Tibia, Hypoplasia Or Aplasia Of, With Polydactyly

A number sign (#) is used with this entry because of evidence that tibial hypoplasia or aplasia with polydactyly (THYP) is caused by heterozygous mutation in an SHH (600725) regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene (605522).

Clinical Features

Werner (1915) reported the case of a 21-year-old woman with polydactyly of the hands, digitalization of the thumb, short lower limbs with aplasia of the tibias, and polydactyly of the toes. Davidson (1918) described a second isolated case.

Ollerenshaw (1925) reported identical twin sisters with unilateral (left) absent tibia and polydactyly. Ten older sibs were healthy. Dankmeyer (1935) reported familial occurrence and predominant involvement of the right lower limb.

Reber (1968) described a boy with the full phenotype whose father had triphalangeal thumbs only.

Eaton and McKusick (1969) reported a family in which 4 persons in 3 successive generations had bilateral hypoplasia of the tibia with polydactyly in the feet and hands. The fibula in these cases was thickened. The affected grandfather lacked the tibial feature of the syndrome.

Pratt (1971) described congenital cardiac malformations in association with absent tibia and polydactyly. Pfeiffer and Roeskau (1971) described a boy with tibial agenesis, fibula duplication, mirror foot, and normal upper limbs whose mother had the same anomalies on the left but only prehallucal polydactyly on the right. (See 135750.) They offered a classification.

Yujnovsky et al. (1974) reported a family with patients in 3 generations. The full-blown syndrome was present in only 1 case. They suggested that triphalangeal thumb is an especially consistent feature. Syndactyly was also a feature in the hands.

Canki (1977) described mother and daughter with postaxial polydactyly, hypoplasia of the tibia, and unusually depressed nasal tip due apparently to hypoplasia of the major alar cartilages.

Lo (1981) described a patient with bilateral aplasia or hypoplasia of the tibia and unilateral syndactyly of fingers 3 and 4. Cousins of the mother had identical unilateral syndactyly.

Canun et al. (1984) described a kindred in which manifestation of the trait could be identified in members of 4 generations and by implication in a fifth. Bilateral absence of the tibia was the most severe manifestation. Prenatal diagnosis of a normal fetus (tibias normal) was made at gestational age 20.5 weeks. Canun (1986) provided further information indicating reduced penetrance: a clinically and radiologically normal male of the kindred they studied, married to an unrelated female, sired a girl with the most severe manifestations (absent tibiae, triphalangeal thumbs, and polydactyly).

Cordeiro et al. (1986) reported a case with possible occurrence of the disorder in males in 3 successive generations. They referred to the condition as 'Werner syndrome,' an undesirable designation because of potential confusion with another disorder (277700).

Vargas et al. (1995) described a Brazilian family with 10 affected members in 3 generations. They found reports of about a dozen families. The hand is characterized by 5 triphalangeal digits in which the thumb is nonopposable, similar to the type (190600) thought to result from duplication of the index finger in association with agenesis of the normal thumb. Supportive of this hypothesis was the presence of an extra distal triradius at the base of the triphalangeal thumb of almost all affected persons in this family. Absence of the tibias was associated with duplication of the fibulas in the propositus but not in other affected members. The findings in the propositus were similar to those described by Laurin et al. (1964) (see 135750) and Pfeiffer and Roeskau (1971). Temtamy and McKusick (1978) did not consider fibular dimelia a part of the phenotypic spectrum of the syndrome discussed here.

Al-Awadi et al. (1987) described a 5-year-old boy who had hypoplastic bowed tibias and postaxial polysyndactyly. The parents were first cousins. The father and 4 relatives had postaxial polysyndactyly. A sister had polysyndactyly. The mother had only cutaneous syndactyly, but her grandfather had polysyndactyly and another relative of hers had either syndactyly or polysyndactyly. Richieri-Costa et al. (1990) described what appears to be the same disorder in 3 members of a Brazilian family. Radioulnar synostosis was present in 2 of the 3 patients.

Agarwal et al. (1996) described a kindred with 7 affected individuals in 3 generations showing bilateral 5-fingered hands, pedal polydactyly with syndactyly, and agenesis of the tibia and distal end of the radius. There was no incidence of male-to-male transmission.

Kantaputra and Chalidapong (2000) reported a Thai man with triphalangeal thumb-polysyndactyly syndrome (174500) whose daughter had tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome. The authors proposed that these conditions are actually the same disorder with wide variability. They suggested that this condition be called 'tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome.'

Goldenberg et al. (2003) reported a Yugoslavian patient born with severe limb malformations characterized by absent thumbs, 5 triphalangeal digits, preaxial polydactyly of the hands, short lower legs due to tibial hypoplasia on one side and absent tibia on the other side, clubfeet, and preaxial polysyndactyly of the feet. He also had bilateral cryptorchidism and Hirschsprung disease (142623). High-resolution cytogenetic studies were normal, excluding a contiguous gene syndrome. Clinical and radiographic studies of the parents were normal. Goldenberg et al. (2003) noted that Hall (1981) had reported Hirschsprung disease in a patient with hypoplasia of the tibia and polydactyly.

Wieczorek et al. (2010) reported a Turkish family in which the male proband presented at 43 years of age with short stature, shortened forearms, mildly shortened femora with severely shortened distal legs, and bilateral preaxial polydactyly of the hands and feet. The proband's father had only PPD of the right hand. The proband's wife became pregnant with twins after intracytoplasmic sperm injection, and 1 of the fetuses was found to have severely shortened legs with aplasia of the fibulae and tibiae as well as syndactyly of the right hand. Selective feticide was performed, and the remaining twin was born healthy. Wieczorek et al. (2010) also restudied the Brazilian family originally reported by Vargas et al. (1995), providing additional radiographs and photographs of affected family members demonstrating severe tibial hypoplasia, fibular bowing, and triphalangeal thumbs.

Norbnop et al. (2014) observed both intra- and interfamilial variability in 4 Thai patients from 2 unrelated families. However, bilateral 'triphalangeal first fingers' were consistently present in all 4 patients; the authors emphasized that the digits had features of fingers rather than thumbs, with no thenar muscles, no first web spaces, and inability to oppose. In 1 of the families, a 2-year-old boy, his father, and his paternal grandfather demonstrated anticipation as well as clinical variability, with increasing severity of the lower limb phenotype: the grandfather had a hypoplastic right tibia with a normal left tibia, whereas the father had bilateral tibial aplasia, and the proband had bilateral tibial aplasia with bilaterally dislocated knees. The proband had 7 digits on each foot whereas his father and grandfather had 6; the first toes were triphalangeal in all 3. The patient in the other family was a 1-year-old girl who, in addition to bilateral triphalangeal first fingers, had a preaxial extra digit on the right hand, right tibial hypoplasia, 6 digits on the left foot and 7 on the right, with a biphalangeal left first toe, triphalangeal right first toe, and bifid right great toe.

Molecular Genetics

In a Turkish family with polydactyly and tibial hypoplasia, Wieczorek et al. (2010) analyzed the 772-bp ZRS region within intron 5 of the LMBR1 gene (605522) and identified a point mutation (404G-A; 605522.0003) that segregated with disease in the family and was not found in 100 Turkish controls. Wieczorek et al. (2010) noted that this mutation previously had been detected by Lettice et al. (2003) in a Cuban family diagnosed with PPD2 (174500; Zguricas et al., 1999). Reevaluation of the published clinical data, however, showed that the Cuban index patient also had tibial hypoplasia. Wieczorek et al. (2010) also identified a different mutation at the same nucleotide (404G-C; 605522.0015) in a large Brazilian family originally reported by Vargas et al. (1995), in which all affected individuals had triphalangeal thumbs and PPD of the feet, 2 had tibial defects, and 1 had duplicated fibulae.

In 3 affected members over 3 generations of a Thai family with polydactyly and tibial hypoplasia, Norbnop et al. (2014) identified heterozygosity for a novel point mutation in the ZRS region of LMBR1 (406A-G; 605522.0017). In an unrelated affected Thai girl, they identified heterozygosity for the 404G-A mutation.

VanderMeer et al. (2014) reported a large 5-generation Mexican kindred in which 31 family members had isolated triphalangeal thumb, 14 had preaxial polydactyly with triphalangeal thumbs (see PPD2, 174500), and the proband had tibial and radioulnar hypoplasia with preaxial polydactyly of the hands and feet as well as short triphalangeal thumbs. The proband's parents, who both had abnormal thumbs, were heterozygous for a point mutation in the ZRS region of LMBR1 (c.402C-T; 605522.0021). Noting that the more severely affected daughter was homozygous for the same mutation, VanderMeer et al. (2014) suggested that a dosage effect exists for this mutation.