Rheumatology Case Report: Hand Abnormalities Feature of Fetal Hydantoin Syndrome

A case was reported in the orthopedic literature showing hip dysplasia discovered in a 23-year-old male with hypoplasia of fingernails and distal tapering of fingers due to fetal hydantoin syndrome.⁶ However, the same patient also had mild mental retardation, which fortunately was not the case in our patient.

Fetal hydantoin syndrome affects males and females in equal numbers. The exact incidence and prevalence of the disorder are unknown. Various studies have suggested an approximate incident rate of 5–10% of fetal hydantoin syndrome in infants exposed to phenytoin in utero.

No diagnostic testing 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 has been also noted that the majority of infants born to women who take pheny­toin during pregnancy will not develop fetal hydantoin syndrome. It is not clear 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 metabolites. The potential role of other factors, such as genetic influences that affect phenytoin metabolism or additional environmental factors (e.g., smoking), remains unclear. 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.

Evidence is accumulating from clinical reports and animal experiments to support the notion that mild distal digital hypoplasia is a relatively specific marker for in utero exposure to the drug. More severe digital involvement has also been identified, although to a lesser extent, in animal experiments and in only a few humans exposed to the drug in utero.

Apart from digital involvement, an association between in utero exposure to diphenyl-hydantoin and more proximal (carpal metacarpal) anomalies has yet not been reported.⁷ The frequent finding of low arch dermal ridge patterning on affected fingertips indicates that the fetal fingertip pads were hypoplastic by 15–20 weeks of fetal life, the age when dermal ridge development and patterning is established. The severity of defects varies from the more common mild hypoplasia of nails and distal phalanges, as in our patient, to the more unusual gross deficiency of whole digits, as reported in some cases.⁸