Liebenberg syndrome: brachydactyly with joint dysplasia (MIM 186550): a second family
- * Servizio di Genetica Medica, IRCCS “Bambino Gesù”, Piazza S Onofrio 4, 00165 Roma, Italy
- † Servizio di Radiologia, IRCCS “Bambino Gesù”, 00165 Roma, Italy
- ‡Reparto di Ortopedia, IRCCS “Bambino Gesù”, 00165 Roma, Italy
- Dr Giannotti,
Editor—In 1973, Liebenberg1described a five generation pedigree with unusual anomalies of the elbows, wrists, and hands and autosomal dominant inheritance (MIM 186550). The same family was re-examined in 1985 by Beighton with corroboration of the distinctive phenotype.2 3 The most prominent features were dysplasia of all the bony components of the elbow joint, abnormally shaped carpal bones, and brachydactyly. Since then, no other families have been described.
We report on a mother and two sons whose clinical and radiological features closely resemble those of Liebenberg syndrome.
The pedigree of our patients is showed in fig 1. When last examined, the two affected children, III.4 and III.5, were 3 years and 1 year old, respectively. Their older sister, III.3, was aged 6 and was thought to be unaffected. The affected mother, II.2, was 33 and her husband, II.3, 36 years old and were healthy and non-consanguineous. The mother's parents, I.1 and I.2, were said to be unaffected.
Patient III.5 was born at term. Pregnancy and delivery were uneventful. Birth weight was 3800 g, length 50 cm, and head circumference 35 cm. His development milestones were normal. At 1 year he was able to sit alone and spoke his first words. There were no health problems. His joint anomalies were noticed at birth.
We examined the patient at the ages of 6 months and 1 year. At 1 year weight was 12 kg (>90th centile), height 80.6 cm (>97th centile), and OFC 47 cm (>50th centile). In the “anatomical position”, the elbow joints were slightly flexed and active extension from that position was not possible. Pronosupination was slightly limited. The wrist joints were radially deviated. Flexion, extension, abduction, and adduction at the wrists were somewhat stiff but almost normal in range. The fingers were short and bilateral camptodactyly of the fifth finger was present.
X rays of the arms, forearms, and hands showed enlarged and poorly modelled distal humeral, proximal radial, and proximal ulnar metaphyses, abnormally long radius and ulna, a very large triquetrum the size of that of a 3½ year old child, and shortness of all the components of the digital rays, but especially marked in the distal phalanges (fig 2). No synostoses were noted. X rays of the whole skeleton showed no other relevant anomalies.
Patient III.4 was born at term. Pregnancy and delivery were uneventful. Birth weight was 3400 g, length 45 cm, and head circumference 35 cm. Development milestones were normal. He was able to sit alone at 9 months and to walk at 12 months. He spoke his first words at 12 months and the first sentences at 2 years. He had no health problems. His joint anomalies were noticed at birth.
We examined the patient at the ages of 2½ and 3 years. At 3 years weight was 18.5 kg (>97th centile), height was 106 cm (>97th centile), and OFC was 49.6 (>25th centile). Flexion at the elbow joints, radial deviation of the wrists, and limitation in the range of movement at the elbow and wrist joints were slightly more marked than in his younger brother. Brachydactyly, bilateral camptodactyly of the fifth fingers and partial bilateral syndactyly between the second and third fingers were evident. Thex ray features were very similar to those of III.5. The size of the triquetrum was that of an 8 year old child (fig3). His symptoms improved after one year of physiotherapy.
The mother, II.2, was 33 years old at the time of examination. Weight was 60 kg (>50th centile), height was 165 cm (>50th centile), and OFC was 53 cm (>25th centile). She denied any health problems and was of normal intelligence. Her joint anomalies had been present since birth and she had not noticed any worsening of her symptoms. She had never received any rehabilitation therapy.
In the anatomical position, flexion at the elbow joints was 10° and active extension from that position was impossible (fig 4). Pronosupination was slightly limited. The wrist joints were radially deviated. At the wrist, flexion was limited to about 60° while extension, abduction, and adduction were almost normal. The hands showed brachydactyly and bilateral camptodactyly of the fifth finger (fig5).
X rays of the arms, forearms, and hands showed enlarged and poorly modelled distal humeral, proximal radial, and proximal ulnar metaphyses, abnormally shaped carpal bones, scaphoid-lunate fusion, large triquetrum, and shortness of all the components of the digital rays, especially marked at the distal phalanges (figs 6 and 7). No synostoses were present.X rays of the whole skeleton showed no other relevant anomalies.
The unusual association of brachydactyly, abnormally shaped carpal bones, and elbow dysplasia in our family and that described by Liebenberg in 19731 could be ascribed to the same autosomal dominant clinical condition. Our patients showed only some slight differences from Liebenberg's family.
In our family, the bony components of the elbow joints were consistently enlarged and poorly modelled. In Liebenberg's patients the radial head had a “bulbous appearance” while the humeral condyles and the ulnar olecranon and coronoid processes were “underdeveloped”. The large triquetrum and camptodactyly of the fifth fingers, which were described only in the 7 year old child of the family of Liebenberg,1 were constant findings in our patients. Moreover, patient III.4 had bilateral partial syndactyly between the second and third fingers. Triqueto-pisiform fusion, which was present in all Liebenberg's patients, was not found in our family. However, since the ossification centre of the pisiform appears at about 10 years,4 triqueto-pisiform fusion would not be expected to be seen in the children III.4 and III.5. Yet, in the mother, II.2, the fusion is between the scaphoid and lunate.
The differential diagnosis between Liebenberg syndrome and the other skeletal disorders involving elbow dysplasia/carpal synostoses and brachydactyly, such us the multiple synostoses or facioaudiosymphalangism syndrome (MIM 186500),5 the tarsal, carpal, and digital synostoses syndrome (MIM 186400),6 and the Banki syndrome (MIM 109300)7 is essential for prognosis and genetic counselling. Indeed, Liebenberg syndrome seems to cause no other relevant problem apart from limited flexion-extension of the elbows and wrists while the evolution of the other disorders is often more severe.
The presence of tarsal synostoses and symphalangism clearly differentiates both the multiple synostoses syndrome (SYNS1) (MIM 186500) and the tarsal, carpal, and digital synostoses syndrome (MIM 186400) from Liebenberg syndrome which features only carpal synostosis. Moreover, most SYNS1 patients have conductive deafness and a characteristic facies with a broad hemicylindrical nose without alar flare. Our patients do not show any facial dysmorphism and, although audiological evaluation was not performed, they apparently have no significant hearing problem. No mention of facial dysmorphism and deafness was made in the paper of Liebenberg.1 Finally, elbow dysplasia is not a feature of Banki syndrome.
The recent discovery that point mutations in theNOG gene in the 17q22 region are the cause of both proximal symphalangism (SYM1) and SYNS18 raises the question of whether Liebenberg syndrome is also caused by mutations in the same gene. The NOG gene codes for the polypeptide noggin that acts as an inhibitor of bone morphogenetic proteins (BMP), which are members of the transforming growth factor β superfamily of signalling proteins (TGFβ-FM).8 9 Thus, mutations in the NOG gene are likely to cause an increased BMP activity which leads to excess cartilage and failure of joint formation.9 Considering the wide variability of the phenotypic effects of NOGgene mutations, which range from simple symphalangism to the full SYNS1 syndrome, it would not be surprising if Liebenberg syndrome and some of the other syndromes featuring synostoses were also caused byNOG gene mutations.