P-040 an Exceptionally Rare Syndrome Characterized by Early-Onset Type 2 Diabetes Mellitus, Short Stature, Polydactyly, and Premature Greying Hair

Abstract Introduction While 90–95% of diabetes cases are type 2 and 5–10% are type 1, less than 1% are due to monogenic or syndromic causes. Here, we present an exceptionally rare syndromic case with early-onset type 2 diabetes mellitus (DM), short stature, polydactyly, and premature greying of hair. Clinical Case A 24-year-old female presented with fatigue, weight loss and new onset diabetes. She had undergone bilateral cataract surgery at age 10. Her early development was reported to be normal, until the age of nine when growth retardation had become evident. She was the third child of consanguineous parents; family history was unremarkable. On examination, she was 145 cm tall and weighed 28 kg (BMI: 14. 2 kg/m²). Tanner staging showed breast development at stage 4. Other findings included premature graying and thinning of scalp, axillary, and pubic hair; left-sided polydactyly (six toes), bilateral exophthalmos; bird-like facies and distal muscle atrophy (Figure 1). Type 1 diabetes mellitus was excluded due to negative autoantibodies and normal C-peptide levels (Table 1). Additional findings included subclinical hypothyroidism, hyperlipidemia (Table 1-2), and osteoporosis. Her bone age and her growth and sex hormone profiles were within the normal reference ranges. Genetic analysis revealed a homozygous c. 755₇58del (Lys252Serfs*2) mutation in exon 8 of the WRN gene (NM₀00553), confirming the diagnosis of Werner syndrome (WS). Screening for malignancy and cardiovascular disease yielded normal echocardiography, abdominal ultrasonography, and thorax computerized tomography findings. The patient was given insulin glargine and pioglitazone to control diabetes, but pioglitazone was discontinued due to facial edema. Metformin was started and titrated to 500 mg twice daily. Hyperlipidemia was treated with fenofibrate (250 mg/day). Current glycemic and lipid profiles remain within target ranges. Conclusion WS is a rare autosomal recessive disorder characterized by features of premature aging. Clinical diagnosis is typically made in the third or fourth decade, with affected individuals often dying by the age of 40–50 due to atherosclerotic complications or malignancies. Characteristic features include juvenile-onset bilateral cataracts, scleroderma-like skin changes (e. g. , atrophic skin, clavus, callus), progeroid hair changes (premature greying, thinning), short stature, soft tissue calcification (especially of the Achilles tendon), bird-like facies, and a hoarse voice. Aging-related conditions such as type 2 diabetes mellitus (DM), hypogonadism, osteoporosis, and atherosclerosis are also common. WS is caused by loss-of-function mutations in the WRN gene on chromosome 8p12. In our patient, a homozygous c. 755₇58del (Lys252Serfs*2) mutation in exon 8—an infrequently reported variant—was identified. WS should be considered in the differential diagnosis of young adults presenting with features of premature aging, diabetes, and atypical physical findings. Figure 1: Table 1: Laboratory evaluation of the patient* C-peptide was evaluated after the resolution of glucotoxicity. Table 2: Hormonal evaluation of the patient