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“Leprechaunism” with a Novel Mutation in the Insulin Receptor Gene

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“Leprechaunism” with a Novel Mutation in the Insulin Receptor Gene Case Report A case of Donohue syndrome “Leprechaunism” with a novel mutation in the insulin receptor gene Birgül Kirel1, Özkan Bozdağ2, Pelin Köşger2, Sultan Durmuş Aydoğdu2, Eylem Alıncak2, Neslihan Tekin3 1Osmangazi University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Eskişehir, Turkey 2Osmangazi University, Faculty of Medicine, Department of Pediatrics, Division of General Pediatrics, Eskişehir, Turkey 3Osmangazi University, Faculty of Medicine, Department of Pediatrics, Division of Neonatalogy, Eskişehir, Turkey Cite this article as: Kirel B, Bozdağ Ö, Köşger P, Durmuş Aydoğdu S, Alıncak E, Tekin N. A case of Donohue syndrome “Leprechaunism” with a novel mutation in the insulin receptor gene. Turk Pediatri Ars 2017; 52: 226-30. Abstract She was diagnosed as having Donohue syndrome. Metformin and continuous nasogastric feeding were administrated. During fol- Donohue syndrome (Leprechaunism) is characterized by severe low-up, relatively good glycemic control was obtained. However, insulin resistance, hyperinsulinemia, postprandial hyperglycemia, severe hypertrophic obstructive cardiomyopathy and severe malnu- preprandial hypoglycemia, intrauterine and postnatal growth retar- trition developed. She died aged 75 days of severe heart failure and dation, dysmorphic findings, and clinical and laboratory findings pneumonia. Her insulin receptors gene analysis revealed a com- of hyperandrogenemia due to homozygous or compound heterozy- pound heterozygous mutation. One of these mutations was a p.R813 gous inactivating mutations in the insulin receptor gene. A female (c.2437C>T) mutation, which was defined previously and shown also newborn presented with lack of subcutaneous fat tissue, bilateral in her father, the other mutation was a novel p.777-790delVAAF- simian creases, hypertrichosis, especially on her face, gingival hy- PNTSSTSVPT mutation, also shown in her mother. The parents pertrophy, cliteromegaly, and prominent nipples. Her laboratory were heterozygous for these mutations. tests revealed hyperandrogenism, postprandial hyperglycemia and Keywords: Donohue syndrome, hyperandrogenism, hyperinsulin- preprandial hypoglycemia, and very high concurrent insulin levels. ism, insulin receptor, insulin resistance, newborn Introduction vere insulin resistance and hyperinsulinism develop in these patients. Patients are lost in early infancy Insulin is an anabolic hormone that is involved in because of intervening infections and heart failure. cellular uptake of glucose, the inhibition of hepat- Rabson-Mendenhall syndrome is another phenotype ic gluconeogenesis, reduction of lipolysis, increase of this condition. In this syndrome, patients have been reported to have the same clinical findings as in lipogenesis, and prevention of protein destruc- seen in Donohue syndrome with a slightly lower de- tion (1). gree of severity and can live up to the second decade (2-4). Donohue syndrome is a condition in which binding of insulin to insulin receptors (INSR) and signaliza- In this article, a patient with Donohue syndrome who tion of insulin is disrupted. This condition is caused was followed up from the neonatal period because by autosomal recessive, homozygous or compound of problems caused by severe insulin resistance and heterozygous loss-of-function mutations in the INSR compensatory hyperinsulinism and was found to have gene (19th chromosome). More than 150 mutations compound heterozygous mutation in the INSR gene is have been reported in the insulin receptor gene. Se- presented. Address for Correspondence: Birgül Kirel E-mail: [email protected] Received: 29.07.2015 Accepted: 19.06.2016 ©Copyright 2017 by Turkish Pediatric Association - Available online at www.turkpediatriarsivi.com 226 DOI: 10.5152/TurkPediatriArs.2017.3193 Turk Pediatri Ars 2017; 52: 226-30 Kirel et al. Donohue syndrome: a case report Case Table 1. Sex hormone levels of our patient on the post- natal 14th day Our patient was a female baby who was born at the 37th FSH (mIU/mL) 0.27 gestational week by normal vaginal spontaneous delivery LH (mIU/mL) 0.1 from the first pregnancy of a 29-year-old mother who Estradiol (pg/mL) 84.67 developed polyhydramnios and hypertension during DHEA-S (μg/mL) 224 her pregnancy. There was no consanguinity between the 17 OH Progesterone (ng/mL) 50.2 mother and father. The physical examination revealed a birth height of 43 cm (<3 p) and a birth weight of 1630 Total testosterone (ng/dL) 196 g (<3rd percentile). She had a cachectic and old appear- Androstenedione (ng/mL) 10 ance, coarse face, extraverted nostrils, dry and loose skin, DHEAS: Dihydroepiandrostenedione sulphate; FSH: Follicle-stimulating hor- decreased subcutaneous adipose tissue, bilateral simi- mone; LH: Luteinizing hormone; 17 OH Progesterone: 17 hydroxyprogesterone an creases, diffuse hypertrichosis, which was especially 300 prominent on the face, gingival hypertrophy, cliteromeg- Glukoz mg/dL Metformin Metformin aly, and prominent nipples (Picture 1-2). Laboratory tests 250 50 mg/kg 100 mg/kg revealed hyperandrogenism (Table 1). Cliteromegaly 200 and the presence of hyperandrogenism suggested the diagnosis of congenital adrenal hyperplasia (CAH). Her 150 karyotype was found to be 46 XX. Hypoglycemia attacks 100 were observed in the first postnatal days. Hypoglycemia was thought to occur in relation with low birth weight 50 or CAH. Adrenal insufficiency and CAH were not found 0 on normal-dose adrenocorticotropic hormone (ACTH) Gün 1 Gün 3 Gün 5 Gün 7 Gün 9 stimulation test. Hyperinsulinism was considered when Gün 11 Gün 13 Gün 15 Gün 17 Gün 19 Gün 21 Gün 23 Gün 25 Gün 27 Gün 29 Gün 31 Gün 33 Gün 35 Gün 37 Gün 39 Gün 41 Gün 43 Gün 45 Gün 47 Gün 49 Gün 51 Gün 53 Gün 55 Gün 57 postprandial hyperglycemia (270 mg/dL) and prepran- Graphic 1. Blood glucose level monitoring of our patient dial hypoglycemia attacks were found on the postnatal ventilation and supportive treatment (antibiotic, digitalis, 21st day. In this period, the blood glucose levels were found as 178 mg/dL and 22 mg/dL, respectively, whereas diuretic) were initiated. The patient was lost at the age of concurrent insulin levels were found to be >1000 mIU/ 75 days when she had a body weight of 1800 g. Hepati- mL and 516 mIU/mL, and C-peptide (CPE) levels were tis and severe pneumonia were found on postmortem found as 58 ng/mL and 12 ng/mL. A diagnosis of Dono- biopsy. hue syndrome was made with these clinical and labo- ratory findings. Metformin at a dose of 50 mg/kg was Obesity, acanthosis nigricans, hyperinsulinism, and initiated to correct hyperinsulinism and the dose was in- disrupted glucose tolerance were found in the patient’s creased to 100 mg/kg subsequently. Continuous nasoga- parents. The father’s glycated hemoglobin (HbA1c) val- stric feeding was initiated. The blood glucose levels were ue was within the normal limits, but the mother’s was kept between 60 and 120 mg/dL with these approaches found as 6.45%. (Graphic 1). On the 42nd day, a small atrial septal defect and minimal septal hypertrophy were found on echocar- New-generation sequence analysis (Intergen Labora- diography and proponolol treatment was initiated. In the tory) revealed a compound heterozygous mutation in follow-up echocardiogram performed on the 49th day, it exon 12 region of the INSR gene in our patient. One was found that severe hypertrophic cardiomyopathy de- of these mutations was a 14- amino acid deletion mu- veloped and a diuretic drug was added to the treatment. tation (p.777-790delVAAFPNTSSTSVPT), which has not In the follow-up, direct hyperbilirubinemia and neph- been previously reported, and was found in our pa- rocalcinosis developed. Pelvic ultrasonography revealed tient’s mother as a heterozygous mutation. The other marked enlargement in the ovaries (right ovary 29 x 15 mutation was a known nonsense p.R813(c.2437C>T) mm, left ovary 24 x 14 mm). The patient did not gain mutation, which caused the occurrence of an early stop weight despite sufficient nutritional supplement. Severe codon in the 813th amino acid position, and was found weight loss and subcutaneous adipose tissue loss devel- as a heterozygous mutation in the father. oped. She was internalized in the intensive care unit be- cause of severe pneumonia and heart failure. Mechanical Verbal consent was obtained from the patient’s family. 227 Kirel et al. Donohue syndrome: a case report Turk Pediatri Ars 2017; 52: 226-30 irregularities in some tissues might be involved in the growth retardation that develops in these patients (2, 4). Severe marasmus developed in our patient who did not gain any weight in the follow-up. In absence of insulin receptors or IGF receptors, the present receptor has been shown to execute the oth- er receptor’s function (1, 6). Therefore, hyperinsulinism causes pseudoacromegalic growth in many soft tissues, although severe growth retardation is found in patients with Donohue syndrome. This condition is especially prominent in androgen-dependent tissues (2). Pseudo- acromegalic findings include elfin faces; large and low- set ears; wide nostrils; thick lips; gingival hypertrophy; large mouth, hands and feet; hypertrichosis; dysplastic nails; and acanthosis nigricans (2, 3-5). Similar clinical Picture 1-2. Appearance of our patient’s face and nipples findings were observed in our patient. It has been re- Discussion ported that organ disorders including abdominal swell- ing, renal and hepatic enlargement, cholestasis, and he- Severe insulin resistance develops in Donohue syn- patic fibrosis may
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