Rare pediatric cases of isolated pancreatic exocrine enzyme deficiencies were reported in the 1960s and in the years up to the early 1990s. These patients were without known causes of pancreatic insufficiency such as pancreatitis, tumor, and congenital syndromes. The deficiency is determined by enzymatic activity assays in pancreatic juices. Deficient enzymes include lipase, colipase, and trypsinogen. The pancreatic morphology is not described in these reports except for one case of trypsinogen deficiency whose pancreas showed “immature acini” and lack of zymogen granules. Mutational analysis of the gene encoding pancreatic lipase performed on six members of a consanguineous family identified a missense mutation that shows segregation between the genotype state and the serum pancreatic lipase activity.

Enteropeptidase is a serine protease that activates the pancreatic proenzyme trypsinogen, which, in turn, releases active digestive enzymes from their inactive pancreatic precursors. Therefore, congenital enteropeptidase deficiency may mimic cystic fibrosis manifesting with failure to thrive and diarrhea. But this enzyme is produced from the intestinal brush border in the proximal small intestine, not from the pancreas. Nonsense mutations and a frame shift mutation have been identified in the proenteropeptidase gene.

The maturation of amylase production is normally delayed, and the adult level of amylase activity is reached at the age of 18 months to 2 years. Therefore, alleged cases of isolated amylase deficiency in young children are controversial. Rare adult cases of selective deficiency of pancreatic amylase have been described.

When the shape of the pancreas is grossly preserved but the exocrine acini are largely replaced by adipose tissue, the condition is termed lipomatous atrophy, lipomatosis, or, when extensive, lipomatous pseudohypertrophy. The pancreas shows relatively preserved endocrine components including islets of Langerhans and scattered small but well-preserved exocrine acinar elements. These acini do not show signs of injury. No fibrosis or fat necrosis is seen. Lipomatosis has been described in a number of pathologic processes (38) including Bannayan syndrome, Shwachman-Diamond syndrome, Johanson-Blizzard syndrome, and rare proteolytic and lipolytic enzyme deficiencies.

Of note, focal replacement of the exocrine pancreas with mature fat is a relatively common histologic change. It usually correlates directly with BMI and presence of diabetes mellitus.

With an incidence estimated at 1 in 200,000 births, the Shwachman-Diamond syndrome (39) is the most common cause of pancreatic insufficiency after cystic fibrosis. Pancreatic exocrine insufficiency is accompanied by growth restriction, short stature, bone marrow depression with neutropenia, and skeletal changes, predominantly metaphyseal dysostosis (40). Cases with anal atresia, Hirschsprung disease, and possibly asphyxiating thoracic dystrophy have been described (41). The marrow dysfunction, neutropenia in most instances, may be fixed or cyclical and is associated with the development of myelodysplasia and later leukemias, usually acute myelogenous leukemia. The pancreatic insufficiency may be profound and appears shortly after birth; less often, it is mild and improves and normalizes with age in about half of these patients. Replacement of the bulk of the pancreas by fatty tissue gives the appearance of a lipomatous pseudohypertrophy (42). Acinar tissue is absent, without scarring or fibrosis, and the pancreatic ducts and endocrine elements are preserved (Figure 16-10). The characteristic lipomatous pancreas can be demonstrated by magnetic resonance imaging.

Shwachman-Diamond syndrome is an autosomal recessive disorder. The gene involved (SBDS) resides at 7q11. Its 1.6-kb transcript encodes a predicted protein of 250 amino acids. A pseudogene copy (SBDSP) with 97% nucleotide sequence identity is in a locally duplicated genomic segment. Recurring mutations resulting from gene conversion (substitution of genetic material from another gene) were found in 89% of unrelated individuals of Shwachman-Diamond syndrome. The converted segments include pseudogene-like sequence changes that result in protein truncation. In a study of 23 unrelated patients, molecular genetic and hematologic evaluations demonstrated a poor genotype/phenotype correlation (43).

First reported in 1971 (44), the Johanson-Blizzard syndrome comprises congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absence of permanent teeth, and malabsorption resulting from pancreatic insufficiency. Subsequent reports described urogenital abnormalities and imperforate anus associated with this syndrome. Postmortem examination of the pancreas reveals a total absence of acini with complete replacement of the pancreas by adipose tissue and a few remaining islets with connective tissue around the ducts (45). In contrast, an autopsy of a 4-year-old patient showed a pancreas consisting only of the head with immature-appearing acinar cells, centrally placed islets, periductal fibrosis, and ductular squamous metaplasia, but without significant fat replacement (46). A report regarding specimens from 2 fetuses (21 and 34 weeks of gestation) and a newborn baby revealed acinar tissue loss that increased with gestational age, accompanied by inflammatory infiltrates (47). There was no evidence of increased apoptosis in acinar cells by TUNEL assay, suggesting that the pancreatic defect may not be due to perturbed acinar development, but may rather be gradual destruction of previously formed acinar cells. Mutations in the gene UBR1 have been detected in affected individuals from 12 of 13 families (47). UBR1 encodes one of E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system. The UBR1 protein substrate, presumably impaired degradation of which causes Johanson-Blizzard syndrome, is not yet known. Using antibody to UBR1 and immunofluorescence microscopy, no UBR1 protein was observed in the pancreas from individuals with Johanson-Blizzard syndrome, while it is readily detectable in the cytosol of acinar cells in the control pancreas. Immunofluorescence pattern for trypsinogen indicated that there was no primary defect of zymogen synthesis. Hypoplasia of the exocrine pancreas in association with facial anomalies, micrognathia, posterior cleft palate, and dental hypoplasia has been referred to as the Donlan syndrome, but overlap with the Johanson-Blizzard syndrome seems likely (48).

Pearson et al. (49) described a syndrome characterized by pancreatic insufficiency, refractory sideroblastic anemia, and variable neutropenia in which the marrow is normocellular but the cells are vacuolated. A number of mitochondrial DNA deletions have been reported in affected individuals. The pancreatic pathologic features differ from those of the Shwachman-Diamond or Johanson-Blizzard syndrome in that acinar atrophy with fibrosis, not lipomatosis, is present (49,50).

A neonate with Pearson syndrome and diabetes mellitus (50) suggests a connection with Kearns-Sayre syndrome. The features of Kearns-Sayre syndrome, a mitochondrial myopathy, may develop later in life in patients who survive the early manifestations of Pearson syndrome. It has been postulated that a phenotypic shift from a predominantly hematopoietic disorder (Pearson syndrome) to a disease with muscle dysfunction (mitochondrial myopathy) and an eventual evolution to a full picture of Kearns-Sayre syndrome depends on the distribution of deleted mitochondrial DNA (51).

Neonatal hemochromatosis is unrelated to adult-type hereditary hemochromatosis. In neonatal hemochromatosis, hemosiderin deposition in the pancreatic acini is massive. The islets are generally spared, at least in the early stages (52) (Figure 16-11). Nevertheless, one case of neonatal diabetes due to neonatal hemochromatosis has been reported. Islets have been described to be increased in size in some cases, but the illustrations are less convincing. Acinar iron deposition in the absence of reticuloendothelial iron deposition is not pathognomonic of hemochromatosis; it was also seen in some control cases (53). Two siblings with a neonatal hemochromatosis phenotype that included pancreatic iron deposition also had hypertelorism and trichomalacia, a trichohepatoenteric syndrome (54).

Fanconi et al. in 1936 and then Anderson in 1938, while investigating causes of malabsorption, discovered in some of their patients a condition they termed cystic fibrosis of the pancreas. Recognition of the pancreatic lesion preceded the clinical delineation of the disease. Farber (55) proposed mucous plugging of all secretory glands (mucoviscidosis) to be the pathogenetic key in 1944.

Cystic fibrosis is caused by defects in the cystic fibrosis conductance regulator gene (CFTR), localized to 7q31.2. Pancreatic insufficiency is not obligatory, and 15% of patients are clinically pancreas “sufficient.” The degree of pancreatic disease varies widely at any age, although the disease is progressive and leads to increasingly more severe changes with time. The final stage of cystic fibrosis is characterized by obstruction of the pancreatic ducts by viscous secretion leading to complete acinar atrophy accompanied by fibrosis and lipomatosis (56,57).

The tissue alteration can be recognized even before 40 weeks of gestation (3,57,58). The ratio of acinar to connective tissue volume is 0.5 at 32 weeks after conception, increasing to 2.0 at 52 weeks in normal controls (3). In the pancreas, the ratio of acinar to connective tissue, low to begin with, decreases from 0.5 at 35 weeks to 0.3 at 52 weeks after conception. Further degeneration of exocrine tissue supervenes postnatally.

The earliest visible lesions are eosinophilic concretions in acini and ductules, which may lead to acinar or ductular dilation and flattening of the lining epithelium (56). These concretions generally stain with periodic acid-Schiff (PAS) and contain calcium. The changes may be focal in preterm infants and in mildly affected cases. Postnatal acceleration of the pathogenetic train of inspissation, obstruction, dilation, epithelial damage, atrophy, cell destruction, and fibrosis with minimal inflammation leads to progressive acinar loss with replacement by fibrous tissue (Figure 16-12; eFigure 16-3) and adipose tissue.

Cystic fibrosis in the older child can be associated with large single or multilocular cysts (59). The pancreatic pseudocyst, caused by rupture of a duct into the lesser sac or abdominal cavity, consists of a fibroinflammatory wall around an autodigested cavity. In addition to cystic fibrosis, pseudocysts are caused by trauma, surgery, or inflammation (pancreatitis). The fibrous wall of the cyst has no epithelial lining.

Even though acinar tissue may disappear, islet tissue is preserved until very late. The endocrine changes in cystic fibrosis are considered later in this chapter.

Baggenstoss (60) described the widespread inspissation of secretions in centroacinar cell-lined ductules in patients with uremia. The finding is not restricted to uremia but is also seen in children dying with acidosis, dehydration, cardiac failure, or sepsis. Inspissation may also be seen in the pancreas of children who have experienced prolonged hyperalimentation, but they usually have many of the other conditions listed.

Striking oncocytic changes of the ducts and centroacinar cells have been observed in an infant with mitochondrial myopathy, lactic acidosis, and “ragged red” muscle fibers (MELAR syndrome). Centroacinar hyperplasia of an impressive degree was observed in a young adult with HIV infection (eFigure 16-4).

Blunt trauma is recognized as a cause of immediate or delayed pancreatitis in children (Figure 16-13A) and an important cause of pancreatic pseudocyst. A pancreatic pseudocyst may occur as the result of child abuse, but bicycle injuries are the most common cause in children.

The pancreas may be the seat of any disseminated infection, such as herpes simplex, cytomegalovirus infection (Figure 16-13B), or bacterial sepsis, but this may not result in clinically relevant pancreatitis (65,66). In some instances, the late consequences of a previous infectious pancreatitis are serious.

Rubella may cause an interstitial pancreatitis as part of the expanded congenital rubella syndrome, and pancreatic
insufficiency or even diabetes mellitus can ensue (67). Mumps is a classic cause of pancreatitis in late childhood. Diffuse necrosis and pseudocyst formation has been reported in a surgical specimen (66). Coxsackievirus may selectively involve the exocrine or endocrine components of the pancreas with parenchymal hemorrhage (65,66). Parainfluenza 3 pancreatitis, confirmed by immunohistochemistry, produced multinucleated giant cells in the pancreas of a child with severe combined immunodeficiency. Varicella-zoster infection (chicken pox) resulted in pancreatitis in individuals succumbed to the disease. The postmortem examination revealed focal pancreatic necrosis (66). Chronic coxsackievirus B interstitial pancreatitis in the absence of a meningoencephalomyocarditis in a child with α1-antitrypsin deficiency has been reported (68). Pancreatitis is a well-recognized consequence of bone marrow transplantation. Adenovirus infection may be the causative agent in some cases. In most cases of pancreatitis in children with acquired immunodeficiency syndrome (AIDS), the disease is mild and reflects systemic disease status. The incidence of opportunistic infections is low, although nonspecific inflammatory changes such as focal lymphoplasmacytic aggregates are common (69). Escherichia coli pancreatitis usually accompanies septicemia. Congenital syphilis causes a pancreatitis in which ductular obliteration, acinar loss, and exuberant interstitial fibrosis with concentric perivascular accentuation are noted (70) (Figure 16-4). Gummas are rare.

Pancreatitis can accompany childhood collagen vascular diseases, such as lupus, but it may be difficult to distinguish between the effects of disease and those of treatment, particularly drugs. Pancreatitis has been described in Henoch-Schönlein purpura, Reye syndrome, hemolytic-uremic syndrome, and Crohn disease.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a rare X-linked recessive disorder of immune regulation manifesting with neonatal onset diabetes mellitus, severe enteropathy, eczema, anemia, thrombocytopenia, and hypothyroidism. The disorder had been known by alternative names including X-linked polyendocrinopathy, immune dysfunction and diarrhea, and X-linked autoimmunity and allergic dysregulation. A mutant mouse strain, scurfy (sf) resembles IPEX, and the disease-causing gene Foxp3 encoding scurfin was identified. Subsequently, the human IPEX locus was mapped to Xp11.23-q13.3, and mutations have been identified in the human ortholog (JM2, FOXP3) (71). Patients with protein-truncating mutations have been reported to demonstrate an absence of FOXP3-nuclear positive lymphocytes in their small and large intestines (72). Postmortem pancreatic histology is almost always abnormal; the findings include mild-to-dense lymphocytic infiltrate, acinar loss with fibrosis (chronic sclerosing pancreatitis), dilated ducts, and cystic changes (Figure 16-14). Islets of endocrine cells are decreased or absent in most cases with severe diabetes mellitus (73).

Some of the causes of biliary/obstructive pancreatitis in children have already been mentioned in the section on congenital malformations, such as annular pancreas, gastric duplications that connect to the pancreatic duct system, and anomalies of the pancreaticobiliary junction. Other causes include choledochal cyst, biliary sludge, and gallstone (74). Children with biliary/obstructive pancreatitis are more likely to present with jaundice and elevated serum levels of amino transferases. Cystic fibrosis is the prototype of a chronic obstructive pancreatitis.

In most studies, medications attribute to less than one quarter of pediatric acute pancreatitis. The 2007 American Gastrointestinal Association Technical Bulletin on Acute Pancreatitis lists and categorizes medications as having “definite,” “probable,” or “possible” association with acute pancreatitis (75). To be included as drug-associated pancreatitis, the medication needs to be taken before the onset of acute pancreatitis (76). The most common medications in pediatric studies are valproic acid, L-asparaginase, prednisone, 6-mercaptopurine, mesalamine, and trimethoprim/sulfamethoxazole. However, interpretation of the causeand-effect relation is difficult because many patients who are on the listed medications have systemic illnesses that may predispose to pancreatitis. The comorbidities include seizure disorders, acute lymphocytic leukemia, Crohn disease, ulcerative colitis, transplants/graft versus host disease, AIDS, asthma, renal disorders, and acute myeloid leukemia (76).

The concept of hereditary pancreatitis was first described by Comfort and Steinberg in 1952 as “chronic relapsing pancreatitis” in a family of three generations. More than 200 kindreds have since been documented, with variable prevalence worldwide. It is an autosomal dominant disorder with an 80% penetrance and variable expressivity. Classically, hereditary pancreatitis diagnosis is defined by the presence of recurrent acute pancreatitis or chronic pancreatitis occurring in two first-degree relatives or three or more second-degree relatives, in two or more generations in the absence of precipitating factors (77). The discovery of mutations within the cationic trypsinogen gene, also referred to as serine protease 1 gene (PRSS1), has resulted in the development of genetic testing. Currently, the diagnosis can also be established by the presence of a mutation of the PRSS1 gene with or without clinical or radiologic manifestations of chronic pancreatitis. Cationic trypsinogen is one of the three isoforms of the digestive proenzyme trypsinogen and represents approximately two-thirds of total trypsinogen in the pancreatic juice. Activation of trypsinogen to trypsin normally occurs in the duodenum by the brush-border localized enterokinase and also by autoactivation by trypsin. The mutations either increase stability or increase autoactivation of trypsin (77).

A major motivation for identifying patients with hereditary pancreatitis is the increased risk for developing pancreatic adenocarcinoma. Despite this increased risk of cancer, however, a national study performed in France demonstrated that hereditary pancreatitis patients do not have an excess mortality risk as compared with the general population, irrespective of gender, tobacco use, or diabetes mellitus (78).

The histopathology of PRSS1 hereditary pancreases varies among reports. An earlier study of two adult pancreatic specimens described paucicellular thick fibrosis and distorted and dilated ducts, without dysplasia or a mention of fatty replacement (79). Singhi et al. examined 12 total pancreatectomy specimens and suggested a sequential pattern of changes with increasing age (80). In pediatric patients, the pancreas was generally grossly normal, but there was microscopic variation in lobular size and shape, and parenchymal loss in the central portion of the pancreas accompanied by loose perilobular and interlobular fibrosis. The periphery was, however, replaced by mature adipose tissue. With older individuals, the pancreas showed progressive atrophy and extensive replacement by mature adipose tissue with scattered endocrine isles consistent with lipomatous atrophy. Smaller intra- and interlobular ducts were scarred, and the larger interlobular ducts were dilated with intraductal calcification. Pancreatic intraepithelial neoplasia (PanIN), a precursor of infiltrating ductal adenocarcinoma, was identified in only 3 patients. No high-grade PanINs (PanIN-3) was identified. This report is in contrast to a study by Rebours et al. (81), which identified PanIN lesions in 10 of 13 partial
pancreatectomy specimens. One 7-year-old boy showed a focus of high-grade dysplasia (PanIN-3).

Identification of genetic alterations in hereditary pancreatitis has provided a significant tool to investigate other pathogenic factors of acute and chronic pancreatitis. Chronic pancreatitis is a persistent inflammation of the pancreas that results in irreversible morphologic changes and impairment of both exocrine and endocrine functions. Genetic studies of familial and so-called idiopathic forms of chronic pancreatitis have characterized four other susceptibility genes. Witt et al. reported a close linkage of sequence alterations in SPINK1 to chronic pancreatitis. SPINK1 encodes a natural antagonist of trypsinogens, serine protease inhibitor, Kazal type I, also known as pancreatic secretory trypsin inhibitor, which binds reversibly to trypsin and inhibits its activity. Loss-offunction variants in trypsin-degrading enzyme chymotrypsin C gene (CTRC) increase the risk of chronic pancreatitis in European and Asian populations. Most recently, variants in the gene encoding carboxypeptidase A1 (CPA1) have been shown to be strongly associated with early-onset chronic pancreatitis (82). CPA1 is one of the isoforms of digestive carboxypeptidases that hydrolyzes C-terminal peptide bond. After trypsinogens, proCPA1 is the second largest component of pancreatic juice. Sequence variations of CFTR, the gene responsible for cystic fibrosis, are also associated with chronic pancreatitis. PRSS1, SPINK1, CTRC, and CPA1 are expressed in the acinar cells in the human pancreas, while CFTR is expressed in the ductal and centroacinar cells. The expressed protein CFTR is believed to dilute and alkalinize the protein-rich acinar secretions, preventing the formation of protein plugs that predispose to pancreatic injury. There is evidence to support the hypothesis that risk of pancreatitis is related to the balance between degrees of pancreatic acinar preservation and pancreatic ductal obstruction, which are associated with CFTR dysfunction in opposing directions (83). Coinheritance of a CFTR mutation that inhibits bicarbonate conductance but maintains chloride conductance and SPINK1 variants is shown to increase risk of pancreatitis. However, another report argues that the contributions of CFTR variants to chronic pancreatitis in transheterozygous status are overestimated (84).

Idiopathic chronic pancreatitis has been a traditional clinical diagnosis describing the lack of an identifiable cause. As more genes and/or more mutations are identified that cause or predispose to chronic pancreatitis, the number of patients with “idiopathic” disease seems to be decreasing. At the same time, the spectrum of diseases associated with the CTFR mutant genes keeps expanding.

Pancreatoblastoma (91), also called pancreaticoblastoma, is an epithelial neoplasm that exhibits multiple lines of differentiation including acinar differentiation, often with a lesser degree of endocrine and ductal differentiation, and is associated with squamoid corpuscles (92). A distinct mesenchymal component can also be seen. Some view this as the infantile or “blastomatous” form of acinar cell carcinoma. In support of this interpretation, a considerable overlap exists among pancreatoblastoma and acinar cell carcinoma (93). Pancreatoblastomas occur most frequently in young children, but rare congenital cases discovered by prenatal imaging have been reported (94). There is a close association of infantile and congenital pancreatoblastomas with Beckwith-Wiedemann syndrome.