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. More than 50 cases have been reported in the medical literature since the disorders first description in 1967.
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.
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