The spectrum of hand and foot malformations in patients with Greig cephalopolysyndactyly

Abstract

Purpose: Greig cephalopolysyndactyly (GCPS) (OMIM 175700), a rare autosomal dominant disorder, is characterized by a distinct combination of craniofacial, hand and foot malformations. The hand and foot malformations often require orthopedic assessment and treatment. The disorder is caused by point mutations or deletions in the GLI3 gene, located on chromosome 7p14.3. Herewith, we review the hand and foot malformations in a cohort of 13 patients referred for genetic testing.

Methods: We reviewed the medical files of 13 patients with GCPS seen at the Center for Human Genetics in Leuven between 2003 and 2005. Clinical, molecular and radiological findings, when available, were recorded.

Results: We identified six different point mutations in the GLI3 gene, two microdeletions and three larger chromosomal deletions. In the hands, preaxial polydactyly was never observed, but the malformations included postaxial polydactyly, broad thumbs, clinodactyly of the thumbs and various degrees of syndactyly. In the feet the spectrum of malformations included preaxial polydactyly, postaxial polydactyly, different degrees of syndactyly and broad halluces. Syndactyly of the toes and hallux abnormalities were present in all patients. Most frequently, syndactyly was present between toes 1-2-3. The broadening of the hallux was either due to a complete or partial duplication of the first toe or to broadening of the distal phalanx. Mental retardation was found in three cases and was associated with a large chromosomal deletion of the GLI3 region.

Conclusion: We found the classic hand and foot malformations associated with GCPS in our cohort of patients. Patients with a large chromosomal deletion had mental retardation, but no structural brain anomalies were found.

Fig. 1

Typical craniofacial appearance of GCPS patients: frontal bossing, hypertelorism, a high forehead and a broad nasal bridge

Fig. 2

The spectrum of hand malformations in patients with GCPS. a Various degrees of syndactyly in GCPS patients. Clear cutaneous syndactyly of digits 3 and 4 is seen in SNNE. The cutaneous syndactyly of digits 2–3 and 3–4 is less obvious in DRGO. In DAMI, a bony fusion of the distal phalanges of digits 3 and 4 is visible on the radiographs. b Postaxial polydactyly in the hands usually consists of a pedunculated postminimus. c Broadening of the thumb can be due to broadening of the distal phalanx (BOHA) and irregular proximal epiphyis of the distal phalanx (MOBL) or a duplication of the distal phalanx (TALA). d Clinodactyly of the thumb

Fig. 2

The spectrum of hand malformations in patients with GCPS. a Various degrees of syndactyly in GCPS patients. Clear cutaneous syndactyly of digits 3 and 4 is seen in SNNE. The cutaneous syndactyly of digits 2–3 and 3–4 is less obvious in DRGO. In DAMI, a bony fusion of the distal phalanges of digits 3 and 4 is visible on the radiographs. b Postaxial polydactyly in the hands usually consists of a pedunculated postminimus. c Broadening of the thumb can be due to broadening of the distal phalanx (BOHA) and irregular proximal epiphyis of the distal phalanx (MOBL) or a duplication of the distal phalanx (TALA). d Clinodactyly of the thumb

Fig. 3

The spectrum of foot abnormalities in patients with GCPS. a Cutaneous syndactyly of toes 1–2 with broadening of the first toe. b Preaxial polydactyly with cutaneous syndactyly of toes 1–2, 2–3 and 3–4. c Preaxial polydactyly with complete duplication of the distal phalanx. d Deformation of the first metatarsal resulting in abnormal articulation with the base of the second metatarsal (BRER and MOBL)