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Last updated:
March 12, 2018
Years published: 1993, 2001, 2015, 2018
NORD gratefully acknowledges Kimford J. Meador, MD, Professor, Department of Neurology & Neurological Sciences, Stanford Comprehensive Epilepsy Center, Stanford University School of Medicine, for assistance in the preparation of this report.
Summary
Fetal hydantoin syndrome is a characteristic pattern of mental and physical birth defects that results from maternal use of the anti-seizure (anticonvulsant) drug phenytoin (Dilantin) during pregnancy. The range and severity of associated abnormalities will vary greatly from one infant to another. However, characteristic features may include distinctive skull and facial features, growth deficiencies, underdeveloped (hypoplastic) nails of the fingers and toes, and/or mild developmental delays. Other findings occasionally associated with this syndrome include cleft lip and palate, a head circumference that is smaller than would be expected based upon an infant’s age and gender (microcephaly), and skeletal malformations particularly of the fingers or hands. The exact risk of a fetus developing fetal hydantoin syndrome is not fully understood, but only approximately 5-10% of fetuses exposed to phenytoin develop the disorder.
Introduction
Anti-seizure medications, also known as antiepileptic or anticonvulsant medications are among the most common teratogens prescribed to women of childbearing age. A teratogen is a drug that interferes with the development of a fetus. Affected infants often develop similar symptoms regardless of the associated drug, particularly symptoms affecting the head and face region (craniofacial abnormalities). Studies have indicated that fetal valproate syndrome is associated with greater risk of neurological and cognitive abnormalities than other anti-seizure medications. NORD has a separate report on fetal valproate syndrome.
Although some disorders due to specific drugs (e.g. fetal hydantoin syndrome) are rare, many researchers believe that when considering the teratogenic effects of all antiepileptic drugs collectively these disorders are not rare. The concept of fetal antiepileptic syndromes in this regard is less useful than in the past and the broad consideration of the major and minor congenital malformations, various cognitive impairments, and behavioral abnormalities taken as a broader, collective concept is more appropriate.
The specific symptoms and physical features associated with fetal hydantoin syndrome can vary greatly from one infant to another. Symptoms may not be noticeable at birth (congenital), but will become apparent as an affected child grows older.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of genes or other factors influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
Affected infants may be small at birth due to growth deficiency during development (prenatal growth deficiency). Growth deficiency may be mild to moderate in severity and can continue during the newborn period (postnatal growth deficiency).
Distinctive facial features may be present including a flat, broad bridge of the nose; a short nose; eyes that are farther apart from each other than usual (hypertelorism); crossed eyes (strabismus); eyelids that droop (ptosis); a large, wide mouth; malformed ears; mild webbing of the neck (pterygium colli); and microcephaly. Affected infants often have a gap or cleft of missing tissue of the upper lip (cleft lip) and/or a gap or cleft of missing tissue on the roof of the mouth (cleft palate).
Affected infants may also exhibit stiff, tapered fingers, underdeveloped fingers and toes, toes that resembled fingers (digitalized toes), and malformed, underdeveloped fingernails and toenails. An increased number of fingerprint arches have also been noted. Some infants may have increased hair on the body and face.
Some infants and children may experience delays in reaching developmental milestones such as learning to sit up or crawl (developmental delays). As affected children grow older, the developmental delays improve, but studies suggest that children may remain slightly behind unexposed siblings. The neurological effects of phenytoin exposure in utero have not been clearly established by studies, which have demonstrated conflicting results. Borderline to mild intellectual disability has been reported in some cases, and some studies have suggested that children exposed to phenytoin in the womb have a greater risk of developing learning disabilities, particularly in verbal skills. Reports in the medical literature disagree as to the likelihood of infants with fetal hydantoin syndrome experiencing developmental delays or intellectual disability. The exact risk of these findings in these children is not fully understood. More research is necessary to determine the specific long-term risks in neurological development of infants and children exposed to phenytoin in utero.
Additional symptoms occurring with varying frequencies have been reported in the medical literature including congenital heart defects, cardiac rhythm disturbances, behavioral abnormalities such as attention deficit hyperactivity disorder, ocular defects including nearsightedness (myopia), joint laxity, kidney abnormalities, and inguinal and umbilical hernia. Inguinal hernia is when a portion of the intestines pushes through the muscular layers of the abdominal wall. An umbilical hernia is when the intestines or fatty tissue pushes through the area near the bellybutton.
Case reports in the medical literature have suggested that infants with fetal hydantoin syndrome may be at an increased risk for the occurrence of certain benign or malignant tumors such as neuroblastoma, Wilm’s tumor, or ectodermal tumors, but such an increased risk is not proven.
Maternal use of anti-seizure medications such as phenytoin, which is often used to treat epileptic seizures, can result in multiple effects on the developing embryo and fetus, including fetal hydantoin syndrome. The specific amount of phenytoin ingestion required to cause the disorder has not been determined. Phenytoin is often given with other anti-seizure drugs and other (adjunct) medications that may influence development of the disorder. Fetal hydantoin syndrome may be caused by a combination of specific genetic and environmental factors.
It is not known whether the adverse effects of phenytoin during fetal development are due to the drug itself or if they are caused by one of phenytoin’s by-products (metabolites). In addition, the potential role of other factors remains unclear, such as genetic influences that affect phenytoin metabolism or additional environmental factors (e.g. smoking). There have been reports in the medical literature that women with mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are at an increased risk of having an infant with fetal hydantoin syndrome. Researchers believe that the protein product of this gene plays a role in the proper breakdown (metabolism) of phenytoin or one of its metabolites.
Another theory speculates that intermediate metabolites of phenytoin are responsible for its teratogenesis. These intermediate metabolites are free radicals that bind to DNA, proteins and lipids adversely affecting neurodevelopment. Genetic differences in formation of these free radicals, drug clearance, and repair mechanisms may explain different susceptibility across individuals.
Determining the precise, underlying reasons why fetal hydantoin syndrome develops, requires further research to discover the specific genetic and environmental factors that play a role in the development of the disorder.
Fetal hydantoin syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder is unknown. Studies have suggested that approximately 5%-10% of infants exposed to phenytoin during pregnancy will develop fetal hydantoin syndrome.
There is no diagnostic testing that can identify fetal hydantoin syndrome. A diagnosis is made clinically based upon identification of characteristic symptoms in an affected infant in conjunction with a history of phenytoin exposure during gestation. It is important to note that the majority of infants born to women who take phenytoin during pregnancy will not develop fetal hydantoin syndrome.
Prevention
It is recommended that women be treated with a single anticonvulsant prior to conception and throughout pregnancy, since it appears that children exposed to multiple anticonvulsants may be at a greater risk for significant birth defects.
Also, it is recommended that women taking phenytoin take folic acid supplements, both before conception and during pregnancy as a preventive measure against malformations.
Counseling is recommended for women to discuss the risks that seizures prevent for both the developing fetus and the expectant mother as well as the risks to the developing fetus involved with taking anti-seizure medications during pregnancy.
Treatment
The treatment of fetal hydantoin 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, oral surgeons, plastic surgeons, neurologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Infants with fetal hydantoin syndrome can benefit from early developmental intervention to ensure that affected children reach their potential. Affected children may benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Additional medical, social and/or vocational services may be necessary. Psychosocial support for the entire family is essential as well.
When cleft lip and/or palate are present, the coordinated efforts of a team of specialists may be used to plan an affected child’s treatment and rehabilitation. Cleft lip may be surgically corrected. Generally surgeons repair the lip when the child is still an infant. A second surgery is sometimes necessary for cosmetic purposes when the child is older. Cleft palate may be repaired by surgery or covered by an artificial device (prosthesis) that closes or blocks the opening. Surgical repair can be carried out in stages or in a single operation, according to the nature and severity of the defect. The first palate surgery is usually scheduled during the toddler period.
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
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Jones KL, Jones MC, del Campo Casanelles. Eds. Fetal Hydantoin Syndrome (Fetal Dilantin Syndrome). In: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:734.
Rodeck CH, Whittle MJ. Eds. Fetal Anticonvulsant Syndromes. In: Fetal Medicine: Basic Science and Clinical Practice. 2nd ed. Churchill Livingston Elsevier; 2009:173.
Buehler BA, Finnell R. Fetal Hydantoin Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:192-193.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Hydantoin Embryopathy. In: Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:21-22.
JOURNAL ARTICLES
Bromley R, Weston J, Adab N, et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst Rev. 2014;10. https://www.ncbi.nlm.nih.gov/pubmed/25354543
Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12:244-252. https://www.ncbi.nlm.nih.gov/pubmed/23352199
Cohen MJ, Meador KJ, Browning N, et al. Fetal antiepileptic drug exposure: adaptive and emotional/behavioral functioning at age 6 years. Epilepsy Behav. 2013;29:308-315. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902100/
Meador KJ, Baker GA, Browning N, et al. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age. Brain. 2011;134:396-404. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030767/
Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy – focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Neurology. 2009;73:133-141. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475194/
Meador KJ, Baker G, Cohen MJ, Gaily E, Westerveld M. Cognitive/behavioral teratogenetic effects of antiepileptic drugs. Epilepsy Behav. 2007;11:292-302. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713059/
Mowery TM, McDowell AL, Garraghty PE. Chronic developmental exposure to phenytoin has long-term behavioral consequences. Int J Dev Neurosci. 2008;26:401-407. https://www.ncbi.nlm.nih.gov/pubmed/18455350
Dean J, Robertson Z, Reid V, et al. Fetal anticonvulsant syndromes and polymorphisms in MTHFR, MTR, and MTRR. Am J Med Genet A. 2007;143A:2303-2311. https://www.ncbi.nlm.nih.gov/pubmed/17853476
Oguni M, Osawa M. Epilepsy and pregnancy. Epilepsia. 2004;45:37-41. https://www.ncbi.nlm.nih.gov/pubmed/15610193
Moore S, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37:489-497. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734633/
Dean JC, Moore SJ, Osborne A, Howe J, Turnpenny PD. Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene. Clin Genet. 1999;56:216-220. https://www.ncbi.nlm.nih.gov/pubmed/10563481
Beuhler BA, Rao V, Finnell RH. Biochemical and molecular teratology of fetal hydantoin syndrome. Neurol Clin. 1994;12:741-748. https://www.ncbi.nlm.nih.gov/pubmed/7845340
Buehler BA, Delimont D, van Waes M, Finnell RH. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med.1990;322:1567-1572. https://www.ncbi.nlm.nih.gov/pubmed/2336087
INTERNET
Caughey AB. Seizure Disorders in Pregnancy.Medscape. May 02, 2016. Available at: https://emedicine.medscape.com/article/272050-overview#a1 Accessed March 7, 2018.
Robert-Gnansia E. Fetal Hydantoin Syndrome. Orphanet Encyclopedia, February 2006. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1912 Accessed March 7, 2018.
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