|Year : 2021 | Volume
| Issue : 1 | Page : 105-107
Werner syndrome: A rare cause of young-onset diabetes
Ana Soraya Palmira Dos Remedios Monteiro1, Praveen V Pavithran1, Sheela Nampoothiri2, Dhanya Yesodharan2
1 Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India
2 Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India
|Date of Submission||14-May-2020|
|Date of Decision||07-Jul-2020|
|Date of Acceptance||08-Jul-2020|
|Date of Web Publication||25-Dec-2020|
Dr. Ana Soraya Palmira Dos Remedios Monteiro
Department of Endocrinology, Amrita Institute of Medical Sciences, Ponekkara P.O, Kochi 682041, Kerala.
Source of Support: None, Conflict of Interest: None
A 36-year-old male presented with young-onset diabetes and advanced peripheral vascular disease. He had a history of bilateral juvenile cataracts and premature aged appearance. Closer scrutiny unraveled multiple endocrine and nonendocrine abnormalities. Genetic studies revealed a novel pathogenic variant (homozygous c.3233+2T>c) confirming and expanding the mutation spectrum of Werner syndrome. This report highlights the need for precise diagnosis, which has important implications for prognosis and genetic counseling.
Keywords: Diabetes, progeroid, Werner syndrome
|How to cite this article:|
Monteiro AS, Pavithran PV, Nampoothiri S, Yesodharan D. Werner syndrome: A rare cause of young-onset diabetes. J Diabetol 2021;12:105-7
| Introduction|| |
Werner syndrome (WS) is a rare inherited autosomal recessive adult progeroid syndrome, characterized by accelerated aging. It results from homozygous or compound heterozygous loss of function mutations in the Werner syndrome RecQ like helicase gene (WRN), a member of the RecQ subfamily of DNA helicase proteins. It plays an important role in the maintenance of genome stability by playing a role in DNA repair, replication, transcription, and telomere maintenance.
We report here a genetically proven case of WS in a young patient who presented to us with young-onset diabetes and advanced peripheral vascular disease.
| Case Presentation|| |
A 36-year-old male of Asian Indian origin consulted our institute’s Endocrinology-Podiatry clinic for a nonhealing ulcer of the great toe and gangrene of the second toe of his left foot. The ulcer had developed spontaneously 6 months earlier and had failed to heal after basic ulcer care elsewhere.
Diabetes had been diagnosed at the age of 26 years, when he was evaluated for a similar foot ulcer. He weighed 60 kg at the time and initial high blood glucose levels (>300 mg/dL) had prompted insulin initiation. This was soon replaced by oral hypoglycemic agents once the ulcer had healed. His recent records showed excellent glycemic control (HbA1c 6%–7%) on metformin and sitagliptin. Primary hypothyroidism (initial TSH of 13.14 mIU/L and negative Anti-TPO antibodies) was diagnosed 6 months prior to presentation. He was currently euthyroid (TSH 2.14 mIU/L) on 50 mcg of levothyroxine. Alcohol consumption (6 units/day) and smoking habits (2–3 cigarettes /day) picked up in his late teens had been overcome 1 year prior to presentation. His records showed no evidence of micro or macrovascular complications. His unusual appearance prompted detailed history.
Born out of nonconsanguineous parentage, he was developmentally normal till adolescence. He underwent surgical management for bilateral juvenile cataracts at 18 years of age. He gave history of progressive premature graying and thinning of hair, atrophic skin changes, and progressive weight loss despite a normal appetite over the last few years, making him appear older than his chronological age.
He revealed that his elder sister and one maternal uncle were similarly affected [Figure 1]: pedigree chart] with a prematurely aged appearance, history of premature cataracts, and both expired before the fifth decade of life without a definite diagnosis.
|Figure 1: The patient’s pedigree traced up to three generations. The patient is married with a 5-year-old son|
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On examination, short stature was evident. Height measurement being compromised by his inability to bear weight on his affected limb, his length measured was an approximate value of 153cm (–2.78 SDS). A beaked nose with a bird-like face, sparse gray hair, thin extremities, bilateral finger contracture, and skin changes (tight and atrophic) were noted [[Figure 2]. His voice was high pitched and hoarse. Laryngoscopic examination revealed an exophytic right vocal cord growth, which needed detailed evaluation but the patient declined.
|Figure 2: (A) A picture of our patient few years ago (30 years of age). (B) His aged appearance when he presented to our institution (36 years of age). (C) Bilateral finger contractures observed in our patient|
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Genital examination revealed a bilateral testicular volume of 6 cc but he denied history suggestive of sexual dysfunction.
Patient’s routine blood parameters (including serological testing for HIV) were normal. His total cholesterol, triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were 161.6, 132.7, 36.5, and 108.2 mg/dL, respectively. C-peptide and islet cell antibody levels were not evaluated as his records (excellent glycemic control on oral agents) suggested a good β-cell reserve.
Screening abdominal ultrasound for pancreatic/liver or splenic abnormalities and ECHO revealed no abnormalities. A peripheral MR angiography was ordered as peripheral arterial disease was clinically suspected, which revealed generalized atherosclerotic changes of the entire arterial course. X-ray foot taken in relation to the foot ulcer for osteomyelitis screening revealed no achilles tendon calcifications.
The history of juvenile cataracts and premature aged appearance along with family history led to the consideration of a premature aging syndrome. Criteria for “Probable” WS were fulfilled and genetic testing confirmed our diagnosis. Next-generation sequencing revealed a novel mutation: homozygous 5′ splice site variation in intron 26 of the WRN gene (chr8: 30999293T>C; Depth 62x) that affects the invariant GT donor splice site of exon 26 (c.3233+2T>c; ENST00000298139.5, not previously reported in the available literature. This variant has not been detected in 1000 genomes/ExAC databases and in silico predictions of this variant was damaging by Mutation taster 2 and Human splicing finder suggesting pathogenicity. We could not get the patient’s parents genetic testing done as they hailed from Madhya Pradesh.
His diabetes remained well controlled with minimal doses of insulin (~0.35 U/kg/day) necessitated by the wound infection and hospital inpatient procedures. He underwent a mid-foot amputation and the stump healed over 6 months.
| Discussion|| |
WS was originally described by a German medical student, Otto Werner in 1904, who reported four siblings, ages 31–40 years who presented with Cataracts, short stature, and premature graying of hair. The prevalence of this syndrome is 1/100,000 live births worldwide with the highest prevalence in Japan, reported as high as 1/20,000- 40,000 live births. The condition is being increasingly recognized, with five published case reports from the Indian subcontinent in the last decade.,,,,,
Reduced puberty growth spurt is frequently the first manifestation of the disease resulting in reduced final adult height.
An aged appearance develops by the 3rd decade of life along with thin extremities due to lipoatrophy. Noninsulin-dependent DM, resembling adult-onset DM develops in 70% of WS individuals by the fourth decade of life., One possible mechanism is lipoatrophy related, whereas other possible mechanisms remain unclear. Loss of signal transduction after normal insulin binds to normal insulin receptors resulting in insulin resistance has been seen in in-vitro experiments.
Hyperlipidemia type IIb or IV, characterized by intractable hypertriglyceridemia and hypercholesterolemia is a biochemical hallmark of WS. 30% of WS individuals develop accelerated atherosclerosis by the early 5th decade of life. Unlike Athero-Sclerotic Cardio-Vascular Disease (ASCVD), diabetic microvascular complications in genetically proven WS individuals have not yet been reported in the literature. Although metformin remains the first line in insulin-resistant DM, thiazolidinediones may be useful in WS. However, available literature is sparse and controversial.
Beyond diabetes, this syndrome’s aging phenomenon also includes other endocrinopathies [Table 1]. Although limited endocrine workup was pursued in view of the infected foot ulcer, thyroid dysfunction, and hypogonadism as evidenced by the mid-pubertal testicular volume were apparent.
Though no known therapeutic options currently exist to halt this disease’s progression, regular screening for known manifestations helps in early diagnosis and improve quality of life by timely management.
| Conclusion|| |
Young-onset diabetes, premature juvenile cataracts, and peripheral vascular disease should prompt consideration of a premature aging syndrome which has profound implications for therapeutic decision making and genetic counseling.
We gratefully acknowledge the role of our podiatry surgery team of doctors and staff in the treatment of our patient. We also appreciate the cooperation of our patient and his relatives.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]