EXT1 – Trichorhinophalangeal syndrome type II

Trichorhinophalangeal syndrome type II (TRPS II; Langer–Giedion syndrome) is a rare autosomal dominant contiguous gene deletion disorder characterized by craniofacial dysmorphism, sparse scalp hair, bulbous nose, and multiple cartilaginous exostoses. Haploinsufficiency of the EXT1 gene at chromosome 8q24.11, often in combination with TRPS1 deletion, underlies the classic skeletal and ectodermal features of TRPS II. Genetic testing typically identifies de novo interstitial deletions spanning EXT1, confirmed by array comparative genomic hybridization or cytogenomic techniques.

Genetic evidence includes at least seven unrelated probands with 7.5–15 Mb interstitial deletions encompassing EXT1, all presenting TRPS II features ([PMID:15523607]; [PMID:22315192]; [PMID:26673557]). A 3.2 Mb minimal critical region defined in two unrelated patients reinforces the pivotal role of EXT1 haploinsufficiency in Langer–Giedion syndrome ([PMID:35290978]). De novo origin is demonstrated by normal parental copy number in all reported cases.

EXT1 haploinsufficiency disrupts heparan sulfate polymerization, as shown in biochemical assays and EXT1/EXT2 complex studies, leading to abnormal bone growth and exostosis formation ([PMID:10639137]). Mouse knockout models of Ext1 exhibit skeletal defects and embryonic lethality consistent with impaired HSPG biosynthesis, supporting a loss-of-function mechanism.

No conflicting reports dispute the association between EXT1 deletion and TRPS II. The contiguous gene deletion mechanism predicts full penetrance, with variable expressivity of exostoses, facial features, and growth deficiency.

In summary, strong clinico-genetic and functional concordance supports a Strong association between EXT1 haploinsufficiency and trichorhinophalangeal syndrome type II. Deletion screening of EXT1 should be part of diagnostic workup for patients with TRPS II features.

Key Take-home: EXT1 deletion causing heparan sulfate deficiency is a critical driver of the skeletal anomalies in TRPS II, and targeted deletion analysis aids clinical diagnosis.

References

• American journal of medical genetics. Part A • 2004 • Pronounced short stature in a girl with tricho-rhino-phalangeal syndrome II (TRPS II, Langer-Giedion syndrome) and growth hormone deficiency. PMID:15523607
• American journal of medical genetics. Part A • 2012 • Third case of 8q23.3-q24.13 deletion in a patient with Langer-Giedion syndrome phenotype without TRPS1 gene deletion. PMID:22315192
• Molecular cytogenetics • 2015 • Annular pancreas in Trichorhinophalangeal syndrome type II with 8q23.3-q24.12 interstitial deletion. PMID:26673557
• Cytogenetic and genome research • 2022 • Minimal Critical Region and Genes for a Typical Presentation of Langer-Giedion Syndrome. PMID:35290978
• Proceedings of the National Academy of Sciences of the United States of America • 2000 • The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. PMID:10639137

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