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Unique Case of Mosaic 8q21.1-q24.3 deletion and duplications Linked to Langer-Giedion and Cornelia de Lange Syndromes Presenting with Recurrent Fractures

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Langer-Giedion's syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPS II; MIM: 150230), is a contiguous gene deletion syndrome located at 8q23.2-q24.1, resulting from haploinsufficiency of the TRPS1 and EXT1 genes (Chen et al., 2013; Selenti et al., 2015). Cornelia de Lange's syndrome (CdLS) is a genetically heterogeneous dysmorphic syndrome linked to heterozygous mutations in the RAD21 gene, which are associated with a milder clinical presentation (CdLS type 4; MIM: 614701). The RAD21 gene is situated between TRPS1 and EXT1. Here, we present a novel case of complex mosaic duplication and deletion involving the 8q21.1-q24.3 region, which encompasses all three genes.

 

Case Presentation
The patient is a female who initially visited our genetics clinic at age two. She presented with multiple congenital features, including microcephaly, plagiocephaly, polydactyly, and dysmorphic facies characterized by a prominent philtrum and a thin upper lip. She had previously undergone surgical correction for right hip dysplasia and polydactyly, with overlapping toes noted on her left foot. X-rays revealed numerous osteochondromas in multiple long bones. She had a history of frequent falls, including a recent right femur fracture sustained after tripping, for which she was in a cast for about five weeks. Family history was notable for her mother’s half-brother's son with Noonan’s syndrome and polydactyly in a paternal great-grandmother.

Diagnostic Workup
Microarray analysis identified a 21.5 Mb mosaic interstitial duplication of 8q21.2-q23.1, a 13.01 Mb mosaic interstitial deletion of 8q23.1-q24.12, and a 25.78 Mb mosaic terminal duplication of 8q24.12-q24.3. Approximately 10% of the nucleated blood specimen exhibited the duplicated segments, while the interstitial mosaic deletion was present in about 75% of nucleated blood cells (primarily granulocytes). These findings indicate a structural rearrangement on chromosome 8, with mosaicism contributing to variability in affected tissues and clinical outcomes. The duplication regions encompass several OMIM genes, with 8q21.2-q23.1 (from LRCC1 to OXR1) and 8q24.12-q24.3 (proximal gene ENPP2) containing potentially dosage-sensitive genes, although their effects remain unclear. Mosaic gains at 8q24 have been linked to cardiac defects. The deletion at 8q23.1-q24.12 includes significant genes: TRPS1, RAD21, and EXT1, associated with Langer-Giedion syndrome, Cornelia de Lange syndrome type 4, and hereditary multiple osteochondromas, respectively. Other genes in the deleted interval, in combination with mosaicism, may influence the clinical phenotype. The patient returned at age four with a new fracture of the left wrist. Facial features were re-examined, revealing synophrys, a broad nose, and prominent ears. While LGS is primarily associated with skeletal abnormalities such as exostoses, scoliosis, and hip dysplasia, it is not typically linked to an increased risk of fractures. The presence of exostoses may lead to bone deformities and pain, but fractures are not commonly reported as a direct feature of LGS. Only two publications document severe osteoporosis with or without fractures in patients with TRPS II (Macchiaiolo et al., 2014; Shao et al., 2011). We performed an osteogenesis imperfecta panel, which returned negative. X-rays confirmed bilateral hip dysplasia and multiple osteochondromas of the humerus and scapula. A DEXA bone scan revealed a lumbar spine bone mineral density of 0.375 g/cm² with a Z-score of -2.6.

 

Treatment and Management
Given the history of frequent fractures and low bone density, we initiated pamidronate infusion at a dosage of 1 mg/kg (Macchiaiolo et al., 2014). The patient was referred to orthopedics for further management of the multiple osteochondromas.

Outcome and Follow-Up
Since initiating pamidronate infusion, the patient has not experienced any further fractures.

Discussion
This is the first reported case of mosaic duplication and deletion in the 8q21.1-q24.3 region associated with Langer-Giedion syndrome and Cornelia de Lange syndrome, manifesting with recurrent fractures. The identified duplication and deletion broaden the clinical phenotypes observed, prominently featuring multiple osteochondromas, osteoporosis, and recurrent fractures. This represents the second documented case in which bisphosphonate therapy was utilized to treat bone fragility in a patient with TRPS II-associated osteoporosis and fractures.

Conclusion
More data are needed to evaluate the effectiveness and long-term impact of bisphosphonate treatment for osteoporosis and fractures in patients with an 8q21.1-q24.3 deletion. We will continue to closely monitor both the treatment’s effectiveness and the patient’s disease progression.

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