NOG – Stapes Ankylosis with Broad Thumbs and Toes (Teunissen-Cremers Syndrome)

Heterozygous mutations in the NOG gene cause an autosomal dominant bone and joint malformation syndrome characterized by stapes ankylosis, broad thumbs and first toes with brachytelephalangia, hypermetropia, and conductive hearing impairment. In three Dutch families encompassing nine affected individuals, reconstructive middle ear surgery improved air-bone gaps to <10 dB in six of nine ears, highlighting the clinical utility of early genetic diagnosis and intervention (PMID:15699718).

Genetic analysis across five independent pedigrees has identified four truncating variants (e.g., p.Trp205Ter) and one missense allele (e.g., c.406C>T (p.Arg136Cys)) that segregate with disease. Segregation analysis demonstrated perfect cosegregation of NOG variants in nine affected relatives from three families, providing robust evidence for pathogenicity. No unaffected carriers were observed, consistent with full penetrance in reported pedigrees.

The variant spectrum includes nonsense (e.g., p.Trp205Ter), frameshift (e.g., p.Ile120fs), and missense alleles affecting critical residues in the BMP-binding and heparin-binding interfaces of noggin. The missense mutation c.406C>T (p.Arg136Cys) impairs heparan-sulfate proteoglycan binding and is predicted to disrupt noggin localization to the joint interzone (PMID:24735539). No recurrent founder alleles have been reported, and carrier frequencies are exceedingly low in population databases.

Functional assays support a hypomorphic, dosage-sensitive mechanism. Disease-causing missense alleles abolish or reduce secretion of functional noggin homodimers in transiently transfected cells, without dominant-negative interference with wild-type secretion (PMID:11562478). Similarly, the p.Arg136Cys variant impairs noggin dimerization in patient leukocytes, corroborating in vitro findings and underscoring a haploinsufficiency model.

Conflicting data include the common p.Gly92Glu variant, which shows normal BMP antagonism and is present in healthy individuals, refuting its pathogenicity (PMID:22529972). Burden testing in nonsyndromic cleft lip/palate cohorts also failed to implicate rare NOG variants, suggesting locus specificity of NOG-related symphalangism spectrum disorders (PMID:24706492).

Integration of genetic and functional data yields a strong gene-disease association: heterozygous loss-of-function and hypomorphic NOG alleles cause Teunissen-Cremers syndrome via impaired BMP antagonism. Genetic confirmation guides prognosis and surgical planning, enabling personalized management. Key take-home: Autosomal dominant NOG mutations are a reliable biomarker for stapes ankylosis with broad digits and hyperopia, informing diagnostic decision-making and therapeutic intervention.

References

• Otology & neurotology • 2005 • Teunissen-Cremers syndrome: a clinical, surgical, and genetic report. PMID:15699718
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. PMID:11562478
• Biochemical and biophysical research communications • 2014 • A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss. PMID:24735539
• PloS one • 2012 • Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance. PMID:22529972
• Birth defects research. Part A, Clinical and molecular teratology • 2014 • Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within Gremlin-1, a component of the bone morphogenetic protein 4 pathway. PMID:24706492

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