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.

A new case of 17p13.3p13.1 microduplication resulted from unbalanced translocation: clinical and molecular cytogenetic characterization

“…On the contrary, in the patients whose extremities were not afflicted but who suffered from mental retardation, 17p13.3 duplications were large in size (1.1 Mb on average) and did not break the region of genes ABR-TUSC5 . This suggests that disturbance of neighboring, supposedly regulatory, elements (for example, in region ABR-TUSC5 ) of gene BHLHA9 might be a complementary factor promoting occurrence of hand/foot malformations with long bone deficiency [ 27 ].…”

“…In our case, hand/foot malformations with long bone deficiency were not noted. According to literature, 17p13.3 duplications with hand/foot malformation affliction of extremities were relatively small This suggests that disturbance of neighboring, supposedly regulatory, elements (for example, in region ABR-TUSC5) of gene BHLHA9 might be a complementary factor promoting occurrence of hand/foot malformations with long bone deficiency [27].…”

Sonographic Prenatal Diagnosis of Ectrodactyly: A Case Study

“…However, the most common presentation is the absence or underdevelopment of the central digits with a median cleft of the autopod and possible fusion of the lateral digits (syndactyly). [1][2][3] There can also be variability in the clinical presentation within first and multiple generation family members affected or between limbs of a single person. 4 The condition has been further classified as either typical or atypical.…”

“…There is great variability in both clinical and genetic presentation. [1][2][3][4] This report describes a case of fetal ectrodactyly diagnosed with sonography, at 20 weeks gestation.…”

Estudo genômico de indivíduos com deficiência congênita de membros

“…Esta associação decorre de ganhos no número de cópias do gene BHLHA9, gerando um aumento no nível de apoptose em AER. A dosagem gênica pode alterar a gravidade do fenótipo, assim como o controle da expressão gênica influência no adequado crescimento do membro (Klopocki et al, 2012;Paththinige et al, 2019). Pesquisas recentes em camundongos mostraram que BHLHA9 é expresso na região ectodérmica, face ventral e dorsal, próximo a AER, e sua expressão acontece nos estágios iniciais da fase embrionária.…”