A NEW COHORT STUDY OF ALLGROVE SYNDROME: THE CRITICAL ROLE OF DETAILED ANAMNESIS AND COMPREHENSIVE APPROACH

Öz

Objective: Allgrove syndrome (Triple-A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency, often accompanied by neurological and autonomic findings. Its clinical heterogeneity and rarity frequently delay diagnosis. The aim of our study is to emphasize the importance of a thorough physical examination and family history, as well as to raise awareness about the syndrome.

Materials and Methods: We describe six patients from four unrelated families diagnosed with Allgrove syndrome in eastern Türkiye. Detailed clinical evaluations and genetic analyses were conducted. Aladin WD Repeat Nucleoporin (AAAS) gene variants were identified using next-generation sequencing and Sanger sequencing.

Results: All patients presented with alacrima and achalasia; adrenal insufficiency was absent in one patient. Neurological manifestations were noted in four patients. Homozygous AAAS variant c.1066_1067delCT (p.Leu356Valfs*8) was identified in five cases; one patient carried the c.1432C>T (p.Arg478*) variant. Consanguinity was present in three families. Despite the rarity of this syndrome, two patients were diagnosed by a family physician unfamiliar with the condition, based on careful anamnesis.

Conclusion: This study adds to the growing literature on Allgrove syndrome by highlighting the high frequency of the c.1066_1067delCT variant, suggesting a founder effect in eastern Türkiye. The phenotypic variability observed—even among siblings—supports previous findings of limited genotype–phenotype correlation. Our report highlights the critical diagnostic role of primary care physicians in rare disease detection. Our findings emphasize raising awareness of Allgrove syndrome and integrating regional variant data into diagnostic algorithms. Early recognition by non-specialists can significantly reduce diagnostic delays in multisystemic genetic disorders.

Anahtar Kelimeler

• Allgrove syndrome
• Triple-A
• Alacrima
• Achalasia
• Adrenal insufficiency
• AAAS

ALLGROVE SENDROMUNDA YENİ BİR KOHORT ÇALIŞMASI: AYRINTILI ANAMNEZ VE KAPSAMLI YAKLAŞIMIN ÖNEMİ

Öz

Amaç: Allgrove sendromu (3-A sendromu), alakrima, akalazya ve adrenal yetmezlik ile karakterize, nadir görülen otozomal resesif bir hastalıktır ve genellikle nörolojik ve otonomik bulgularla birlikte seyreder. Klinik heterojenliği ve nadir görülmesi tanının gecikmesine neden olabilir. Çalışmamızın amacı, detaylı bir fizik muayene ve aile öyküsünün önemini vurgulamak ve sendrom hakkında farkındalık yaratmaktır.

Gereç ve Yöntemler: Türkiye’nin doğusundan tanı alan, akraba olmayan dört aileden altı Allgrove sendromu hastası tanımlandı. Tüm hastalara ayrıntılı klinik değerlendirme ve genetik analiz yapıldı. Aladin WD Repeat Nucleoporin (AAAS) genindeki varyantlar yeni nesil dizileme ve Sanger dizileme yöntemleri ile tespit edildi.

Bulgular: Tüm hastalarda alakrima ve akalazya mevcuttu; adrenal yetmezlik yalnızca bir hastada görülmedi. Dört hastada nörolojik bulgular vardı. Beş olguda homozigot c.1066_1067delCT (p.Leu356Valfs*8) varyantı, bir hastada ise c.1432C>T (p.Arg478*) varyantı saptandı. Üç ailede akraba evliliği vardı. Nadir görülmesine rağmen, iki hasta bu hastalığı tanımayan bir aile hekimi tarafından dikkatli anamnez yoluyla tanı aldı.

Sonuç: Bu çalışma, Allgrove sendromuna ilişkin literatüre katkı sağlamakta ve Doğu Türkiye’de c.1066_1067delCT varyantının yüksek sıklığını vurgulayarak kurucu etki (founder effect) olasılığına işaret etmektedir. Kardeşler arasında bile gözlemlenen fenotipik değişkenlik, daha önce bildirilen sınırlı genotip-fenotip korelasyonunu desteklemektedir. Özellikle bu çalışmada, birinci basamak hekimlerinin nadir hastalıkların tanısındaki kritik rolü açıkça ortaya konmuştur. Bulgularımız, Allgrove sendromu farkındalığının artırılmasının ve bölgesel varyant verilerinin tanı algoritmalarına entegre edilmesinin önemini vurgulamaktadır. Uzman olmayan hekimler tarafından bile erken tanı konulması, multisistemik genetik hastalıklarda tanı gecikmesini önemli ölçüde azaltabilir.

Anahtar Kelimeler

• Allgrove sendromu
• 3-A
• Alakrimi
• Akalazya
• Adrenal yetmezlik
• AAAS

Kaynakça

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