genetic disorders of the pancreas

Gastroenterol Clin N Am

32 (2003) 763–787

Genetic disorders of the pancreas

Veronique Morinville, MD, Jean Perrault, MD*Division of Gastroenterology and Nutrition, McGill University Health Center, Montreal

Children’s Hospital, 2300 Tupper Street #D562, Montreal, QC H3H 1P3 Canada

Our understanding of the physiology and pathophysiology of thepancreas has soared recently with the uncovering of the genetic loci forcystic fibrosis, followed soon afterwards by the identification of geneticmarkers for pancreatitis. In time, physicians are witnessing a notableshrinkage of the once prominent category of chronic idiopathic pancreatitis.The authors review the presently known genetic loci affecting prematureactivation of the enzymes (pancreatitis) or poor exocrine function(pancreatic insufficiency), and their basic cellular mechanisms.

Pancreatitis

Pancreatitis, an inflammation of the pancreas gland, is a relativelyuncommon condition, especially in children. When it does occur, it is mostcommonly an acute and self-limited event, often with a precipitating factoridentified (trauma, infection, medication, and similar factors); the injury tothe gland tends to be self-limited, without persistent damage. Chronicpancreatitis is even rarer, but is characterized by chronic damage andensuing exocrine or endocrine dysfunction in many. For a long time itscause was mostly unknown, except for the known deleterious effect ofalcohol; but great strides have been achieved since the identification ofa genetic abnormality in hereditary pancreatitis, brought to attention byWhitcomb et al in 1996 [1]. This discovery has opened the door to a betterunderstanding of the pathophysiology of the condition, although muchremains to be learned.

The suggestion that pancreatic endopeptidases might be prematurelyactivated and participate in auto-digestion was raised more than a centuryago, but the incipient mechanism was never well demonstrated; among some

* Corresponding author.

E-mail address: [email protected] (J. Perrault).

0889-8553/03/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0889-8553(03)00053-0

mailto:[email protected]

764 V. Morinville, J. Perrault / Gastroenterol Clin N Am 32 (2003) 763–787

of the considerations were the back diffusion of pancreatic secretions in thepancreatic parenchyma, or the premature activation of the endopeptidasesthrough the influence of excess calcium, medication, or other factors.Physiologists now know that the pancreas is enveloped by a self-protectionmechanism, whereby it produces a measurable amount of inhibitorsprotecting the gland from autodigestion, notably pancreatic secretorytrypsin inhibitor [2,3].

At present, the concept of repeated or uninterrupted episodes of acutepancreatitis leading to chronic pancreatitis remains viable, where the glanddevelops more and more destruction, with gradual deposition of fibrosis,leading eventually to loss of parenchyma and loss of exocrine and endo-crine functions [4]. In adults, the main factor is alcohol, whereas in childrenhereditary factors might be playing a large role; in both age groups,idiopathic pancreatitis will be diagnosed in as many as 20% to 30% ofinstances but this number is constantly dropping as more studies on thegenetic factors are published.

Physiologists do know that whatever inciting event is at fault, it calls intoplay an interrelationship between the pancreatic parenchyma and elementsof the immune system [5,6]; mononuclear cells, especially CD4+ and CD8+

cells, are regularly identified in the parenchyma of patients with chronicpancreatitis, along with macrophages. These cells are likely activated by therelease of chemokines from the areas of inflammation, as suggested by insitu hybridization and Northern blot analyses demonstrating increasedmRNA activity for the production of IL-8, ENA-78 (epithelial neutrophil-activating peptide), MCP-1 (monocyte chemoattractant protein), andRANTES (regulate on activation, normal T expressed and secreted) inparticular [5]. In acute pancreatitis, TNFa (tumor necrosis factor a) is likelyreleased early, as was demonstrated in the animal model [7] and this isfurther suggested by the apparent improvement of the clinical picture withneutralization of the effect of TNFa [7], or the administration of the anti-inflammatory mediator IL-10 [5]. Other pro-inflammatory conditions, suchas the participation of phospholipase A2 and the upregulation of MHC class1 and class 2 molecules have also been identified [5]. The result is an intenseinflammatory reaction, leading to the symptomatic presentation physicianshave come to recognize. It is worth repeating that the clinical and laboratorypresentations are in no way helpful in distinguishing one cause of pan-creatitis from another.

Repeated events promote gradual destruction of tissue, with release ofgrowth factors and growth factor receptors, and in turn a transformation ofthe parenchyma with the deposition of fibrous tissue because of the activityof fibroblasts. It seems that the pancreatic stellate cell (PSC), very similar tothe hepatic stellate cell implicated in the fibrotic reaction of the liver, is atfirst implicated in regeneration of the pancreas after an acute necroticprocess [8]; in a rat model, PSCs were stimulated by different cytokinesinvolved in acute pancreatitis [9,10]. However, these same PSCs become an

765V. Morinville, J. Perrault / Gastroenterol Clin N Am 32 (2003) 763–787

active participant in the fibrotic response of the pancreas after repeatedinflammatory injuries [9].

As readers will soon see, the incipient event in pancreatitis has been betterdelineated following the remarkable studies on at least 3 genes associatedwith pancreatitis, namely SPINK1, PRSS1, and cystic fibrosis trans-membrane conductance regulator (CFTR) (Table 1) [4,11–32], and thismight pave the way for a more elaborate exposition of events heretoforediagnosed as idiopathic pancreatitis.

Hereditary pancreatitis

Historical background

The first family with hereditary pancreatitis was described by Comfortand Steinberg in 1952 [33]. They observed that the episodes of pancreatitiswere very similar to any other pancreatitis attack, but the patients hadan earlier age of onset, had a strong family history, had more frequentidentification of stones in the pancreas, and there was a gradual progressiontoward destruction of the gland. An autosomal dominant mode of in-heritance was already suggested.

With the description of more families, the character of the conditionbecame clearer: same sex frequency; gradual development of complicationswith time; absence of anatomic malformations to explain the onset of thecondition. The close monitoring of the families affected with this conditionplayed an important role in the identification of their genetic anomaly; the Sfamily, described by McElroy and Christiansen in 1972 [34], was to playa pivotal role in helping Whitcomb et al 25 years later to uncover the

Table 1

Recent genetic information on pancreatitis in children

Gene Chromosome Mutations References

Cationic trypsinogen

(protease, serine1; PRSSI)

7q35 R122H; N29I

A16V; others

[4,11–19]

Pancreatic trypsin inhibitor

(PSTI) (SPINK1-serine

protease inhibitor,

Kazal Type 1)

5 N34S [20–22]

CFTR-cystic fibrosis

transmembrane regulator

7 DF508; R117H;

Q493X R560T;

R553X; 5Tallele;

621 + 1(G!T)

and others

[23–27]

Parathyroid cell receptor

(CaR)

3 (3q21-24) N178D; R220Q;

P221S; R648X; others

[28–30]

Lipoprotein lipase (LPL) 8 (8p22) N291S, S447X; G715A [31,32]

Apolipoprotein C-II

(apoC-II)

19 (19q13.2) Val 18, Gln 2 and others [31]


chromosomal [11], then the genetic abnormality [1], while in France LeBodic et al [12] identified a very similar anomaly in a family described in1963 by Cornet et al [35]. Some families seemed to have a slightly differentanatomic picture, with hypertrophy of the sphincter of Oddi as observed byRobecheck [36]. In time, this keen observation would lead to identificationof a new mutation [14].

The phenotypes

The episodes of clinical pancreatitis were essentially indistinguishablefrom any other episodes of pancreatitis: most presented with typicalabdominal pain, of similar severity and duration, with similar elevationsof serum amylase and lipase. Some episodes could lead to quite severecomplications, with pseudocyst formation, ascites, or splenic vein throm-bosis. Many abdominal films lit up with large calcified stones.

Gross [37] put together a large series of 340 adult patients, combining hisown experience with cases already published and noted that 39% hadcalcifications, 30% developed diabetes mellitus and 21% became pancreaticinsufficient. Carcinoma was also noted to develop in some of these patients,as clearly demonstrated later on by Lowenfels et al [38,39].

With respect to childhood presentation, Konzen et al [40] compared theclinical manifestations of 42 children with hereditary pancreatitis, with 28patients who had recurrent pancreatitis without a family history, referredto as idiopathic pancreatitis. All patients in both groups presented withabdominal pain, frequently radiating to the back, but the course was usuallymore complicated in the patients with hereditary pancreatitis, and in timethey required more surgical procedures.

More phenotypic presentations have been reviewed recently [41],including families whose later age of onset and milder clinical featuresmay represent a different genetic alteration.

The genotypes

Within a few months of each other, 3 groups [11–13] from differentcountries published their findings of a mutation among the cationictrypsinogen gene (protease, serine, 1; PRSS1), located on chromosome7q35. The mutation is an arginine (R) to histidine (H) substitution on exon3, codon 122 (R122H, previously numbered 117). Shortly afterwardsWhitcomb et al [1] presented the pathophysiologic consequence of thisgenetic mutation: the trypsin hydrolysis site is altered sufficiently to restrictinactivation of the prematurely activated trypsin.

Another mutation at exon 2, codon 29 (asparagine to isoleucinesubstitution; N29I, previously 21) was soon described [14]. These 2mutations represent the most frequently recognized mutations known ashereditary pancreatitis [15]. The pathophysiologic mechanisms remain


a subject of debate; recent in vitro studies suggest that both are accompaniedby premature activation of trypsinogen, but ineffective alteration ofprematurely activated trypsin is also a factor with R122H mutation [42].Other mutations have also been uncovered, but without the frequency,penetrance, or known pathophysiology of the first two mutations [4,15,19].

One mutation of particular interest to the pediatric population is theA16V mutation described by Witt et al [15,16]. A substitution of alaninewith valine on exon 2, codon 16, was described in 4 of 44 children andadolescents with pancreatitis, 1 with a family history and 3 without, while 95controls were negative for this mutation. Yet, in all cases one parent wascarrying the mutation, although usually not affected, suggesting a lowpenetrance, as opposed to the known 80% penetrance in the more commonmutations. This same mutation was also identified by Pfutzer andWhitcomb [17] (5 of 600 patients) and Chen et al [18], at a lower frequency,but in a less-well described study population. Pfutzer and Whitcomb [17]also found CFTR R117H mutation in one family affected with A16Vmutation, leading them to raise the question as to whether this lattermutation might represent a modifier gene requiring another mutation,rather than an independent risk factor, for development of pancreatitis. Tonote that Witt et al [43] did not identify any of the more common mutationsof CFTR in their study population. Although the findings of mutationalfrequency differed between these groups, all agree that genetic testing isstrongly recommended in chronic idiopathic pancreatitis.

What remains unsettled is the pathophysiology of the formation of largepancreatic stones in these patients. Premature activation of pancreaticenzymes would not seem to be a satisfactory explanation; repeated attacks ofinflammation are not a prerequisite since young patients are often affected inthe early stages (personal observations). Lithostatin, or secretory pancreaticstone protein [44], is a gene product mapping to chromosome 2p12 involvedin stabilization of pancreatic juice [45]. It may play a role in the pathogenesis,as it is found in lower concentration and in precipitated form in chroniccalcifying pancreatitis, and may play a role in its pathogenesis. Sarles et al[46,47] observed different patterns of stone formation, some with pre-dominant calcium salts, some with more of a protein moiety; the latter stonesseemed to be more commonly found in patients with a family history (10 of36 patients). Although lithostatin is in normal concentration, its molecularcomposition is abnormal in patients with protein lithiasis. In contrast, Suzukiet al [48] could not confirm an involvement of the lithostatin gene inhereditary pancreatitis, leaving the question still wide open.

Pancreatic secretory trypsin inhibitor

As it was appropriately hypothesized that early activation of trypsincould lead to the development of pancreatitis, it would also seem logical that


unsuccessful or incomplete inactivation of trypsin might be accompanied bythe same disastrous events. Chen et al [49] looked for mutations in thepancreatic secretory trypsin inhibitor (PSTI) gene, located on chromosome5. They did identify seven different DNA variants of the gene (also calledSPINK1-serine protease inhibitor, Kazal type 1), but without clear rel-ationship to the development of chronic pancreatitis. On the other hand,Witt et al [20] studied 96 unrelated children and adolescents with chronicpancreatitis, and found mutations in 23% of the patients, with only one of279 controls showing heterozygosity to one of the more common missensemutations (a substitution of asparagine by serine at codon 34 in exon 3,N34S); these results suggested an association of a mutation in PSTI(SPINK1) with chronic pancreatitis.

Buoyed by these findings, Chen et al [21] studied 187 unrelated patientswith chronic pancreatitis, and found 12 with the N34S missense mutation;5 of 34 patients (14.7%) less than 20 years of age were carriers of themutation, a much more meaningful rate than previously noted [49]. Pfutzeret al [22] had reported similar findings, and while not suggesting a directcausative link with pancreatitis, they saw a disease modifying effect, possiblyenabling other genetic or environmental factors to manifest themselves (eg,Witt et al [50] have observed that several of their patients were heterozygousfor both N34S and a CFTR mutation, as also demonstrated by Noone et al[23]) (see later in this discussion).

Cystic fibrosis transmembrane conductance regulator mutations

and pancreatitis

That patients with the phenotype of cystic fibrosis may developpancreatic dysfunction is a well-accepted fact. Their clinical presentationsof pancreatic disease are diverse and complex, and will not be covered in thisarticle. The authors would instead refer readers to excellent reviews byDurie [51], Mickle [52], and Freedman [53].

However, what has become apparent in the past few years is that CFTRgenotype mutations may be associated with varied phenotypic presentations(Table 2) including pancreatic disease not confined to that described in thecontext of cystic fibrosis. One such association is the congenital bilateralabsence of vas deferens [54,55]. Another more recent observation is theassociation between non cystic fibrosis-causing CFTR mutations andidiopathic pancreatitis.

Two groups concurrently described the relationship between mutationsof the cystic fibrosis gene and idiopathic pancreatitis [24,25]. Sharer’s group[24] studied 134 consecutive patients with chronic pancreatitis but no clini-cal criteria of cystic fibrosis (71 alcohol-related; 2 hyperparathyroidism, 1hypertriglyceridemia, 60 idiopathic). DNA was analyzed for the 22 mostcommon CFTR mutations in the local population; 18 of 134 patients


(13.4%) had a CFTR mutation on one chromosome, and 14/134 (10.4%)had an allele associated with decreased production of CFTR mRNA, the 5Tallele, which causes the production of poorly functional or nonfunctionalcopies of CFTR. Mutations, including delta F508, R117H, Q493X, 621 + 1(G!T), R560T, R553X, were found at 2.5 times the frequency expected inthe general population studied (600 controls included). Cohn’ s group [25]studied 27 patients (22 females) with idiopathic pancreatitis. Their DNAwas tested for 17 CFTR mutations and for the 5T allele. Ten of twenty-seven (37%) had at least one abnormal CFTR allele (deltaF508, R117H,N1303K, and the 5T allele), none with criteria diagnostic of cystic fibrosis.The frequency of a single CFTR mutation was 11 times the expectedfrequency in the baseline population and the frequency of two abnormalalleles (found in 3 patients if the 5T allele was included) was 80 times theexpected frequency. As the normal function of CFTR in the pancreas is topromote the dilution and alkalinization of pancreatic juice [56], it was feltthat severe impairment might cause pancreatic insufficiency, while lesssevere impairment would cause pancreatitis.

Similar results have since been published in the medical literature[23,26,27]. Mutations of CFTR include: deltaF508, R117H, D1152H,P574H, 3120 G > A, 621 + 1 G > T, G1069R, N1303K. Noone et al [41]looked at the presence of CFTR mutations in conjunction with anotherdescribed predisposition to pancreatitis, mutations of PRSS1. They found

Table 2

The different clinical presentations of the CFTR genotype

CFTR genotype

Severe/severe

mutation

Severe/mild

mutation

Mild/mild or

5T allele

Amount of functional

CFTR

0–2% 2–5% 5–10%

CF lung disease Yes Yes No

Elevated sweat chloride Yes Yes No

Pancreas

acute recurrent pancreatitis No Yes Yes

‘‘idiopathic’’ chronic

pancreatitis

No Yes Yes

Pancreatic insufficiency Yes No No

Congenital bilateral absence

of the vas deferens

(CBAVD)

Yes Yes Yes

Clinical diagnosis CF

CF with pancreatic

insufficiency

CF or possibly

ICP

ICP

CBAVD

Abbreviations: CBAVD, congenital bilateral absence of the vas deferens; CF, cystic fibrosis;

CFTR, cystic fibrosis transmembrane conductance regulator; ICP, idiopathic chronic

pancreatitis.

Adapted from Cohn JA, Powell PS. Are mutations in the cystic fibrosis gene important in

chronic pancreatitis? Surg Clin N Am 1999;79:723–31; with permission.


increased risk with either CFTR or PRSS1 mutations, and an impressive900-fold increased risk by having both. The greatest risk for pancreatitis wasassociated with compound heterozygote genotypes of CFTR containing onesevere mutation plus one mild-variable mutation (the latter accounting forthe residual CFTR function of 5% to 25% normal, protecting them againstdevelopment of CF lung disease, but perhaps enough activity to predisposeto pancreatitis [51]).

The link between pancreatitis risk and CFTR loss of function issupported in some way by extrapancreatic clinical findings observed incompound heterozygotes. These manifestations, at times subtle, includeabnormal sweat chloride, sputum colonized with CF-typical pathogens,congenital absence of the vas deferens and sinusitis (Table 2). However, asthese same CFTR mutations may be present in the normal population,without ever manifesting any clinical signs of pancreatitis, one mustimplicate incomplete penetrance, gene–gene or gene–environment inter-actions [23,51]. Moreover, as only a fraction of known CFTR genemutations have been tested for in recurrent pancreatitis, more ‘‘idiopa-thic’’ cases may become regrouped as ‘‘CFTR-associated’’ in upcomingresearch.

Metabolic conditions

Many varied metabolic conditions have been associated with episodes ofpancreatitis, through different mechanisms, some of which remain un-explained. The authors review only those for which they have clear geneticmarkers.

Hypercalcemia and acute pancreatitis

Introduction

Although hypercalcemia is considered a risk factor in the developmentof acute pancreatitis, the mechanism is not well understood, and theassociation is not clear-cut. Some investigators in the 1970s and 1980squestioned whether there was a cause-and-effect relationship between thetwo [57], but a more recent study of primary hyperparathyroidism (PHPT)and pancreatitis has refocused the issue. Chart reviews of 1435 patientsoperated for PHPT [58], including all primary PHPT cases without biliarystones, revealed that 40 patients with PHPT (3.2%) had pancreatitis (acutein 18, subacute in 8, and chronic in 14). This rate was higher than fora random hospital population. The only difference between havingpancreatitis or not was the serum calcium level which was significantlyincreased in PHPT with pancreatitis. Hence they concluded that thepancreatitis—PHPT association was not incidental: pancreatitis was theconsequence and not the cause of PHPT; hypercalcemia seemed to be


a major factor in the development of pancreatitis in PHPT patients, andcure of PHPT led to healing of acute pancreatitis, although it did not seemto affect the evolution of subacute and chronic pancreatitis (those patientsprogressed to complications such as diabetes, pancreatic duct stenosis).What remains unclear, however, is whether hypercalcemia is a cause ofpancreatitis, or whether it is simply associated with another as yet un-identified factor responsible for the inflammation.

Pathway

A few animal studies individually showed necrotizing pancreatitis, acinarcell necrosis, disorganization of acinar polarization, excessive zymogengranule precipitation in the basolateral cell area, amylase release,trypsinogen activation, generalized edema, and leukocyte infiltration [59–61]. It was felt that acute experimental hypercalcemia caused dose-dependent morphologic alterations characteristic of acute pancreatitis, withhyperamylasemia, possibly from early ectopic trypsinogen activation. Thisserved to offer a possible pathogenic mechanism for excess calcium causingclinical pancreatitis.

The mechanism in humans is far from clear, some suggesting that excesscalcium leads to microcrystal formation in the pancreatic ducts, and othersadhering to the animal model of early activation of trypsinogen. It alsoseems that whereas hypercalcemia from solitary adenomas of the para-thyroid is indeed accompanied by pancreatitis [58,62], PHPT in the contextof multiple endocrine neoplasia syndromes does not seem to have the samepropensity. One intriguing association is that of pancreatitis and familialhypocalciuric hypercalcemia (FHH).

FHH Genotypes

Pancreatitis is an unusual complication of the usually benign disorderFHH. It has been described, however, in several kindreds and hence isworthy of mention. Family studies seem to suggest that FHH is autosomaldominant in inheritance, with nearly 100% penetrance. The major genelocus implicated in FHH is the parathyroid cell receptor (CaR) gene locatedon chromosome 3 (3q21-24) [28,63]. It encodes the calcium-sensing receptorprotein, a plasma membrane G-coupled protein that is expressed in theparathyroid hormone-producing chief cells of the parathyroid gland. It isactivated by extracellular calcium ions and controls PTH secretion.Polymorphisms of the locus might affect the magnitude of PTH secretionand the clinical severity of primary hyperparathyroidism [29]. In addition,a loss of heterozygosity at the CaR locus has been found in 10% of sporadicparathyroid adenomas [63] which would suggest that altered calciumsensitivity might be an important stimulus for the excessive proliferation ofthose cells.


Recent studies have included the description of three kindreds withrecurrent pancreatitis whose mutations in CaR segregated with thehypercalcemia. The mutations identified were N178D, R220Q, P221S, noneof which were found to be common polymorphisms in unrelated controls[30]. As of 2001, there had been over 30 mutations associated with FHHdescribed worldwide [28].

Lipoprotein lipase and apoprotein C-11

Lipoprotein lipase (LPL), found on the luminal side of capillaryendothelial cells, is the rate-limiting enzyme for the hydrolysis oftriglycerides (TG). With the intermediary of its activator apoprotein C-11,produced in the liver before its release into plasma, it regulates lipoproteinmetabolism by hydrolyzing the core triglycerides of circulating chylomi-crons and very low-density lipoprotein. Defective LPL or apoprotein C-11activity leads to massive accumulation of chylomicrons in plasma witha corresponding increase of TG concentration; the hypertriglyceridemia thatensues is linked to the development of acute pancreatitis.

Phenotype

Index cases typically present in infancy with intolerance to dietary fat,hepatosplenomegaly, eruptive xanthomas, severe hypertriglyceridemia withfasting chylomicronemia, and abdominal pain with or without pancreatitis[64–66]. Complete deficiency of the gene product is present in approximately1 of 1,000,000 people, and the heterozygous state in 1 of 500 [67].Heterozygous carriers manifest age-dependent familial hypertriglyceridemiawith reduced LDL and HDL cholesterol concentrations (type IV hyper-lipoproteinemia) [68]. Diagnosis, often clinically suspected by observationof lactescent plasma, is confirmed by low LPL activity or with theidentification of a structural defect in the LPL gene alleles [64,69]. Theserum level of triglycerides usually surpasses 11 mmol/L (1000 mg/dL) forpancreatitis to develop, although the exact mechanism has not yet been welldelineated.

Genotype

Familial lipoprotein lipase deficiency and familial apoprotein C-11deficiency are both inherited as autosomal recessive disorders. Type Ihyperlipoproteinemia, or familial hyperchylomicronemia, results eitherfrom LPL deficiency (8p22 locus) or from the absence of LPL cofactor,apolipoprotein C-11 (apoC-11, chromosome 19q13.2) [31]. Several pedigreeshave reinforced the suspected association between hyperlipoproteinemiasyndromes and pancreatitis. In a kindred with apolipoprotein C-11deficiency, several family members had marked fasting chylomicronemia


and 5 had a history of pancreatitis, presenting as young as 6 years old [70].Another family with hyperchylomicronemia and 5 members with recurrentpancreatitis was found to have absent LPL catalytic activity due to a G715Asubstitution defect (Ser154Gly) [32].

Several mutations of the LPL gene have now been defined, eitheracting at the site of catalysis or altering attachment or entrance of lipidsto the catalytic site. In some, a more direct effect is a large increase of thetriglycerides in the serum, whereas in others a more indirect mechanism isimplied, but in all there would be an increased risk of recurrentpancreatitis. Insertions, deletions, splicing defects, nonsense, and missensemutations all have been described [31,65,68,71–76]. Several patients willneed an additional requirement before developing pancreatitis: theintroduction of exogenous estrogen (oral contraceptive agent [64]) ora pregnancy [77–81]. These predisposing factors modulate lipid levels byaffecting both the rate of production and the efficiency of removal ofplasma TG-rich lipoproteins. Other ‘‘modulating’’ factors may yet bedefined for this genetic potential to be expressed. Paralleling this, othergenotypes may require similar ‘‘environmental tinkering’’ to producea particular phenotype, accounting for the variable expressivity seen in somany conditions.

In all these circumstances, a proper diet will keep the level of triglyceridesat a tolerable level, dramatically reducing the frequency of episodes ofpancreatitis. In certain conditions, high levels of antioxidants have providedexcellent protection against recurrent episodes of pancreatitis [82]. When anepisode does develop, heparin or insulin have resulted in a rapid resolution[73,83]; plasmapheresis is another option [84].

Other metabolic conditions

Byler disease, otherwise known as progressive familial intrahepaticcholestasis (PFIC-1), involves a defect of cannalicular bile acid transport,an ATPase encoded by a gene locus on chromosome 18q21-q22 namedFIC1 [85]. Patients usually present in the first 6 months of life withcholestasis, hepatomegaly, severe pruritus, growth failure, pancreatic in-sufficiency, and fat-soluble vitamin deficiency [86]. As they are prone tocholelithiasis, their cause of pancreatitis is sometimes by way of thisintermediate.

Several metabolic disorders have been linked to pancreatitis, includingurea cycle defects (ornithine transcarbamylase deficiency [87], citrullinemia[88], and others), aminoacidemias (methylmalonic acidemia, isovalericacidemia [89]), aminoacidurias (maple syrup urine disease, and homocys-tinuria [90–93]), among many others. Pancreatitis is not typically thepresenting symptom in these conditions, and the pathophysiology remainsto be clearly determined.


Future directions in pancreatitis

The past decade has witnessed exceptional progress in better definingcertain predispositions to pancreatitis. As is made obvious by the examplesmentioned earlier, many ‘‘idiopathic’’ cases of pancreatitis will have to beredefined and regrouped as genetic tests become more readily available. Allinterested parties now have some better understanding of the pathophys-iology in well-defined populations, and their knowledge keeps expanding.The eventual hope is to tailor therapy and preventive measures to thedifferent underlying risks.

Pancreatic insufficiency

Although chronic pancreatitis may lead to pancreatic insufficiency, thereverse is not implied, nor is it necessarily common, especially in children.However, as physicians have observed with their expanding knowledge ofCFTR, different phenotypic presentations may be imputed to variableanomalies of one particular gene. Other chromosomal causes of pancreaticinsufficiency have now been identified, after many painstaking years ofwork. The researchers discuss a few examples of exocrine pancreatic in-sufficiency where a genetic defect has now been identified or suggested.

Shwachman–Diamond syndrome

Historical perspective

Two separate groups from each side of the Atlantic, Shwachman,Diamond, Oski and Khaw from the USA [94], and Bodian, Sheldon, andLightwood from Great Britain [95], published in 1964 their experienceinvolving children with failure to thrive from infancy, diarrhea related toexocrine pancreatic insufficiency, and variable hematologic abnormalitiesincluding anemia and thrombocytopenia (and more often than notneutropenia, especially cyclic neutropenia). Bodian et al [95] added 18patients from the literature, all with pancreatic biopsies available, reveal-ing fatty replacement of the acini, but preservation of the endocrine tissue.Most of these patients were first thought to represent an atypicalmanifestation of cystic fibrosis, but with time it became clear that notonly were the clinical manifestations different, but their sweat test was alsonormal. Over the years, it was possible to establish an autosomal recessivetrait to this syndrome, and as more patients have been described, morefeatures have been added to the syndrome (see later in this discussion).However, the major features, and those necessary for a diagnosis, remainthe pancreatic and hematologic abnormalities, which should be present inall patients [96].


Phenotype

The exocrine pancreatic insufficiency and hematological disorders areprerequisites for establishing the disorder. Yet, there is no homogeneity inthe presentations, whether in single or multiple affected family members,especially in the hematologic manifestations, although there is a higherdegree of concordance in the pancreatic manifestations [97]. Recently, areview article addressed many of the features of Shwachman–Diamond syndrome (SDS) [98], and the authors highlight the maincharacteristics.

� Pancreatic insufficiency: the ductal function is preserved, so that theproduction of water and electrolytes is maintained, but enzymeproduction is severely curtailed, leading to exocrine insufficiency [96].This finding seems to be universal in infancy, but as yet unexplained isthat the severity of the steatorrhea improves with time, to the point ofnormalization in many by their teens. Obviously, this resolution of thepancreatic insufficiency with time may make it difficult to confirm thediagnosis in some who have eluded early diagnosis. Since an alterationof the exocrine pancreatic function is crucial in establishing a diagnosis,evaluation of this function needs to be done early. The difficulty, and inmany centers the unavailability, of measuring the quantitative output ofpancreatic enzymes in the duodenum has lead to the development oftwo non-invasive tests to help in the diagnosis: a serum trypsinogen level[99], expectedly low in pancreatic insufficiency, and more recently, thevalidation of measuring serum isoamylase as a marker of an alteredproduction of pancreatic enzymes [100]. The former is quite valuable inthe early years of life, readily distinguishing pancreatic sufficient frominsufficient patients, but as the pancreatic function improves with time,so does the trypsinogen level. On the other hand, serum isoamylase,which is normally low in many controls in the first 3 years of life, doesnot seem to normalize with time in patients with pancreatic dysfunction,and remains low at all ages in SDS [100]. Combining both tests mayindeed help define the SDS pancreatic phenotype [100].

� Hematologic abnormalities: these are as essential to the diagnosis as isthe pancreatic dysfunction. Decreases in the white cell count, at timesaccompanied by increased susceptibility to infections, are the morecommon manifestations, but any cell lineage may be affected, fromanemia to thrombocytopenia and even pancytopenia. It is now apparentthat these patients are at increased risk for developing myelodysplasiaand hematologic malignancy in as many as 33% of patients. In a recentstudy, Dror and Freedman [101] studied 11 children with SDS, andshowed that these patients had more frequent apoptosis, whether or notthey had a myelodysplastic syndrome. The predisposing factor for thisbone marrow failure seems to be linked to the overexpression of the Fas


antigen, a membrane glycoprotein in a central apoptosis pathway [101].A marker on bone marrow biopsy tissue, the p53 gene, was tentativelyidentified as an early indicator of significant DNA alteration in thesepatients [102].

� Other features not considered crucial to the diagnosis, but seenfrequently enough to raise suspicion are short stature, skeletalabnormalities, and abnormal liver enzymes (Table 3). In a series of 25patients with SDS presented by Mack et al [96], 76% had some form ofskeletal abnormality, and 13 of 23 (51%) had elevation of aspartateaminotransferase (AST); as with serum trypsinogen, the AST tended toreturn toward normal with advancing age.

Genotype

From early on there was a suggestion that SDS was transmittedaccording to a recessive trait, and this was strongly affirmed by segregationanalysis of a sufficiently large study population, composed of 84 patientsfrom 70 families [103]. None of the parents were affected, nor did they showany abnormality of serum trypsinogen when compared with controls.

Table 3

Varied manifestations of the Shwachman-Diamond syndrome

Systems involved Manifestations

Gastrointestinal

Pancreas Exocrine insufficiency

Liver Elevated transaminases

Steatosis, fibrosis

Growth Short stature

Pubertal delay

Hematologic

Peripheral counts Neutropenia

Anemia

Thrombocytopenia

Bone marrow Hypocellularity

Aplastic anemia

Myelodysplasia

Leukemia

Abnormal cytogenetics

Infectious diseases Respiratory

Systemic

Skeletal Rib cage malformations

Metaphyseal dysostoses

Cardiologic Myocardial fibrosis

Developmental Delayed development

Low IQ

Learning disorders

Modified from Rothbaum R et al. Shwachman-Diamond syndrome: report from an inter-

national conference. J Peds 2002;141:267; with permission.


The chromosomal analysis of one young patient with exocrine pancreaticinsufficiency and bone marrow dysfunction showed a de novo balancedreciprocal translocation t(6;12) (q16.2; q21.2), raising the question as towhether these translocation breakpoints might represent a possible geneticlocus in this condition [104]. Further studies in 13 families with 2 or 3affected children met with negative lod scores, thus ruling out thiscytogenetic abnormality in most cases of SDS [105].

Using linkage analysis, Goobie et al [106] studied 13 multiplex and 8simplex families; they found that one locus on chromosome 7, D7S1830, hadachieved significance as the potential site. Genotyping of families with 2 or 3affected members confirmed the position, which includes the centromericregion. The SDS community can now expect the description of the involvedgene in the near future.

Pearson marrow–pancreas syndrome

In 1979 Pearson and colleagues [107] described 4 infants with a disorderaffecting the hematopoietic system and exocrine pancreas, now named thePearson marrow-pancreas syndrome (PMPS).

Phenotype

The initial description of the syndrome was striking in its involvement ofthe bone marrow and exocrine pancreas. The patients had a macrocytic,aregenerative anemia with low levels of reticulocytes, and the bone marrowshad vacuolization of erythroid and myeloid precursors. All had evidence ofpancreatic dysfunction, ranging from malabsorption and deficient responseto secretin-pancrozymin stimulation, to absent stool and duodenal trypsinactivity; histopathologic studies of the pancreas revealed acinar atrophy,fibrosis, and hemosiderosis. Impaired volume and bicarbonate responseswere the most important aspects of stimulation studies, although there werealso blunted releases of lipase and amylase The endocrine function wasuniformly maintained in all early descriptions of patients [107], not unlikethe Shwachman–Diamond syndrome, although these can be differentiatedbased on physical and laboratory parameters (Table 4) [94–100,102,106–126]. With further observations, more phenotypic variations have beenreported, including hyperlactacidemia [111–113], renal Fanconi syndrome,diabetes mellitus and organic aciduria [113], vomiting and gastroparesis,cirrhosis, liver failure, and hepatocellular hemosiderosis [114].

Genotype

The identification of persistently high lactate/ pyruvate molar ratios inplasma led Rotig et al [117] to postulate that Pearson’s syndrome belongedto the mitochondrial cytopathies family. Details of the mitochondrial

Table
4

Phenotypeandgenotypecomparisonofvaried

pancreaticinsufficiency

syndromes

Clinicalfeature

Shwachman–Diamond

syndrome

PearsonMarrow–pancreas

syndrome

Johanson–Blizzard

syndrome

Physicalexam

FTT

FTT

FTT/dwarfism

Short

stature

(norm

alvelocity)

Maydevelop:

Absentpermanentteeth

Skeletalabnorm

alities

[96,97]

cardiomyopathy

Congenitalaplasia

ofalaenasi

metaphysealdysplasia

cardiacconductiondefects

Deafness

short

orflaredribs

cerebellarataxia

dextrocardia

thoracicdystrophy

deafness

Imperforate

anus/

clinodactyly

ophthalm

oplegia

rectourogenital

abnorm

alities

longbonetubulationdefects

retinaldegeneration

Midlineectodermal

scalp

defects

neurodegeneration[124]

Microcephaly

Mentalretardation

[126,131]

Laboratory

Abnorm

alliver

enzymes

(AST)[96]

Hyperlactacidem

ia[108–111]

Hypothyroidism

Renaltubulardysfunction

Highlactate/pyruvate

ratio

Sensorineuraldeafness

Organic

aciduria

Fanconianem

ia

Diabetes

mellitus

Hepatocellularhem

osiderosis

Cirrhosis/liver

dysfunction

Pancreaticfunction

acinar

Decreasedenzyme

production[96]

Dysfunctionofvariable

degree

mildbluntingoflipase

and

amylase

release

[107]

Decreasedacinar

secretionof:

low

serum

trypsinogen

[99]

trypsin,colipase,lipase

low

serum

isoamylase

[100]

Low

serum

trypsinogen

[133]

Ductal
Norm

alwaterandelectrolyte

excretion

Impaired

volumeandbicarbonate

responses[107]

Preservationofductular

outputoffluid

and

electrolytes[133]

Endocrine

Norm

alendocrine

function[94,95]

Norm

alendocrinefunction[107]

Pancreasbiopsy

Fattyreplacementof

acinionbx[95]

Acinaratrophy,fibrosis,[107]

hem

osiderosis

Replacementof

pancreaswith

adipose

tissue[134]

Hem

atological

peripheral

anem

ia[94,95,98]

Refractory

sideroblastic

anem

ia[107]

Noparticular

abnorm

alities

described

todate

thrombocytopenia

cyclic

neutropenia

Aregenerativeanem

ia

pancytopenia

Increasedfetalhem

oglobin

increasedfetalhem

oglobin

Bonemarrow

Red

cellhypoplasia

vacuolizationoferythroid

andmyeloid

precursors

[107]

Increasedrisk

ofmyelodysplasia

andhem

atological

malignancies

[101]

Genetic/chromosomal

defect

Bonemarrow:overexpression

ofFasantigen

(apoptosis

pathway)[102]

Mitochondrialgenomedefect:

2.9–7.37kbpdeletions[112,117–122]

Modeofinheritance

uncertain,butmaybe:

Autosomalrecessiveinheritance

chromosome7locus,

D7S1830[106]

Samedeletionsasinvolved

in

Kearns-Sayre

syndrome[125]

autosomalrecessive

[127,134]

Other

mutations[135]

X-linked

lethal

[126,132]

Abbreviations:

bx,biopsy;FTT,failure

tothrive.


genome had been published in 1981 by Anderson et al [127]. Consisting of16,569 base pairs, it codes for the 12S and 16S rRNAs, tRNAs, cytochromec oxidase subunits I, II, and III, ATPase subunit 6, cytochrome b and otherpredicted protein coding genes. The unique nature of mitochondrial DNAcontributes to the presentation of PMPS. Most components of mtDNA areinvolved in generating cellular energy, by way of the respiratory chaincomplexes. Mutations are frequent, in part because of the high density ofcoding information, lack of redundancy, and lack of efficient repairmechanism. When heteroplasmy of mitochondria exists, the normal andmutant mtDNAs segregate randomly to daughter cells during mitoses. Oncethe mutant mtDNAs reach a critical level, somewhat variable depending ontissue, organ, and host, cellular phenotype changes rapidly from normalto abnormal [128] partially as a consequence of altered tissue ATP produc-tion [129].

Rotig et al [111,117] described the molecular defect leading to thephenotype of PMPS: a mitochondrial respiratory enzyme defect withrearrangements of the mitochondrial genome between directly repeatedsequences. In 1990, Cormier et al [130] found deletions in several tissues(such as pancreas, gut, bone marrow, blood leukocytes) including organswhich were not apparently clinically involved (including brain, skeletalmuscle, heart, lung, and endocrine glands).

It seems that the syndrome does not involve a standard base pair defect,but instead involves heterogeneous mutations. Defects include the pro-duction of a 14 kb mtDNA product [130], a 4977 bp deletion [117–120]; a 4.5kb deletion [119,121]; a 7374 bp deletion [122], and a 2905 bp deletion [123].The amount of deleted mtDNA molecules differs between different patientsand cannot be correlated to clinical severity [128,130,131].

The Kearns–Sayre syndrome (KSS) is a mitochondrial disordercharacterized by infantile to adolescent development of cardiomyopathyor conduction defects, diabetes mellitus and other endocrine abnormalities,cerebellar ataxia, deafness, ophthalmoplegia and retinal degeneration, andmultifocal neurodegeneration [108]. The distinction between Pearson’ssyndrome and Kearns–Sayre syndrome has been blurred by the identifica-tion of the same base pair deletions in similar tissues in these twophenotypically different disorders [124]. Some cases even seem to blend fromone to the other as the disease progresses [108,120,123]. The issue of whycertain patients present with the phenotype of one to progress to the other isunclear now.

Future directions in pancreatic insufficiency

Research into the inheritance patterns of Shwachman–Diamond Syn-drome has made this entity a more defined genetic condition, as opposed tothe sporadic condition it was once thought to represent. A similar fate may


yet await other syndromes such as the Johanson–Blizzard syndrome,a condition involving the constellation of congenital aplasia of the alae nasi,deafness, hypothyroidism, dwarfism, absent permanent teeth, and malab-sorption (Table 4) [109]. Familial occurrence has been reported in severalkindreds [125,132–134]. Presence of consanguinity [110] in some suggestedan autosomal recessive mode of inheritance, while occurrence in females andKlinefelter patients in others suggest an X-linked dominant mode [109,126].

Summary

The venues opened to all by the remarkable studies of the genome are juststarting to become manifest; they can now distinguish different variants ofa disease; they are given the tools to better understand the pathophysiologyof illness; they hope to be able to provide better treatment alternatives toour patients. The examples described in this review demonstrate theapplicability of these concepts to pancreatic disorders. Researchers may bejust scratching the surface at this time, but the potential is enormous.

Many philosophic and ethical questions need to be answered as physiciansmove along: Should all family members of an index case be screened? Whoshould pay for testing? Who should get results? But, without the partici-pation of so many patients, their family members, and numerous volunteers,researchers would not have witnessed the bridging of so many gaps as theyhave so far. All of us may now look forward to the application of thisincredible knowledge to the therapeutic solutions so eagerly awaited.

Acknowledgment

The authors thank Ms. Rita Biancospino for the invaluable secretarialassistance in the preparation of this manuscript.

References

[1] Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by

a mutation in the cationic trypsinogen gene. Nat Genet 1996;14:141–5.

[2] Horii A, Kobayashi T, Tomita N, et al. Primary structure of human pancreatic secretory

trypsin inhibitor (PSTI) gene. Biochem Biophys Res Commun 1987;149:635–41.

[3] Drenth JPH, Morsche R, Jansen JBMJ. Mutations in serine protease inhibitor Kazal type

1 are strongly associated with chronic pancreatitis. Gut 2002;50:687–92.

[4] Etemad B, Whitcomb DC. Chronic pancreatitis: Diagnosis, classification, and new genetic

developments. Gastroenterology 2001;120:682–707.

[5] Esposito I, Friess H, Buchler MW. Molecular mechanisms in chronic pancreatitis.

Zentralbl Chir 2001;126:867–72.

[6] Bruno MJ. Current insights into the pathogenesis of acute and chronic pancreatitis. Scand

J Gastroenterol 2001;36(Suppl 234):103–8.

[7] Gukovskaya AS, Gukovsky I, Zaninovic V, et al. Pancreatic acinar cells produce, release,

and respond to tumor necrosis factor-a: Role in regulating cell death and pancreatitis.

J Clin Invest 1997;100:1853–62.


[8] Zimmermann A, Gloor B, Kappeler A, et al. Pancreatic stellate cells contribute to

regeneration early after acute necrotising pancreatitis in humans. Gut 2002;1:574–8.

[9] Mews P, Phillips P, Fahmy R, et al. Pancreatic stellate cells respond to inflammatory

cytokines: potential role in chronic pancreatitis. Gut 2002;50:535–41.

[10] Jaster R, Sparmann G, Emmrich J, Liebe S. Extracellular signal regulated kinases are key

mediators of mitogenic signals in rat pancreatic stellate cells. Gut 2002;51:579–84.

[11] Whitcomb DC, Preston RA, Aston CE, et al. A gene for hereditary pancreatitis maps to

chromosome 7q35. Gastroenterology 1996;110:1975–80.

[12] Le Bodic L, Bignon JD, Raguenes O, et al. The hereditary pancreatitis gene maps to long

arm of chromosome 7. Hum Mol Genet 1996;5:549–54.

[13] Pandya A, Blanton SH, Landa B. Linkage studies in a large kindred with hereditary

pancreatitis confirms mapping of the gene to a 16-cM region on 7q. Genomics 1996;38:

227–30.

[14] Gorry MC, Gabbaizedeh D, Furey W, et al. Mutations in the cationic trypsinogen gene

are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997;113:

1063–8.

[15] Witt H, Becker M. Genetics and chronic pancreatitis. J Pediatr Gastroenterol Nutr

2002;34:125–36.

[16] Witt H, Luck W, Becker M. A signal peptide cleavage site mutation in the cationic

trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology

1999;117:7–10.

[17] Pfutzer RH, Whitcomb DC. Trypsinogen mutations in chronic pancreatitis [letter].

Gastroenterology 1999;117:1507–8.

[18] Chen JM, Raguenes O, Ferec C, et al. The A16V signal peptide cleavage site mutation

in the cationic trypsinogen gene and chronic pancreatitis [letter]. Gastroenterology

1999;117:1508–9.

[19] Chen JM, Montier T, Ferec C. Molecular pathology and evolutionary and physiological

implications of pancreatitis-associated cationic trypsinogen mutations. Hum Genet

2001;109:245–52.

[20] Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease

inhibitor, Kazal type I are associated with chronic pancreatitis. Nat Genet 2000;25:

213–6.

[21] Chen JM, Mercier B, Audrezet MP, et al. Mutations of the pancreatic secretory trypsin

inhibitor (PSTI) gene in idiopathic chronic pancreatitis. Gastroenterology 2001;120:

1061–2.

[22] Pfutzer RH, Barmada MM, Brunskill APJ, et al. SPINK1/PSTI polymorphisms act as

disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology

2000;119:615–23.

[23] Noone PG, Zhou Z, Silverman LM, et al. Cystic fibrosis gene mutations and pancreatitis

risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastro-

enterology 2001;121:1310–9.

[24] Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients

with chronic pancreatitis. N Engl J Med 1998;339:645–52.

[25] Cohn JA, Friedman KJ, Peadar GN, et al. Relation between mutations of the cystic

fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339:653–8.

[26] Castellani C, Bonizzato A, Rolfini R, et al. Increased prevalence of mutations of the cystic

fibrosis gene in idiopathic chronic and recurrent pancreatitis. Am J Gastroenterol

1999;94:1993–5.

[27] Truninger K, Malik N, Ammann RW, et al. Mutations of the cystic fibrosis gene in

patients wit chronic pancreatitis. Am J Gastroenterol 2001;96:2657–61.

[28] Jap TS, Wu YC, Jeng SF, et al. A novel mutation in the calcium-sensing receptor gene in

a Chinese subject with persistent hypercalcemia and hypocalciuria. J of Clin Endo Metab

2001;86:13–5.


[29] Yamauchi M, Sugimoto T, Yamaguchi T, et al. Association of polymorphic alleles of the

calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism.

Clin Endocrinol (Oxf) 2001;55:373–9.

[30] Pearce SH, Wooding C, Davies M. Calcium-sensing receptor mutations in familial

hypocalciuric hypercalcemia with recurrent pancreatitis. Clin Endocrinol 1996;45:675–80.

[31] Brunzell JD, Deeb SS. Familial lipoprotein lipase deficiency, Apo C–II deficiency, and

hepatic lipase deficiency. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Vogelstein B,

Childs B, editors. The Metabolic and Molecular Bases of Inherited Disease. NY:

McGraw–Hill; 2000. [chapter 117].

[32] Bruin T, Tuzgol S, van Diermen DE. Recurrent pancreatitis and lipoprotein lipase. J

Lipid Res 1993;34:2109–19.

[33] Comfort MW, Steinberg AG. Pedigree of a family with hereditary chronic relapsing

pancreatitis. Gastroenterology 1952;21:54–63.

[34] McElroy R, Christiansen PA. Hereditary pancreatitis in a kinship associated with portal

vein thrombosis. Am J Med 1972;52:228–41.

[35] Cornet E, Dupon H, Giraudet J. Pleuresis hemorragiques d’origine pancreatique: 3

observations parmi 17 cas de pancreatite familiale). Ann Chir Thorac Cardiovasc

1963;2:100–7.

[36] Robechek PJ. Hereditary chronic relapsing pancreatitis: a clue to pancreatitis in general?

Am J Surg 1967;113:819–24.

[37] Gross JB. Hereditary pancreatitis. In: Go VLW, editor. The Exocrine Pancreas: Biology,

Pathobiology, and Diseases. New York: Raven Press; 1986. p. 829–39.

[38] Lowenfels A, Maisonneuve P, DiMagno E, et al. Hereditary pancreatitis and the risk of

pancreatic cancer. J Nat Cancer Inst 1997;89:442–6.

[39] Lowenfels AB, Maisonneuve P, Whitcomb DC. The International Hereditary Pancreatitis

Study Group. Smoking and the risk of pancreatic cancer in patients with hereditary

pancreatitis (HP). Pancreas 1999;19:430.

[40] Konzen KM, Perrault J, Moir C, et al. Long-term follow-up of young patients with

chronic hereditary or idiopathic pancreatitis. Mayo Clin Proc 1993;68:450.

[41] Perrault J. Hereditary pancreatitis—Historical perspectives. Med Clin NA 2000;84:

519–29.

[42] Sahin–Toth M, Toth M. Gain-of-function mutations associated with hereditary

pancreatitis enhance autoactivation of human cationic trypsinogen. Biochem Biophys

Res Commun 2000;278:286–9.

[43] Witt H, Luck W, Becker M. Reply to ‘‘The A16V signal peptide cleavage site mutation in

the cationic trypsinogen gene and chronic pancreatitis’’. Gastroenterology 1999;117:1509.

[44] Sarles H. Chronic pancreatitis: generally a pancreatic lithiasis. Eur J Gastroenterol

Hepatol 1991;3:957–63.

[45] Gharib B, Fox MF, Bartoli C, et al. Human regeneration protein/lithostathine genes map

to chromosome 2P12. Ann Hum Genet 1993;57:9–16.

[46] Sarles H, Camarena J, Gomez–Santana C. Radiolucent and calcified pancreatic lithiasis:

two different diseases. Role of alcohol and heredity. Scand J Gastroenterol 1992;27:71–6.

[47] Sarles H, Camarena J, Bernard JP, et al. Two forms of hereditary chronic pancreatitis.

Pancreas 1996;12:138–41.

[48] Suzuki T, Matozaki T, Matsuda K. Analysis of pancreatic stone protein gene of

hereditary pancreatitis. Japanese J of Gastroenterol 1992;89:63–8.

[49] Chen JM, Mercier B, Audrezet MP, et al. Mutational analysis of the human pancreatic

secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis.

J Med Genet 2000;37:67–9.

[50] Witt H, Hennies HC, Becker M. SPINK1 mutations in chronic pancreatitis.

Gastroenterology 2001;120:1060–1.

[51] Durie P. Pancreatic aspects of cystic Fibrosis and other inherited causes of pancreatic

dysfunction. Medical Clinics of North America May 2000;84:609–20.


[52] Mickle JE, Cutting GR. Genotype-phenotype relationships in cystic fibrosis. Medical

Clinics of North America May 2000;84(3):597–607.

[53] Freedman SD, Blanco P, Shea JC, et al. Mechanisms to explain pancreatic dysfunction in

cystic fibrosis. Medical Clinics of North America May 2000;84:657–64.

[54] Claustres M, Guittard C, Bozon D, et al. Spectrum of CFTR mutations in cystic fibrosis

and in congenital absence of the vas deferens in France. Hum Mutat 2000;16:143–56.

[55] Chillon M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in patients with

congenital absence of the vas deferens. N Engl J Med 1995;332:1475–80.

[56] Marino CR, Matovcik LM, Gorelick FS, et al. Localization of the cystic fibrosis

transmembrane conductance regulator in pancreas. J Clin Invest 1991;88:712–6.

[57] Bess MA, Edis AJ, van Heerden JA. Hyperparathyroidism and Pancreatitis: Chance or

causal association? JAMA 1980;243:246–7.

[58] Carnaille B, Oudar C, Pattou F, et al. Pancreatitis and primary hyperparathyroidism:

forty cases. Aust N Z J Surg 1998;68:117–9.

[59] Mithofer K, Fernandez–del Castillo C, Frick TW, et al. Acute hypercalcemia causes acute

pancreatitis and ectopic trypsinogen activation in the rat. Gastroenterology 1995;109:

239–46.

[60] Frick TW, Wiegand D, Bimmler D, et al. A rat model to study hypercalcemia-induced

acute pancreatitis. Int J Pancreatol 1994;15:91–6.

[61] Frick T, Spycher M, Kaiser A, et al. Electron microscopy of the exocrine pancreas in

experimental acute hypercalcemia. Helv Chir Acta 1991;57:713–6 [in German; English

abstract].

[62] Banks PA. Acute pancreatitis. In: Haubrich WS, Schaffner F, Berk JE, editors. Bockus’

Gastroenterology. 3rd edition. Philadelphia: WB Saunders Company; 1995. p. 2888–917.

[63] Thompson DB, Samowitz WS, Odelberg S, et al. Genetic abnormalities in sporadic

parathyroid adenomas: loss of heterozygosity for chromosome 3q markers flanking the

calcium receptor locus. J Clin Endocrinol Metab 1995;80:3377–80.

[64] Feoli–Fonseca JC, Levy E, Godard M, et al. Familial lipoprotein lipase deficiency in

infancy: clinical, biochemical, and molecular study. J Pediatr 1998;133:417–23.

[65] Previato L, Guardamagna O, Dugi KA, et al. A novel missense mutation in the C-

terminal domain of lipoprotein lipase (Glu410!Val) leads to enzyme inactivation and

familial chylomicronemia. J Lipid Res 1994;35:1552–60.

[66] Siafakas CG, Brown MR, Miller TL. Neonatal pancreatitis associated with familial

lipoprotein lipase deficiency. JPGN 1999;29:95–8.

[67] Foubert L, Benlian P, Turpin G. Lipoprotein lipase: a multifunctional enzyme in

lipoprotein metabolism. Presse Med 1996;25:207–10.

[68] Wilson DE, Hata A, Kwong LK, et al. Mutations in exon 3 of the lipoprotein lipase gene

segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent

diabetes. J Clin Invest 1993;92:203–11.

[69] Fojo SS, Brewer HB. Hypertriglyceridaemia due to genetic defects in lipoprotein lipase

and apolipoprotein C–II. J Intern Med 1992;231:669–77.

[70] Cox DW, Breckenridge WC, Little JA. Inheritance of apolipoprotein C–II deficiency with

hypertriglyceridemia and pancreatitis. NEJM 1978;299:1421–4.

[71] Ma Y, Ooi TC, Liu MS, et al. High frequency of mutations in the human lipoprotein

lipase gene in pregnancy-induced chylomicronemia: possible association with apolipo-

protein E2 isoform. J Lipid Res 1994;35:1066–75.

[72] Kao JT, Hsiao WH, Yu CJ. Newly identified missense mutation reduces lipoprotein lipase

activity in Taiwanese patients with hypertriglyceridemia. J Formos Med Assoc 1999;

98:606–12.

[73] Hoffmann MM, Jacob S, Luft D. Type I hyperlipoproteinemia due to a novel loss of

function mutation of lipoprotein lipase Cys (239) ! Trp, associated with recurrent severe

pancreatitis. J of Clin Endocrinol Metab 2000;85:4795–8.


[74] Zhu Y, Bujo H, Takahashi K, et al. Severe hypertriglyceridemia with plasma inhibitory

factor (s) on lipoprotein lipase activity in a patient with a common Ser 447-Ter LPL

mutation. Clin Chim Acta 2001;308:139–46.

[75] Causeret AS, Souillet AL, Marcais C, et al. Familial hyperchylomicronemia with a new

mutation of the lipoprotein lipase gene. Ann Dermatol Venereol 2001;128:343–5 [in

French].

[76] Peterson J, Ayyobi AF, Ma Y. Structural and functional consequences of missense

mutations in exon 5 of the lipoprotein lipase gene. J of Lipid Research 2002;43:398–406.

[77] Lykkesfeldt G, Bock JE, Pedersen FD. Excessive hypertriglyceridemia and pancreatitis in

pregnancy. Association with deficiency of lipoprotein lipase. Acta Obstet Gynecol Scand

1981;60:79–82.

[78] Keilson LM, Vary CP, Sprecher DL, et al. Hyperlipidemia and pancreatitis during

pregnancy in two sisters with a mutation in the lipoprotein lipase gene. Ann Intern Med

1996;124:425–8.

[79] Henderson H, Leisegang F, Hassan F, et al. A novel Glu421Lys substitution in the

lipoprotein lipase gene in pregnancy-induced hypertriglyceridemic pancreatitis. Clin Chim

Acta 1998;269:1–12.

[80] Suga S, Tamasawa N, Kinpara I, et al. Identification of homozygous lipoprotein lipase

gene mutation in a woman with recurrent aggravation of hypertriglyceridemia induced by

pregnancy. J Intern Med 1998;243:317–21.

[81] Gosnell JE, O’Neill BB, Harris HW. Necrotizing pancreatitis during pregnancy: a rare

cause and review of the literature. J Gastrointest Surg 2001;5:371–6.

[82] Heaney AP, Sharer N, Rameh B, et al. Prevention of recurrent pancreatitis in familial

lipoprotein lipase deficiency with high-dose antioxidant therapy. J Clin Endocrinol Metab

1999;84:1203–5.

[83] Miller JP. Serum triglycerides, the liver and pancreas. Curr Opin Lipidol 2000;11:

377–82.

[84] Piolot A, Nadler F, Cavallero E, et al. Prevention of recurrent acute pancreatitis in patients

with severe hypertriglyceridemia: value of regular plasmapheresis. Pancreas 1996;13:96–9.

[85] Knisely AS. Progressive familial intrahepatic cholestasis: a personal perspective. Ped Dev

Pathol 2000;3:113–25.

[86] Jacquemin E, Dumont M, Bernard O, et al. Evidence for defective primary bile acid

secretion in children with progressive familial intrahepatic cholestasis (Byler disease). Eur

J Pediatr 1994;153:424–8.

[87] Anadiotis G, Ierardi–Curto L, Kaplan PB, et al. Ornithine transcarbamylase deficiency

and pancreatitis. J Pediatr 2001;138:123–4.

[88] Tatsumato T, Yamamoto K, Kudo J, et al. An autopsy case of citrullinemia type II

complicated with chronic pancreatitis. Fukuoka Igaku Zasshi 1992;83:43–50.

[89] Kahler SG, Sherwood WG, Woolf D, et al. Pancreatitis in patients with organic

acidemias. J Pediatr 1994;124:239–43.

[90] Makins RJ, Gertner DJ, Lee PJ. Acute pancreatitis in homocystinuria. J Inherit Metab

Dis 2000;23:190–1.

[91] Hong HS, Lee HK, Kwon KH. Homocystinuria presenting with portal vein thrombosis

and pancreatic pseudocyst. Paediatr Radiol 1997;27:802–4.

[92] Collins JE, Brenton DP. Pancreatitis and homocystinuria. J Inherit Metab Dis

1990;13:232–3.

[93] Lowenheim M, Batra S. Homocystinuria: an unusual cause of chronic relapsing

pancreatitis [abstract]. J Pediatr Gastroenterol Nutr 1997;25:457.

[94] Shwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of pancreatic

insufficiency and bone marrow dysfunction. J Pediatr 1964;65:645–63.

[95] Bodian M, Sheldon W, Lightwood R. Congenital hypoplasia of the exocrine pancreas.

Acta Paediat 1964;53:282–93.


[96] Mack DR, Forstner GG,Wilschanski M, et al. Shwachman syndrome: exocrine pancreatic

dysfunction and variable phenotypic expression. Gastroenterology 1996;111:1593–602.

[97] Ginzberg H, Shin J, Ellis L, et al. Shwachman syndrome: phenotypic manifestations of

siblings sets and isolated cases in a large patient cohort are similar. J Pediatr 1999;135:81–8.

[98] Rothbaum R, Perrault J, Vlachos A, et al. Shwachman–Diamond Syndrome: Report from

an international conference. J Peds 2002;141:266–70.

[99] Moore DJ, Forstner GG, Largman C, et al. Serum immunoreactive cationic trypsinogen:

a useful indicator of severe exocrine pancreatic dysfunction in the paediatric patient

without cystic fibrosis. Gut 1986;27:1362–8.

[100] Ip WF, Dupuis A, Ellis L, et al. Serum pancreatic enzymes define the pancreatic

phenotype in patients with Shwachman–Diamond syndrome. J Peds 2002;141:259–65.

[101] Dror Y, Freedman MH. Shwachman–Diamond syndrome marrow cells show abnormally

increased apoptosis through the Fas pathway. Blood 2001;97:3011–6.

[102] Elghetany MT, Alter B. p53 protein overexpression in bone marrow biopsies of patients

with Swachman–Diamond syndrome has a prevalence similar to that of patients with

refractory anemia. Arch Pathol Lab Med 2002;126:452–5.

[103] Ginzberg H, Shin J, Ellis L, et al. Segregation Analysis in Shwachman–Diamond

Syndrome: Evidence of recessive inheritance. Am J Hum Genet 2000;66:1413–6.

[104] Masuno M, Imaizumi K, Nishimura G, et al. Shwachman syndrome associated with de

novo reciprocal translocation t(6:12)(q16.2;q21.2). J Med Genet 1995;32:894–5.

[105] Goobie S, Morrison J, Ginzberg H, et al. Exclusion of linkage of Shwachman–Diamond

syndrome to chromosome regions 6q and 12q implicated by a de novo translocation. Am J

Med Genet 1999;85:171–4.

[106] Goobie S, Popovic M, Morrison J, et al. Shwachman–Diamond syndrome with exocrine

pancreatic dysfunction and bone marrow failure maps to the centromeric region of

chromosome 7. Am J Hum Genet 2001;68:1048–54.

[107] Pearson HA, Lobel JS, Kocoshis SA, et al. A new syndrome of refractory sideroblastic

anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction.

J Peds 1979;95:976–84.

[108] Schoffner JM. Mitochondrial myopathy diagnosis. Neurol Clin 2000;18:105–23.

[109] Johanson A, Blizzard R. A syndrome of congenital aplasia of the alae nasi, deafness,

hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. J Pediatr 1971;

79:982–7.

[110] Vanlieferinghen PH, Borderon C, Francannet CH, et al. Johanson–Blizzard syndrome:

a new case with autopsy findings. Genet Couns 2001;12:245–50.

[111] Rotig A, Cormier V, Blanche S, et al. Pearson’s marrow-pancreas syndrome:

a multisystem mitochondrial disorder in infancy. J Clin Invest 1990;86:1601–8.

[112] Cormier V, Rotig A, Bonnefont JP, et al. Syndrome de Pearson. Pancytopenie avec

insuffisance pancreatique externe: une nouvelle maladie mitochondriale dans la premiere

enfance [Pearson’s syndrome. Pancytopenia with exocrine pancreatic insufficiency: new

mitochondrial disease in the first childhood]. Arch Fr Pediatr 1991;48:171–8 [in French].

[113] Superti–Furga A, Schoenle E, Tuchschmid P, et al. Pearson bone marrow-pancreas

syndrome with insulin-dependent diabetes, progressive renal tubulopathy, organic

aciduria and elevated fetal haemoglobin caused by deletion and duplication of

mitochondrial DNA. Eur J Pediatr 1993;152:44–50.

[114] Gurakan B, Ozbek N, Varan B, et al. Fatal acidosis in a neonate with Pearson syndrome.

Turk J Pediatr 1999;41:361–4.

[115] Jones NL, Hofley PM, Durie PR. Pathophysiology of the pancreatic defect in Johanson–

Blizzard syndrome: a disorder of acinar development. J Pediatr 1994;125:406–8.

[116] Daentl DL, Frias JL, Gilbert EF, et al. The Johanson–Blizzard syndrome: case report and

autopsy findings. Am J Med Genet 1979;3:129–35.

[117] Rotig A, Colonna M, Bonnefont JP, et al. Mitochondrial DNA deletion in Pearson’s

marrow-pancreas syndrome [letter]. Lancet 1989;1(8643):902–3.


[118] Sano T, Ban K, Ichiki T, et al. Molecular and genetic analyses of two patients with

Pearson’s marrow-pancreas syndrome. Pediatr Res 1993;34:105–10.

[119] Gurgey A, Rotig A, Gumruk F, et al. Pearson’s marrow-pancreas syndrome in 2 Turkish

children. Acta Haematol 1992;87:206–9.

[120] McShane MA, Hammans SR, Sweeney M, et al. Pearson syndrome and mitochondrial

encephalomyopathy in a patient with deletion of mtDNA. Am J Hum Genet 1991;48:

39–42.

[121] Park YD, Yanagihara I, Saitoh S, et al. Hematologic improvement of Pearson’s syndrome

confirmed by mitochondrial DNA analysis. Rinsho Ketsueki 1999;40:390–5 [in Japanese;

English abstract].

[122] Morikawa Y, Matsuura N, Kakudo K, et al. Pearson’s marrow/pancreas syndrome:

a histological and genetic study. Virchows Arch A Pathol Anat Histopathol 1993;423:

227–31.

[123] Becher MW, Wills ML, Noll WW, et al. Kearns–Sayre syndrome with features of

Pearson’s marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA

deletion. Hum Pathol 1999;30:577–81.

[124] Fischel–Ghodsian N, Bohlman MC, Prezant TR, et al. Deletion in blood mitochondrial

DNA in Kearns–Sayre syndrome. Pediatr Res 1992;31:557–60.

[125] Mardini MK, Ghandour M, Sakati NA, et al. Johanson–Blizzard syndrome in a large

inbred kindred with three involved members. Clin Genet 1978;14:247–50.

[126] Grand RJ, Rosen SW, di Sant’ Angese PA, Kirkham WR. Unusual case of XXY

Klinefelter’s syndrome with pancreatic insufficiency, hypothyroidism, deafness, chronic

lung disease, dwarfism and microcephaly. Am J Med 1966;41:478.

[127] Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human

mitochondrial genome. Nature 1981;290:457–65.

[128] Gillis L, Kaye E. Diagnosis and management of mitochondrial diseases. Pediatr Clin

North Am 2002;49:203–19.

[129] Lestienne P. Mitochondrial DNA alterations and genetic diseases: a review. Biomed

Pharmacother 1994;48:199–214.

[130] Cormier V, Rotig A, Quartino AR, et al. Widespread multitissue deletions of the

mitochondrial genome in the Pearson marrow-pancreas syndrome. J Peds 1990;117:

599–602.

[131] van de Corput MP, van den Ouweland JM, Dirks RW, et al. Detection of mitochondrial

DNA deletions in human skin fibroblasts of patients with Pearson’s syndrome by two-

color fluorescence in situ hybridization. J Histochem Cytochem 1997;45:55–61.

[132] Guzman C, et al. Two siblings with exocrine pancreatic hypoplasia and orofacial

malformations (Donian syndrome and Johanson–Blizzard syndrome). J Pediatr Gastro-

enterol Nutr 1997;25:350–3.

[133] Moeschler JB, Lubinsky MS. Johanson–Blizzard syndrome with normal intelligence. Am

J Med Genet 1985;22:69–73.

[134] Helin I, Jodal U. A syndrome of congenital hypoplasia of the alae nasi, situs inversus, and

severe hypoproteinemia in two siblings. J Pediatr 1981;99:932–4.

[135] Boocock GRB, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with

Shwachman-Diamond syndrome. Nat Genet 2003;33:97–101.

genetic disorders of the pancreas

Documents