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Molecular Genetics 379

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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Table45.2 Genotypephenotype correlations andmultiorgan syndromes.

Genotype (variants) Phenotype (syndromes) Comment

PRSS1 Hereditary pancreatitis Genetic counseling recommended

sev

CFTR

sev

CFTR

SPINK1/SPINK1 Familial pancreatitis Usually progresses to severe CP

bicarb

CFTR

any

CFTR

CTRC/SPINK1 RAP/CP Pancreas only– not well studied

CASR/SPINK1 RAP/CP Pancreas only– not well studied

CFTR: sev, severe mutations (typically functional class I–III); m- v, mild- variable mutations, (typically CFTR functional class IV); bicarb,

bicarbonate conductance- disrupting variant (e.g., p.R75Q); any, either severe, mild- variable, or bicarbonate- disrupting variants; CP: chronic pancreatitis; RAP: recurrent acute pancreatitis; CBAVD: congenital bilateral absence of the vas deferens.

sev

/CFTR

m- v

/CFTR

any

/CFTR

/SPINK1 RAP/CP Pancreas only

Cystic fibrosis (CF) Manage with a CF center

Atypical CF Manage with a CF center

Pancreas/sinus/CBAVD Newly defined syndrome

The most common PRSS1 mutations are p.R122H and p.N29I (~90%). Less common mutations include p.A16V, p.R122C, p.N29T, p.D22G, and p.K23R. Mutations have primarily been identified in exons 2 and 3, but rare variants have also been identified in the 5′UTR, introns 1–4, and exons 4 and 5 (see http://www.pancreasgenetics. org). Copy number variations of the PRSS1- PRSS2 locus have also been associated with chronic pancreatitis[33].

SPINK1

The serine protease inhibitor, Kazal type 1 (SPINK1; PST1) is a trypsin inhibitor secreted from pancreatic acinar cells. Loss- of- function mutations in SPINK1 reduce its protective function and predispose to pancreatitis [34]. Mutations are found in ~2% of the population and confer a 12- fold increased risk for pancreatitis[34]. Still, less than 1% of SPINK1 carriers develop pancreatitis. Biallelic loss of function mutations in SPINK1 may lead to autosomal recessive pancreatitis. However, the majority of affected patients with SPINK1 mutations are heterozygous, indicating the presence of complex gene–gene and gene– environment interactions[35]. For example, SPINK1 can act as a disease modifier, and compound heterozygosity for pathogenic variants in SPINK1/PRSS1 and, more commonly, SPINK1/CFTR has been reported[25,36].

SPINK1 mutations are detected in ~20% of patients with idiopathic chronic pancreatitis. The most common high- risk haplotype identified in the United States and Europe is SPINK1 p.N34S. The SPINK1 IVS3 +2T>C splicing variant is common in East Asian populations.

CFTR

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) are common among patients with idiopathic chronic pancreatitis. CFTR mutations

may impair both chloride and bicarbonate conductance (e.g., severe mutations), or only bicarbonate conductance[36,37]. Homozygosity or compound heterozygosity for two “severe” CFTR mutations generally causes cystic fibrosis (CF), while “mild- variable” or other mutations are associated with RAP, CP, pancreas sufficient CF and CFTR- related disorders[38]. CFTR carriers that develop pancreatitis are also likely to have an additional genetic (e.g., SPINK1, CTRC) or other (e.g., pancreas divisum) risk factors[25,36]. CFTR- associated pancreatitis is considered in Chapter4.10. The use of CFTR modulators in pancreatic sufficient CF suggest that specific new therapies may be available in the future[39].

CTRC

Chymotrypsinogen C (CTRC) is a digestive enzyme and the primary regulator of trypsin. The action of chymotrypsinogen C is twofold and dependent on calcium concentrations. In the calcium- rich duo denum, chymotryp sin C promotes trypsinogen activation, but in solutions with lower calcium concentrations, it mediates trypsin degradation[40]. As with SPINK1, chymotrypsin C is believed to protect the pancreas from premature trypsin activation, with genetic defects increasing the risk of trypsinmediated pancreatitis[41,42]. Two mutations, p.R254W and p.K247_R254del, were found to be overrepresented in patients with idiopathic or hereditary chronic pancreatitis [41]. The c.180T>G variant has been identified in about 10.8% of persons of European ancestry in North America and moderately increases the risk of progression from recurrent acute to chronic pancreatitis, particularly in the presence of alcohol, tobacco, or PRSS1/SPINK1 mutations [43]. The independent effects of pathogenic CTRC variants appears to be low, but they clearly increase the risk of CP in the context of other risk factors such as

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pathogenic CFTR variants [25], and can contribute to familial clustering of CP cases.

Complex Genetics

Single- gene or Mendelian diseases are caused by highly penetrant pathogenic mutations in a single gene that follow a clear pattern of inheritance (e.g., autosomal dominant, autosomal recessive). Mendelian forms of pancreatitis, such as PRSS1- HP, are rare. Instead, most patients have a complex etiology resulting from multiple low- to- moderate effect risk alleles in combination with environmental and physiologic risk factors. Complex risk variants are defined as variants with variable effect sizes, ranging in frequency from rare to common, that do not cause disease in isolation. Instead, the combination of multiple interacting risk variants and other factors work in concert to initiate the disease process. In patients with pancreatitis, several common risk variants have been identified, including the CTRC c.180T>G (p.G60=) and SPINK1 p.N43S variants (described above), a PRSS1- PRSS2 haplotype[44], risk alleles in CLDN2[44], and the CEL- HYB risk allele[45]. Heterozygous carriers of CFTR variants associated with cystic fibrosis or a CFTR- related disorder have also been associated with an increased risk for pancreatitis as a part of a complex etiology [46]. Known risk factors for pancreatitis are outlined in the Toxic- metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive Pancreatitis Risk/Etiology Checklist (TIGAR- O_ V2) [27], which functions as an organizational tool to document and track patient risk and etiological factors. Although the identification of complex risk variants may lend insights into a patient’s disease process, the quantification of risk to develop pancreatitis in asymptomatic patients or to progress to severe disease in symptomatic patients based on multiple complex variants and nongenetic factors remains challenging and imprecise.

Genetic Testing andCounseling

When a patient or family is suspicious for hereditary pancreatitis, a (minimum) three- generation pedigree should be collected, including family history of pancreatitis, age of onset, age at diagnosis for multiple pancreatic episodes, and pancreatic cancer [47]. Other information valuable for assessment of a family includes smoking and alcohol exposure, diabetes mellitus, pancreatic insufficiency, male infertility, cystic fibrosis, chronic sinusitis, and nasal polyps [47]. Calculation of risk in a family depends on genotype, pattern of inheritance in the family, and environmental exposures (e.g.,tobacco, alcohol).

Indications to offer genetic testing in a symptomatic patient include unexplained recurrent acute pancreatitis and/or chronic pancreatitis, a first- or second- degree relative with pancreatitis, and/or unexplained pancreatitis in a child requiring hospitalization. Genetic testing is commercially available for several genes, including

CASR, CEL, CFTR, CLDN2, CPA1, CTRC, GGT1, PRSS1, PRSS2, SBDS, SPINK1, and UBR1. Deletion/duplication

analysis should be considered in a proband if a mutation is not identified from sequencing or targeted mutation analysis.

Genetic testing should always be preceded and followed by appropriate genetic counseling. Results may have implications for patient risk, risk to other family members, and family planning[48]. Another concern for genetic testing in this patient population, especially in the United States, is insurance discrimination[48]. The Genetic Information Nondiscrimination Act of 2008 (GINA, Pub. L, 110–233) protects against genetic discrimination in health insurance and employment in the United States, but does not cover life, disability, or longterm care insurance. Patients and families should understand the benefits, limitations, and costs of genetic testing before the test is ordered. Therefore, clinicians must understand the consequences of genetic testing and should provide counseling directly or refer patients to a genetic counselor to obtain appropriate informed consent.

Genetic testing in a symptomatic patient can clarify etiology and provide information on risk for related complications, such as pancreatic cancer. Identification of a responsible mutation may clarify risk for family members and provide information relevant to family planning. PRSS1- related hereditary pancreatitis follows an autosomal inheritance pattern, and each child of a parent with a PRSS1 mutation, has a 50% or 1in 2 chance to inherit the deleterious allele. About 80% of individuals who inherit a PRSS1 mutation develop pancreatitis. Therefore, each child of a parent with a PRSS1 mutation has a ~40% chance of developing hereditary pancreatitis. However, variation in penetrance and severity exists between HP kindreds, and family history should always guide interpretation of results and risk calculation. Identifying a responsible genetic mutation in a family may also expedite diagnosis of family members and prevent unnecessary evaluation for other etiologies.

Predictive genetic testing in an asymptomatic individual is available when a mutation has been identified in a close family member. Testing for this mutation can clarify risk to develop pancreatitis and risk to descendants. Genetic testing may also identify family members who would benefit from lifestyle interventions to reduce risk and severity, such as avoidance of alcohol, smoking, and fatty foods.

References 381

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A negative test result in a patient from a family with a known mutation reduces but does not remove the risk for hereditary pancreatitis. Families may share additional, unidentified risk factors that predispose to pancreatic disease. Furthermore, not all hereditary pancreatitis- appearing families have an identifiable mutation. In a family without an identifiable mutation, genetic testing of asymptomatic family members will be uninformative, and discussions of risk must be tailored according to the presentation of disease within the family.

Genetic Testing inChildren

The decision to pursue genetic testing in a child is the responsibility of the parents or legal guardian. When a

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Epidemiology andPathophysiology ofTropical Chronic Pancreatitis

Shailesh V. Shrikhande1 and Savio G. Barreto

Gastrointestinal and Hepato- Pancreato- Biliar y Surgical Oncology, Tata Memorial Centre, Mumbai, Maharashtra, India

Division of Surgery and Perioperative Medicine, Flinders Medical Centre, Adelaide, South Australia, Australia

College of Medicine and Public Health, Flinders University, South Australia, Australia

2,3

383

Introduction

In 1937, Kini[1] published a report on chronic calcific pancreatitis from India. Similar findings in autopsy studies were reported from southern India in 1954[2]. While the features presented in those report were strikingly similar to the report on 45malnourished patients from Indonesia published a couple of decades later, the credit for describing tropical (chronic) pancreatitis (TCP) as a distinct entity rests with Zuidema[3,4]. These patients were from economically weaker sections and were suffering from protein calorie malnutrition.

GeeVarghese [5,6] provided a detailed description of features that constituted TCP based on his analysis of patients in Kerala, southern India. This body of work now forms the framework on the basis of which our understanding of TCP resides.

TCP is considered a distinct subtype of CP comprising calcifying, nonalcoholic CP afflicting younger, generally malnourished individuals from the tropical regions of Asia[7–11], Africa[12–15], and even South America [16,17]. A male predominance was also noted[18–20]. However, there has been the occasional report of the disease from developed nations more often due to diagnosis of the disease in migrants arriving from the developing world [21]. In the past, the entity has been referred to by numerous terminologies including tropical calcific pancreatitis, tropical pancreatic diabetes, nutritional pancreatitis, juvenile pancreatitis syndrome, Afrocalculous pancreatopathy, and fibrocalculous pancreatopathy, or fibrocalculous pancreatic diabetes (FCPD). However, the terminology most commonly employed today is TCP [22,23]. GeeVarghese summarized the

Asian pancreatitis, tropical

natural history of TCP in the adage, “recurrent abdominal pain in childhood, diabetes around puberty and death at the prime of life”[5]. Barman and colleagues presented the triad of symptoms that comprised TCP, namely, abdominal pain, maldigestion and steatorrhea, and diabetes mellitus[24].

To date, there remains a paucity of large- scale epidemiological data on the prevalence of TCP. A field study from Kerala in southern India, involving 28,567 inhabitants, determined the prevalence of TCP to be 1 : 793 in that region[8] based on well laid out criteria for diagnosis of the disease. The study revealed that contrary to previous hospital reports, TCP in Kerala appeared to have a female preponderance (male: female ratio of 1 : 1.8), older age at disease onset (mean 23.9 yr), and evidence of milder disease. Prior attempts at understanding the nature of thedisease had included hospital studies and a couple of monographs published by GeeVarghese[5,22] based on his experience of more than 1500 patients with the disease. The criticism by Balaji etal.[8] of these prior studies was the possibility that their findings were potentially influenced by need for healthcare (patients presenting only when symptomatic) as well as access to healthcare being preferentially available to males.

A large nationwide study from India that included 1086 CP patients has determined that idiopathic CP is now the most common subtype of the disease in the country (accounting for 60% of cases)[25]. This finding is not too dissimilar from the 70% of patients from India and China labeled to have idiopathic CP based on a survey in the Asia- Pacific region[9]. Interestingly, in the study by Balakrishnan etal.[25], when well- defined criteria for TCP were applied, TCP was found in only 3.8% of patients. The authors conjectured that these findings

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

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may reflect a prior overrepresentation of the disease owing to the interchangeable use of the terms idiopathic CP and TCP with the possibility that the true incidence of TCP lies somewhere in between this wide variation. The declining incidence of TCP has been noted in other studies from India, too[26,27]. Whether this is a reflection of improving socioeconomic conditions accompanied by improved nutrition [25,28], an increase in smoking and alcohol consumption amongst youngsters [26], or simply a better elucidation of the entity “idiopathic CP,” leading to more individuals fitting these criteria rather than TCP[29], may remain a question left unanswered.

Pathophysiology

The initial documentation of cases of TCP in malnourished patients from the tropics and from financially weaker sections of society[1,4] instinctively led researchers to focus on dietary components as a cause for the disease[30]. Over the years, detection of TCP in apparently healthy individuals with a normal nutritional status (as per their body mass index) [31,32] has led to micronutrient deficiency being more intensively investigated. Eloquent studies teasing out pathological changes [33] and genetic mutations and comparing these with other subtypes of CP have heralded a possibly more objective approach to the understanding of the entity[34,35].

Pathology

Gross appearance of the gland depends on the duration of disease, degree of fibrosis, the presence of cysts, and location and size of calculi[36]. With the passage of time, the gland undergoes uneven fibrosis and atrophy often leading to an eccentric ductal location [23] with the gland often left appearing finger- like with a nodular and irregular surface[37].

One of the hallmarks of TCP is the presence of large calculi composed of 95.5% calcium carbonate (mainly in the form of calcite[38]), a small amount of calcium phosphate and traces of magnesium, urate, and oxalate distributed throughout the ductal system varying in color, shape, and size [23]. The calculi possess an amorphous nidus and a cryptocrystalline periphery[39]. The biochemical and structural nature of calculi in TCP is not too dissimilar to those in other subtypes of CP [23]. The larger stones tend to form toward the head with their size decreasing toward the tail region.

On microscopic examination, the hallmark of TCP is the degree of intralobular fibrosis[33] that is uniform

throughout the pancreatic parenchyma[40]. Nair[36] suggested that TCP was characterized by a lack of inflammation suggesting the terminology of “tropical calcific pancreatopathy” to be more appropriate. However, these findings have not been corroborated by others. Shrikhande and colleagues [33] compared the histologic appearance of TCP versus alcoholic CP (ACP) and idiopathic CP and uncovered similar histological features and a comparable inflammatory cell reaction in all three subtypes of CP although the extent of the pathological change was variable in the individual types. The degree of endophlebitis and plasma cell density was significantly higher in TCP[33]. This finding of plasma cell infiltration of the pancreas is in keeping with the report of Nagalotimath who also found a lymphocyte infiltration mainly around the ducts [37]. Cyriac and colleagues [41] have recently demonstrated that stellate cell activation occurs in a similar manner to other subtypes of CP. Total fatty replacement of parenchyma has been noted to be a striking feature in TCP, seen exclusively in diabetics with gross atrophy of islets of Langerhans [40]. Moreover, in patients with established diabetes secondary to TCP (FCPD) histopathological examination as well as immunohistochemistry have revealed varying extents of acinar atrophy and parenchymal destruction[23] along with paucity of alpha and beta cells and reduction in glucagon positivity and areas of nesidoblastosis[37,42].

An interesting observation in the pathological assessment of tissues of patients with TCP when compared with alcoholic and idiopathic has been the increase in neural tissue and neural alterations associated with progression of the disease toward a stage amenable to surgery[43], a hallmark of pain accompanying CP[44]. It is not only the neural alterations that are identical but other histologic aspects including the degree of endophlebitis, overall density of plasma cells, and inflammatory cell reaction leading to the inference that independent of the underlying etiology, the pathologic changes accompanying CP eventually reach a common immunologic stage beyond which CP appears to progress as a single distinctive entity[33].

Nutrition (Including Cassava)

The initial reports of TCP originating from regions in the developing world coupled with the clinical picture of young emaciated patients, intuitively led clinicians to focus on the nutritional aspect, or more specifically, protein calorie malnutrition[4,12,45]. However, over the years, possibly a more objective approach to investigating the role of malnutrition as a causative agent has led pancreatologists to infer that

malnutrition, in

Pathophysiology 385

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itself, is not the main cause for TCP[46] and the nutritionally deprived state may rather be an effect of the malabsorption associated with disease [47,48]. Patients with kwashiorkor, do not develop features of TCP [23,49]. Moreover, while malnutrition exists in many other countries in the world, there are no reported cases of TCP/FCPD from them [50], while on the flipside TCP cases have been reported even among patients from well- nourished families [23]. Nonetheless, cause or effect, malnutrition remains a major issue in TCP and addressing it in its entirety forms an essential part of the workup and management of patients with TCP[51].

While malnutrition may not be the only etiological factor in the causation of TCP, it is very likely that micronutrient deficiency, along with varying degrees of macronutrient deficiency and oxidant stress are cofactors in the causation of TCP.

Cassava Toxicity

Cassava (tapioca, Manihot esculenta Crantz) was implicated as a cofactor in the causation of TCP based on three hypotheses, namely, the geographic coincidence of cassava being the staple diet of the low socioeconomic class of people in Kerala and the high incidence of TCP reported there [52]; the cyanogenic glycoside composition of cassava (93% linamarin and 7% lotaustralin), which requires sulfur derived from the sulfur- containing amino acids (such as cysteine and methionine) for its detoxification— believed to be inherently deficient in malnourished individuals[53]; and experimental induction of hyperglycemia on feeding cyanide to rats[30] or hypoinsulinemia and histopathological changes of necrosis, hemorrhage, and fibrosis of the exocrine and endocrine portions of the pancreas in dogs fed on cassava[54].

While the activity of the cyanogen detoxifying enzyme, rhodanase, has been shown to be reduced accompanied by a decrease in sulfur- containing amino acids and antioxidants such as glutathione in TCP patients[55], neither this study[55], nor any of the other case- control or cohort clinical studies [49,56,57] were able to conclusively prove the role of cassava consumption in the causation of TCP. Besides, TCP has been reported even from regions where cassava is not consumed [9,25]. Even in the experimental setting, long- term ingestion of tapioca by rats failed to result in the development of diabetes or pancreatitis[58].

Antioxidants (Including Micronutrients)

It has been hypothesized that escalating oxidative stress within the acinar cells as a result of cytochrome p450 superfamily induction, deficiency of micronutrients

required to maintain stores of reduced glutathione, and exposure to bioactivated chemicals[59,60] plays a role in the development of CP.

In TCP patients, the surrogate marker for p450I activity, namely, theophylline clearance was found to be faster in cases as compared to controls [61]. Additionally, the bioavailability of ascorbic acid and beta-

carotene that predispose to pancreatic oxidative stress was found to be significantly reduced in South Indians (from Chennai) with TCP as compared to patients with CP from Manchester [35]. Girish and colleagues[62] observed enhanced lipid peroxidation with concomitant decrease in antioxidant status in patients with TCP as compared to healthy subjects. Moreover, in the same study, they noted that zinc deficiency appeared to affect the oxidative status in patients with TCP. The same group also noted a correlation between zinc deficiency and exocrine and endocrine insufficiency in CP patients [63]. They observed a marked effect of diabetes in zinc levels in patients with TCP as compared to those with ACP[63]. Other postulated mechanisms by which zinc deficiency could contribute to the progression of CP include reduction of free radical scavengers, increased collagen deposition, and possibly an alteration in immune function[64].

Genetics of TCP and Familial Clustering

The finding of an aggregation of patients with TCP in certain families[65], reported as occurring in up to 8% of TCP patients[66], raised the possibility of heredity as another potential contributory factor to the development of TCP. However, while there has been no further evidence to support this initial finding, the role played by genetic mutations in important regulators of pancreatic secretion as well as the innate protective mechanisms against premature zymogen activation have been extensively studied in patients with TCP. Table 46.1 provides a list of the most significantly proven mutations involved in the pathogenesis of TCP[34,67–74]. Mahurkar and colleagues[75] presented an interesting model called the “two- hit model” to hypothesize the pathogenesis of TCP. By this model, they believed that the first hit was the presence of persistent “super trypsin” within the acinar cell— the result of a loss of balance between activation events and degradation of active trypsin as a result of mutations in one or more of the aforementioned genes. This would lead to inflammation in the gland. A second hit in the form of another sequence of genetic mutations with/without environmental factors would then lead to the clinical disease entity of TCP.

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386

Table46.1 Gene mutations involved inthe pathogenesis ofTCP.

Gene mutation References

SPINK1

pN34S variant Loss- of- function variant c.- 142T>C

CTSB

Polymorphism p.L26V Polymorphism p.S53G

CTRC

c.217G>A (p.A73T) variant c.703G>A (p.V235I) variant

Carboxypeptidase A1

p.D32H, p.R169H, and p.Y308H variants

Glycoprotein 2

c.1275A>G variant

Calcium-

SPINK1: serine protease inhibitor Kazal type 1; CTSB: cathepsin B; CTRC: chymotrypsin C.

sensing receptor

p.P163R, p.I427S, p.D433H, p.V477A variants74

 67, 69, 70, 84 68

 71, 85 85

 34 34

 72

 73

Natural History ofthe Disease

two mechanisms: the pathogenetic process of tissue fibrosis eliciting CP, and a selective pancreatic beta-

cell impairment [78]. TCP is associated with an increased risk of pancreatic cancer development [79]. In a study from Chennai (India), the relative risk of pancreatic cancer in patients with TCP was estimated to be significantly high at 100 (95% CI: 37–218)[80].

In comparison to the initial reports of the dismal clinical course of TCP which resulted in death by early adulthood [22], a survival analysis of 370 patients in the mid- 1990s determined that patients with TCP were living much longer than before[81] with 80% of patients still alive 35 years from the onset of the first episode of abdominal pain and a mean of 25 years from the diagnosis of diabetes mellitus. The causes of death in TCP include diabetes- related complications, pancreatic cancer[82], and severe infections[24].

Garg and Narayana[83] have recently questioned the need to consider TCP as a unique entity for multiple reasons, including its similarity to idiopathic CP down to the genetic level, in addition to a significant decline in the clinical picture that helped define this entity by the incorrect use of the term “tropical,” which would normally be used for infectious diseases.

In the original reports of TCP, the disease was noted to afflict young individuals between the ages of 10 and 30 years who also demonstrated features of protein and calorie malnutrition, along with bilateral parotid enlargement and occasionally a cyanotic hue to the lips[5,76]. They suffered from recurrent severe upper abdominal pain radiating to the back that was relieved by bending forward. In the ensuing years, it was noted that while some patients developed features of pancreatic exocrine insufficiency such as maldigestion and steatorrhea, others did not do so because of their low- fat diet. They developed diabetes mellitus within 10–20 years from the onset of the initial symptoms of pain [31]. Mohan and colleagues [77] determined that the median time to development of diabetes mellitus in patients with TCP was 9.6 years from diagnosis and this was associated with an older age, higher body mass index, and lower fecal chymotrypsin level. The development of diabetes mellitus in TCP has been hypothesized to result from

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In conclusion, the incidence of TCP is on the decline even in developing countries. The disease is witnessing a paradigm shift in relation to a number of aspects including the reduced emphasis on macronutrient, protein calorie malnutrition, and cassava ingestion as etiological factors, in favor of micronutrient deficiency (including zinc) and oxidant stress, an increased appreciation of the role of gene mutations in the pathogenesis of the disease, and finally, significantly improved survival, possibly as a result of better management of the disease and its attendant complications. The mounting evidence calls for a unified, evidencefraternity to clarify whether TCP should continue to remain a unique entity, or be included under the broad umbrella of idiopathic CP.

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