Brachydactyly-Ectrodactyly With Fibular Aplasia Or Hypoplasia

Description

Ectrodactyly (split-hand/foot malformation) associated with fibular hypoplasia/aplasia is a rare disorder that appears to be inherited in an autosomal dominant fashion with reduced penetrance and variable expression (Evans et al., 2002).

A form of fibular hypoplasia/aplasia associated with oligosyndactyly and tibial campomelia has been reported (FATCO syndrome; 246570). Split-hand/foot malformation associated with tibial hypoplasia/aplasia has also been described (see SHFLD1, 119100).

Clinical Features

Graham and Badgley (1955) described a large Michigan family with split-hand malformation occurring in 6 individuals over 2 generations, 2 of whom also had ulnar and fibular anomalies. One was a 3-month-old girl, born of a mother with right split-hand malformation and hypoplasia of the first ray of her right foot; the infant had severe deformities of both upper extremities, with right monodactyly and left split-hand, as well as bilateral ulnar aplasia and failure of ossification of the distal portion of the right clavicle. The other was a 19-month-old boy, born of a father with right split-hand; the infant had right split-hand and severe bilateral deformities of the lower extremities, including bowing and shortening of the right femur with congenital dislocation and acetabular changes, bilateral fibular aplasia, oligodactyly of both feet, and clubfeet.

Deragna et al. (1966) reported a large pedigree in which aplasia of the fibula and ectrodactyly segregated over 4 generations. The proband was a male infant born with bilateral ectrodactyly ('lobster claw' deformity) of the hands, bilateral total aplasia of the fibulae with shortening and bowing of the tibiae and severe deformity of the tibio-talar joint, with almost complete rotation of the feet. There were no femoral abnormalities, and examination revealed no dysmorphic features or abnormalities of other organ systems. His sister had only fibular aplasia, whereas their father had only right-sided split-hand/foot malformation. Reconstruction of the pedigree with the help of family members showed that there were 4 family members who had only fibular aplasia, 1 who had only ectrodactyly, and 2 who had both. Deragna et al. (1966) suggested that this family might represent recessive inheritance.

Lewin and Opitz (1986) reviewed fibular development and noted that fibular aplasia/hypoplasia is the most common malformation of the long bones. Commenting on the pedigree reported by Deragna et al. (1966), they stated that the fact that an individual with only ectrodactyly, whose transmitting mother was unaffected, had a son with ectrodactyly and fibular agenesis and a daughter with only fibular agenesis argued against the 2 traits segregating independently. Lewin and Opitz (1986) concluded that the phenotype represented a pleiotropic autosomal dominant trait of variable expressivity with reduced penetrance of approximately 50%.

In a 25-year-old woman, Genuardi et al. (1990) observed hypoplasia of the phalanges of both hands, ectrodactyly in both feet, and nearly complete absence of the fibulae bilaterally. The middle phalanx was particularly small in the right index finger, and in the left hand, the second and third fingers had only rudimentary phalanges. The craniofacial and axial skeleton was normal, as were the femora. In a male second cousin, very mild defects of the hands and feet were observed, with normal ulnae, femora, and fibulae. Genuardi et al. (1990) noted that such milder manifestations were not seen in any of the cases of Deragna et al. (1966).

Halal (1991) reported monozygotic male twins in which one had right fibular aplasia and the other had ectrodactyly of the right hand. The first twin had right-sided absence of the fibula, bowed tibia, absent talus and calcaneus, and 1 absent metatarsal and corresponding toe; his upper extremities and left lower extremity were normal. The second twin had anomalies of the right hand, including absence of 1 metacarpal, absence or hypoplasia of phalanges of the second and fourth digits, and fusion of proximal phalanges 2 and 3 and fusion of distal phalanges 4 and 5; his left upper extremity and both lower extremities were uninvolved. Renal ultrasound was normal in both boys. The parents and 2 older sibs were unaffected. Halal (1991) noted that the ectrodactyly in the second twin, which included acral anomalies, might represent 'hypodactyly;' or, if the missing metacarpal was a central ray, it might be considered a mild split-hand anomaly.

Evans et al. (2002) described male infant twins, reportedly monozygotic, 1 of whom had a short, angulated left tibia with fibular aplasia, slightly shortened right tibia and fibula, absence of the second digital ray bilaterally and also of the third ray on the left. Radiologic examination of his hands at 10 months of age showed that carpal ossification on the right was not as well advanced as on the left, and that the right third and fourth metacarpals were slightly hypoplastic, measuring 1 mm narrower than those on the left. His twin brother had no congenital abnormalities, and there was no family history of limb deficiencies or other congenital malformations.

Gieruszczak-Bialek et al. (2006) reported an infant girl with severe ectrodactyly and fibular aplasia who also had ulnar hypoplasia. There were no femoral defects and the craniofacial and axial skeleton appeared normal. The authors noted that using the scale developed by Evans et al. (2002) to determine severity of the syndrome, the score for this patient would be 11, in contrast to the average severity score of 5.4 for reported cases.

Menke et al. (2008) reported a Dutch male infant with normal upper limbs but bilateral hypoplastic femora, fibular aplasia, and short, bowed tibiae, with ectrodactyly of the feet. An unrelated Dutch male infant also had normal upper extremities and normal left leg and foot; however, he had fibular aplasia on the right with a short, bowed tibia and a 3-toed foot with a hypoplastic second ray. Both infants had normal abdominal organs by ultrasonography.

Inheritance

Evans et al. (2002) published a tabular listing of 48 reported cases of fibular aplasia with ectrodactyly, including 23 sporadic and 25 familial cases from 8 pedigrees. The sex ratio was biased toward males, especially in apparently sporadic cases, and was attributed largely to a lower penetrance rate in females. Both affected males and females had affected children, but the risk to offspring was higher when the mother carried the gene, consistent with a mixed model for genetic susceptibility, i.e., the penetrance of the major predisposing gene is acting against a multifactorially determined level of liability. Evans et al. (2002) concluded that the penetrance of this disorder is significantly reduced, especially in females. They stated that although there seemed to be good evidence for a major autosomal predisposing gene, the precise pattern of inheritance is complex. The increased risk to the offspring of affected mothers was consistent with a multifactorial threshold model, and the normalization of the sex ratio in familial cases, i.e., those who would presumably have higher liability on the basis of several affected individuals, was also compatible with such a model (Fraser, 1998). Males and right-sided limbs appeared to be less well buffered against the deleterious effect of the mutation(s) involved. The authors postulated that stochastic factors might stress the developing embryo, increasing the likelihood that a predisposed infant would fail to develop normal limbs. The finding of 4 monozygous twins (2 discordant and 1 concordant) and another discordant dizygous twin among the small number of cases identified with fibular aplasia-ectrodactyly may not be unusual.

Menke et al. (2008) reviewed the 8 family pedigrees previously tabulated by Evans et al. (2002) and concluded that only 2, the families originally reported by Graham and Badgley (1955) and Deragna et al. (1966), convincingly represented familial ectrodactyly with fibular aplasia. The 2 families demonstrated typical split-hand/foot malformation (SHFM) combined with fibular aplasia present in at least 1 patient, multiple affected limbs, and multiple family members affected in at least 2 generations. Menke et al. (2008) suggested, however, that the 2 families may have had typical autosomal dominant SHFM (see SHFM1, 183600) with occasional expression of ulnar and/or fibular aplasia, thus representing an allelic variant of an SHFM subtype.