Congenital Malformations

Recognition of birth defects caused by thalidomide

Thalidomide is a teratogenic drug, meaning that when taken while pregnant, it can have terrible impacts on fetal development and cause irreversible damages.

Phocomelia, a limb atrophy, is the most common malformation linked to thalidomide, but all phocomelia cases aren’t caused by thalidomide. However, due to the notoriety of the thalidomide tragedy, many people have started to associate it exclusively with thalidomide. As a matter of fact, we often hear that persons with phocomelia are “like thalidomiders”, which gives the wrong impression that thalidomide is always involved.

Before considering thalidomide to be the cause of a malformation, regardless of the birth dates involved, people should consider other potential conditions. In fact, upon further investigation, we realize that many conditions have been mistakenly attributed to the drug. In some cases, certain experts might be able to tell the difference, but in others, it can be really hard.

The identification of birth defects attributable to thalidomide was a painful and confusing process. Some countries and pharmaceuticals have done better than others, but many of them could not verify that each petitioner was a true thalidomide victim.

According to Dr. Widukind Lenz, the malformations that we observe in thalidomiders are among the following:

• Absence of the auricles with deafness.
• Defects of the muscles of the eye and of the face.
• Absence or hypoplasia of arms, preferentially affecting the radius and the thumb.
• Thumbs with three joints.
• Defects of the femur and of the tibia.
• Malformations of the heart, the bowel, the uterus, and the gallbladder.

Dr. Lenz continues:

“ Thalidomide may cause quite different malformations in different children. In one case, the ears are missing, there is deafness and paralysis of the muscles of the eyes and the face, but the limbs are normal. In another case, the ears are normal, but the arms are missing. In a third case there are severely shortened arms with only 2 or 3 fingers, often accompanied by internal malformations. In a fourth case, only the thumbs are abnormal with three joints, possibly accompanied by narrowing of the anus. ”

The type of malformations caused by thalidomide depends of the moment the drug was taken. Generally, thalidomide do not have any consequences if taken before the 34th or after the 50th day following the last menstruation. The period that goes from the 35th to the 50th day of pregnancy is critical, because it’s during that time that the fetus develops its limbs and organs.

Still according to Dr. Lenz, if thalidomide is taken during the critical period, the ears, arms, legs and organs can be severely damaged, which often leads to premature death. Given the severity of thalidomide impacts, almost 40% of thalidomide babies die before their first birthday.

The malformations linked to thalidomide are typical enough for an informed eye, but can easily be mistaken with birth defects resulting from other causes. Smithells and Newman wrote a detailed presentation of malformations attributable to thalidomide, of which the summary is presented below. It is relevant to note that when birth defects are the result of a teratogenic agent, the malformations are mostly symmetrical, since both sides of the human body develop simultaneously.

Differential diagnosis

What follows now is a list (with brief definitions) of some of the most common conditions mistaken for thalidomide malformations. The descriptions are, necessarily, very technical — making for dry reading, but it is important that the conditions be presented in this format to ensure that there is no misinterpretation. The article from Smithells and Newman discuss these differential diagnosis with more details.

• Roberts-SC Phocomelia (Pseudothalidomide syndrome, Roberts syndrome, SC syndrome) is an autosomal recessive disorder which includes limb reduction deformities. Some abnormalities associated with this syndrome include but are not limited to: cleft palate, malformed ears with hypoplastic lobules, various degrees of limb reduction, reduction in numbers or length of fingers and/or toes.
• Holt-Oram Syndrome also known as Heart Hand syndrome is an autosomal dominant disorder usually affecting the hands and forearms symmetrically, and associated in almost all cases with congenital heart disease, principally atrial septal defect. Some of the abnormalities noted with this syndrome include but are not limited to: phocomelia, all gradations of defect in the upper limb and shoulder girdle, and the thumbs may be absent, hypoplastic, triphalangeal, or bifid.
• TAR Syndrome (thrombocytopenia-absent radius) is an autosomal recessive disorder in which thrombocytopenia tends to improve and may not be evident after the neonatal period, and in which absent radii (bilateral) are associated with normal thumbs.Abnormalities in the legs are reported in 50% of the cases.
• Cornelia de Lange Syndrome is a syndrome in which the limb defects are asymmetrical. Some other abnormalities associated with this syndrome include but are not limited to: phocomelia and oligodactyly, proximal implantation of thumbs, depressed nasal bridge, and undescended testes.
• Fanconi’s Panmyelopathy includes radial aplasia as a feature, but the blood changes indicate the diagnosis. Some of the abnormalities associated with this condition include but are not limited to: short stature, hypoplasia to aplasia of thumb, small penis, and small testes.
• LADD Syndrome or lacrimo-auriculo-dento-digital syndrome results in radial and external ear defects which may be associated with deafness, eye, cardiac, and dental defects. Limb abnormalities that can be associated with this syndrome include but are not limited to: digitalization of thumb (95%), triphalangeal thumb, syndactyly between index and middle fingers, absent radius and thumb, and shortening of radius and ulna.
• Poland Anomaly (Poland Sequence) is unilateral with the hand defect being associated with agenesis of part of the pectoralis major muscle. There may be homolateral deficiency of the breast, nipple, or ribs. It is estimated that 10% of patients with syndactyly of the hand have Poland sequence, and it is 75% right-sided.
• FFU Syndrome (femur-fibula-ulna) is a syndrome in which the named bones are principally affected, contrasting with thalidomide which affects the radius and humerus before the ulna, and the tibia before the fibula. The defects may be very asymmetrical.
• Goldenhar Syndrome (oculo-auriculo-vertebral dysplasia), which merges with hemifacial microsomia, is characterised by microtia, accessory auricles, epibulbar dermoids, and abnormalities of the certical spine.When unilateral this syndrome tends to be right-sided. Other abnormalities that are associated with this syndrome include but are not limited to: middle ear anomaly with variable deafness, cleft lip, and cleft palate.
• Wildervanck Syndrome (cervico-oculo-acoustic syndrome) is seen predominantly in girls and is characterised by malformed ears, deafness, and defects of the cervical spine. Thalidomide rarely affects the cervical spine. Cleft palate has also been identified as an occasional abnormality associated with this syndrome.
• Möbius Syndrome (Moebius sequence) may manifest as facial/ocular palsies. It “is most commonly a sporadic occurrence in an otherwise normal family.”
• Duane Syndrome is a disorder of ocular movements characterised by (1) decreased abduction, (2) decreased adduction, (3) retraction of the globe on adduction, (4) oblique rise or depression on adduction, (5) partial closure of the eyelids on adduction, (6) deficient convergence. It may be bilateral or unilateral. An association with other defects, especially of the hands and ears, was described as long ago as 1918.
• Vater Association, “a nonrandom association of vertebral defects, imperforate anus, and esophageal atresia with tracheoesophageal fistula has long been appreciated.” Some other abnormalities or defects include but are not limited to: thumb or radial hypoplasia, and defects of the lower limb (23%).
• Amniotic Band Lesions most often affect a single limb, are rarely symmetrical, and resemble ‘congenital amputations’. Ring constrictions may be present on one or more limbs.Amniotic band disruption sequence syndrome also has cleft lip and palate listed as an abnormality that can be associated with it. Failure to understand the cause of this condition can lead to misdiagnosis and inappropriate family and genetic counselling.

To confuse the picture still further, medical publications contain examples of children who appear to show a mixture of features of more than one syndrome, for example Möbius syndrome and Poland anomaly. Whether these children are manifesting two separate syndromes, an entirely different syndrome, or some unusual ‘intermediate’ manifestation can only be a matter for speculation and further research.

There are many syndromes or conditions that exist and have finally been identified. With the ever-increasing developments in the field of genetics, many more will likely be known and better understood in the future. Providing this short list was intended to show that many of the ‘traits’ most commonly associated with thalidomide-related malformations can be found elsewhere either together or separately. It is often left to the patient to provide their doctor (geneticist) with the name of a condition to look up to start them in the right direction. Most important though, is having a CORRECT diagnosis to ensure correct treatment and reproduction information.

RÉFÉRENCES

• Lenz, Widukind, M.D., The History of Thalidomide, Extract from a lecture given at the 1992 UNITH Congress.
• R W Smithells, C G H Newman, Recognition of Thalidomide Defects, J Med Genet 1992.29
• Dick Smithells, Does Thalidomide Cause Second Generation Birth Defects? , Drug Safety 1998 Nov; 19(5)
• Jones, Kenneth Lyons, M.D. Smith’s Recognizable Patterns of Human Malformations, Saunders Co: Philadelphia, 1997
• Edited by Clayton L. Thomas, M.D., M.P.H., Tabers® CYCLOPEDIA MEDICAL DICTIONARY, Edition 18 DICTIONARY, Edition 18