A 3.06-Mb Interstitial Deletion on 12p11.22-12.1 Causes Brachydactyly Type E

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A 3.06-Mb Interstitial Deletion on 12p11.22-12.1 Causes Brachydactyly Type E with Pectus Carinatum and Short Stature

Introduction
Brachydactyly (BD), a congenital disorder characterized by shortened fingers and toes due to hypoplasia or aplasia of metacarpals, metatarsals, or phalanges, is classified into subtypes A–E based on anatomical involvement. Brachydactyly type E (BDE) specifically involves shortening of metacarpals and/or metatarsals, often accompanied by systemic features such as short stature. While isolated BDE is rare and linked to mutations in HOXD13 or PTHLH, syndromic forms frequently associate with additional anomalies. This study investigates a four-generation Chinese family with BDE combined with pectus carinatum (protruding sternum) and short stature, revealing a novel 3.06-Mb chromosomal deletion on 12p11.22-12.1.

Clinical Presentation
The family comprised nine affected individuals across four generations (Figure 1). All exhibited bilateral, generalized brachydactyly with variable severity (Figure 2). Hands and feet appeared stocky, with shortening of metacarpals, metatarsals, and phalanges. Radiographs of patient III8 showed shortened metacarpals I–V, dumbbell-shaped metacarpals II–IV, and irregular joint surfaces in the left ring finger (Figure 3). Epiphyseal fusion was observed in metacarpals II–V of patient IV5. Adults displayed marked short stature (males <165 cm; females ~150 cm), while pediatric patients (IV2, IV5) had heights below age norms.

A consistent feature was pectus carinatum, evident in chest radiographs (Figure 2). Unlike syndromic BDE forms (e.g., Albright hereditary osteodystrophy or acrodysostosis), patients lacked hormonal resistance, intellectual disability, facial dysmorphism, or ectodermal defects. Biochemical analyses (calcium, phosphorus, PTH, TSH, thyroid hormones) were normal.

Genetic Analysis
Whole-Exome Sequencing (WES)
WES performed on three affected individuals (III8, III12, IV2) ruled out pathogenic single-nucleotide variants or small indels in known BD-associated genes (HOXD13, PTHLH, PDE3A, GNAS).

Array Comparative Genomic Hybridization (Array-CGH)
Array-CGH in proband III8 identified a heterozygous 3.06-Mb deletion at chr12:25,473,650–28,536,747 (hg19), spanning 12p11.22-p12.1. This region contains 23 genes, including PTHLH—a known BDE gene. Q-PCR confirmed the deletion segregated with the phenotype in all nine affected family members (Figure 3C).

Breakpoint Characterization
Gap-PCR and Sanger sequencing defined the deletion boundaries (chr12:25,473,650–28,536,747) (Figure 4). Breakpoint analysis revealed a microhomology of “AT” at the junction, suggesting non-homologous end joining (NHEJ) as the mechanism (Figure 5). No repetitive elements (e.g., Alu, LINE) flanked the breakpoints.

Deleted Genes and Pathogenicity
The 3.06-Mb deletion encompassed 23 genes, including:

  1. PTHLH: Encodes parathyroid hormone-like hormone (PTHrP), a critical regulator of endochondral ossification. Haploinsufficiency causes BDE2 (MIM 613382), characterized by metacarpal shortening and short stature.
  2. BHLHE41: Linked to short sleeper syndrome (AD, MIM 612975), but unaffected individuals carried one functional copy without sleep abnormalities.
  3. ITPR2: Associated with autosomal recessive anhidrosis (MIM 106190); heterozygous deletion did not impair sweating.

The phenotype correlated strongly with PTHLH loss. PTHLH regulates chondrocyte proliferation and delays hypertrophic differentiation via PTHrP signaling. Disrupted PTHrP activity accelerates growth plate closure, causing premature epiphyseal fusion, shortened bones, and pectus carinatum due to thoracic cage abnormalities.

Phenotypic Expansion
This family expands the PTHLH-related BDE spectrum:

  1. Pectus Carinatum: Previously unreported in PTHLH cases, sternal protrusion likely stems from defective costochondral junction development. Homozygous Pthlh knockout mice exhibit severe thoracic dysplasia, suggesting haploinsufficiency may cause milder human phenotypes.
  2. Variable Expressivity: Affected individuals showed intra-familial variability. For example, III8 had asymmetrical hand involvement, while IV5 displayed epiphyseal fusion in metacarpals II–V. Such variability may reflect modifier genes or environmental factors.
  3. Generalized Brachydactyly: Unlike typical BDE (isolated metacarpal IV/V shortening), patients had pan-metacarpal and phalangeal involvement, resembling severe BDE3.

Comparison with 12p Deletion Syndromes
Prior reports of 12p deletions overlapping this region (Supplementary Table 4) describe:

  • Brachydactyly (11/14 cases).
  • Short stature (12/14).
  • Intellectual disability (13/14), absent in this family.
    The current phenotype’s lack of neurodevelopmental issues suggests the 3.06-Mb deletion spares genes critical for cognition.

Mechanistic Insights
PTHLH haploinsufficiency disrupts the PTHrP-IHH feedback loop in growth plates. Normally, PTHrP maintains chondrocyte proliferation by suppressing hypertrophic differentiation. Reduced PTHrP accelerates hypertrophy, shortening bones. In mice, Pthlh−/− causes lethal skeletal dysplasia, while heterozygotes appear normal, implying species-specific sensitivity. Human PTHLH mutations cause dominant phenotypes, highlighting dosage sensitivity.

Conclusion
This study identifies a 3.06-Mb deletion on 12p11.22-12.1 as causative for syndromic BDE with pectus carinatum and short stature. PTHLH haploinsufficiency underlies the skeletal anomalies, while the deletion’s size and gene content explain the absence of neurodevelopmental features. The findings underscore PTHLH’s role in endochondral ossification and expand the phenotypic spectrum of 12p deletions. Clinically, this work highlights the importance of CNV analysis in BDE with atypical features.

doi.org/10.1097/CM9.0000000000000327

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