Letter to the Editor

Limb Deficiencies Identified by MalformationsSurveillance Programs

To the Editor:

Yang and associates [1997] presented a carefulanalysis of how birth defects surveillance programscould be used to monitor the potential impact of tha-lidomide when this drug is reintroduced to a popula-tion that includes pregnant women as is expectedsoon in the United States. We have several concernsabout the methods used to identify cases and the re-sults that were cited. These concerns reflect our find-ings in a systematic review of all limb deficiencies iden-tified in a hospital-based malformations surveillanceprogram [Caruso et al., 1997; Nelson and Holmes,1989].

1. Exclusions. The authors excluded limb deficien-cies that were ‘‘clearly chromosomal and single genemutations.’’ We would add to this list infants withspecific syndromes not attributed to either chromo-some abnormalities or single mutant genes at thistime, such as the de Lange syndrome and the limbdeficiency associated with urethral agenesis or obstruc-tion [Perez-Aytes et al., 1993]. In our surveillanceprogram, this entire group, including specific syn-dromes, chromosome abnormalities and single genemutations, accounted for 26% of the infants with limbdeficiencies.

2. Intercalary or preaxial or both. Yang et al. notedthat the limb deficiencies produced by thalidomide are‘‘frequently of the intercalary type.’’ The definition pro-vided for intercalary was ‘‘when proximal parts oflimbs (e.g., humerus, radius and ulna) were absent orseverely hypoplastic, while distal structures (e.g.,hand) were totally or partially present.’’ We find thatthe words ‘‘partially present’’ make it difficult to dis-tinguish between intercalary and preaxial. To ensurethe delineation of this group of phenotypes, we suggestthat the definition be: ‘‘absence or hypoplasia of abone(s) when the distal boney elements or nails arepresent and not hypoplastic.’’ Using this definition, we

have found that there is a small group of individualswith intercalary defects such as (a) shortening of theproximal phalanges of the third fingers; (b) shorteningof the middle phalanges, with normal fingernails; and(c) absence of the radius with a normal thumb. Overallthe intercalary group accounted for 12% (n 4 13) ofall limb deficiencies in our hospital-based series (n 4108).

3. The authors noted that the birth prevalencerates of all limb deficiencies showed a ‘‘slight declinesince 1968, from about 0.7/1000 in the early 1970sto about 0.5/1000 in the early 1990s.’’ One explanationfor this not-so-slight decline could be the impact of elec-tive terminations of pregnancies in which prenatalstudies had identified the presence of a limb deficiency.In our study 22 (20%) of the 108 infants and fetuseswith limb deficiencies were identified among womenwho had planned to deliver at Brigham and Women’sHospital were in pregnancies that were terminatedelectively. Only 7 of the 22 were terminated by aninfusion procedure, which allowed for the completecharacterization of all limb and other abnormalities.Based on our experience, we recommend that surveil-lance programs used to monitor significant exposures,such as thalidomide, should be used only if electiveterminations of pregnancy are identified and included.One would expect the health care providers of thewomen who take thalidomide to monitor the pregnancyfor evidence of fetal abnormalities and if found, electiveterminations would be the outcome in a significantnumber.

We applaud Yang et al. [1997] for beginning the pro-cess of planning for the potential effects of the reintro-duction of thalidomide. We can hope that most, if notall, women who take thalidomide will be enrolled in asupportive, comprehensive health care program. Inturn, this would allow for a more thorough evaluationof all thalidomide-exposed infants rather than havingto rely on more indirect monitoring by a malformationssurveillance program.

REFERENCES

Caruso T, Westgate M-N, McGuirk C, Holmes LB (1997): Prevalence oflimb deficiency in newborn infants. Teratology 55:37.

*Correspondence to: Lewis B. Holmes, Genetics and TeratologyUnit, Pediatric Service, Massachusetts General Hospital, Warren801, 55 Fruit St., Boston, MA 02114-2696.

Received 10 August 1998; Accepted 26 August 1998

American Journal of Medical Genetics 80:541–542 (1998)

© 1998 Wiley-Liss, Inc.

Nelson K, Holmes LB (1989): Malformations due to presumed spontaneousmutations in newborn infants. N Engl J Med 320:19–23.

Perez-Aytes A, Graham JM, Hersh JH, Hoyme HE, Aleck K, CareyJC (1993): Urethral obstruction sequence and lower limb deficiency:Evidence for the vascular disruption hypothesis. J Pediatr 123:398–405.

Yang Q, Khoury MJ, James LM, Olney RS, Paulozzi LJ, Erickson JD(1997): The return of thalidomide: Are birth defects surveillance sys-tems ready? Am J Med Genet 73:251–258.

Lewis B. Holmes*Caroline K. McGuirkJoan M. StolerGenetics and Teratology UnitPediatric ServiceMassauchusetts General HospitalBoston, Massachusetts

Ellice LiebermanMaternal-Fetal MedicineDepartment of Obstetrics and GynecologyBrigham and Women’s HospitalBoston, Massachusetts

542 Holmes et al.