Neslihan TEKİN, Eylem ALINCAK, Birgül KİREL, Sultan Durmuş AYDOĞDU, Pelin KÖŞGER, Özkan BOZDAĞ

Yeni bir insülin reseptör gen mutasyonunun tanımlandığı bir Donohue sendromu “Leprechaunism” olgusu

Donohue sendromu "Leprechaunism", insülin reseptör geninde homozigot ve bileşik heterozigot işlev kaybettirici mutasyonların neden olduğu ağır insülin direnci, hiperinsülinizm, beslenme sonrası hiperglisemi, beslenme öncesi hipoglisemi, rahim içi ve doğum sonrası büyüme geriliği, dismorfik bulgular, klinik ve laboratuvar hiperandrojenizm ile belirgin bir hastalıktır. Yenidoğan bir kız bebeğin fizik bakısında: derialtı yağ dokusu azlığı, iki taraflı simian çizgisi, yüzde belirgin hipertrikozis, diş eti hipertrofisi, klitoris büyüklüğü ve belirgin meme başları; laboratuvar incelemesinde: hiperandrojenizm, beslenme sonrası hiperglisemi ve beslenme öncesi hipoglisemi atakları ile eş zamanlı çok yüksek insülin düzeyleri saptandı. Bu bulgular ile hastaya Donohue sendromu tanısı konuldu. Metformin ve devamlı nazogastrik beslenme başlandı. İzlemde göreceli iyi glisemik kontrol sağlanmasına rağmen ağır hipertrofik obstrüktif kardiyomiyopati ve ağır derecede beslenme bozukluğu gelişti. Hasta 75 günlükken ağır pnömoni ve kalp yetersizliği nedenleriyle kaybedildi. Hastamızın insülin reseptör geninde bileşik heterozigot mutasyon saptandı. Bu mutasyonlardan biri; babasında da heterozigot olarak saptanan, bilinen bir p.R813 (c.2437C>T) mutasyonu, diğeri ise annesinde de heterozigot olarak saptanan yeni bir p.777790delVAAFPNTSSTSVPT mutasyonu idi

A case of Donohue syndrome “Leprechaunism” with a novel mutation in the insulin receptor gene

Donohue syndrome (Leprechaunism) is characterized by severe insulin resistance, hyperinsulinemia, postprandial hyperglycemia, preprandial hypoglycemia, intrauterine and postnatal growth retardation, dysmorphic findings, and clinical and laboratory findings of hyperandrogenemia due to homozygous or compound heterozygous inactivating mutations in the insulin receptor gene. A female newborn presented with lack of subcutaneous fat tissue, bilateral simian creases, hypertrichosis, especially on her face, gingival hypertrophy, cliteromegaly, and prominent nipples. Her laboratory tests revealed hyperandrogenism, postprandial hyperglycemia and preprandial hypoglycemia, and very high concurrent insulin levels. She was diagnosed as having Donohue syndrome. Metformin and continuous nasogastric feeding were administrated. During follow-up, relatively good glycemic control was obtained. However, severe hypertrophic obstructive cardiomyopathy and severe malnutrition developed. She died aged 75 days of severe heart failure and pneumonia. Her INSR gene analysis revealed a compound heterozygous mutation. One of these mutations was a p.R813 (c.2437C>T) mutation, which was defined previously and shown also in her father, the other mutation was a novel p.777-790delVAAFPNTSSTSVPT mutation, also shown in her mother. The parents were heterozygous for these mutations

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1. McDonald A, Williams RM, Regan FM, Semple RK, Dunger DB. IGF-I treatment of insulin resistance. Eur J Endocrinol 2007; 157: 51-6. [CrossRef ]
2. Semple RK, Savage DB, Halsall DJ, O’Rahilly S. Syndromes of severe insulin resistance and/or lipodystrophy. In: Weiss RE, Refetoff S, (eds). Genetic diagnosis of endocrine disorders. USA: Academic Press 2010.p.39-52. [CrossRef ]
3. Nobile S, Semple RK, Carnielli RP. A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure. J Ped End Met 2012; 25: 363-6. [CrossRef ]
4. Semple RK, Williams RM, Dunger DB. What is the best management strategy for patients with severe insulin resistance? Clin Endocrinol 2010; 73: 286-90. [CrossRef ]
5. Çelik AY, Odabaş D, Pirgon O. Leprechaunismli bir infantta bozulmuş glukoz regülasyonu ve dev over kistlerinin yüksek poz insülin glarjin ile tedavisi-olgu sunumu. Güncel Ped 2010: 8: 119-22.
6. Lamothe B, Baudry A, Christoffersen CT, et al. Insulin receptor-deficient cells as a new tool for dissecting complex interplay in insulin and insulin-like growth factors. FEBS Lett 1998; 426: 381-5. [CrossRef ]
7. Tinka H, Bratanic N, Podkrajsek KT, et al. Severe progressive obstructive cardiomyopathy and renal tubular dysfunction in Donohue syndrome with decreased insulin receptor autophosphorylation due to a novel INSR mutation. Eur J Ped 2013; 172: 1125-9. [CrossRef ]
8. Simpkin A, Cochran E, Cameron F, et al. Insulin receptor and the kidney: nephrocalcinosis in patients with recessive INSR mutations. Nephron Physiol 2014; 128: 55-61. [CrossRef ]
9. Hisrchberg AL. Polycystic ovary syndrome, obesity and reproductive implications: hyperandrogenism and insulin resistance. CME released 24.8.2014; valid for credit through 24.8.2010. Available from: https://www.medscape.org/viewarticle/707476.
10. Dokuzeylül N, Kahraman S. Preimplantation genetic diagnosis for Donohue syndrome (Leprechaunism). J TurkGerman Gyn Assoc 2009; 10: 122-3.