Duplication of 10q24 locus: broadening the clinical and radiological spectrum

Abstract

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

Fig. 1

Photographs of patients’ hands and feet. 1 Case 1. Prenatal ultrasound revealing bilateral split hands. Left hand. Note 1–2 and 3–4 syndactyly as well as excessive tissue between 2 and 3. Right hand. Note 1–2 and 3–4 syndactyly. Bilateral split feet. 2 Case 2. Note bilateral monodactyly of hands and feet. 3 Case 3. Note bilateral monodactyly of hands and feet. 4 Case 4. Note bilateral monodactyly of hands and feet. 5 Case 5. Note ectrodactyly of 4 limbs. 6 Case 6. Note ectrodactyly of 4 limbs. 7 Case 7. Note ectrodactyly of 4 limbs. 8 Case 8. Note monodactyly of hands. 9 Case 9. Note split hands, right split-foot and left 2–3–4 toe syndactyly. 10 Case 10. Note normal hands and split feet. 11 Case 11. Note ectrodactyly/syndactyly of 4 limbs. 12 Case 12. Note ectrodactyly of 4 limbs. 18 Case 18. Note ectrodactyly of 4 limbs. 19 Case 19. Note ectrodactyly of 4 limbs. 20 Case 20. Note ectrodactyly of 3 limbs. The right is very mildly affected with a triphalangeal thumb and a radial deviation of the index. 21 Case 21. Note ectrodactyly of 4 limbs. 22 Case 22. Note ectrodactyly of feet and one hand and preaxial polydactyly on other hand. 23 Case 23. Note ectrodactyly of feet. 24 Case 24. Note ectrodactyly and monodactyly of hands and feet. 25 Case 25. Note ectrodactyly of 4 limbs. 26 Case 26. Note ectrodactyly of 4 limbs following surgery for a right hand preaxial polydactyly

Fig. 2

X-rays of patients’ hands and feet. 1 Case 1. Note skin syndactyly of hands and split feet. X-rays performed at 12 months. 2 Case 2. Note monodactyly of hands and feet. X-rays performed at 1 month. 5 Case 5. Note split hands. X-rays performed at 32 years. 6 Case 6. Note ectrodactyly of 4 limbs. X-rays performed at 5 months. 8 Case 8. Note monodactyly of 4 limbs. X-rays performed at 25 years. 11 Case 11. Note skin syndactyly and absent distal phalanges. X-rays performed at 18 months. 12 Case 12. Note ectrodactyly of 4 limbs. X-rays performed at 5 years. 20 Case 20. Note ectrodactyly of the left hand and both feet. Note camptodactyly of the right index. X-rays performed at 30 months. 21 Case 21. Note ectrodactyly of 4 limbs. X-rays performed at 24 weeks’ gestation. 22 Case 22. Note ectrodactyly of feet and preaxial polydactyly of hand. X-rays performed at age 3 months. 23 Case 23. Note ectrodactyly of feet. X-rays performed at age 12 months. 25 Case 25. Note ectrodactyly of feet and monodactyly of hands. X-rays performed at age 39 years. 26 Case 26. Note ectrodactyly of feet and polydactyly/ectrodactyly and distal amputations of hands. X-rays performed at age 3 years. 28 Case 28. Note monodactyly of hands and ectrodactyly of feet. X-rays performed at age 18 years

Fig. 3

Array CGH 10q24 duplications are displayed for all cases tested. All positions have been converted to the build hg38 for this figure. The TAD region shown has been detected in human embryonic stem cells and overlaps with the minimal duplicated region across all cases. Inversion of POLL, DPCD, FBW4 and FGF8 which occurred during vertebrate evolution is shown. All coding and non-coding Ensembl v87 genes overlapping the region chr10:101121147–102503988 are shown, including SUFU and FGF8. The phastCons conservation score for 29 mammals aligned to the human genome was downloaded from UCSC. For every 1000 base window, a mean conservation score between 0 and 1 was calculated indicating the probability of negative selection