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Fetal Retinoid Syndrome

Synonyms of Fetal Retinoid Syndrome

  • Accutane Embryopathy
  • Accutane, Fetal Effects of
  • Isotretinoin Embryopathy
  • Isotretinoin, Fetal Effects of
  • Isotretinoin Teratogen Syndrome
  • Retinoic Acid Embryoppathy

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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.

Symptoms

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).

Causes

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.

Affected Populations

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.

Related Disorders

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

DiGeorge syndrome is a rare immunodeficiency disorder characterized by various congenital abnormalities that develop because of defects that occur during early fetal development. These defects occur in areas known as the 3rd and 4th pharyngeal pouches, which later develop into the thymus and parathyroid glands. Developmental abnormalities may also occur in the 4th branchial arch. Normally 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. The thymus and parathyroid glands are missing or underdeveloped in children with DiGeorge syndrome. The symptoms of this disorder vary greatly, depending upon the extent of the missing thymus and parathyroid tissue. The primary problem caused by DiGeorge syndrome is the repeated occurrence of various infections due to a diminished immune system. (For more information on this disorder, choose "DiGeorge syndrome" as your search term in the Rare Disease Database.)

CHARGE syndrome is a rare disorder that arises during early fetal development and affects multiple organ systems. The term CHARGE comes from the first letter of some of the more common features seen in these children: (C) = coloboma and cranial nerve abnormalities, defects of the eyeball; (H) = heart defects; (A ) = atresia of the choanae (blocked nasal breathing passages); (R) = retardation of growth and development; (G) = genital and urinary abnormalities; (E) = ear abnormalities and hearing loss. Diagnosis is based on a different set of features (see below). In addition to the CHARGE features, most children with CHARGE syndrome have other features, including characteristic facial features, cleft lip or palate, esophageal atresia (blind-ending food pipe) or tracheoesophageal fistula (connection between the wind pipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another. The exact cause of CHARGE is not known. Most cases occur randomly, for no apparent reason (sporadic). There are a few familial cases. (For more information on this disorder, choose "CHARGE" as your search term in the Rare Disease Database.)

Goldenhar syndrome, a term that is often used synonymously with "Oculo-Auriculo-Vertebral (OAV) Spectrum," is a rare disorder that is apparent at birth (congenital). The disorder is characterized by a wide spectrum of symptoms and physical features that may vary greatly in range and severity from case to case. However, such abnormalities tend to involve the cheekbones, jaws, mouth, ears, eyes, and/or bones of the spinal column (vertebrae). Although, in most cases, such malformations affect one side of the body (unilateral), approximately 10 to 33 percent of affected individuals have such malformations on both sides of the body (bilateral), with one side typically more affected than the other (asymmetry). In the majority of such cases, the right side is more severely affected than the left. Due to craniofacial malformations, an affected individual's face may appear smaller on one side than the other (hemifacial microsomia); in addition, if both sides are affected (bilateral), the face may appear dissimilar from one side to the other (facial asymmetry). Craniofacial abnormalities may include underdevelopment of the cheekbones (malar hypoplasia), bones of the upper and lower jaws (maxillary and mandibular hypoplasia), and the bones forming a portion of the lower skull (temporal hypoplasia); incomplete development of certain muscles of the face; an abnormally wide mouth (macrostomia); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and/or abnormalities of the teeth. Affected individuals may also exhibit absence (anotia) and/or malformation (microtia) of the outer ears (auricles or pinnae); narrow, blind ending, or absent external ear canals (atresia); abnormal outgrowths of skin and cartilage on or in front of the ears (preauricular tags); and/or abnormalities affecting the middle and/or inner ears, contributing to or resulting in hearing impairment (i.e., conductive and/or sensorineural hearing loss). In most cases, Goldenhar syndrome (OAV Spectrum) appears to occur randomly, with no apparent cause (sporadic). (For more information on this disorder, choose "Goldenhar" as your search term in the Rare Disease Database.)

Standard Therapies

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.

Investigational Therapies

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

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Fetal Retinoid Syndrome

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., heart disease, etc.)

References

TEXTBOOKS
Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:722-3.

Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:572.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:21.

Magalini SI, et al., eds. Dictionary of Medical Syndromes. 4th ed.New York, NY: Lippincott-Raven Publishers; 1997:283.

JOURNAL ARTICLES
Moerike S, et al. Temporal bone pathology in fetuses exposed to isotretinoin. Pediatr Dev Pathol. 2002;5:405-9.

Nau H. Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol. 2001;45:S183-7.

Lammer EJ. Longitudinal study of infants exposed to isotretinoin (13-cis-retinoic acid) in utero. Toxicologist. 1997;36:54.

Guillonneau M, Jacqz-Aigrain E. Teratogenic effects of vitamin A and its derivatives. Arch Pediatr. 1997;4:867-74.

Coberly S, et al. Retinoic acid embryopathy: case report and review of literature. Pediatr Pathol Lab Med. 1996;16:823-36.

Benifla JL, et al. Fetal tissue dosages of retinoids. Experimental study concerning a case of isotretinoin (Roaccutan) administration and pregnancy. Fetal Diagn Ther. 1995;10:189-91.

Adams J, Lammer EJ. Human isotretinoin exposure: the teratogenesis of a syndrome of cognitive deficits. Neurotoxicol Teratol. 1995;17:386.

Heckel S, et al. Teratogenicity of retinoids. A case and review of literature. J Dynecol Obstet Biol Reprod (Paris). 1993;22:43-47.

Ayme S, et al. Isotretinoin dose and teratogenicity. Lancet. 1988;1:655.

Stern RS, et al. Isotretinoin and pregnancy. J Am Acad Dermatol. 1984;10:851-54.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2003/05/29 00:00:00 GMT+0

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