A Rare Cause of Acute Pancreatitis: Two Siblings With Werner Syndrome

Authors: Kenan Sakar, Baris Akinci, Ilgin Yildirim Simsir, Tahir Atik, Gulhan Akbaba, Nese Cinar

Abstract

Lipodystrophies are rare disorders characterized by loss of body fat resulting in leptin deficiency. Patients are predisposed to metabolic complications such as severe insulin resistance, hypertriglyceridemia, and hepatic steatosis. Werner syndrome (WS) is among the progeroid syndromes in the classification of lipodystrophy. In this case report, we describe two siblings. In the first case, lipodystrophy was suspected when the patient presented with acute pancreatitis and hypertriglyceridemia, and a diagnosis of WS was confirmed. Subsequently, genetic screening of the patient's sister, who had early-onset diabetes, also revealed WS.

Introduction

Lipodystrophies are a group of rare disorders characterized by varying degrees of body fat loss that can be generalized, partial, or localized. The extent of fat loss determines susceptibility to metabolic complications such as insulin resistance, hypertriglyceridemia, and hepatic steatosis [1-3]. Werner syndrome (WS), a rare autosomal recessive progeroid syndrome classified under lipodystrophies, is associated with premature aging and characterized by features such as scleroderma-like skin changes, alopecia, leg ulcers, short stature, cataracts, early-onset atherosclerosis, and osteoporosis. Diagnostic criteria for WS are outlined by the International Registry of Werner Syndrome, with updates based on clinical experience in Japanese patients. Cardinal features include bilateral cataracts, characteristic dermatological findings, short stature, premature graying or thinning of hair, and parental consanguinity or affected siblings. Further signs and symptoms include hypogonadism, osteoporosis, soft tissue calcifications, premature atherosclerosis, and neoplasms, voice changes, and flat feet [4]. Nevertheless, confirming the diagnosis necessitates Werner syndrome ATP-dependent helicase (WRN) gene testing. Classic WS is attributed to homozygous or compound heterozygous loss-of-function mutations in the WRN gene [5]. Patients typically die in their fourth or fifth decade due to malignancies or atherosclerotic complications. The rarity of WS and its diverse clinical manifestations make diagnosis challenging for clinicians.

Case Presentation

In this case report, we present 2 sibling patient cases diagnosed with WS.

Case 1

A 19-year-old male patient hospitalized in the gastroenterology clinic with nonbiliary acute pancreatitis was consulted in our clinic for hypertriglyceridemia and hyperglycemia. He had no history of any chronical disease or medication use in his medical history. The patient had no recent history of alcohol use. His sister was diagnosed with type 2 mellitus at age 29. His father died at age 40 due to cancer of unknown origin. There was no consanguinity between the patient's parents, but his parents were from the same village.

Case 2

The second patient was the sister of the first patient and was followed up in the internal medicine clinic with the diagnosis of type 2 diabetes mellitus for 2 years. She was age 31 years. She was using linagliptin (5 mg once daily) and gliclazide (30 mg once daily) for diabetes mellitus and levothyroxine (50 μg once daily) for primary hypothyroidism for 3 years. There was no history of smoking or alcohol use. The patient reported normal pubertal development, with menarche occurring at age 12. She had a history of one live birth. The patient's menstrual cycles were regular before; however, she had irregular menstrual cycles with intervals of up to 2 months for 1 year.

Diagnostic Assessment

Case 1

The patient had short stature (height:157 cm) and low body weight (weight: 43 kg, body mass index [BMI]: 17.4). He had scleroderma-like skin findings and partial loss of subcutaneous adipose tissue in the extremities on physical examination (Fig. 1A and 1B). Axillary and pubic hair development was consistent with Tanner stage 4. His vital signs were normal. Electrocardiogram (ECG) was in sinus rhythm.

The laboratory results indicated significantly elevated levels of blood glucose and triglycerides. Thyroid function test results were consistent with primary hypothyroidism. There was no acidosis in the venous blood gas analysis. The laboratory results are summarized in Table 1.

We initiated intensive insulin therapy, metformin, as well as fenofibrate and levothyroxine treatment. The patient needed high insulin doses (60 IU/day). We suspected lipodystrophy as a rare cause of hypertriglyceridemia and hyperglycemia. The leptin level was 2.11 ng/mL (2.11 μg/L) (reference range, 0.7-9.1 ng/mL; 0.7-9.1 μg/L). Whole-body dual-energy x-ray absorptiometry (DEXA) revealed increased body fat, predominantly distributed in the trunk area. The trunk-leg ratio of the patients was 2.07, supporting partial lipodystrophy (Table 2).

Genetic analysis revealed a pathogenic variant in the WRN gene (NM_000553.6: c.1105C > T, p.Arg369Ter, homozygous), which is consistent with WS. No osteoporosis was detected on bone densitometry, and there was no pathology in echocardiography. Abdominal ultrasonography revealed grade 2 hepatic steatosis, characterized by diffusely increased hepatic echogenicity. We diagnosed the patient with WS with the present findings and genetic test results.

Case 2

The patient had short stature (height: 147 cm) and low body weight (weight: 40 kg, BMI: 18.53). She had scleroderma-like skin findings and partial loss of subcutaneous adipose tissue in the extremities (Fig. 2A and 2B). The patient's vital signs were normal and her ECG was in sinus rhythm.

Laboratory results are shown in Table 3. The patient had high serum triglyceride levels. The patient's gonadal function tests were consistent with the perimenopausal period, suggesting early gonadal dysfunction. Abdominal ultrasonography revealed grade 2 hepatic steatosis. No pathology was detected on echocardiography. The leptin level was 12.91 ng/mL (12.91 μg/L) (reference range, 0.7-9.1 ng/mL; 0.7-9.1 μg/L). A pathogenic variant in the WRN gene (NM_000553.6: c.1105C > T, p.Arg369Ter, homozygous), similar to her brother's, was detected. We diagnosed the patient with WS with the present findings and genetic test results.

Treatment

Case 1

Treatment for hypothyroidism, diabetes mellitus, and hypertriglyceridemia was continued, including insulin detemir (30 units once daily), insulin aspart (10 units 3 times daily), metformin (1000 mg twice daily), levothyroxine (75 μg once daily), and fenofibrate (267 mg once daily). Additionally, pioglitazone (30 mg/day) was initiated.

Case 2

Dietary counseling and physical activity recommendations were provided to the patient. Treatment of linagliptin and gliclazide was continued since her glycated hemoglobin A1c (HbA1c) level was in the target range. Pioglitazone 30 mg/day and fenofibrate 267 mg/day were initiated for her grade 2 hepatostatosis. The patient could not tolerate metformin due to its gastrointestinal side effects.

Outcome and Follow-up

Case 1

After the initiation of pioglitazone, the patient's insulin requirements decreased. Insulin aspart was discontinued, and the insulin detemir dose was reduced to 24 units once daily, which was maintained thereafter. At the third month of treatment, there was a reduction in HbA1c levels; however, triglyceride levels remained elevated (HbA1c: 6.3%, 45 mmol/mol; 745 mg/dL, 8.42 mmol/L) while his thyrotropin (TSH) level was 4.1 mIU/L (4.1 mIU/L). Leptin analogue therapy was initiated for the patient. Unfortunately, following the initiation of leptin analogue therapy, the patient did not attend follow-up visits, and thus, response to the treatment could not be assessed.

Case 2

At the 3-month follow-up; the patient's HbA1c had increased to 9.5% (80 mmol/mol) and triglyceride levels had risen to 536 mg/dL (6.06 mmol/L). Insulin detemir therapy was initiated due to the patient's irregular use of oral antidiabetic medications. The fenofibrate dose was increased to twice daily, and omega-3 fatty acid supplementation was added. Unfortunately, the patient did not attend subsequent follow-up visits and treatment responses could not be evaluated.

Discussion

The absence of a pubertal growth spurt during adolescence is often the earliest clinical indication of WS, resulting in the characteristic short stature and low body weight seen in affected individuals. A recent analysis of 196 Japanese WS cases revealed that the average height and body weight were 158.3 cm and 45.3 kg for male patients, and 148.5 cm and 37.7 kg for female patients, respectively. As WS individuals reach their 20s and 30s, they typically develop alopecia, graying of the hair, and skin changes resembling scleroderma. These are often followed by the onset of bilateral cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis. Impaired glucose tolerance is noted in 15% to 20% of WS patients, while diabetes mellitus occurs in 55% to 70%, and dyslipidemia in 60% to 85%. The leading causes of mortality in WS patients are complications due to atherosclerosis and cancer. Arteriosclerosis obliterans has been reported in more than 20% of WS patients, while coronary heart disease affects 11% to 16% of this population [4].

Our first patient had short height and low body weight. He had hypertriglyceridemia and diabetes mellitus, but there was no pathology in his cardiac examination. Although acute pancreatitis due to hypertriglyceridemia can be seen in lipodystrophy (15%-20%), first presentation of WS presenting with acute pancreatitis is very rare in the literature [6, 7]. Lazarte et al [8] reported that none of the complications of severe hypertriglyceridemia and pancreatitis were seen in patients with familial partial lipodystrophy type 2 (FPLD2) without diabetes and that the risk of severe hypertriglyceridemia and pancreatitis in FPLD2 may be due to the simultaneous presence of diabetes. Although there is no study in WS, the presence of severe diabetes in our case may have contributed to the development of severe hypertriglyceridemia and pancreatitis.

According to previous studies about patients with partial lipodystrophy, a trunk-to-lower extremity ratio greater than 1.2 in women and greater than 1.7 in men on DEXA fat densitometry has been shown to support the diagnosis of partial lipodystrophy and in our case, the trunk-leg ratio was 2.07, which was consistent with partial lipodystrophy [9, 10]. Although serum leptin levels in individuals with lipodystrophy are generally low (either in absolute terms or relative to BMI), there is no specific cutoff level for serum leptin that can definitively exclude the diagnosis of lipodystrophy [11]. Leptin levels in WS patients are not consistently reported in the literature. In several case reports, serum leptin levels in patients with WS exhibited heterogeneity, being below the reference range (<1.2 μg/L), within the normal range (8.8 μg/L), or even above the reference range (33 μg/L; reference range, 1.8-28 μg/L) [12, 13]. Elevated leptin levels are not commonly observed in WS and would represent an atypical finding.

The genetic basis of WS lies in mutations within the WRN gene, a RecQ helicase that plays a crucial role in DNA repair and maintenance. These mutations lead to genomic instability, contributing to the accelerated aging and increased susceptibility to malignancies observed in WS [14].

According to the Human Gene Mutation Database Professional 2020.4, 95 mutations of the WRN gene causing WS have been recorded. The majority of these mutations are predicted to lead to protein truncation, which typically results in nonsense-mediated decay of the mutant messenger RNA. This process prevents the production of functional proteins, primarily due to the truncation of the C-terminal nuclear localization signals, rendering the WRN protein functionally null [15]. The most common mutations in Japanese patients are c.3139-1 G > C (50.4%) and c.1105 C > T (17.5%) [16], whereas the most common mutation in non-Japanese patients is c.1105 C > T (18.6%) [17], suggesting that c.1105 C > T (rs17847577) is a hot spot mutation across ethnic groups. Our patients had the c.1105C > T mutation. As indicated in the literature, the most commonly observed mutation in non-Japanese patients is the c.1105C > T mutation, which was also present in our patients. In the current literature, there is no clear genotype-phenotype correlation, meaning that a specific mutation has not been conclusively linked to a particular clinical manifestation. However, in Japanese patients, a potential association has been reported between follicular thyroid carcinoma and the c.3139-1G > C mutation, as well as between papillary thyroid carcinoma and the c.1105C > T mutation [18].

Although studies [19] have shown that women with partial lipodystrophy have an increased risk of metabolic complications such as diabetes mellitus and dyslipidemia compared to male patients, a retrospective study [20] on patients with WS indicated that cardinal symptoms are more frequent and appear earlier in male patients. At the molecular level, age-related reductions in double-strand break repair and increased telomere uncapping are more pronounced in postmenopausal women than in men [21, 22]. These findings suggest that estrogen may help delay the aging symptoms of WS in women. WRN expression is upregulated after estrogen administration, indicating that estrogen-induced WRN upregulation may contribute to double-strand break repair and telomere maintenance in women [23].

Metreleptin is a synthetic analogue of human leptin approved by the US Food and Drug Administration in 2014 for the management of metabolic complications in patients with congenital generalized or acquired generalized lipodystrophy. It is intended to be used as an adjunct to diet and lifestyle modifications to help address the metabolic challenges associated with these conditions.

Some findings suggests that metreleptin treatment may be considered for hypoleptinemic (leptin <4 ng/mL, < 4 μg/L) patients with partial lipodystrophy and severe metabolic derangements (HbA1c 8% [64 mmol/mol] and/or triglycerides 500 mg/dL [5.65 mmol/L]) [24]. In case 1, our patient had a leptin level below 4 ng/mL, accompanied by elevated HbA1c and triglycerides. Although the HbA1c level reached the target range with insulin and pioglitazone therapy, triglyceride levels remained elevated despite fenofibrate treatment. Given the patient's history of pancreatitis and persistent hypertriglyceridemia, leptin receptor analogue therapy was initiated.

In conclusion, WS remains a diagnostic challenge due to its rarity, atypical presentation, and overlapping symptoms with other conditions. Early diagnosis, genetic testing, and a collaborative approach are imperative for comprehensive patient care. Future research aimed at elucidating the molecular mechanisms underlying WS could pave the way for more targeted therapeutic interventions.

Learning Points

• Lipodystrophies should be considered in patients presenting with diabetes mellitus with disproportionately high insulin requirements despite a lean physical appearance and severe hypertriglyceridemia.
• Hypertriglyceridemia should be investigated as a potential etiology of acute pancreatitis, and such patients should be evaluated for possible underlying lipodystrophy.
• Comprehensive metabolic management, including glycemic and lipid control, is crucial to reduce long-term complications in WS.
• Metreleptin may be beneficial in WS patients with severe metabolic derangements and low serum leptin levels, particularly in those resistant to conventional therapies.
• The rarity and heterogeneity of WS highlight the need for further studies to elucidate genotype-phenotype correlations and potential population-specific genetic influences.

Contributors

All authors made individual contributions to authorship. K.S. and N.C. were involved in the diagnosis and management of the patients and manuscript submission. G.A., B.A., and I.Y.S. were involved in the diagnosis and treatment of the patients. T.A. contributed to the genetic screening and diagnostic evaluation of the patients. All authors reviewed and approved the final draft.