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Background <p>TANGO2 deficiency disorder is an ultra-rare autosomal recessive condition characterized by life-threatening metabolic crises with rhabdomyolysis and cardiac arrhythmias.</p> <p><?noindent??>Patients with 22q11.2 deletion syndrome are at increased risk when a pathogenic variant occurs in the remaining allele, yet this dual diagnosis remains underrecognized as clinicians often attribute all manifestations to the primary genetic condition.</p> <p><?noindent??>We report a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5 after first metabolic crisis with rhabdomyolysis.</p> Case presentation <p>A girl with 22q11.2 deletion syndrome diagnosed in infancy exhibited global developmental delay and chronic excessive sleepiness attributed to her established diagnosis. At age 5, she experienced her first metabolic crisis during pneumonia with severe rhabdomyolysis (creatine kinase &gt;100,000 U/L), features inconsistent with isolated 22q11.2 deletion syndrome. Two additional metabolic crises occurred at age 7 before exome sequencing revealed a hemizygous TANGO2 variant c.536G&gt;A, confirming TANGO2 deficiency. A previously unreported hemizygous missense variant c.536G&gt;A (p.Gly138Glu) in the TANGO2 gene (NM_152906.7) was identified and verified by NGS-based deep amplicon sequencing and Sanger direct sequencing; segregation analysis confirmed paternal inheritance with the maternal allele deleted within the 22q11.2 region. Following diagnosis, B-vitamin supplementation, coenzyme Q10, L-carnitine, and gastrostomy tube placement were initiated to ensure consistent hydration and prevent prolonged periods without nutrition, a known crisis trigger. The patient achieved 4 years of crisis-free stability with reduced daytime sleepiness. At age 11, she remains stable without further crises.</p> Conclusions <p>This case demonstrates that exome sequencing should be pursued early when atypical features emerge in patients with established genetic diagnoses. The sustained crisis-free period following gastrostomy placement supports proactive nutritional intervention in TANGO2 patients with feeding difficulties. Clinicians must recognize that microdeletion syndrome patients can harbor variants unmasking additional autosomal recessive conditions requiring distinct management.</p>

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TANGO2-related metabolic encephalopathy–arrhythmia syndrome unmasked in 22q11.2 deletion syndrome: hemizygous pathogenic variant, complex phenotype modified by two genetic conditions, and implications for proactive crisis prevention: a case report

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Ewa Grzywna-Rozenek,
  • Łukasz Sędek,
  • Małgorzata Rydzanicz,
  • Agnieszka Borys-Iwanicka,
  • Rafał Płoski,
  • Maria Szczepańska,
  • Kinga Brawańska-Maśluch,
  • Robert Śmigiel

摘要

Background

TANGO2 deficiency disorder is an ultra-rare autosomal recessive condition characterized by life-threatening metabolic crises with rhabdomyolysis and cardiac arrhythmias.

Patients with 22q11.2 deletion syndrome are at increased risk when a pathogenic variant occurs in the remaining allele, yet this dual diagnosis remains underrecognized as clinicians often attribute all manifestations to the primary genetic condition.

We report a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5 after first metabolic crisis with rhabdomyolysis.

Case presentation

A girl with 22q11.2 deletion syndrome diagnosed in infancy exhibited global developmental delay and chronic excessive sleepiness attributed to her established diagnosis. At age 5, she experienced her first metabolic crisis during pneumonia with severe rhabdomyolysis (creatine kinase >100,000 U/L), features inconsistent with isolated 22q11.2 deletion syndrome. Two additional metabolic crises occurred at age 7 before exome sequencing revealed a hemizygous TANGO2 variant c.536G>A, confirming TANGO2 deficiency. A previously unreported hemizygous missense variant c.536G>A (p.Gly138Glu) in the TANGO2 gene (NM_152906.7) was identified and verified by NGS-based deep amplicon sequencing and Sanger direct sequencing; segregation analysis confirmed paternal inheritance with the maternal allele deleted within the 22q11.2 region. Following diagnosis, B-vitamin supplementation, coenzyme Q10, L-carnitine, and gastrostomy tube placement were initiated to ensure consistent hydration and prevent prolonged periods without nutrition, a known crisis trigger. The patient achieved 4 years of crisis-free stability with reduced daytime sleepiness. At age 11, she remains stable without further crises.

Conclusions

This case demonstrates that exome sequencing should be pursued early when atypical features emerge in patients with established genetic diagnoses. The sustained crisis-free period following gastrostomy placement supports proactive nutritional intervention in TANGO2 patients with feeding difficulties. Clinicians must recognize that microdeletion syndrome patients can harbor variants unmasking additional autosomal recessive conditions requiring distinct management.