnormal tearing, increased susceptibility to eye infections, and chronic inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis), potentially causing visual impairment. Affected individuals may also exhibit irregularities of the nails (nail dysplasia); absence and/or abnormal smallness of certain teeth (hypodontia and/or microdontia); a decreased number of hair follicles and/or sebaceous glands; and, in some cases, skin abnormalities including unusual dryness of the skin and scaling, itchy (pruritic) skin rashes. In many cases, additional symptoms and findings may be associated with EEC syndrome including absence of the mucous membrane normally lining the voice box (larynx), causing abnormal breathiness of the voice; abnormalities of the urinary tract; deafness; and/or other abnormalities. The range and severity of symptoms and physical findings associated with the disorder vary widely from case to case. EEC syndrome is inherited as an autosomal dominant disorder and mostly occurs due to new mutations. (For more information on this disorder, choose "ectrodactyly ectodermal" as your search term in the Rare Disease Database.)

Research molecular testing for LADD syndrome is available by contacting:
Jeff Milunsky, M.D.
Associate Director, Center for Human Genetics
Director, Clinical Genetics
Boston University School of Medicine
715 Albany St. W-408
Boston, MA 02118
Phone: 617-638-7083
Fax: 617-638-7092

The treatment of LADD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, specialists who asses and treat hearing problems (audiologists), eye specialists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

Specific treatment options may include surgery, when appropriate, to relieve the discomfort causing by malfunctioning parts of the lacrimal apparatus or to correct abnormalities of the fingers, toes and forearms. Hearing aids may benefit some individuals with hearing loss. Dental care is required on a regular basis. Artificial tear substitutes may be used to treat dry eyes.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

TEXTBOOKS
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:1117-9.

Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:318.

JOURNAL ARTICLES
Milunsky JM, Zhao G, Maher RA, Colby R, Everman DB. LADD syndrome is caused by FGF10 mutations. Clin Genet. 2006;69:349-54.

Rohmann E, Brunner HG, Kayserili H, et al., Mutations in different components of FGF signaling in LADD syndrome. Nat Genet. 2006;38:414-7.

Cortes M, Lambiase A, Sacchetti M, Aronni S, Bonini S. Limbal stem cell deficiency associated with LADD syndrome. Arch Ophthalmol. 2005;123:691-4.

Wiedemann HR. Salivary gland disorders and heredity. Am J Med Genet. 1997;68:222-24.

Lacombe D, Serville F, Marchand D, Battin J. Split hand/split foot deformity and LADD syndrome in a family: overlap between the EEC and LADD syndromes. J Med Genet. 1993;30:700-03.

ON THE INTERNET
LADD Syndrome. Orphanet encyclopedia, March 2006. Available at: http://www.orpha.net/consor/cgi-bin/home.php?Lng=GB Accessed on: May 29, 2006.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:149730; Last Update:06/06/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=149730 Accessed on: May 29, 2007.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:180920; Last Update:06/06/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=180920 Accessed on: May 29, 2007.