Endocrine and Metabolic Abnormalities in a Girl with Childhood W erner Syndrome: Case Report

Werner syndrome (WS) is a rare progeroid syndrome of autosomal-recessive inheritance that German ophthalmologist Otto Werner first reported in 1904. The frequency of WS is as high as 1 in 40,000 in Japan, with consanguineous marriage noted in approximately 40% of cases, although no regional localization of cases has been recognized.1, 2 Most progeroid phenotypes are clinically typical, including the graying and loss of hair; hoarseness and scleroderma-like skin changes emerging in the 20s; and juvenile cataracts, insulin-resistant diabetes mellitus, hypogonadism, ulceration of the skin, osteoporosis, and soft tissue calcification arising in the 30s. The most severe and lethal conditions are malignant tumors and cardiovascular or cerebrovascular diseases resulting from premature atherosclerosis in the 40s and 50s.1-4 Mean age at diagnosis was 36.7 in individuals who presented with typical signs of WS.3 In contrast, individuals who develop the disease in childhood are not usually reported primarily because of the variety of nonspecific symptoms and lack of cardinal signs during the teenage years. The case of a girl diagnosed with WS at 17 is herein reported. The girl's parents were second cousins without a family history suggesting the presence of genetic diseases, including progeroid syndromes. The girl was healthy at birth and exhibited normal growth and development in infancy. Starting at 6 years old, she gradually developed facial erythema (Figure 1) and failure to grow. At 10 years old, her parents consulted a pediatrician regarding her growth failure and chronic fatigue of unknown etiology. Clinical and laboratory examinations identified a diagnosis of hypothyroidism, and levothyroxine treatment was started, but she discontinued the medication after several months. At 17 years old, she again consulted a physician and was referred to the hospital for systematic evaluation. She was 141 cm (3.3 standard deviations below the mean) tall and weighed 33.2 kg (2.7 standard deviations below the mean), and her body mass index was 16.7 kg/m2. She had slightly gray hair, erythema on both cheeks, and dry skin over her entire body. Laboratory findings demonstrated hepatic dysfunction (aspartate aminotransferase, 132 U/L (normal range (NR) 13–33 U/L); alanine aminotransferase, 252 U/L (NR 6–30 U/L); gamma-glutamyl transpeptidase, 51 U/L (NR 10–47 U/L)) and dyslipidemia (triglycerides, 221 mg/dL (NR, 30–149 mg/dL); low-density lipoprotein cholesterol, 140 mg/dL (NR <139)), with normal serum creatine phosphokinase, blood urea nitrogen, and creatinine levels. Metabolic and endocrinological studies revealed hypothyroidism (basal thyroid-stimulating hormone (TSH), 11.22 μU/mL (NR 0.27–4.20 μU/mL); free thyroxine, 0.82 ng/dL (NR 1.00–1.80 ng/dL)) with a remarkably high TSH level after a thyrotropin releasing hormone loading test (58.48 μU/mL at 60 minutes (NR 10–25 μU/mL)). An oral glucose tolerance test with 75-g oral glucose loading showed borderline glucose intolerance with remarkable insulin resistance (blood glucose, 197 mg/dL (NR 60–125 mg/dL); insulin, 563 μU/mL at 120 minutes (NR <300)). Ultrasonography demonstrated an atrophic thyroid and marked fatty liver. Brachial–ankle pulse wave velocity indicated slight arteriosclerotic changes (right 1,188 cm/s, left 1,157 cm/s, mean 952 ± 103 cm/s). Bilateral ovary hypoplasia and a right ovarian cyst were detected on magnetic resonance imaging. Ophthalmological study revealed bilateral cataracts. There were no signs of osteoporosis of the lumbar spine (bone mineral density 0.968 g/cm3; Z-score −0.4). No calcification of the Achilles tendon, a cardinal sign of WS in adulthood,1 was detected on X-ray examination. Genetic tests identified a homozygous mutation of IVS25–1G>C in the WRN gene, one of the most common mutations in Japanese individuals with WS. Medical treatment with levothyroxine sodium hydrate at a dose of 100 μg/d quickly normalized the girl's thyroid function, with an associated increase in her vigor. Subsequent biguanide therapy (750 mg/d) was discontinued within 1 week because of abdominal pain. Based on the clinical features reported in previous studies, the characteristic abnormalities in metabolism observed in individuals with WS are mainly attributed to peripheral lipoatrophy with insulin insensitivity or dyslipidemia.5 Endocrinological problems in the setting of WS primarily derive from the impaired secretion of hormones due to premature aging of endocrine organs, and empirically, hypogonadism, hypothyroidism, and hypopituitarism are the major endocrinological concerns in individuals with WS. Although these conditions may be present in childhood, no clinical studies have reported such features, probably because of the difficulty in diagnosing WS in individuals with nonspecific symptoms. The present case therefore provides important and valuable information. First, hypothyroidism of atrophic thyroid glands in addition to pituitary and hypothalamic dysfunction can appear as early as 10 years of age. Second, marked insulin insensitivity due to a lipodystrophic phenotype can arise in adolescence. Third, the subject gradually exhibited hypergonadotrophic hypogonadism in her teens. Hence, nonspecific metabolic and endocrinological conditions, as well as atrophic skin, growth failure, and bilateral cataracts, may be characteristic findings of WS in childhood. According to previous reports,2 an earlier onset of clinical symptoms is associated with a shorter life span. Hence, it is critically important to make a proper diagnose at an early age to initiate careful and consistent observation and provide early therapeutic intervention. Conflict of Interest: The editor-in-chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other personal conflicts with respect to this work. Author Contributions: Study concept and design: Toda, Ihara. Acquisition of subject and data: Toda, Ihara. Study design and interpretation of the data: Watanabe, Takemoto, Yokote. Preparation of manuscript: Toda, Ihara. Sponsor's Role: No sponsors.