Interpretation
HBsAg
Anti HBs
HBeAg
Anti HBe
Anti HBc
HBV DNA
Stage of HBV infection
Acute HBV
+
−
+
−
IgM
+
Chronic HBV
• Immunotolerant
+
−
+
−
IgG
>20,000 IU/mL
• Immune clearance
+
−
+
−
IgG/IgM
2000–20,000 IU/mL
• Reactivation/Flare
+
−
+/−
−
IgM
>20,000 IU/mL
• HBeAg (−) chronic HBV
+
−
−
+
IgG
>20,000 IU/mL
• Inactive disease
+
−
−
+
IgG
<2000 IU/mL
Resolved past infection
−
+
−
−
IgG
−
Vaccinated
−
+
−
−
−
−
Management
The best management strategy for hepatitis B is prevention by vaccination at birth of all children, but particularly those born to hepatitis B infected mothers.
Once hepatitis infection has occurred treatment depends on the stage of the infection and the presence and severity of liver disease and or hepatocellular cancer. Viral replication can be suppressed with a number of new potent nucleoside analogues with high barriers to viral resistance. Unfortunately treatment is required long term with eventual development of resistance and treatment paradigms including response guided therapy are still under evaluation. Pegylated Interferon is also used as an alternative therapy with a limited duration of treatment, no resistance but a significant side effect profile .
Viral eradication is not yet achievable with current treatments, so the goals of therapy are to prevent serious liver disease including cirrhosis and hepatocellular cancer [101].
Hepatitis C
Definition
History
Epidemiology
Hepatitis C infection is often asymptomatic and thus precise estimates of incidence and prevalence are difficult. The WHO estimates that 3 % of the world population has been infected with hepatitis C and there are 170,000,000 chronic carriers of the infection that are at risk of cirrhosis and liver cancer [104].
Systemic Manifestations
Hepatitis C causes a chronic hepatitis which can lead to cirrhosis and hepatocellular cancer. The exact rate of progression depends on other comorbid factors such as alcohol, iron deposition, fatty liver disease and other concomitant hepatitis virus infection e.g. hepatitis B.
In addition hepatitis C is associated with a number of extrahepatic manifestations including mixed cryoglobulinemia, porphyria cutanea tarda, thyroid disease and polyarteritis [106].
Ophthalmic Manifestations
Ertekin and Tan reported a 9 year old boy who presented with opsiclonus-myoclonus syndrome and on subsequent investigation was found to have hepatitis C with no evidence of neuroblastoma nor encephalitis [107]. He responded to treatment with clonazepam with resolution of the opsoclonus and myoclonus. The etiology of opsiclonus-myoclonus is uncertain but thought to be immune mediated [108, 109] and this is presumed to be the case with the extra-hepatic manifestations of hepatitis C infection [110].
Diagnosis
The presence of HCV RNA in the blood implies HCV infection. Serum HCV antibody implies exposure to HCV virus but cannot distinguish between current or past infection and hence is used as a screening test.
Management
The management of hepatitis C infection has undergone a paradigm shift in the last 5–10 years with the development of all oral pangenotypic regimens which can eradicate the virus. The duration and type of treatment depend on the virus genotype. At present the cost of these treatments are very high and hence their availability may be restricted to those with the most severe disease until they become more affordable [111].
Hepatitis E
Definition
Hepatitis E is a faecal-oral transmitted viral infection [89] caused by a hepevirus (RNA virus) which has a very varied clinical spectrum from asymptomatic infection or clinical hepatitis to liver failure with a high mortality rate in pregnant women and immune-compromised patients [112]. It most commonly occurs as an epidemic disease in areas of poor sanitation but is a recognised cause of post-transfusion hepatitis [113].
History
A water-borne non A and non B form of hepatitis was recognised in large epidemics in the 1980s [113] with the hepatitis E virus (HEV) being identified in 1990 [114]. For many years if was thought to be a disease of countries with poor sanitation but is now recognised as an infrequent cause of hepatitis in all countries [113].
Epidemiology
The incidence and prevalence of hepatitis E is uncertain as there is significant variation around the world and varying sensitivity of serological tests [113].
Systemic Manifestations
Hepatitis E in developing countries presents in a similar fashion to other types of acute viral hepatitis with fever, icterus, abdominal pain, anorexia and pruritus. It may produce fulminant liver failure in pregnant women, young children and a chronic transaminitis in transplant recipients. Alternatively it may be totally asymptomatic and recognised only by serological testing in developed countries [115].
Ophthalmic Manifestations
Yadav et al. have describe a 13 year old girl who presented with altered conscious state as part of the onset of hepatitis E [116]. As she regained consciousness after 5 days she was noted to have a unilateral pupil sparing third nerve palsy and no other focal neurologic findings. Over 2 months there was only partial recovery of the third nerve function [116].
Diagnosis
Diagnosis is based on serological assays which detect anti-HEV IgM in the days prior to clinical infection and may last for 6 months. Anti-HEV IgG may last for up to 12 years and indicates past infection. HEV RNA can also be detected in the stool and blood of patients with acute HEV infection [115].
Management
Management of hepatitis E infection is supportive. Prevention however involves improved hygiene and provision of safe drinking water. There are several candidate vaccines for hepatitis E currently under trial [115].
Congenital Hepatic Fibrosis
Definition
Congenital hepatic fibrosis is a histopathological diagnosis and is defined as “a developmental disorder of the portobiliary system characterized histologically by defective remodelling of the ductal plate (ductal plate malformation), abnormal branching of the intrahepatic portal veins, and progressive fibrosis of the portal tracts” [117]. If there are macroscopic cysts contiguous with the biliary tree it is sometimes called Caroli syndrome and Caroli disease is the much less common occurrence of macroscopic cysts without hepatic fibrosis [117]. The typical clinical features are an enlarged liver with a palpable left lobe, ultrasound evidence of increased echogenicity, with or without macrocysts, good liver function in infancy (often) and evidence of portal hypertension later [117]. Most frequently congenital hepatic fibrosis is associated with the ciliopathies that have renal disease [117, 118]. This group of disorders sometimes referred to as “hepatobiliary fibropolycystic diseases ”.
Joubert syndrome is one of these disorders and a subtype of Joubert syndrome , COACH syndrome , presents with congenital hepatic fibrosis and ocular manifestations [119, 120]. COACH is an acronym that stands for Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, ocular Coloboma, Hepatic fibrosis and is autosomal recessive [120].
History
Congenital hepatic fibrosis was first described by Kerr et al. in 1961 [124]. The association of hepatic fibrosis and ocular manifestations was first described by Hunter et al. in 1974 [125] with a more complete description by Verloes and Lambotte in 1989 [120]. These authors also proposed the acronym COACH.
Epidemiology
Systemic Manifestations
This discussion will be limited to a the systemic features of COACH syndrome . A discussion of the systemic features of the other hepatobiliary fibropolycystic diseases is beyond the scope of this chapter.
Hepatic
Congenital hepatic fibrosis is seen in all cases and may present with signs of portal hypertension such as hematemesis [117, 126]. Liver function is commonly relatively well preserved initially with early onset liver abnormalities being rarely reported [127, 128]. In older affected individuals liver failure may occur [126].
Neurologic
Developmental delay and intellectual disability (oligophrenia ) is present to varying degree [117, 123]. Neonatal tachypnoea (as would be expected with Joubert syndrome ) has been described [122, 125]. Early onset ataxia is frequently observed with choreo-dystonic movement disorders being seen less often [120, 122]. Imaging frequently shows cerebellar vermal hypoplasia or aplasia with the typical molar tooth sign [120–122, 129].
Ophthalmic Manifestations
Retina and Optic Nerve
Chorioretinal and optic disc colobomas are detected in 42–71 % of cases in two larger series [121, 122]. It has been suggested that abnormal optic disc cupping and pallor may be part of a spectrum of optic disc abnormalities seen in COACH syndrome [122]. Optic disc hypoplasia and septo-optic dysplasia has been described in a 7 year old girl with hepatic fibrosis [131]. This child had developmental delay but there is no description of cerebellar findings on imaging. This child did not have neonatal jaundice which is more commonly associated with septo-optic dysplasia [132, 133]. The underlying diagnosis remained uncertain in this child. There is a single case report of congenital hepatic fibrosis and retinal dystrophy (given the diagnosis of Leber congenital amaurosis in the report) [134]. Mutation detection was not performed in this case. Other authors of commented on the rarity of retinal dystrophy in association with COACH syndrome [122].
Eye Movement Abnormality
Diagnosis
The clinical diagnosis is made on the basis of examination findings, liver and renal imaging, brain MRI and confirmed with mutation analysis for in TMEM67, CC2D2A and RPGRIP1L.
Neonatal Hemochromatosis
Definition
Neonatal hemochromatosis is an allo-immune disorder unrelated to hereditary hemochromatosis. It is due to transplacental transfer of a maternally derived antibody directed at fetal liver and resulting in severe fetal liver injury and extrahepatic deposition of iron [137].
History
Neonatal hemochromatosis was formally considered to be part of the spectrum of familial hemochromatosis but in 2010 it was finally recognised that it is the result of liver damage induced by maternally derived antibodies now referred to as gestational allo-immune liver disease [138].
Epidemiology
Neonatal hemochromatosis is a rare cause of liver failure in the neonatal period [139] but more precise incidence and prevalence estimates are not available.
Systemic Manifestations
Neonatal hemochromatosis presents as liver failure at birth with jaundice , coagulopathy, hypoglycaemia and ascites. Many babies show evidence of an intrauterine insult such as oligohydramnios or intrauterine growth retardation [137].
Ophthalmic Manifestations
Maldonado et al. reported a case of neonatal hemochromatosis complicated by severe bilateral retinal edema and subretinal fluid [140]. The retinal edema was so severe that the retinal appearance mimicked the cherry-red spot of metabolic disorders. The ocular manifestations resolved completely after successful liver transplantation. It is of interest in this case report that the authors did not discuss the most likely etiology of the liver disease being gestational allo-immune liver disease.
Diagnosis
Diagnosis is based upon the demonstration of extrahepatic siderosis in a newborn with liver failure. Extrahepatic siderosis may be demonstrated by an oral mucosal biopsy to show iron deposition in submucosal glands. MRI can also be used to demonstrate iron in various tissues in particular pancreas and liver [141]. More recently immunohistochemistry of the liver for C5b-9 has been used to demonstrate complement mediated hepatocyte injury, but use of this modality requires further study [142].
Management
As this is an allo-immune disorder the first affected infant will present with liver failure. Treatment is extremely difficult but entails the use of an anti-oxidant cocktail from birth together with supportive therapy for liver failure. Survival with this treatment is reported between 10 and 20 %. Liver transplantation can be offered but is associated with all the risk of transplantation in growth retarded infants [141]. Once the index case has been identified, the mother can undergo pre-emptive treatment during subsequent pregnancies with intravenous immunoglobulin. This therapy has been remarkably successful and has resulted in survival of the infants without liver disease in 48 of 52 mothers treated [143].
Hypopituitism and Neonatal Jaundice
Definition
Neonatal jaundice secondary to hypopituitism.
History
Epidemiology
Neonatal hypopituitism occurs in about one in 53,000 births and is a rare cause of neonatal cholestasis [145]. The exact frequency of this association is uncertain but a retrospective study over 20 years found that 7 of 20 patients (35 %) with hypopituitarism presented with cholestatic jaundice [146].
Systemic Manifestations
Hyperbilirubinemia may be conjugated or unconjugated and presents at around 7 weeks of age. Other clinical manifestations include microphallus, persistent hypoglycaemia, hepatosplenomegaly and ophthalmic manifestations as described below [145].
Ophthalmic Manifestations
Diagnosis
Hardikar Syndrome
Definition
History
Epidemiology
Hardikar syndrome is an extremely rare disorder.
Systemic Manifestations
Hepatic
Neonatal jaundice and abnormalities of the biliary drainage system with late complications of cirrhosis (varices) and liver failure have been reported [151].
Gastrointestinal
Malrotation, jejunal septum, gastroesophageal reflux and celiac disease have all been reported [151].
Cardiac
Patent foramen ovale, mild pulmonary artery stenosis and anomalous pulmonary venous drainage have been described [151].
Central Nervous System
Minor narrowing of the basilar and vertebral arteries and hearing loss have also been described [151].
Ophthalmic Manifestations
Retinopathy
Pigmentary retinopathy was described in the original case report and has been described in all subsequent cases [147–150]. The fundus is described as being albinotic with areas of pigmentary clumping in the shape of a cat’s paw (bear tracks) [148]. In the peripheral retina there may be focal areas of chorioretinal degeneration.
Diagnosis
There is no diagnostic test and diagnosis is made on the basis of pattern recognition.
Intestinal Disease
Polyposis Syndromes
This is a group of genetic disorders associated with multiple bowel polyps and variable extra-intestinal manifestations, often classified according to the histological types of polyps found in the bowel and the underlying genetic mutation. Most of these disorders are associated with a risk of both intestinal and non-intestinal malignancy. Of these syndromes, the following conditions are discussed in this chapter: Familial adenomatous polyposis, Peutz-Jegher syndrome and Cowden syndrome .
Familial Adenomatous Polyposis
Definition
Familial adenomatous polyposis is an autosomal disorder associated with the development of hundreds to thousands of adenomatous polyps in the intestine. It is cause by a mutation in the APC (adenomatous polyposis coli) gene (OMIM 611731, 5q22.2) [152]. For many years Gardner syndrome was the expression used to describe familial adenomatous polyposis with extra-colonic features but it is now know that most people with familial adenomatous polyposis have at least one extra-colonic feature and Gardner syndrome is considered to be a variant of familial adenomatous polyposis [153]. They are both the result of mutations in the APC gene . There is some overlap between familial adenomatous polyposis and the mismatch repair cancer syndrome (Turcot syndrome ) [154]. This syndrome is manifest as intestinal polyposis with brain tumours. Four loci have been identified, none of which suggest that this disorder is allelic with APC.
History
In 1951, Gardner described the association of intestinal polyposis colonic and carcinoma of the colon in a large family [155]. Subsequently he and others recognised many extracolonic manifestations including desmoids, dental anomalies, osteomas and epidermoid cysts [156].
Epidemiology
Familial adenomatous polyposis is the most common inherited polyposis syndrome in childhood with the prevalence being between one in 5000 and one in 17,000 [159].
Systemic Manifestations
The lifetime risk for colorectal neoplasia is 100 %. Familial adenomatous polyposis can be associated with extra-colonic manifestations including tumours in the duodenum, thyroid, pancreas, brain and hepatoblastoma. In addition, bony lesions, desmoid tumours, nasopharyngeal angiofibromas, dental anomalies, and adenomas in the stomach, duodenum, jejunum and ileum may occur. APC gene mutations are considered to be highly penetrant with variable expressivity [152, 160, 161].
Ophthalmic Manifestations
Retina
The pigmented ocular fundal lesions seen in familial adenomatous polyposis are often called congenital hypertrophy of the retinal pigment epithelium (CHRPE ) (see Fig. 10.1). Typical CHRPE are pigmented lesions with a variable area of depigmentation within (lacuna) or around the lesion [162–164]. The hypopigmentation may form a “tail” to the lesion directed towards the macula [163]. The lesions vary in size and photography and fluorescein angiography may reveal lesions not easily seen with an indirect ophthalmoscope [165]. OCT shows some photoreceptor loss over these lesions [166, 167]. These may occur singly or be multiple. The presence multiple pigmented fundal lesions is considered to be highly specific for familial adenomatous polyposis if there is a family history of familial adenomatous polyposis [168–170]. The incidence of isolated CHRPE in the general population is approximately 1 % with Coleman and Barnard identifying 25 CHRPE in 21 patients from a population of 1745 [171]. CHRPE tend to enlarge slowly [164] with occasional development of a nodular appearance or even tumours in adulthood [172, 173].
Fig. 10.1
Multifocal congenital hypertrophy of retinal pigment epithelium in a patient with familial adenomatous polyposis. (Courtesy of Dr. Carol Shields)
The association of CHRPE with familial adenomatous polyposis has been discussed in many reports [157, 168–170, 174–191]. Traboulsi et al. showed bilateral pigmented lesions or greater than four lesions or both had a high specificity and sensitivity for familial adenomatous polyposis [168]. There are clear differences between pedigrees with familial adenomatous polyposis and controls families with the familial adenomatous polyposis family members having more pigmented lesions than controls [177, 179]. There is not a perfect correlation between the presence of CHRPE and familial adenomatous polyposis within families [175, 179, 182]. This is thought to be due to differing genotype-phenotype correlation for different mutations within APC [187, 188, 190]. There is little doubt that the finding multiple pigmented lesions in a possible carrier of an APC gene mutation greatly increases the risk of subsequent development of polyps and later carcinomas [169, 178, 183]. The lack of pigmented lesions in a possible carrier is less significant and such individuals still require monitoring for the development of polyps or mutation detection [152, 185, 191]. The finding of an isolated or even multiple CHRPE in an individual is probably of little value in assigning a risk of developing familial adenomatous polyposis [162, 181]. In a younger individual a family history of polyps or bowel cancer should be sought. Aiello et al. reported a premature baby who was found to have multiple pigmented lesions during assessment for retinopathy of prematurity and a positive family history for probable familial adenomatous polyposis was elicited [184]. Ganesh et al. described a 3 year old boy with exotropia who was found to have multiple pigmented lesions of varying size and an epiretinal membrane in the presence of an APC mutation [192].
Tumours
There are reports of less frequent ocular manifestations of familial adenomatous polyposis. Kochhar et al. reports a 16 year old girl with proptosis secondary to an orbital osteoma as her presenting feature of Gardner syndrome [193]. While being investigated for her proptosis she had painless rectal bleeding and was found to have intestinal polyposis. Retinal examination was described as normal and there is no mention of a family history of gastrointestinal malignancy [193]. Armstrong et al. described a 16 year old girl with orbital rhabdomyosarcoma who developed bloody diarrhoea during treatment and was then found to have colon polyps and a 5q- deletion [194]. The relationship between her orbital tumour and her familial adenomatous polyposis remains uncertain. An association with 5q deletion has been demonstrated with some rhabdomyosarcomas [195]. Kiratli et al. reported a case of sporadic unilateral retinoblastoma that was then followed by acute lymphoblastic leukemia and then the discovery of bowel polyps [196]. There is unfortunately no mention of any retinal findings in the fellow eye nor was any genetics undertaken.
There have been two reports of ophthalmic presentations of Turcot syndrome . The first involves a 14 year old girl who had a history of intestinal polyposis and then developed a juvenile pilocytic astrocytoma of one optic nerve with loss of vision [197]. There was no mention of retinal examination, family history nor genetic studies to help determine the etiology of this girl’s condition. Lima et al. reported the case of a 17 year old boy with a history of intestinal polyposis who presented with diplopia due to a fourth nerve palsy and was found to have a germinoma in the tectal plate [198]. He was subsequently found to have a mutation in the APC gene . There was a family history of polyposis with his mother requiring a colectomy. He had a single pigmented lesion in each retina [198]. This case is much more in keeping with familial adenomatous polyposis.
Diagnosis
Diagnosis should be considered after the finding of numerous adenomatous polyps (usually >100) which develop after the first decade. A careful family history of polyposis, colorectal and other cancers should be sought. Genetic testing can identify a wide variety of mutations in the APC gene which cause familial adenomatous polyposis.
Management
Individuals with APC mutations have a 90 % risk of developing colonic adenomas, with the risk increasing with age. Management involves careful surveillance for colorectal cancers and colectomy. Patients with APC mutations also have a significantly increased risk of developing other cancers including desmoid tumours, ampullary cancers, hepatoblastoma and duodenal cancers. Regular surveillance for these cancers is also recommended according to the American College of Gastroenterology guidelines [199].
Peutz-Jeghers Syndrome
Definition
Peutz-Jeghers syndrome is an autosomal dominant familial polyposis disorder due to mutations of the STK11 gene (OMIM 602216, 19p13.3). It is characterised by mucocutanous melanosis, gastrointestinal polyposis, gastrointestinal cancer and extra-intestinal cancer [200].
History
Epidemiology
The incidence of Peutz-Jeghers syndrome is estimated to be between one in 8300 and one in 200,000 births and has a lifetime risk of developing cancer of between 37 and 93 % [201].
Systemic Manifestations
Peutz-Jeghers syndrome is associated with the development of hamartomatous polyps in the gastrointestinal tract, together with skin pigmentation and a significant life time risk of cancer in the gastrointestinal tract as well as in breast, testicle, ovary, uterus, cervix and pancreas [200]. Ninety-five percent of children with Peutz-Jeghers syndrome have pigmentation of the lips, buccal mucosa or perianal skin [200]. Presentation is often in infancy because of the pigmentary changes or with rectal bleeding, intussusception or anemia [200]. The polyps have a characteristic histological appearance being multilobated with a papillary surface epithelium covering a core of arborizing smooth muscle resembling a branching tree [206].
Ophthalmic Manifestations
There is a single report of ocular manifestation in a child with Peutz-Jeghers syndrome. Raizis et al. reported the case of a girl who was diagnosed with bilateral retinoblastoma at 6 months of age and then was found to have a pineal tumour [207]. She survived with appropriate treatment and at 9 years of age was noted to develop buccal pigmentation. At 17 years of age she had an intussusception and at operation was found to have multiple intestinal polyps. Subsequent genetic testing confirmed a mutation in the STK11 gene but not evidence of any abnormality in the RB1 gene (OMIM 614041, 13q14.2) or its product pRB. The authors suggest that a mutation in the STK11 gene and subsequent altered gene product may have interacted with pRB to cause the development of trilateral retinoblastoma. They were unable to completely exclude the possibility of an in-frame, intronic mutation in RB1 or mosaicism [207].
Diagnosis
Diagnosis is based on the combination of clinical features described above including hamartomatous gastrointestinal polyps and peri-oral pigmentation. Genetic testing for mutations in SRK11 can be performed.
Management
Management of this condition involves regular surveillance endoscopy and removal of polyps which can cause obstruction and intussusception as well as lifelong surveillance for the high risk of other systemic cancers. As these conditions are rare, guidelines for surveillance are based on expert consensus [199].
Cowden Syndrome
Definition
Cowden syndrome is a an autosomal dominant hereditary cancer syndrome caused by mutations in the PTEN gene (OMIM 601728, 10q23.31) in 80 % of cases [208]. It results in increased risk for breast, thyroid, renal, uterine, intestinal and other cancers as well as benign neoplasias and neurodevelopmental abnormalities [208]. Lhermitte–Duclos disease or dysplastic cerebellar gangliocytoma is a phenotypic variant of Cowden syndrome and is also caused by PTEN mutations [209]. Bannayan–Riley–Ruvalcaba syndrome (characterized by macrocephaly, benign hamartomas, pigmented macules of the glans penis, lipomas, hemangiomas, and the developmental delay) is allelic in 60 % of cases [209]. It has been suggested that these three condition should be referred to as the ‘ PTEN hamartoma-tumour syndromes ’ [209, 210]. It has also been suggested that Proteus syndrome may overlap with Cowden syndrome [209] while others have suggested there is no overlap and cases of “Proteus syndrome” with PTEN mutations are in fact misdiagnosed Cowden syndrome [211].
History
Epidemiology
Systemic Manifestations
Patients with Cowden syndrome develop multiple hamartomas most commonly on the skin and mucous membranes but they can be anywhere including the intestines. Other features include gastrointestinal polyps, ovarian cysts and leiomyomas. Patients are also at risk of other cancers including breast, thyroid, and uterine cancers. Affected individuals may have macrocephaly and a small percentage have intellectual disability.
Ophthalmic Manifestations
Optic Disc
Nuss et al. reported an 24 year old man diagnosed with Cowden syndrome who had “pseudotumour cerebri” at 16 years of age [215]. No further clinical details were given. Wells et al. described a 16 year old girl in 1994 who presented with signs of raised intracranial pressure and a sixth nerve palsy who was found to have a cerebellar mass that on biopsy was consistent with Lhermitte–Duclos disease [216]. On subsequent ophthalmic assessment she was noted to have choroidal hamartoma and conjunctival papilloma. She had a past history of partial thyroidectomy. These findings were considered to be consistent with a diagnosis of Cowden syndrome [216]. Arch et al. reported a 18 month old boy with Bannayan–Riley–Ruvalcaba syndrome who was noted to have pseudopapilledema and anisometropia [217]. Subsequent testing revealed a mutation in PTEN and the authors suggested Bannayan–Riley–Ruvalcaba syndrome and Cowden syndrome are allelic [217].
Cornea
Schaffer et al. reported a 5 year old boy with multiple nonencapsulated neuromas of the vermillion border of the upper lip, digits, palms and shins with prominent corneal nerves and PTEN mutation [218]. No other features of Cowden syndrome were reported.
Diagnosis
Clinical Diagnosis is made by a combination of three or more major criteria or two major and three minor criteria based on a systematic review by Pilarski and colleagues. Recommendations for which patients should undergo genetic testing are also contained in these guidelines [219].
Management
As with other syndromes in which the cancer risk is significant, management involves a program of regular screening for cancers including breast, thyroid, uterine etc. Surgery, laser therapy and chemical peels may be used to treat some of the skin lesions. Clinical trials using rapamycin and sirolimus are currently underway after the demonstration of regression of cutaneous lesions and other features in a mouse model with a PTEN deletion.
Inflammatory Bowel Disease
Definition
Crohn disease and ulcerative colitis are chronic , inflammatory diseases of the bowel with some unique and some overlapping features. Crohn disease is manifested by inflammation of the bowel anywhere from mouth to anus. The child may present with diarrhoea, abdominal pain, PR bleeding and weight loss [220]. The disease is characteristically not continuous and commonly involves extra-intestinal manifestations including musculoskeletal, hepatobiliary, skin and eye involvement. Crohn disease may predominantly involve the oral cavity and lips-, so called orofacial granulomatosis. It may also be predominantly perianal with fistulas and skin tags and relatively little in the way of bowel involvement. Histologically, Crohn disease is characterised by discontinuous involvement and granulomas. In contrast, ulcerative colitis is limited to the colon and is usually continuous starting distally and becoming more proximal. It can also be associated with extra-intestinal manifestations of the same spectrum as seen in Crohn disease. In children, the distinction between Crohn disease and ulcerative colitis maybe difficult at diagnosis. The presence of certain antibodies may assist. Anti- saccharomyces cerevisiae (ASCA) IgG is a specific but not sensitive marker in patients with Crohn disease while Anti-neutrophil cytoplasmic antibodies (pANCA) are present in more than half of patients with ulcerative colitis [221]. If the distinction cannot be made, patients are labelled as “IBDU ”- inflammatory bowel disease unclassified until the clinical pattern becomes clearer with time.
History
Crohn disease was first distinguished from other inflammatory bowel diseases by Crohn et al. in 1932 [224]. In the original description only involvement of the ileum was identified and the name “regional ileitis” was suggested. Ulcerative colitis was first described by Samuel Wilks in 1859 as chronic continuous inflammation limited to the large bowel, starting distally in the rectum and continuing proximally to a variable extent [225].
The association between gastrointestinal disease and ocular inflammation has long been known with the 1918 report of Maxwell and Kiep linking infective dysentery and uveitis being the earliest in the English literature [226]. Paradoxically Crohn reported the association between ulcerative colitis and ocular lesions in 1925 [227] some 7 years before he published his description of the disease that bears his name [224].
The earliest series of patients with ulcerative colitis and ocular manifestations was published in 1967 by Billson et al. [228]. They described 3.7 % of 465 patients with ulcerative colitis having ocular manifestations. Their patients were predominately adults.
The first reference to uveitis in association with Crohn disease is probably that of Korelitz and Coles in 1967 [229]. These authors report 13 individual’s with inflammatory bowel disease and uveitis four of whom probably had Crohn disease (“granulomatous colitis”), though there is some diagnostic uncertainty. The first systematic documentation of a large series of patient’s with ocular disease and Crohn disease was that of Hopkins et al. published in 1974 [230]. In this series 21/332 (6.3 %) had one or more ocular complaints [230]. Sixty-seven of the 332 (20 %) patients studied were under 19 years of age and four of these were reported to have “eye lesions” but not uveitis .
Epidemiology
The prevalence of Crohn disease and ulcerative colitis is increasing, with large scale, population based studies from several countries demonstrating this phenomenon [231–234].
There is extremely wide geographic variation in the incidence of extra-intestinal manifestations of Crohn disease with estimates varying from 7 % in a Korean population [235] to 42 % in a Spanish population [236]. The Korean study reported no ocular manifestations while the Spanish study noted 2 % had ocular manifestations. The Korean study was only adults while the Spanish study did include some children (age range 10–80 years). In one study from Turkey a prevalence of 60 % of Crohn disease patients with ophthalmic abnormalities was ascribed to the ascertainment bias of a tertiary referral centre [237].
Systemic Manifestations
Bowel
The main features of inflammatory bowel disease depend on the distribution of the disease in an individual patient. Inflammation of the colon, either in Crohn disease or ulcerative colitis, presents with diarrhoea, abdominal pain and PR bleeding. This may be accompanied by systemic symptoms of fever, weight loss and malaise. Crohn disease may associated with mouth ulcers, small bowel strictures, isolated oral involvement (orofacial granulomatosis) or isolated perianal disease.
Musculoskeletal
Musculoskeletal pain is the most common extra-intestinal manifestations of inflammatory bowel disease and occurs in up to 50 % of patients. Arthritis may involve peripheral joints, or the axial skeleton such as the spine and sacroiliac joints. The peripheral arthritis may be pauciarticular and correlate well with disease activity or polyarticular, long lasting, and independent of disease activity [238].
Dermatological
A number of skin manifestations are associated with inflammatory bowel disease and the most common are erythema nodosum, pyoderma gangrenosum and psoriasis. Erythema nodosum occurs in 7 % of patients and presents with painful erythematous or bruise like nodules often on the anterior shins. Their presence parallels disease activity in the bowel and treatment is directed at managing bowel inflammation [239]. Pyoderma gangrenosum consists of a papule or nodule which breaks down into an ulcerated lesion. It can occur anywhere on the body, most commonly on the legs and can be seen in up to 10 % of patients with ulcerative colitis and up to 20 % of patients with Crohn disease [240].
Hepatobiliary
Primary sclerosing cholangitis is the most common and severe hepatobiliary manifestation of inflammatory bowel disease and may precede or follow the development of bowel disease. It is found in 5 % of patients with ulcerative colitis and 2 % of patients with Crohn disease . It causes progressive structuring of bile ducts, cholestasis and end stage liver disease which may require transplantation. Primary sclerosing cholangitis may also recur in the transplanted liver graft. Other hepatobiliary manifestations include choledocholithiasis and portal vein thrombosis.
Ophthalmic Manifestations
Ophthalmic extra-intestinal manifestations of inflammatory bowel disease are relatively common and in the majority of cases mild and often asymptomatic [223]. These complications may be a primary feature of inflammatory bowel disease or secondary to treatment (most commonly corticosteroid therapy) or co-incidental observations [241]. Ocular involvement can occur prior to the diagnosis of inflammatory bowel disease, be diagnosed at the same time or some time subsequently. In a large Italian series, ocular manifestations were diagnosed prior to systemic diagnosis in 11 % of cases of inflammatory bowel disease, at the same time in 19 % and following diagnosis in 70 % [242].
With the exception of anterior uveitis, cataract and ocular hypertension reports of reports of ocular manifestations have been in small case series or single case reports. There are two prospective cross-sectional studies of the ophthalmic manifestations of inflammatory bowel disease in paediatric populations [243, 244].
Anterior Uveitis
Asymptomatic uveitis in children is the most commonly reported ocular manifestation of inflammatory bowel disease with reported prevalence of 0–32 % [230, 243–245]. Hofley et al. assessed 97 children with Crohn’s disease and reported 6/97 (6.2 %) had asymptomatic uveitis (defined as flare or inflammatory cells in the anterior chamber) [243]. No patients with ulcerative colitis in this series were reported to have uveitis and no other ophthalmic abnormalities were reported by these authors [243]. Rychwalski et al. examined 18 children with Crohn’s disease and 14 with ulcerative colitis [244]. 3/18 (17 %) of the Crohn’s disease patients and 1/14 (7 %) of the ulcerative colitis patients had asymptomatic uveitis with cells and flare [244]. In the majority of children reported to have anterior uveitis and inflammatory bowel disease the uveitis is mild and often asymptomatic and consists of mild flare and cells [228, 230, 243–245].
The association between activity of inflammatory bowel disease and presence of anterior uveitis is uncertain. Hofley et al. reported no association between the activity of the Crohn disease and uveitis [243]. Rychwalski et al. reported three of four children with anterior uveitis who had active systemic disease at the time of detection of uveitis [244]. The principle location of the Crohn disease was reported to be the colon in 4/6 children with uveitis in one series [243]. This is similar to the association reported in adults [246]. Anterior uveitis may precede bowel disease with Korelitz and Cole reporting three of the four patients with granulomatous colitis (Crohn disease) developing iritis before the diagnosis of the bowel disease [229].
The natural history of asymptomatic uveitis associated with inflammatory bowel disease is uncertain [243, 244, 247]. Daum et al. examined five children 6 months after the detection of asymptomatic uveitis and found 4/5 had resolved and the remaining one was improving (the sixth patient was lost to follow-up) [245]. None of these patients had received any treatment specifically for their uveitis.
Conjunctival Lesions
Conjunctival lesions have been described in children with Crohn disease on two occasions.
Blase et al. described a 13 year old boy who developed granulomatous conjunctivitis at the same time as his gastrointestinal symptoms [248]. He was noted to have normal vision, moderate bilateral conjunctival injection and gelatinous nodules at the limbus with mild anterior uveitis. Biopsy of a conjunctival lesion revealed “chronic round cell infiltration of the substantia propria with discrete nodules of epithelial and giant cells”[248]. The conjunctival changes revolved rapidly with systemic corticosteroid therapy. Knox et al. reported a 17 year old boy with a small limbal infiltrate in association with episcleritis and mild anterior uveitis [241]. Biopsy showed acute inflammation and no granuloma. This boy had a history of recurrent iritis and this episode was preceded by a flare-up of this gastrointestinal symptoms.
Episcleritis
Episcleritis is infrequently reported as an extra-intestinal manifestation of inflammatory bowel disease. This may be because it is mild and self-limited. Hopkins et al. found a prevalence of 0.6 % for episcleritis in a series of 332 adult and paediatric patients with Crohn disease [230] and Billson et al. reported an incidence of 1.5 % in a similar population with ulcerative colitis [228]. Pediatric patients with episcleritis have been described by Ellis and Gentry [249] Salmon et al. [250] and Knox et al. [241]. The case reported by Ellis and Gentry was an 11 year old girl with ulcerative colitis [249]. She had a protracted course with respect to ocular manifestations having episcleritis followed by iridocyclitis, neuroretinitis, lateral rectus weakness, further iritis, episcleritis and scleritis and ultimately inflammatory mass around the trochlea. She developed a mild posterior subcapsular cataract as the result of steroid therapy [249]. The case reported by Salmon et al. was described as nodular episcleritis and it was noted that episcleritis was seen in association with active bowel disease and settled with systemic therapy for this [250].
Scleritis
Scleritis is infrequently described in adults with Crohn disease and to date has not been reported in the pediatric population. Salmon et al. describe 19 and 20 year old female patients with diffuse and necrotizing scleritis respectively [250]. In both patients the onset of the scleritis was after tapering systemic corticosteroid treatment for long-term treatment of recurrent bowel inflammation.
Blepharitis
Keratitis
Keratitis is infrequently reported in the pediatric population with inflammatory bowel disease. The case of Blase et al. had unilateral superficial corneal infiltrates in association with conjunctival granulomas [248]. In their prevalence study Hopkins et al. report a 0.3 % rate of keratitis [230]. Lind reported 2 cases of keratitis in their series of 214 cases of Crohn disease [253]. Macoul described a 17 year old male with Crohn disease who developed marginal corneal infiltrates after a complex preceding ocular history of bilateral iridocyclitis followed by bilateral posterior uveitis with bilateral papillitis [254]. Sahel described a 12 year old girl who had corneal infiltrates (as well as episcleritis and scleritis) 4 years prior to her diagnosis of Crohn disease [255]. Severe corneal pathology has been described as a complication of anti-tumor necrosis factor treatment by Fasci-Spurio et al. [252]. This 16 year old boy with Crohn disease had keratitis, corneal scar formation and corneal melts.
Cataract
The most frequently describe cataract morphology seen in association with inflammatory bowel disease is posterior subcapsular. It is generally assumed this is a complication of long-term corticosteroid use [244, 256]. In the report of Rychwalski et al. 3/18 patients with Crohn disease had posterior subcapsular cataract but no comment is made about the vision of these children other than to state “No patient had … photophobia, or visual disturbance” [244]. Tripathi et al. described 12/58 (21 %) children with inflammatory bowel disease who developed posterior subcapsular cataract following treatment with corticosteroid [256]. The development of these cataracts “was not correlated …. with the total dose of prednisone, duration of treatment, average daily dose, or number of days on high doses” though it was assumed that the development of cataract was secondary to corticosteroid treatment.
Visually significant cataract in children with inflammatory bowel disease has not been described .
Ocular Hypertension
Ocular hypertension secondary to systemic corticosteroid use has been described in children with Crohn disease [257]. There have been no reports of steroid induced glaucoma in children with Crohn’s disease.
Vitritis
Vitritis has only been described in the report of Macoul of a 17 year old boy with Crohn disease who had protracted pan uveitis, papillitis and reduced vision [254].
Papillitis and Papilledema
Papillitis has been described twice in children with inflammatory bowel disease [254, 258]. Both children had reduced visual acuity with marked disc swelling and hemorrhages. The case of Hutnik et al. was investigated with CT and MRI scan and lumbar puncture all of which were normal [258]. This 17 year old boy was diagnosed with Crohn disease immediately following his presentation with reduced vision.
There is a case report of pseudotumour cerebri and associated papilledema in a 16 year old boy with Crohn disease [259]. This occurred following steroid withdrawal on four occasions and necessitated long term diuretic treatment.
Central Retinal Artery Occlusion
There is a single case report of central retinal artery occlusion in a 9 year old boy with Crohn disease [260]. Fortunately this child had a cilioretinal vessel and central vision was preserved.
Serous Retinal Detachment
Ernst et al. described one child with serous retinal detachment in their small series of patients with inflammatory bowel disease and posterior segment pathology [261]. This 15 year old boy noted slightly reduced vision in one eye 2 weeks after the diagnosis Crohn disease . Despite resolution of the retinal detachment following treatment with systemic corticosteroid he was left with slightly reduced visual acuity of 20/40.
Dacryoadenitis
Dacryoadenitis has been reported twice in children with Crohn disease [262, 263]. Dutt et al. reported 16 year old boy who developed bilateral dacryoadenitis at the same time as a relapse of his Crohn disease [262]. The diagnosis in this case was made on clinical finding and imaging only. The 10 year old girl reported by Rafiei et al. had bilateral dacryoadenitis as part of her initial presentation of Crohn disease [263]. The diagnosis in this case was made on examination findings alone.
Nasolacrimal Duct Obstruction
Acquired nasolacrimal duct obstruction is well known to occur in adults with inflammatory bowel disease [264]. but has only been reported in a child once [265]. This 16 year old boy had bilateral nasolacrimal duct obstruction that required dacryocystorhinostomy procedures. Nodular tissue was found in both lacrimal sacs and histopathology showed granulomatous inflammation.
Orbital Pseudotumour
Orbital pseudotumour has been reported on five occasions in the pediatric age group [249, 266–269]. Interestingly all cases have been in girls and with one exception all have been in association with Crohn disease [249]. In all cases there was involvement of extraocular muscles and in four cases this was well seen on imaging [266–269]. In the earlier report of Ellis and Gentry a mass was described as being over the trochlea and superior oblique sheath and no imaging was performed [249]. This report gave no other details about eye movement findings .
Co-incidental Ophthalmic Findings (Strabismus, Amblyopia and Refractive Error)
One child was found to have esotropia and amblyopia and another unilateral high myopia both of which were probably co-incidental findings [244].
Diagnosis
The diagnosis of Crohn disease and ulcerative colitis relies predominantly on endoscopy of the upper and lower bowel and histology of biopsies. Supportive evidence of small bowel or perianal involvement in Crohn disease is obtained by MRI and capsule endoscopy (tiny camera that is swallowed and wirelessly transmits images of the small intestine). A new screening tool, stool calprotectin has excellent sensitivity and specificity in identifying inflammation of the bowel and is also used in disease monitoring [270]. Some authors have recommended routine screening for ophthalmic manifestations [244, 247] while others have commented that the evidence base for doing this is uncertain and the disease impact is low as the uveitis is usually so mild. Further long-term study of these patients is needed [243].
Management
The goal of treatment is to attain mucosal healing. The treatment of inflammatory bowel disease involves immunosuppression and immunomodulation. The mainstay of paediatric management includes steroids, 5ASA preparations, thiopurines, methotrexate and anti-TNF preparations including infliximab and adalimumab. Tacrolimus is also used for refractory colitis. An 8 week trail of exclusive enteral nutrition has been shown to be as effective as steroids in attaining mucosal healing in children with Crohn disease [271]. Colectomy may be required if colitis cannot be controlled with medical therapy. In Crohn disease, stricturing of the bowel may be amenable to balloon dilatation or may requires resection. In addition, perianal disease and fistulas may require the placement of setons to aid healing. With the newer therapies, the long term survival in children with inflammatory bowel disease is excellent. However there is a significant increased risk of cancer [272].
Ophthalmic management may be observation alone for asymptomatic anterior uveitis [243–245]. Other more significant inflammatory processes such as episcleritis, scleritis, conjunctival granuloma, keratitis, papillitis, dacryoadenitis or orbital pseudotumour respond well to topical and systemic corticosteroids [249, 250, 254, 258, 262, 263, 266–269]. Visual outcomes are usually excellent.
Hirschsprung Disease
Definition
Hirschsprung disease is the result of a failure of development of the enteric nervous system resulting in a congenital absence of parasympathetic ganglia in the submucosal and myenteric plexi of the distal bowel extending for a variable distance continuously from the internal anal sphincter [273]. The genetics of this condition are complex and may involve mutations of one of several genes including RET (OMIM 164761, 10q11.21), EDNRB (OMIM 131244, 13q22.3) and EDN3 (OMIM 131242, 20q13.32) [273].
History
Epidemiology
Hirschsprung disease is estimated to have an incidence of one in 5000 live births with a male:female ratio of approximately 4:1 [277].
Systemic Manifestations
Hirschsprung disease usually presents within the first few months of life with constipation, delayed passage of meconium, feed intolerance or uncommonly as enterocolitis with bowel perforation. Children with very short segment disease may present later in life with constipation.
Long term complications include the risk of enterocolitis which is more common in patients with Down syndrome, ongoing constipation and faecal incontinence [278].
Ocular Manifestations
Many ocular manifestations have been reported in association with syndromic Hirschsprung disease and these are tabulated in Table 10.2 [280–293].
Table 10.2
Syndromes associated with Hirschsprung Disease with ocular findings
Syndrome | Systemic features | Ocular manifestations |
|---|---|---|
Bardet-Biedl | Obesity, intellectual disability, polydactyly, hypogenitalism, renal abnormalities | Retinal dystrophy [280], cataract, strabismus |
Congenital central hypoventilation | Hypoxia, reduced ventilatory drive, neuroblastoma | Fixed dilated pupils, strabismus, Marcus Gunn jaw winking [281] |
Familial dysautonomia (Riley-Day syndrome ) | Sensory and autonomic dysfunction (including abnormal sweat, tear, and saliva production) | Alacrimia, corneal surface abnormalities [282] |
Fryns syndrome | Distal digital hypoplasia, diaphragmatic hernia, congenital heart disease, craniofacial, intellectual disability | Congenital glaucoma, microphthalmia, coloboma [283] |
Goldberg-Shprintzen syndrome | Craniofacial, microcephaly, intellectual disability, polymicrogyria | |
Intestinal neuronal dysplasia | Abnormal intestinal innervation with giant ganglia | Miosis with denervation pupillary hypersensitivity [286] |
Multiple endocrine neoplasia 2A | Medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism, lip/tongue nodules | Prominent corneal nerves [287] |
Multiple endocrine neoplasia 2B | Medullary thyroid carcinoma, pheochromocytoma, mucosal and intestinal neuromas, skeletal abnormalities | Prominent corneal nerves, eyelid neuromas, lid margin eversion or thickening, subconjunctival neuroma, and ptosis [288] |
Mowat-Wilson syndrome | Intellectual disability, microcephaly, craniofacial, congenital heart disease, agenesis of the corpus callosum, epilepsy, short stature | Microphthalmia, coloboma, cataract, Axenfeld-Rieger spectrum anomalies, myopia, strabismus, ptosis [289] |
Neurofibromatosis 1 | Café-au-lait spots, axillary/inguinal freckling, neurofibromas, bony dysplasia, developmental delay | Lisch nodules, thickened corneal nerves, optic pathway glioma, glaucoma, sphenoid wing aplasia [290] |
Smith-Lemli-Opitz | Intellectual disability, hypospadias, syndactyly, congenital heart disease, craniofacial abnormalities | Ptosis, cataract, strabismus, optic nerve hypoplasia, atrophy and swelling [291] |
Waardenburg syndrome type 4 (Waardenburg-Shah syndrome) | Pigmentary abnormalities, deafness |
Diagnosis
The diagnosis of Hirschsprung disease is made by rectal biopsy.
Management
The management of Hirschsprung disease is primarily surgical with removal of the most of the aganglionic segment and anastomosis distally with four main “pull-through” operations (Swenson, Soave, Duhamel and Rehbein) [294].
Celiac Disease
Definition
Celiac disease is defined as “an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals and characterised by the presence of a variable combination of gluten-dependent clinical manifestations, celiac disease-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy” [295]. The celiac disease specific antibodies are autoantibodies against tissue transglutaminase type 2 (anti-TG2), endomysial antibodies (EMA ) and antibodies against deamidated forms of gliadin peptides (anti-DGP) [295]. In children and adolescents the presentation of celiac disease can be quite non-specific and testing is recommended for chronic or intermittent diarrhea, unexplained weight loss, chronic fatigue, etc. Testing is also recommended in children and adolescents with conditions that are known to have increased risk of developing celiac disease such as type 1 diabetes mellitus, Down syndrome, autoimmune thyroid disease , Turner syndrome , Williams syndrome , selective immunoglobulin A (IgA) deficiency, autoimmune liver disease, and first-degree relatives with celiac disease [295, 296]. The understanding of the pathogenesis of this disease continues to improve with evidence that changes in the microbiome, antirotavirus VP7 antibodies and the Parkinson’s disease seven gene may all have a role in the development of the celiac disease [297].
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