Fetal retinoid syndrome is a characteristic pattern of mental and physical birth defects that results from maternal use of retinoids, the synthetic derivatives of vitamin A, during pregnancy. The most well known retinoid is isotretinoin (Accutane), a drug used to treat severe cystic acne. The range and severity of associated abnormalities will vary greatly from case to case. However, characteristic features may include growth delays before and after birth (prenatal and postnatal growth retardation); malformations of the skull and facial (craniofacial) region; central nervous system abnormalities; heart abnormalities; and/or additional physical findings.
Characteristic features of infants with fetal retinoid syndrome include abnormalities of the head and face (craniofacial) region, central nervous system, and cardiovascular system. The specific symptoms and physical findings will vary from one infant to another. Affected infants will not have all of the symptoms listed below. For example, an affected infant may have below average intelligence and learning disabilities, but no major structural abnormalities; another infant may have serious medical complications.
Affected infants often display small, low-set ears (microtia) with narrowing (stenosis) of the ear canals. Abnormalities of the middle and inner ears may also be present. Additional craniofacial findings include widely spaced eyes (hypertelorism), incomplete closure of the roof of the mouth (cleft palate), an abnormal groove in the upper lip (cleft lip), and/or underdevelopment of the middle area of the face (midface hypoplasia). In some cases, affected infants may experience paralysis (palsy) of certain facial nerves. Affected infants may also have a condition known as microcephaly, which indicates that the head circumference is smaller than would be expected for age and sex.
Some infants with fetal retinoid syndrome will develop cardiovascular abnormalities including structural (anatomical) malformations of the heart including transposition of the great vessels; hypoplastic left heart syndrome; ventricular septal defects (VSDs); and a condition known as tetralogy of Fallot. Hypoplastic left heart syndrome is characterized by underdevelopment of the left ventricle, the aortic and/or mitral valves, and the ascending aorta.
VSDs are abnormal openings that may occur in any portion of the ventricular septum, the fibrous partition that divides the heart’s two lower chambers (ventricles). The size and location of the defect determine the severity of the symptoms. Small VSDs may close without treatment (spontaneously) or become less significant as affected children mature and grow. Due to moderately-sized defects, the heart may be unable to pump blood effectively (congestive heart failure), resulting in an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), and/or failure to grow and gain weight at the expected rate (failure to thrive). In some cases, without appropriate treatment, large VSDs may cause life-threatening complications during infancy.
Tetralogy of Fallot is a rare form of cyanotic heart disease. Cyanosis is abnormal bluish discoloration of the skin and mucous membranes that occurs due to low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs due to an abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis); a displaced aorta that causes blood to flow into the aorta from both the right and left ventricles; and abnormal enlargement of the right ventricle.
Some infants with fetal retinoid syndrome may develop central nervous system abnormalities including a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain, resulting in a variety of symptoms (hydrocephalus). Affected infants may also develop cysts in an area of the brain that houses the brainstem and cerebellum (posterior fossa). Infants with fetal retinoid syndrome may have below average intelligence, experience learning disabilities, and exhibit delays in reaching developmental milestones such as sitting or crawling. In some cases, the forebrain (prosencephalon) may fail to develop (holoprosencephaly).
Infants with fetal retinoid syndrome often experience abnormalities of thymus function. The thymus gland is located below the thyroid gland in the neck and front of the chest and is the primary gland of the lymphatic system, which is necessary for the normal functioning of the immune system. The parathyroid glands, located on the sides of the thyroid gland, are responsible for the maintenance of normal levels of calcium in the blood.
Additional abnormalities that may occur in some cases include webbing of the fingers (syndactyly), skeletal malformations affecting the legs and spines, and/or low muscle tone (hypotonia).
Maternal use of synthetic vitamin A (retinoids) such as isotretinoin (Accutane) during pregnancy can result in multiple effects on the developing embryo and fetus including miscarriage, premature delivery and a variety of birth defects. Additional retinoids include actiretin (Soriatane), etretinate (Tegison), and retinoin (Vesanoid).
A heightened risk of birth defects exists in women who become pregnant while taking retinoids such as Accutane. There is disagreement in the medical literature as to the specific risks present. One source in the medical literature estimated that a 35 percent risk of fetal retinoid syndrome exists in children of women who take Accutane beyond the 15th day following conception. Some researchers believe that birth defects do not occur in women who discontinue Accutane use one month before conception. It is also unknown what specific dosage of retinoids may result in birth defects. Some women taking low doses of retinoids have had children with severe symptoms of fetal retinoid syndrome. More research is necessary to determine the specific risks and long-term effects of taking retinoids such as isotretinoin (Accutane) during pregnancy.
The structures of the body most often affected in infants with fetal retinoid syndrome are the brain, the heart, and craniofacial structures especially the ears and palate.
Fetal retinoid syndrome affects males and females in equal numbers. The exact incidence of fetal retinoid syndrome is unknown and because many cases of fetal retinoid syndrome often go unrecognized, the disorder is under-diagnosed, making it difficult to determine the true frequency of the disorder in the general population.
According to the medical literature, women who are considering taking isotretinoin (Accutane) must first be given a pregnancy test approximately two weeks to a month before starting therapy. Woman on Accutane are encouraged to use two forms of contraception.
The treatment of fetal retinoid 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, cardiologists, specialists who asses and treat hearing problems (audiologists), eye specialists, and additional health care professionals may need to systematically and comprehensively plan an affected child's treatment.
Other treatment is symptomatic and supportive.
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