Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature

Abstract

Background: Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD.

Case presentation: The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother.

Conclusions: We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.

Keywords: 17p13.3 duplication; BHLHA9; Ectrodactyly; Split hand/foot malformation; Split hand/foot malformation with long bone deficiency.

Fig. 1

Clinical photographs of the hands and the feet of the proband showing ectrodactyly involving three limbs, with the absence of the third digit on the left hand, absence of 2 digits on the right hand with malformed fingers (except the thumb) and the fixed clubfoot deformity with only 2 toes on the right foot

Fig. 2

Radiological images of the upper limbs and pelvis of the proband showing complete absence of the metacarpal and the phalanges of the third digit on the left hand and absent metacarpals and phalanges of two digits on the right hand. Rest of the upper limbs and upper femur were radiologically normal

Fig. 3

Clinical photographs of the hands of the mother showing bilateral ectrodactyly involving both hands, with the absence of the third digit on the right hand and two digits on the left hand, with bi-phalangeal left 5th digit