Abstract
BackgroundHOXA genes cluster plays a fundamental role in embryologic development. Deletion of the entire cluster is known to cause a clinically recognizable syndrome with mild developmental delay, characteristic facies, small feet with unusually short and big halluces, abnormal thumbs, and urogenital malformations. The clinical manifestations may vary with different ranges of deletions of HOXA cluster and flanking regions.Case presentationWe report a girl with the smallest deletion reported to date involving the entire HOXA cluster at 7p15.2-p14.3. The patient was the third child born to a healthy and non-consanguineous Italian couple. She was born at the 34th week of gestation by caesarean section due to cholestasis of pregnancy. Her birth weight, length, and occipitofrontal circumference were 2,140 g (25-50th centile), 46 cm (50th centile), and 33 cm (75-90th centile), respectively. The Apgar scores were 8 at both the 1st and 5th minutes. The patient presented with typical mild facial anomalies, hand and feet abnormalities, urinary anomalies, and mild speech delay. Unexpectedly, the patient demonstrated complex unusual features of multiple episodes of oxyhemoglobin desaturation, laryngeal stridor and a branchial cyst. Chromosome analysis of the patient revealed an apparently normal karyotype at the 550 band level. Based on array comparative genomic hybridization, a 2.5 Mb interstitial deletion was detected at 7p15.2p14.3 (chr7: 26,333,553-28,859,312), involving the entire HOXA cluster and a small number of other genes as SNX10, SKAP2, EVX1, HIBADH, TAX1BP1, JAZF1, and CREB5.ConclusionsThis report improves our understanding of the genotype-phenotype correlations of HOXA genes cluster deletions via the identification and characterization of the smallest deletion (as well as critical region) reported to date. In particular we discuss the possible implications of preterm and haploinsufficiency in the pathogenesis of the unusual findings, furthermore opening new discussion and interpretation cues.
Highlights
HOXA genes cluster plays a fundamental role in embryologic development
This report improves our understanding of the genotype-phenotype correlations of HOXA genes cluster deletions via the identification and characterization of the smallest deletion reported to date
Genotype-phenotype analyses suggest that deletions involving HOXA13 show Hand-foot-genital syndrome (HFGS) features, which is characterized by small feet with unusually short and big toes and abnormal thumbs, and urogenital malformations
Summary
All previously reported deletions involving HOXA13 show HFGS features, namely bilateral and symmetrical limb malformations with incompletely penetrant urogenital defects, and some additional findings in comparison to mutation of the single gene, such as mild dysmorphic facies, developmental delay, feeding difficulties in the first months of life, and mild intellectual disability. These observations are based on clinical findings of seven patients with deletions of about 8.8 ± 3.2 Mb (the deletion described by Kosaki [7], was detected by FISH, so the breakpoints are not available, but it was visible at G-banding chromosome analysis) encompassing the entire HOXA cluster (Figure 4; Table 1) [3,4,5,6,7]. All authors have read and approved the final version of the manuscript
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