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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

Fetal hydantoin syndrome may be caused by a combination of specific genetic and environmental factors.Common causes of fetal hydantoin syndrome may include anti-seizure(anticonvulsant) drug phenytoin (Dilantin) during pregnancy.[1]

Differential Diagnosis

Fetal hydantoin syndrome must be differentiated from other diseases that cause Hypoplastic nails and growth retardation along with some similar facial features are also found in the Coffin-Siris,[8] Hypopiasia of distal phalanges in Noonan's syndrome and Nail hypoplasia in Robinson's disease[9]

Epidemiology and Demographics

The exact incidence and prevalence of the fetal hydantoin syndrome is unknown.The risk appears to be 2-3 times greater than normal in the children of epileptic women taking anticonvulsant drugs than in the general population[10]. 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]Fetal hydantoin syndrome affects males and females equally.

Risk factors

Common risk factors in the development of fetal hydantoin syndrome include exposure of fetus to antiepileptic drugs phenytoin(Dilantin)

Diagnosis

Diagnostic Study of Choice

There are no established criteria for the diagnosis of fetal hydantoin syndrome. The diagnosis is based on the clinical features along with a history of phenytoin exposure during pregnancy.[9]

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

Laboratory Findings

  1. 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.
  2. 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. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Hanson JW, Smith DW (1975). "The fetal hydantoin syndrome". J Pediatr. 87 (2): 285–90. doi:10.1016/s0022-3476(75)80604-4. PMID 50428.
  9. 9.0 9.1 Nanda A, Kaur S, Bhakoo ON, Kapoor MM, Kanwar AJ (1989). "Fetal hydantoin syndrome: a case report". Pediatr Dermatol. 6 (2): 130–3. doi:10.1111/j.1525-1470.1989.tb01011.x. PMID 2501774.
  10. Speidel BD, Meadow SR (1972). "Maternal epilepsy and abnormalities of the fetus and newborn". Lancet. 2 (7782): 839–43. doi:10.1016/s0140-6736(72)92209-x. PMID 4116552.
  11. 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.