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==Pathophysiology== | ==Pathophysiology== | ||
It is understood that fetal hydantoin syndromes is the result of infants born to mothers with [[seizure]] disorders treated with [[anticonvulsant]] medications during pregnancy are at an increased risk for [[teratogenic]] effects.<ref name="pmid23082254">{{cite journal| author=Singh R, Kumar N, Arora S, Bhandari R, Jain A| title=Fetal hydantoin syndrome and its anaesthetic implications: a case report. | journal=Case Rep Anesthesiol | year= 2012 | volume= 2012 | issue= | pages= 370412 | pmid=23082254 | doi=10.1155/2012/370412 | pmc=3469078 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23082254 }} </ref>Although the exact pathogenesis of [[phenytoin]] (PTN) embryo toxicity is not clear, some possible mechanisms have been proposed.<ref name="pmid16611127">{{cite journal| author=Webster WS, Howe AM, Abela D, Oakes DJ| title=The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin. | journal=Curr Pharm Des | year= 2006 | volume= 12 | issue= 12 | pages= 1431-48 | pmid=16611127 | doi=10.2174/138161206776389868 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16611127 }} </ref> Phenytoin inhibits [[sodium]] (Na) and [[calcium]] (Ca) channels which act as membrane stabilizers, as a result of which [[free radicals]] are released and cause endothelial damage, [[myocardial depression]], [[bradycardia]], and consequently [[fetal hypoxia]]. [[Phenytoin]] induces [[cytochrome P450]] activation which ends up within the release of [[teratogenic]] [[free radicals]], sourced via the metabolism of [[epoxides]], [[folate]], and [[vitamin K]] within the [[liver]].<ref name="pmid24323366">{{cite journal| author=Nilsson MF, Ritchie H, Webster WS| title=The effect on rat embryonic heart rate of Na+, K+, and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age. | journal=Birth Defects Res B Dev Reprod Toxicol | year= 2013 | volume= 98 | issue= 5 | pages= 416-27 | pmid=24323366 | doi=10.1002/bdrb.21084 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24323366 }} </ref><ref name="pmid11283972">{{cite journal| author=Azarbayjani F, Danielsson BR| title=Phenytoin-induced cleft palate: evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage. | journal=Teratology | year= 2001 | volume= 63 | issue= 3 | pages= 152-60 | pmid=11283972 | doi=10.1002/tera.1026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11283972 }} </ref> The characteristic features of fetal hydantoin synrome include abnormalities of [[growth]] such as pre and [[postnatal]] growth deficiency and [[microcephaly]] abnormalities of performance such as [[developmental]] delay or dull mentality to frank mental deficiency; and [[dysmorphic]] [[craniofacial]] features commonly including [[short nose]] with [[broad depressed bridge]] and inner [[epicanthic folds]], [[mild ocular hypertelorism]], [[ptosis]] of the eyelid, [[strabismus]], [[wide mouth]], [[sutural ridging]], and [[short neck]] with mild [[webbing]]; less commonly [[cleft lip]] and [[palate]] (Figs. 1,2), and limb anomalies including [[hypoplasia]] of the [[nails]] and [[distal phalanges]] with an increased frequency of low arch digital dermal ridge patterns, and fingerlike thumb (Figs. 3-5). Less commonly children displaying these dysmorphic [[craniofacial]] and limb features were reported to have major anomalies in other systems, including [[cardiac anomalies]]. It was also shown an increased incidence of major [[genitourinary]] and central nervous system anomalies, more serious limb reduction defects, and [[diaphragmatic hernia]].<ref name="pmid7131169">{{cite journal| author=Hanson JW, Buehler BA| title=Fetal hydantoin syndrome: current status. | journal=J Pediatr | year= 1982 | volume= 101 | issue= 5 | pages= 816-8 | pmid=7131169 | doi=10.1016/s0022-3476(82)80339-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7131169 }} </ref> | It is understood that fetal hydantoin syndromes is the result of infants born to mothers with [[seizure]] disorders treated with [[anticonvulsant]] medications during pregnancy are at an increased risk for [[teratogenic]] effects.<ref name="pmid23082254">{{cite journal| author=Singh R, Kumar N, Arora S, Bhandari R, Jain A| title=Fetal hydantoin syndrome and its anaesthetic implications: a case report. | journal=Case Rep Anesthesiol | year= 2012 | volume= 2012 | issue= | pages= 370412 | pmid=23082254 | doi=10.1155/2012/370412 | pmc=3469078 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23082254 }} </ref>Although the exact pathogenesis of [[phenytoin]] (PTN) embryo toxicity is not clear, some possible mechanisms have been proposed.<ref name="pmid16611127">{{cite journal| author=Webster WS, Howe AM, Abela D, Oakes DJ| title=The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin. | journal=Curr Pharm Des | year= 2006 | volume= 12 | issue= 12 | pages= 1431-48 | pmid=16611127 | doi=10.2174/138161206776389868 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16611127 }} </ref> Phenytoin inhibits [[sodium]] (Na) and [[calcium]] (Ca) channels which act as membrane stabilizers, as a result of which [[free radicals]] are released and cause endothelial damage, [[myocardial depression]], [[bradycardia]], and consequently [[fetal hypoxia]]. [[Phenytoin]] induces [[cytochrome P450]] activation which ends up within the release of [[teratogenic]] [[free radicals]], sourced via the metabolism of [[epoxides]], [[folate]], and [[vitamin K]] within the [[liver]].<ref name="pmid24323366">{{cite journal| author=Nilsson MF, Ritchie H, Webster WS| title=The effect on rat embryonic heart rate of Na+, K+, and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age. | journal=Birth Defects Res B Dev Reprod Toxicol | year= 2013 | volume= 98 | issue= 5 | pages= 416-27 | pmid=24323366 | doi=10.1002/bdrb.21084 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24323366 }} </ref><ref name="pmid11283972">{{cite journal| author=Azarbayjani F, Danielsson BR| title=Phenytoin-induced cleft palate: evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage. | journal=Teratology | year= 2001 | volume= 63 | issue= 3 | pages= 152-60 | pmid=11283972 | doi=10.1002/tera.1026 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11283972 }} </ref>The severity of associated abnormalities will vary greatly from one infant to another. The characteristic features of fetal hydantoin synrome include abnormalities of [[growth]] such as pre and [[postnatal]] growth deficiency and [[microcephaly]] abnormalities of performance such as [[developmental]] delay or dull mentality to frank mental deficiency; and [[dysmorphic]] [[craniofacial]] features commonly including [[short nose]] with [[broad depressed bridge]] and inner [[epicanthic folds]], [[mild ocular hypertelorism]], [[ptosis]] of the eyelid, [[strabismus]], [[wide mouth]], [[sutural ridging]], and [[short neck]] with mild [[webbing]]; less commonly [[cleft lip]] and [[palate]] (Figs. 1,2), and limb anomalies including [[hypoplasia]] of the [[nails]] and [[distal phalanges]] with an increased frequency of low arch digital dermal ridge patterns, and fingerlike thumb (Figs. 3-5). Less commonly children displaying these dysmorphic [[craniofacial]] and limb features were reported to have major anomalies in other systems, including [[cardiac anomalies]]. It was also shown an increased incidence of major [[genitourinary]] and central nervous system anomalies, more serious limb reduction defects, and [[diaphragmatic hernia]].<ref name="pmid7131169">{{cite journal| author=Hanson JW, Buehler BA| title=Fetal hydantoin syndrome: current status. | journal=J Pediatr | year= 1982 | volume= 101 | issue= 5 | pages= 816-8 | pmid=7131169 | doi=10.1016/s0022-3476(82)80339-9 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7131169 }} </ref> | ||
==Causes== | ==Causes== | ||
Common causes of fetal hydantoin syndrome may include [[anti-seizure]](anticonvulsant)drug [[phenytoin]] (Dilantin) during [[pregnancy]]. | Common causes of fetal hydantoin syndrome may include [[anti-seizure]](anticonvulsant)drug [[phenytoin]] (Dilantin) during [[pregnancy]].<ref name="pmid6263127">{{cite journal| author=Jimenez JF, Seibert RW, Char F, Brown RE, Seibert JJ| title=Melanotic neuroectodermal tumor of infancy and fetal hydantoin syndrome. | journal=Am J Pediatr Hematol Oncol | year= 1981 | volume= 3 | issue= 1 | pages= 9-15 | pmid=6263127 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6263127 }} </ref> | ||
==Differential Diagnosis== | |||
Revision as of 08:55, 10 May 2021
Overview
Fetal hydantoin syndrome (FHS), characterized by altered growth and development, has been well described in recent years in the fetus of epileptic mothers taking phenytoin or other hydantoin anticonvulsants during the gestational period.[1]
Historical Perspective
Fetal hydanoin syndrom was first discovered by Meadow et al. in 1968. Manson and Frederic clarified the teratogenic effects of hydantoin in their epidemiological studies in 1973.[2]
Classification
There is no established system for the classification of Fetal hydantoin syndrome.
Pathophysiology
It is understood that fetal hydantoin syndromes is the result of infants born to mothers with seizure disorders treated with anticonvulsant medications during pregnancy are at an increased risk for teratogenic effects.[3]Although the exact pathogenesis of phenytoin (PTN) embryo toxicity is not clear, some possible mechanisms have been proposed.[4] Phenytoin inhibits sodium (Na) and calcium (Ca) channels which act as membrane stabilizers, as a result of which free radicals are released and cause endothelial damage, myocardial depression, bradycardia, and consequently fetal hypoxia. Phenytoin induces cytochrome P450 activation which ends up within the release of teratogenic free radicals, sourced via the metabolism of epoxides, folate, and vitamin K within the liver.[5][6]The severity of associated abnormalities will vary greatly from one infant to another. The characteristic features of fetal hydantoin synrome include abnormalities of growth such as pre and postnatal growth deficiency and microcephaly abnormalities of performance such as developmental delay or dull mentality to frank mental deficiency; and dysmorphic craniofacial features commonly including short nose with broad depressed bridge and inner epicanthic folds, mild ocular hypertelorism, ptosis of the eyelid, strabismus, wide mouth, sutural ridging, and short neck with mild webbing; less commonly cleft lip and palate (Figs. 1,2), and limb anomalies including hypoplasia of the nails and distal phalanges with an increased frequency of low arch digital dermal ridge patterns, and fingerlike thumb (Figs. 3-5). Less commonly children displaying these dysmorphic craniofacial and limb features were reported to have major anomalies in other systems, including cardiac anomalies. It was also shown an increased incidence of major genitourinary and central nervous system anomalies, more serious limb reduction defects, and diaphragmatic hernia.[7]
Causes
Common causes of fetal hydantoin syndrome may include anti-seizure(anticonvulsant)drug phenytoin (Dilantin) during pregnancy.[1]
Differential Diagnosis
Epidemiology and Demographics
The risk of neurological impairment estimated to be 1% to 11% is 2 to 3 times higher than in the general population. The risk of oral clefts and cardiac anomalies is 5 times than others in hydantoin exposed infants. Less frequently observed abnormalities include microcephaly, ocular defects, hypospadias, umbilical and inguinal hernias.[3]
Diagnosis
Diagnostic Study of Choice
There are no established criteria for the diagnosis of fetal hydantoin syndrome.
History and Symptoms
The patient with fetal hydantoin syndrome has a positive history of exposure to phenytoin during pregnancy. Common symptoms of fetal hydantoin syndrome include microcephaly, mental retardation, limb defects including hypoplastic nails and distal phalanges, heart defects.
Physical Examination
Common physical examination findings of fetal hydantoin syndrome include
- microcephaly, distinctive facial and limb anomalies, ocular defects, growth deficiency, congenital heart defects, cardiac rhythm disturbances, and variable systemic abnormalities involving the nervous, renal, and gastrointestinal systems.
- Congenital heart diseases associated with fetal hydantoin syndrome include pulmonary or aortic valvular stenosis, coarctation of aorta, patent ductus arteriosus, and ventricular septal defects.[8]
Laboratory Findings
- ↑ 1.0 1.1 Jimenez JF, Seibert RW, Char F, Brown RE, Seibert JJ (1981). "Melanotic neuroectodermal tumor of infancy and fetal hydantoin syndrome". Am J Pediatr Hematol Oncol. 3 (1): 9–15. PMID 6263127.
- ↑ Ozkinay F, Yenigün A, Kantar M, Ozkinay C, Avanoğlu A, Ulman I (1998). "Two siblings with fetal hydantoin syndrome". Turk J Pediatr. 40 (2): 273–8. PMID 9677735.
- ↑ 3.0 3.1 Singh R, Kumar N, Arora S, Bhandari R, Jain A (2012). "Fetal hydantoin syndrome and its anaesthetic implications: a case report". Case Rep Anesthesiol. 2012: 370412. doi:10.1155/2012/370412. PMC 3469078. PMID 23082254.
- ↑ Webster WS, Howe AM, Abela D, Oakes DJ (2006). "The relationship between cleft lip, maxillary hypoplasia, hypoxia and phenytoin". Curr Pharm Des. 12 (12): 1431–48. doi:10.2174/138161206776389868. PMID 16611127.
- ↑ Nilsson MF, Ritchie H, Webster WS (2013). "The effect on rat embryonic heart rate of Na+, K+, and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age". Birth Defects Res B Dev Reprod Toxicol. 98 (5): 416–27. doi:10.1002/bdrb.21084. PMID 24323366.
- ↑ Azarbayjani F, Danielsson BR (2001). "Phenytoin-induced cleft palate: evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage". Teratology. 63 (3): 152–60. doi:10.1002/tera.1026. PMID 11283972.
- ↑ Hanson JW, Buehler BA (1982). "Fetal hydantoin syndrome: current status". J Pediatr. 101 (5): 816–8. doi:10.1016/s0022-3476(82)80339-9. PMID 7131169.
- ↑ Hegde A, Kaur A, Sood A, Dhanorkar M, Varma HT, Singh G; et al. (2017). "Fetal Hydantoin Syndrome". J Pediatr. 188: 304. doi:10.1016/j.jpeds.2017.05.018. PMID 28578158.