Fibular dimelia and mirror polydactyly of the foot in a girl presenting additional features of the VACTERL association.

CONTEXT: The association between fibular dimelia and mirror polydactyly of the foot is considered to be a very rare lower-limb abnormality. On the other hand, VACTERL is an acronym for a nonrandom association of congenital anomalies for which the etiology is still poorly understood. CASE REPORT: The patient was a seven-month-old white girl whose mother had used misoprostol in the second month of pregnancy to induce abortion. On clinical evaluation, she was small for her age and presented hypotonia, anteverted nares, long philtrum and carp-like mouth. Her left hand had a reduction defect, with absence of the extremities of the second, third and fifth fingers and camptodactyly of the fourth finger. The ipsilateral lower limb presented significant shortening, especially rhizomelic shortening. Her left foot had a mirror configuration with seven toes and no identifiable hallux. The pelvis was hypoplastic. Esophageal atresia with tracheoesophageal fistula and imperforate anus were detected during the neonatal period. Abdominal ultrasound identified agenesis of the right kidney and left pyelocaliceal duplication. Radiographic evaluation on the left side showed iliac and femoral hypoplasia, absence of the tibia with a duplicated fibula and seven metatarsals and toes with no identifiable hallux on the foot. Echocardiography demonstrated an atrial septal defect. Based on the literature, we believe that the spectrum of malformations presented by our patient may be related to the vascular disruptive effect of the misoprostol. However, we cannot rule out the possibility that this association might simply be a coincidence.

Fibular dimelia and mirror polydactyly of the foot in a girl presenting additional features of the VACTERL association / Dimelia fibular e polidactilia em espelho do pé em uma menina apresentando achados adicionais de associação VACTERL

CONTEXT: The association between fibular dimelia and mirror polydactyly of the foot is considered to be a very rare lower-limb abnormality. On the other hand, VACTERL is an acronym for a nonrandom association of congenital anomalies for which the etiology is still poorly understood. CASE REPORT: The patient was a seven-month-old white girl whose mother had used misoprostol in the second month of pregnancy to induce abortion. On clinical evaluation, she was small for her age and presented hypotonia, anteverted nares, long philtrum and carp-like mouth. Her left hand had a reduction defect, with absence of the extremities of the second, third and fifth fingers and camptodactyly of the fourth finger. The ipsilateral lower limb presented significant shortening, especially rhizomelic shortening. Her left foot had a mirror configuration with seven toes and no identifiable hallux. The pelvis was hypoplastic. Esophageal atresia with tracheoesophageal fistula and imperforate anus were detected during the neonatal period. Abdominal ultrasound identified agenesis of the right kidney and left pyelocaliceal duplication. Radiographic evaluation on the left side showed iliac and femoral hypoplasia, absence of the tibia with a duplicated fibula and seven metatarsals and toes with no identifiable hallux on the foot. Echocardiography demonstrated an atrial septal defect. Based on the literature, we believe that the spectrum of malformations presented by our patient may be related to the vascular disruptive effect of the misoprostol. However, we cannot rule out the possibility that this association might simply be a coincidence.

CONTEXTO: A associação entre dimelia fibular e polidactilia em espelho do pé é considerada uma anormalidade de membro inferior bastante rara. Por outro lado, VACTERL é um acrônimo para uma associação não aleatória de anomalias congênitas cuja etiologia ainda é pouco compreendida. RELATO DO CASO: A paciente era uma menina branca de sete meses de idade, cuja mãe utilizou misoprostol no segundo mês de gravidez para indução de aborto. Na avaliação clínica, ela era pequena para a idade e apresentava hipotonia, narinas antevertidas, filtro longo e boca em carpa. A mão esquerda apresentava um defeito de redução com ausência das extremidades do segundo, terceiro e quinto dedos e camptodactilia do quarto. O membro inferior ipsilateral apresentava um importante encurtamento, especialmente rizomélico. O pé possuía uma configuração em espelho com sete dedos e nenhum hálux identificável. A pelve era hipoplásica. Atresia de esôfago com fístula traqueoesofágica e imperfuração anal foram detectadas durante o período neonatal. O ultrassom abdominal identificou agenesia do rim direito e duplicidade pielocalicial à esquerda. A avaliação radiográfica mostrou, no lado esquerdo, hipoplasia do osso ilíaco e do fêmur, ausência da tíbia com duplicação da fíbula, e presença de sete metatarsos e dedos, sem um hálux identificável, no pé. A ecocardiografia identificou um defeito do septo atrial. Acreditamos, com base na literatura, que o espectro de anormalidades apresentado por nossa paciente possa estar relacionado com o efeito disruptivo vascular do misoprostol. Entretanto, não podemos excluir a possibilidade de que essa associação possa ter sido simplesmente uma coincidência.

Cleft palate and toe malformations in a child with fetal methotrexate exposure.

Methotrexate, a commonly administered chemotherapeutic agent, is a well-known human teratogen. Exposure of a fetus between 6 and 8 weeks of gestation is postulated to cause birth defects. However, fetal exposure to this drug after this critical period is thought to have little to no effect on eventual fetal development and growth. The authors report a case of an infant whose mother was exposed to methotrexate during pregnancy. The infant was evaluated at their clinic for an incomplete cleft palate and associated asymmetric deformities of the toes on both feet.

Pathogenesis of retinoic acid-induced abnormal pad patterns on mouse volar skin.

BACKGROUND: Abnormal dermatoglyphs on human volar skin have been reported in many syndromes, but little is known about the pathogenesis. Patterns of pads on rodent limb volar skin are homologous to human dermatoglyphs. METHODS: In previous studies, we showed that transplacental exposure to teratogens induced abnormal pads in mouse fetuses. Moreover, teratogens caused abnormal pad patterns at levels below those that caused skeletal malformations. In this study, we examined morphology and cytokinetics in developing abnormal pads. Pregnant mice were treated with all-trans-retinoic acid at 20 mg/kg orally at embryonal day (E) 12.5 (vaginal plug = E0). The hindlimbs of the embryos were harvested and observed under a light microscope and by scanning electron microscopy. Cell proliferation and cell death were estimated by 5-bromo-2'-deoxyuridine (BrdU) labeling, Nile blue A vital staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RESULTS: Retinoic acid induced aplasia of the fibular tarsal pad and supernumerary interdigital pads on hindlimbs. Cell proliferation was observed in the area of developing pad, but cell death was very rarely seen in either normal or abnormal pads. CONCLUSIONS: Retinoic acid disturbed pad patterning as a whole rather than individual pad formation.

[Pregnancy, labor and early puerperium in a patient with Wilson's disease]. / Priebeh gravidity, pôrodu a vcasného sestonedelia u pacientky s m. Wilson.

Pregnancy should have a successful outcome in a patient with treated Wilson's disease if complications are excluded before conception. Chelating treatment must be maintained, although there is some concern about its teratogenicity. We describe the course of pregnancy in a patient with Wilson's disease treated with D-penicillamine and zinc sulfate.

Polydactyly and fetal hydantoin syndrome: an additional component of the syndrome?

We report a 3-year-old girl with fetal hydantoin syndrome (FHS) whose mother had received phenytoin 600 mg/day throughout gestation. She had growth retardation, mental deficiency, craniofacial dysmorphism and iris colomobata specific to FHS. However, the patient did not have the distal phalangeal hypoplasia which is associated with FHS; instead, she had polydactyly of the right foot. This seems to be the first FHS case in the literature with polydactyly.

Dose-response relationship of teratogenicity and prenatal-toxic risk estimation of 6-mercaptopurine riboside in mice.

6-Mercaptopurine riboside (6-MPr) is used as a cytostatic chemotherapeutic. The teratogenic potential in rodents has been well known for several decades. In this study, the teratogenic risk of low doses of 6-MPr in NMRI mice was estimated based on a dose-response study. The effective doses corresponding to the incidences of 5%, 1%, and 0.1% were calculated using the probit and Weibull model. The evaluation was performed on the basis of both the fetus and the litter by evaluating the variable all gross structural abnormalities. From these experiments, benchmark doses were obtained which were used in low-dose risk assessment to define a reference dose. Depending on the biometrical model and the statistical unit used, values between 1.9 and 5.2 mg/kg (benchmark ED1) and 3.8 and 6.7 mg/kg (benchmark ED5) were obtained. These values were compared to the no observed adverse effect level (NOAEL) which was determined experimentally. The NOAEL was found to be 5 mg/kg, which is quite similar to the ED5 benchmark doses.

Limb deficiency with or without Möbius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy.

Misoprostol, a synthetic analog of prostaglandin, has been widely used in Brazil as an abortifacient. Abortion is illegal in Brazil. An uncertain number of these abortion attempts are unsuccessful and the pregnancy continues. We report on 7 patients whose mothers attempted to abort using this drug in the first trimester of gestation without success. The 7 patients presented with limb defects and in 4 of them a diagnosis of Möbius sequence was made.

Aluminium sulphate in water in north Cornwall and outcome of pregnancy.

OBJECTIVE: To determine whether the excess aluminum sulphate accidentally added to the local water supply in north Cornwall in July 1988 had an adverse effect on the outcome of pregnancies. DESIGN: Outcomes of all singleton pregnancies in the affected area at the time of the incident (n = 92) were compared with those in two control groups: pregnancies in this area completed before the incident (n = 68) and pregnancies in a neighbouring area (n = 193). SUBJECTS: Mothers in the three groups, among whom there were 13 miscarriages, five terminations of pregnancy, and 336 live births. MAIN OUTCOME MEASURES: Fetal and perinatal loss, birth weight, gestation, obstetric complications, neonatal condition, and congenital defects. RESULTS: Among 88 pregnancies in women exposed to excess aluminum sulphate there was no excess of perinatal deaths (n = 0), low birthweight (n = 3), preterm delivery (n = 4), or severe congenital malformations (n = 0). There was, however, an increased rate of talipes in exposed fetuses (four cases, one control; p = 0.01). CONCLUSIONS: Because of small numbers it is not possible to say that high doses of aluminum sulphate are safe in pregnancy, but there is no evidence from this study of major problems apparent at birth.

[Neural pattern and limb development--normal development of the hindlimb nerve in the mouse and its aberrations induced by 5-fluorouracil].

Many ways of approach are available for the elucidation of the pathogenesis of congenital limb malformation. We examined the time course of the development of the nerve pattern in the whole mounted hindlimbs of mouse embryo stained with Karnovsky's method. The normal development and its aberrations induced with maternal administration of 5-fluorouracil at day 10.0 of gestation were studied. The basic development of the nerve pattern in normal limbs and 5-fluorouracil-induced poly-dactylic+ limbs was similar. At the stage of digital ray formation, distal tips of the nerve fibers were still reaching the base of the foot plate. Nerve fibers seem to reach the tip of the digit as a secondary phenomenon following formation of digital rays. These findings indicate that the developmental pattern of nerves in the mouse hindlimb is largely determined by the mesenchyme, rather than by the nerves themselves.

Characteristics of the limb malformations induced by maternal exposure to cadmium in the mouse.

Single doses of 2,3,4,6,8,10, and 15 mg/kg of cadmium chloride were administered (SC) to groups of MF1 mice on one of days 7 to 12 of gestation. Fetuses collected on day 18 were observed for limb malformations, and alizarin red-S stained skeletons were examined for their skeletal bases. Ectrodactyly, postaxial polydactyly, syndactyly, brachydactyly, adactyly, phocomelia, meromelia, and malrotation of the limbs were detected in a significant number of fetuses. Days 7 to 10 were greatly susceptible for induction of these malformations. Postaxial ectrodactyly was more frequent in the forepaws, and sidedness was not significant. Preaxial ectrodactyly preferentially affected the left hindpaws in the 9th-day treatment group. Postaxial polydactyly was predominently right sided and mostly involved the forepaws. Day 8 was particularly susceptible for induction of adactyly. Malrotation of the limbs together with edema and caudal narrowing resulted in a 'penguin-like' appearance. Ossification of the long bones, the carpals, tarsals, and phalanges were affected. Even those limbs that were not externally malformed had skeletal dysgenesis. Limb buds examined histologically at midgestation showed scanty and poorly organized mesenchyme, extensive elaboration of marginal sinsus, reduced thickness of the apical ectodermal ridge (AER), and discontinuous basement membrane. It is speculated that such histologic alterations at early stages of development could have contributed to the defective morphogenesis of limbs in this animal model.