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Clinical and genetic characterisation of a series of patients with triple A syndrome

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Abstract

Triple A syndrome (TAS) or Allgrove syndrome (OMIM #231550) is a rare autosomal recessive disorder characterised by adrenocorticotropic hormone-resistant adrenal insufficiency, alacrima, achalasia, and neurological and dermatological abnormalities. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Between 2006 and 2017, we evaluated six patients with a clinical diagnosis of TAS, based on the presence of at least two symptoms, usually adrenal insufficiency and alacrima. In all cases, genetic analysis revealed homozygous mutations in the AAAS gene. One novel mutation was detected: a homozygous 10-bp deletion (c.1264_1273del, p.Q422NfsX126) in exon 14 of the AAAS gene that caused a frameshift that introduced an aberrant stop codon after 126 amino acids. This genetic variant is likely to be pathogenic because it caused a significant change in protein structure. A precise genotype–phenotype correlation was impossible to establish.

Conclusions: Based on our experience, we recommend that molecular analysis should be performed in the presence of alacrima and at least one more symptom of TAS. Our cases share many clinical features of TAS and underline the variability in this syndrome, as well as the need for thorough investigation following a multidisciplinary approach.

What is known:

• Triple A syndrome is characterised by achalasia, alacrima, adrenal insufficiency, neurological impairment, and dermatological abnormalities.

• A precise genotype–phenotype correlation has proved impossible to establish.

What is new:

• These cases add to a large number of similar case reports with limited novel information.

• The newly identified AAAS gene mutation was reported.

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Abbreviations

ACTH :

Adrenocorticotropic hormone

ALADIN :

Alacrima, Achalasia, Adrenal Insufficiency, Neurological Disorder

DTR :

Deep tendon reflexes

NPC :

Nuclear pore complex

PRA :

Plasma renin activity

WD :

Tryptophan–aspartic acid

TAS :

Triple A syndrome

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Author information

Author notes

  1. Marco Bonomi and Semra Çetinkaya contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Endocrinology, Dr. Sami Ulus Obstetrics and Gynecology and Pediatrics Training and Research Hospital, Altındağ, 06020, Ankara, Turkey

    Erdal Kurnaz, Zehra Aycan, Şenay Savaş-Erdeve, Nursel Muratoğlu Şahin, Melişah Keskin, Elvan Bayramoğlu & Semra Çetinkaya

  2. Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Cusano Milano, Milan, Italy

    Paolo Duminuco & Marco Bonomi

  3. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Marco Bonomi

Authors
  1. Erdal Kurnaz
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  2. Paolo Duminuco
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  3. Zehra Aycan
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  4. Şenay Savaş-Erdeve
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  7. Elvan Bayramoğlu
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  8. Marco Bonomi
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  9. Semra Çetinkaya
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Contributions

Study concept and design: EK, PD, ZA, MB, and SC. Acquisition of data: EK, ZA, SSE, NMS, MK, EB, MB, and SC. Analysis and interpretation of data: EK, PD, and MB. Drafting the manuscript: EK and MB. Critical revision of the manuscript for important intellectual content: EK, MB, and SC. Final approval of the version to be published: all authors.

Corresponding author

Correspondence to Erdal Kurnaz.

Ethics declarations

Ethical approval

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Local Ethics Committee.

Informed consent

Blood samples from patients and family members were collected for genetic testing after obtaining written informed consent.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Communicated by Peter de Winter

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Kurnaz, E., Duminuco, P., Aycan, Z. et al. Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr 177, 363–369 (2018). https://doi.org/10.1007/s00431-017-3068-8

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  • DOI: https://doi.org/10.1007/s00431-017-3068-8

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