CHRNG – Autosomal Recessive Multiple Pterygium Syndrome (Escobar Syndrome)

Escobar syndrome (autosomal recessive multiple pterygium syndrome; MONDO:0009926) is caused by biallelic variants in CHRNG (Gene Symbol), which encodes the fetal γ-subunit of the nicotinic acetylcholine receptor. Affected individuals present with multiple pterygia, congenital joint contractures, facial dysmorphism and variable musculoskeletal anomalies. Inheritance is autosomal recessive, with affected probands homozygous or compound heterozygous for CHRNG variants.

Genetic studies have identified 17 novel probands from five unrelated cohorts: two siblings with homozygous missense CHRNG c.428C>G (p.Pro143Arg) (2 probands) (PMID:25411939), a consanguineous Pakistani family with homozygous CHRNG c.136C>T (p.Arg46Ter) (1 proband) (PMID:30461311), five Tunisian patients including a novel composite heterozygote and two recurrent alleles (5 probands) (PMID:36292632), seven nonlethal MPS cases with long-term follow-up (7 probands) (PMID:30868735), and two unrelated contracture-only cases lacking pterygia (2 probands) (PMID:24254455). Combined with 57 previously published individuals, >64 patients confirm a robust phenotype–genotype correlation (PMID:30868735).

Variant spectrum comprises five truncating alleles (including c.136C>T (p.Arg46Ter), c.117dup (p.Asn40GlnfsTer?), c.459dup (p.Val154fs)), one splice donor site (c.351-1G>A) and six missense substitutions (e.g., c.428C>G (p.Pro143Arg), c.715C>T (p.Arg239Cys), c.794T>G (p.Leu265Arg)). A founder effect is suggested for c.753_754del (p.Asn40GlnfsTer?) observed in Tunisian patients (PMID:36292632).

Segregation analyses in consanguineous pedigrees demonstrate homozygous or compound heterozygous variants in affected individuals with heterozygous parents and unaffected siblings, corroborating autosomal recessive inheritance (PMID:30461311).

Functional assessments reveal acetylcholine receptor deficiency in vitro for truncating variants (p.Arg46Ter) and neuromuscular junction abnormalities on muscle biopsy. Whole-body MRI shows predominant fatty infiltration and muscle bulk reduction, particularly of paravertebral and distal limb muscles, aligning with clinical contractures and scoliosis (PMID:30868735).

Integration of genetic and experimental data supports loss-of-function as the disease mechanism. CHRNG variant testing provides definitive diagnosis, informs genetic counseling and prenatal diagnosis for families at risk.

References

• Journal of pediatric orthopedics. Part B • 2015 • Orthopaedic manifestations and treatment outcome of two siblings with Escobar syndrome and homozygous mutations in the CHRNG gene PMID:25411939
• Genetic testing and molecular biomarkers • 2018 • Molecular Diagnosis of Rare Autosomal Recessive Escobar Syndrome in a Consanguineous Pakistani Family PMID:30461311
• Genes • 2022 • Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome PMID:36292632
• American journal of medical genetics. Part A • 2019 • CHRNG-related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings PMID:30868735
• Orthopaedic surgery • 2013 • Is webbing (pterygia) a constant feature in patients with Escobar syndrome? PMID:24254455

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