Abstract
Hepatocyte nuclear factor-1 beta (HNF1B) gene is predominantly expressed in the liver, kidney, lung, genitourinary tract, and pancreas. It is an important transcription factor that regulates pancreas development. Mutation or absence of this gene is rare and can cause incomplete pancreatic development known as the agenesis of the dorsal pancreas. This rare genetic abnormality is associated with other disorders like maturity-onset diabetes of the young, abnormal liver function tests, genitourinary tract malformation, pancreatitis, and renal cysts. Diagnosing this genetic abnormality is difficult, especially in patients presenting with symptoms specific to only one system. Management is based on disease manifestation and involves a multidisciplinary approach. Our case describes a 51-year-old female with poorly controlled diabetes mellitus and Mullerian duct anomalies who presented with abdominal pain, fatigue, dizziness, and electrolyte derangement. Contrast-enhanced computed tomography (CECT) of the abdomen showed a multicystic kidney and a pancreatic head with a missing body and tail. Further workup revealed an HNF1B mutation.
Introduction
Agenesis of the dorsal pancreas (ADP) is the absence of a dorsal pancreatic bud resulting in a missing body and tail of the pancreas. It is a rare genetic disorder, first reported as an autopsy finding in 1911 by Schnedl. 1 The prevalence of this disorder is not exactly known due to the complexity of the diagnosis. Sexual or racial comparison has also not been reported. A detailed mechanism of this disorder is not understood. However, some cases have been linked to a heterozygous mutation in the gene that codes for the transcription factor, hepatocyte nuclear factor-1 beta (HNF1B). 2 This mutation is also known to be the most common monogenic cause of developmental kidney disease with renal cysts being the most manifestation. 3 The majority of patients are asymptomatic. For those who are symptomatic, about 92.9% present with abdominal pain due to pancreatic dysfunction, while 50% have hyperglycemia. 4 Pancreatitis has been reported in about 30% of the cases. Comprehensive multimodality imaging and genetic testing are required for accurate diagnosis and delineation of pancreatic ductal anatomy.
Case Presentation
A 51-year-old Caucasian female with a medical history significant for poorly controlled maturity-onset diabetes of the young who has been on insulin for longer than 5 years presented to the emergency department with chief complaints of intermittent abdominal pain that radiates to the back, unintentional 40 lbs weight loss in 5 months associated with fatigue, poor appetite, dizziness, falls, and polyarthralgia. She denied diarrhea or abdominal distension. The patient reported a history of a congenital blind vaginal pouch and an abnormal uterus. Surgical history was positive for hysterectomy and reconstructive vaginal surgery at the age of 15. She also endorsed a family history of congenital malformation with electrolyte derangements. Examination findings were significant for positive orthostatic vitals and a body mass index of 17.9 kg/m2 (18.5-24.5). Laboratory findings include potassium of 3.1 mEq/L (3.5-5), ionized calcium of 1.06 mmol/L (1.12-1.38), magnesium of 1.5 mg/dL (1.8-2.4) remained low despite replacement (Figure 1), phosphorus of 3.2 mg/dL (2.5-4.5), alkaline phosphatase of 190 U/L (45-117), aspartate aminotransferase of 75 U/L (15-37), alanine aminotransferase of 117 U/L (12-78), gamma-glutamyl transferase of 662 U/L (5-85), total bilirubin of 1.5 mg/dL (0.2-1), albumin of 2.8 gm/dL (3.1-4.5), glycosylated hemoglobin (A1C) of 15.4% (4-6), C peptide of 1.1 (1.1-4.4), and anti-nuclear antibody of >1:80 with a speckled pattern. Persistently low magnesium despite replacement resulted in pursuing further urinary studies, which showed 24-hour urine phosphorus of 433 mg (340-1000), 24-hour urine magnesium of 222 mg (73-122), 24-hour urine potassium of 59 mEq (25-125), 24-hour urine sodium of >300 mEq (40-220), and 24-hour urine calcium <5 mg (50-150) which were suggestive of Gitelman pattern. Viral hepatitis, lipase, alpha 1 antitrypsin, complements C3/C4, anti-DNA double stranded antibody, glutamic acid decarboxylase (GAD) autoantibody, islet autoantibody, c peptide, thyroid function test, cortisol, and fecal fat were unremarkable. A whole-body bone scan was carried out due to a history of polyarthralgia, which was unremarkable. CECT of abdomen and pelvis showed multiple renal cystic lesions and incidental finding of absent body and tail of the pancreas with no evidence of surgical pancreatectomy (Figure 2). Further imaging was pursued with magnetic resonance imaging (MRI), which confirmed the absent tail and body of the pancreas, numerous simple and proteinaceous cystic lesions on the left kidney, unremarkable liver, and bile duct (Figure 3). At this point, there was a high suspicion of a congenital defect associated with a rare gene mutation predisposing to the patient presentations. Her history of weight loss necessitated an esophagogastroduodenoscopy and a colonoscopy, which were negative. The patient was started on amiloride 2.5 mg daily, magnesium 400 mg 3 times daily, midodrine 2.5 mg 3 times daily, oral pancreatic enzyme replacement therapy 24k units daily, and indomethacin 75 mg daily. She improved and was discharged home. During outpatient follow-up, genetic testing for HNF1B gene mutation reported positive for heterozygous deletion of all coding exons of the HNF1B gene, with an autosomal pattern of inheritance. A liver biopsy was done due to up trending liver enzymes which revealed nodular regenerative hyperplasia, and dense perisinusoidal fibrosis consistent with diabetic hepatosclerosis. The patient’s insulin regimen was changed to an insulin pump for better blood glucose control and to help decrease the progression of liver disease. A tilt table test was confirmatory for orthostatic hypotension.
Electrolyte trend on admission reflecting Gitelman pattern.
CECT of the abdomen showing a head of the pancreas with no body and tail (blue arrow), and multicystic left kidney (red arrow).
MRI confirming missing body and tail of the pancreas (blue arrow).
Discussion
The pancreas and other gastrointestinal organs are derivatives of the endodermal layer. Embryonically, it develops from the ventral and dorsal pancreatic buds on both sides of the foregut. The ventral pancreatic bud contributes to the head of the pancreas, while the dorsal forms the body and the tail. Morphogenesis of the pancreas begins with the proliferation of the epithelial multi-potent progenitor cells, followed by a secondary transition to form the ductal, acinar, and endocrine cells. 5 ADP can be partial or complete. In partial ADP, the duct of Santorini, pancreatic body, and minor papilla are present, whereas in complete ADP as seen in our patient, the body, tail of the pancreas, the duct of Santorini, and minor papilla are absent. The exact mechanism causing ADP though remains poorly understood, some genetic mutations have been identified, which include HNF1B, HNF 1A, pancreas transcription factor 1alpha (PTF1A), and insulin promoter factor-1 (PDX1). 6 While these mutations remain rare, HNF1B is the most frequent mutation associated with ADP. 6 This gene is located on chromosome 12p17. Most HNF1 B-associated disorder display autosomal dominant inheritance. 7 Sporadic mutations can occur as well. The most common manifestation of this anomaly is abdominal pain and maturity-onset diabetes of the young type 5 characterized by early-onset diabetes, pancreas hypoplasia, and multicystic kidney dysplasia. In a systematic review by Schnedl et al, 1 of the 58 cases reviewed, 28 had hyperglycemia. Truncating variants and deletion spanning multiple exons of the whole gene have also been associated with hypomagnesemia, hypokalemia, and hepatic abnormalities.8,9 This variant as seen in our patient has been observed at a frequency of <0.014% (3/21530 alleles) in the general population according to the Broad institute gnomAD and database of genomic variants. Other rare disorders such as heterotaxy syndrome, polysplenia syndrome, Gitelman syndrome, renal agenesis, Mullerian duct abnormalities, and ovarian ectopia have also been reported to be associated with this anomaly. Most reported ADP presented with 1 or 2 systemic manifestations. This makes our case very interesting and unique as our patient presented with not only diabetes mellitus but also Mullerian duct anomalies, multicystic kidney, Gitelman pattern of electrolyte derangement, and diabetic hepatosclerosis. Orthostatic hypotension as seen in our patient has not been directly associated with ADP or HNF1B mutation. However, the study by Fedorowski et al 10 on orthostatic hypotension and novel blood pressure-associated gene variant identified PDX1 on chromosome 13 and developmentally down-regulated gene (NEDD4L) on chromosome 18 as an essential regulator of sodium retention in the distal nephron to be associated with altered postural systolic blood pressure response. Various imaging modalities have been used in the diagnosis of ADP. The cost-effectiveness and availability of ultrasound have made it the first modality used by clinicians in diagnosing causes of abdominal pain. Its diagnostic efficiency is however limited by the inability to visualize the tail and body of the pancreas due to an overlying bowel gas pattern. 11 Our patient’s abdominal pain was typical of pancreatic pain; thus, CECT of the abdomen was our first modality. Abdominal CT can detect ADP but is not able to provide enough information on the ductal anatomy. Magnetic resonance cholangiopancreatography (MRCP) is the imaging technique for confirming a diagnosis of ADP due to its ability to visualize 90% of the pancreatic duct.12,13 Endoscopic retrograde cholangiopancreatography (ERCP), on the other hand, is considered the gold standard in the evaluation of the biliary tree due to its superior spatial resolution. Endoscopic ultrasound (EUS) is as good as ERCP but has more advantages in terms of providing the opportunity to take fine needle aspiration for cytology, especially in patients with complications such as ampulla carcinoma, mucinous adenocarcinoma, and pancreatic neuroendocrine tumor.14,15 Our patient’s diagnosis of ADP was confirmed with MRI with no further indication for pursuing ERCP or EUS. Treatment of ADP and its disorders is multidisciplinary and involves psychosocial counseling, medical management of symptoms, and surgery.
Footnotes
Author Contributions
T.M. evaluated the patient and presented the case to O.U. who did a literature review and wrote the manuscript, then submitted it to T.M., M.K., and A.S. for final review and corrections.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent
Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
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