Clin J Gastroenterol (2014) 7:48–51 DOI 10.1007/s12328-013-0418-6
CASE REPORT
Dealing with congenital hepatic fibrosis? Remember COACH syndrome B. C. Acharyya • M. K. Goenka • S. Chatterjee • U. Goenka
Received: 15 July 2013 / Accepted: 15 August 2013 / Published online: 11 December 2013 Ó Springer Japan 2013
Abstract Coach Syndrome is a rare cause of Congenital Hepatic Fibrosis associated with neurological features. COACH is a mnemonic comprising of Cerebellar vermis hypo/aplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma and Hepatic fibrosis. Here we describe a 12 years boy who presented with hepatic encephalopathy. He was subsequently found to have marked developmental delay, bilateral ptosis and ataxia. CT scan revealed brain stem molar tooth sign, ophthalmoscopy showed optic disc coloboma and elastography showed hepatic fibrosis to confirm him as a case of COACH Syndrome. Keywords COACH Hepatic fibrosis Ataxia Coloboma Molar tooth sign
Introduction COACH Syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypo/aplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma and Hepatic fibrosis. The vermis hypoplasia is a type of mid-hind brain malformation called the molar tooth
B. C. Acharyya M. K. Goenka Institute of Gastroenterology, Apollo Gleneagles Hospitals, Kolkata, India B. C. Acharyya (&) AMRI Hospital, Saltlake, Kolkata, India e-mail: [email protected] S. Chatterjee U. Goenka Department of Radiology, Apollo Gleneagles Hospitals, Kolkata, India
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sign (MTS) and therefore COACH Syndrome is considered a Joubart Syndrome related disorder (JSRD). We describe a 12 years old boy, who presented with hepatic encephalopathy and renal failure and was found to have developmental delay, bilateral ptosis with nystagmus and ataxia. Further investigations revealed him to be having brain stem MTS, hepatic fibrosis and optic disc coloboma to confirm him to be suffering from COACH Syndrome.
Case report 12 years old boy presented in emergency with drowsiness. He was the 2nd child of non-consanguineous parents. He had a normal birth history but had marked developmental delay in all aspects of milestones. Though he started to walk at 3 years, he had ataxic gait. His speech was still limited to 2–3 word sentences and he had significant mental retardation. Past history revealed that he had been admitted to different hospitals on previous occasions starting at the age of 6 years with history of haematemesis. He was diagnosed to have esophageal varices and was treated with endoscopic variceal ligation (EVL) for esophageal varices as well as cyanoacrylate glue injection for gastric varices in a few occasions. He also had history of sobbing respiration when asleep in infancy. He had an elder sister who died at the age of 12 years, the cause of death was not known. She, however also had developmental delay albeit less severe. Physical examination confirmed that the child had retarded growth; Weight and Height were at 3rd centile. He had 2 cm liver palpable below right costal margin and a huge, 12 cm firm palpable spleen. There was no ascites. He was in grade 2 hepatic encephalopathy. Laboratory investigation showed Hb % of 6.6 gm %, total leucocyte count
Clin J Gastroenterol (2014) 7:48–51
of 16910/dL, and platelets of 18000/dL. His blood urea was 180 mg/dL (normal \40), creatinine 3.4 mg/dL and liver function test showed a bilirubin of 3 mg/d, albumin of 2.5 gm/L, SGOT 251U/L, SGPT 127U/L, GGT 70U/L and prothrombin time of 22.2 s (control 14.4 s.) He responded well to anti encephalopathy measures. A detailed clinical examination revealed bilateral ptosis, horizontal nystagmus and mild hypertelorism. He had ataxia with a mental and developmental age of \4 years. Upper GI endoscopy showed grade III oesophageal varices, fundal varices with some scarring due to previous glue injection (Fig. 1). A CT scan brain showed thickened superior cerebellar peduncle, with perpendicular projection dorsally from brain stem (molar tooth like appearance). Fourth ventricle was wide (umbrella or batwing appearance) with hypoplastic cerebellar vermis (Fig. 2a, b). Examination of his retina revealed bilateral Coloboma of
Fig. 1 Fundal varices
49
optic disc with surrounding pigmentary changes (Fig. 3). Ultrasound scan of Kidney showed increased cortical echogenicity (Fig. 4). A liver biopsy was planned and was not done due to very low platelet count and a deranged prothrombin time. Liver Elastography was carried out which showed an acoustic radiation force impulse (ARFI) value of 2.74 suggestive of grade 4 fibrosis. Patient was diagnosed as COACH Syndrome and was put on regular EVL programme. Parents are also being counselled for living donor liver transplantation.
Review of literature COACH is a mnemonic comprising of Cerebellar Hypoplasia, Oligophrenia, Ataxia, Coloboma and Hepatic fibrosis. In 1974 Hunter et al. [1] described a clinical syndrome comprising of hepatic fibrosis, polycystic kidney, colobomata and encephalopathy though the name COACH was not coined at that time. Similar case was subsequently described by Thompson et al. [2], who described it as an autosomal recessive mental retardation with hepatic fibrosis and renal cysts. In 1989 Verlos and Lambotte gave a description of 3 more children who had mental retardation, hepatic fibrosis, renal abnormalities, colobomas, subtotal cerebellar vermis hypoplasia with ataxia and a few other dysmorphic features including hypertelorism [3]. They introduced the acronym COACH describing the major clinical features. Till 2010 only 43 cases of COACH Syndrome have been reported in literature [5]. Familial occurrence of this syndrome in the form of multiple cases in single sibship does suggest an autosomal recessive inheritance. In a recent comprehensive review 13 sets of siblings have been described. The affection of older sister of the present case might have
Fig. 2 a Axial noncontrast CT section shows thickened bilateral superior cerebellar peduncles with molar tooth like appearance and batwing shaped fourth ventricle. b Axial Noncontrast CT section at lower level shows absence of cerebellar vermis with cleft separating bilateral cerebellar hemispheres (Rombencephaloschisis)
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Fig. 3 Ophthalmoscopy showing a defect in the optic disc (coloboma) with surrounding pigmentation
Fig. 4 Ultrasound of Kidney showing loss of cortico-medullary differentiation and increased echogenicity of renal medulla
added another sibship though due to the premature death of the child the exact diagnosis could not be proven. The genetics behind this Syndrome have been identified. Three genes have been described, mutation of which lead to Joubart syndrome related disorder. Mutation in MKS3 is responsible for the majority of COACH Syndrome with minor contributions from CC2 D2A and RPGRIP1L. It has been suggested that MKS3 mutation should be tested first in any suspected case of Joubart Syndrome related disorder [5].
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Clin J Gastroenterol (2014) 7:48–51
The first presentation of our patient was at the age of 6 years with severe upper GI bleed due to varices. That time he was found to have bilateral ptosis but he was not investigated further. Presence of family history in the form of death of older sibling led us suspect the possibility of some genetic disorder. Congenital hepatic fibrosis is the component that differentiates COACH Syndrome from typical Joubart Syndrome. The liver biopsy findings of broad septa of fibrous tissue containing abundant bile ducts, portal tracts enlarged by fibrosis and preserved lobular architecture are the hallmark [6]. A low platelet count and high prothrombin time prevented a percutaneous liver biopsy in our patient. Elastography of liver however did confirm the presence of advanced fibrosis. The CT/MRI finding of Joubart related disorder is very typical. CT finding was first mentioned by Verlos et al. [3]. Our patient had all the features of midbrain MTS and cerebellar vermis hypoplasia. That was very much corroborative. In Joubart Syndrome, children have a very typical episodic sobbing respiration or hyper ventilation. In COACH syndrome it might be present in infancy but usually disappear later on. In our case mother gave a history of abnormal respiratory pattern during sleep in infancy which disappeared completely after the age of 4 years [7]. Involvement of eye is another important feature that had been described in almost all COACH Syndrome. Coloboma is the typical of COACH whereas abnormal eye movement is classically seen in Joubart syndrome. In our case ophthalmological assessment showed bilateral ptosis, mild hypertelorism, horizontal nystagmus and coloboma of optic disc. Though not considered earlier, Kumar et al. [8] described that renal insufficiency could be a part of COACH Syndrome. They found that progressive renal insufficiency is a common feature of COACH syndrome and described fibrocystic changes in renal biopsy. Lewis et al. [9] also reported two children with COACH clinical components having medullary cystic disease of the kidney. Our child presented with significant renal impairment. His renal ultrasonography revealed loss of cortico-medullary differentiation, increased echogenicity of renal medulla suggestive of nephronophthisis (Fig. 4). COACH Syndrome patients often become complicated with progressive portal hypertension with variceal bleeds, features of hypersplenism and renal insufficiency. In the cohort of 26 subjects in 23 families described by Doharty et al. [5], portosystemic shunt was performed in two(8 %) and liver transplantation was required in 1(4 %).In the same cohort end stage renal disease developed in 3(13 %) and renal transplant was needed in two(8 %). Our patient is presently being successfully managed by conservative treatment including variceal band ligation and is being prepared for a liver transplantation.
Clin J Gastroenterol (2014) 7:48–51 Disclosures Conflict of Interest: The authors declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
References 1. Hunter AGW, Rothman SJ, Hwang WS, et al. Hepatic fibrosis, polycystic kidney, colobomata and encephalopathy in siblings. Clin Genet. 1974;6:82–9. 2. Thompson E, Baraitser M. An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts. Am J Med Genet. 1986;24:151–8.
51 3. Verloes A, Lambotte C. Further delineation of syndrome of cerebellar vermis aplasia/hypoplasia, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis. Am J Med Genet. 1989;32:127–32. 4. Mitsui F, Aikata H, Azakami T, et al. The first Japanese case of COACH Syndrome. Hepat Res. 2009;39:318–23. 5. Doherty D, Parisi MA, Finn LS, et al. Mutations in 3 genes(MKS3, CC2D2Aand RPGRIP1L) cause COACH syndrome. (Joubert Syndrome with congenital hepatic fibrosis). J Med Genet. 2010;4:8–21. 6. Gentile M, Di Carlo A, Susca F, et al. COACH Syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia and ataxia and mental retardation. Am J Med Genet. 1996;64:514–20. 7. Barzilai M, Ish-shalom N, Lerner A, Lancu TC. Imaging findings in COACH Syndrome. AJR. 1998;170:1081–2. 8. Kumar S, Rankin R. Renal insufficiency is a component of COACH Syndrome. Am J Med Genet. 1996;61:122–6. 9. Lewis SME, Roberts EA, Marcon MA, et al. Joubart Syndrome with congenital hepatic fibrosis: an entity in the spectrum of oculoencephalo-hepato-renal disorders. Am J Med Genet. 1994;52: 419–26.
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CASE REPORT
Dealing with congenital hepatic fibrosis? Remember COACH syndrome B. C. Acharyya • M. K. Goenka • S. Chatterjee • U. Goenka
Received: 15 July 2013 / Accepted: 15 August 2013 / Published online: 11 December 2013 Ó Springer Japan 2013
Abstract Coach Syndrome is a rare cause of Congenital Hepatic Fibrosis associated with neurological features. COACH is a mnemonic comprising of Cerebellar vermis hypo/aplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma and Hepatic fibrosis. Here we describe a 12 years boy who presented with hepatic encephalopathy. He was subsequently found to have marked developmental delay, bilateral ptosis and ataxia. CT scan revealed brain stem molar tooth sign, ophthalmoscopy showed optic disc coloboma and elastography showed hepatic fibrosis to confirm him as a case of COACH Syndrome. Keywords COACH Hepatic fibrosis Ataxia Coloboma Molar tooth sign
Introduction COACH Syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypo/aplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma and Hepatic fibrosis. The vermis hypoplasia is a type of mid-hind brain malformation called the molar tooth
B. C. Acharyya M. K. Goenka Institute of Gastroenterology, Apollo Gleneagles Hospitals, Kolkata, India B. C. Acharyya (&) AMRI Hospital, Saltlake, Kolkata, India e-mail: [email protected] S. Chatterjee U. Goenka Department of Radiology, Apollo Gleneagles Hospitals, Kolkata, India
123
sign (MTS) and therefore COACH Syndrome is considered a Joubart Syndrome related disorder (JSRD). We describe a 12 years old boy, who presented with hepatic encephalopathy and renal failure and was found to have developmental delay, bilateral ptosis with nystagmus and ataxia. Further investigations revealed him to be having brain stem MTS, hepatic fibrosis and optic disc coloboma to confirm him to be suffering from COACH Syndrome.
Case report 12 years old boy presented in emergency with drowsiness. He was the 2nd child of non-consanguineous parents. He had a normal birth history but had marked developmental delay in all aspects of milestones. Though he started to walk at 3 years, he had ataxic gait. His speech was still limited to 2–3 word sentences and he had significant mental retardation. Past history revealed that he had been admitted to different hospitals on previous occasions starting at the age of 6 years with history of haematemesis. He was diagnosed to have esophageal varices and was treated with endoscopic variceal ligation (EVL) for esophageal varices as well as cyanoacrylate glue injection for gastric varices in a few occasions. He also had history of sobbing respiration when asleep in infancy. He had an elder sister who died at the age of 12 years, the cause of death was not known. She, however also had developmental delay albeit less severe. Physical examination confirmed that the child had retarded growth; Weight and Height were at 3rd centile. He had 2 cm liver palpable below right costal margin and a huge, 12 cm firm palpable spleen. There was no ascites. He was in grade 2 hepatic encephalopathy. Laboratory investigation showed Hb % of 6.6 gm %, total leucocyte count
Clin J Gastroenterol (2014) 7:48–51
of 16910/dL, and platelets of 18000/dL. His blood urea was 180 mg/dL (normal \40), creatinine 3.4 mg/dL and liver function test showed a bilirubin of 3 mg/d, albumin of 2.5 gm/L, SGOT 251U/L, SGPT 127U/L, GGT 70U/L and prothrombin time of 22.2 s (control 14.4 s.) He responded well to anti encephalopathy measures. A detailed clinical examination revealed bilateral ptosis, horizontal nystagmus and mild hypertelorism. He had ataxia with a mental and developmental age of \4 years. Upper GI endoscopy showed grade III oesophageal varices, fundal varices with some scarring due to previous glue injection (Fig. 1). A CT scan brain showed thickened superior cerebellar peduncle, with perpendicular projection dorsally from brain stem (molar tooth like appearance). Fourth ventricle was wide (umbrella or batwing appearance) with hypoplastic cerebellar vermis (Fig. 2a, b). Examination of his retina revealed bilateral Coloboma of
Fig. 1 Fundal varices
49
optic disc with surrounding pigmentary changes (Fig. 3). Ultrasound scan of Kidney showed increased cortical echogenicity (Fig. 4). A liver biopsy was planned and was not done due to very low platelet count and a deranged prothrombin time. Liver Elastography was carried out which showed an acoustic radiation force impulse (ARFI) value of 2.74 suggestive of grade 4 fibrosis. Patient was diagnosed as COACH Syndrome and was put on regular EVL programme. Parents are also being counselled for living donor liver transplantation.
Review of literature COACH is a mnemonic comprising of Cerebellar Hypoplasia, Oligophrenia, Ataxia, Coloboma and Hepatic fibrosis. In 1974 Hunter et al. [1] described a clinical syndrome comprising of hepatic fibrosis, polycystic kidney, colobomata and encephalopathy though the name COACH was not coined at that time. Similar case was subsequently described by Thompson et al. [2], who described it as an autosomal recessive mental retardation with hepatic fibrosis and renal cysts. In 1989 Verlos and Lambotte gave a description of 3 more children who had mental retardation, hepatic fibrosis, renal abnormalities, colobomas, subtotal cerebellar vermis hypoplasia with ataxia and a few other dysmorphic features including hypertelorism [3]. They introduced the acronym COACH describing the major clinical features. Till 2010 only 43 cases of COACH Syndrome have been reported in literature [5]. Familial occurrence of this syndrome in the form of multiple cases in single sibship does suggest an autosomal recessive inheritance. In a recent comprehensive review 13 sets of siblings have been described. The affection of older sister of the present case might have
Fig. 2 a Axial noncontrast CT section shows thickened bilateral superior cerebellar peduncles with molar tooth like appearance and batwing shaped fourth ventricle. b Axial Noncontrast CT section at lower level shows absence of cerebellar vermis with cleft separating bilateral cerebellar hemispheres (Rombencephaloschisis)
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50
Fig. 3 Ophthalmoscopy showing a defect in the optic disc (coloboma) with surrounding pigmentation
Fig. 4 Ultrasound of Kidney showing loss of cortico-medullary differentiation and increased echogenicity of renal medulla
added another sibship though due to the premature death of the child the exact diagnosis could not be proven. The genetics behind this Syndrome have been identified. Three genes have been described, mutation of which lead to Joubart syndrome related disorder. Mutation in MKS3 is responsible for the majority of COACH Syndrome with minor contributions from CC2 D2A and RPGRIP1L. It has been suggested that MKS3 mutation should be tested first in any suspected case of Joubart Syndrome related disorder [5].
123
Clin J Gastroenterol (2014) 7:48–51
The first presentation of our patient was at the age of 6 years with severe upper GI bleed due to varices. That time he was found to have bilateral ptosis but he was not investigated further. Presence of family history in the form of death of older sibling led us suspect the possibility of some genetic disorder. Congenital hepatic fibrosis is the component that differentiates COACH Syndrome from typical Joubart Syndrome. The liver biopsy findings of broad septa of fibrous tissue containing abundant bile ducts, portal tracts enlarged by fibrosis and preserved lobular architecture are the hallmark [6]. A low platelet count and high prothrombin time prevented a percutaneous liver biopsy in our patient. Elastography of liver however did confirm the presence of advanced fibrosis. The CT/MRI finding of Joubart related disorder is very typical. CT finding was first mentioned by Verlos et al. [3]. Our patient had all the features of midbrain MTS and cerebellar vermis hypoplasia. That was very much corroborative. In Joubart Syndrome, children have a very typical episodic sobbing respiration or hyper ventilation. In COACH syndrome it might be present in infancy but usually disappear later on. In our case mother gave a history of abnormal respiratory pattern during sleep in infancy which disappeared completely after the age of 4 years [7]. Involvement of eye is another important feature that had been described in almost all COACH Syndrome. Coloboma is the typical of COACH whereas abnormal eye movement is classically seen in Joubart syndrome. In our case ophthalmological assessment showed bilateral ptosis, mild hypertelorism, horizontal nystagmus and coloboma of optic disc. Though not considered earlier, Kumar et al. [8] described that renal insufficiency could be a part of COACH Syndrome. They found that progressive renal insufficiency is a common feature of COACH syndrome and described fibrocystic changes in renal biopsy. Lewis et al. [9] also reported two children with COACH clinical components having medullary cystic disease of the kidney. Our child presented with significant renal impairment. His renal ultrasonography revealed loss of cortico-medullary differentiation, increased echogenicity of renal medulla suggestive of nephronophthisis (Fig. 4). COACH Syndrome patients often become complicated with progressive portal hypertension with variceal bleeds, features of hypersplenism and renal insufficiency. In the cohort of 26 subjects in 23 families described by Doharty et al. [5], portosystemic shunt was performed in two(8 %) and liver transplantation was required in 1(4 %).In the same cohort end stage renal disease developed in 3(13 %) and renal transplant was needed in two(8 %). Our patient is presently being successfully managed by conservative treatment including variceal band ligation and is being prepared for a liver transplantation.
Clin J Gastroenterol (2014) 7:48–51 Disclosures Conflict of Interest: The authors declare that they have no conflict of interest. Human/Animal Rights: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008(5). Informed Consent: Informed consent was obtained from all patients for being included in the study.
References 1. Hunter AGW, Rothman SJ, Hwang WS, et al. Hepatic fibrosis, polycystic kidney, colobomata and encephalopathy in siblings. Clin Genet. 1974;6:82–9. 2. Thompson E, Baraitser M. An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts. Am J Med Genet. 1986;24:151–8.
51 3. Verloes A, Lambotte C. Further delineation of syndrome of cerebellar vermis aplasia/hypoplasia, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis. Am J Med Genet. 1989;32:127–32. 4. Mitsui F, Aikata H, Azakami T, et al. The first Japanese case of COACH Syndrome. Hepat Res. 2009;39:318–23. 5. Doherty D, Parisi MA, Finn LS, et al. Mutations in 3 genes(MKS3, CC2D2Aand RPGRIP1L) cause COACH syndrome. (Joubert Syndrome with congenital hepatic fibrosis). J Med Genet. 2010;4:8–21. 6. Gentile M, Di Carlo A, Susca F, et al. COACH Syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia and ataxia and mental retardation. Am J Med Genet. 1996;64:514–20. 7. Barzilai M, Ish-shalom N, Lerner A, Lancu TC. Imaging findings in COACH Syndrome. AJR. 1998;170:1081–2. 8. Kumar S, Rankin R. Renal insufficiency is a component of COACH Syndrome. Am J Med Genet. 1996;61:122–6. 9. Lewis SME, Roberts EA, Marcon MA, et al. Joubart Syndrome with congenital hepatic fibrosis: an entity in the spectrum of oculoencephalo-hepato-renal disorders. Am J Med Genet. 1994;52: 419–26.
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