COACH Syndrome

COACH Syndrome
Classification and external resources
ICD-10 Q04.3
OMIM 216360

COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD) due to mutation in the gene TMEM67 in majority of cases.[1] Renal insufficiency was also found in some cases.[2]

History

Year Author Method Unique Findings Reference
1989 Verloes, A. 3 affected children in 2 sibships The acronym COACH (Cerebellar vermis hypoplasia, Oligophrenia, congenital Ataxia, Coloboma, Hepatic fibrocirrhosis) is suggested. [3]
1992 Wiesner, G. L Autopsy of sister at 46 years Billiary duct proliferation due to hepatic fibrosis [4]
1994 Lewis SM two unrelated children with Joubert syndrome and hepatosplenomegaly Joubert syndrome appears to be one of a spectrum of congenital malformation syndromes involving the central nervous system, eye, liver and kidneys. [5]
1996 Gentile M 2 brothers of Italian descent Phenotypic overlap with Joubert and Meckel syndromes [6]
1996 Kumar S 2 sisters 23 years and 6years AR inheritance, Renal insufficiency [2]
1999 Satran D 100 Case review with cerebellar vermis hypoplasia, and ocular or renal involvement (a) hypoplasia of the cerebellar vermis, especially the anterior vermis, is often associated with a complex brainstem malformation;

(b) the latter comprises a "molar tooth" brainstem and vermis hypoplasia-dysplasia malformation complex;

(c) this complex may include the Dandy-Walker malformation, occipital cephalocele, and some abnormalities of the cerebrum as evidenced by frequent mental retardation;

(d) the "molar tooth" sign or malformation is causally heterogeneous as it occurs in several distinct malformation syndromes including Joubert syndrome, Arima syndrome, Senior-Löken syndrome, COACH syndrome, and probably familial juvenile nephronophthisis.

 [7]
2002 Coppola G 3 children (2 siblings aged 10 and 3 years, and 1 sporadic case aged 13 years) Coloboma and renal involvement were absent. [8]
2009 Brancati F Analysis of MKS3 in 14 COACH families COACH as a distinct JSRD (Joubert Syndrome (JS) and Related Disorders (JSRDs)) subgroup with core features of JS plus CHF(congenital hepatic fibrosis), which major gene is MKS3 (approved symbol TMEM67),8 (58%) and further strengthen gene-phenotype correlates in JSRD [9]
2010 Doherty D In a cohort of 251 families with JSRD, 26 subjects in 23 families Mutations in MKS3 are responsible for the majority (83%) of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L [1]

Genetics

Location

Gene Locus

4p15.32

CC2D2A

8q22.1

TMEM67 (83%)

16q12.2

RPGRIP1L

[1]

Pathology

Liver Biopsy

Congenital Hepatic Fibrosis (CHF) is hallmark of COACH syndrome.[10] Multiple hepatic tumors has also been reported in some cases.[11] Septal fibrosis and pseudolobules, inflammatory infiltrates, signs of cholestasis, and reduced numbers of intrahepatic bile ducts progresses to live cirrhosis.[12]

Renal Biopsy

Showed mild interstitial fibrosis and amyloid deposit, but had no functional impairment.[3]

Clinical Features

Neurologic abnormalities are the first symptoms in most cases. Hypotonia in infancy with later development of ataxia, developmental delay/mental retardation, abnormal breathing pattern (tachypnoea and/or apnoea) and abnormal eye movements (typically, nystagmus, oculomotor apraxia (OMA) or difficulty with smooth visual pursuit).[1][13][14][15]

Other features variably reported in JSRD include dysmorphic facial features, polydactyly, retinal dystrophy, chorioretinal colobomas, renal disease (cysts or juvenile nephronophthisis), hepatic fibrosis, and tongue papules or oral frenulae.[15][16]

The majority of cases were diagnosed late in childhood or adolescence. Complications of the hepatopathy contribute extensively to the morbidity and lethality in the course of the disease. Major complications are portal hypertension, esophageal varices, and gastrointestinal bleeding.[17]

Imaging

CT Brain

Cerebellar vermis hypoplasia can be seen.[1]

MRI Brain

Cogenital Vermian Hypoplasia (CVH) in COACH syndrome was accompanied by elongation of the superior cerebellar peduncles and a deep interpeduncular fossa, all features that constitute the molar tooth sign (MTS), the key feature of Joubert syndrome and related disorders (JSRD).[1]

CT Abdomen

Hepatospleenomegaly with portal hypertension.[10]

Treatment

Successful liver and kidney transplantation have been done in some cases.[18]

See also

Joubert Syndrome

Congenital Hepatic Fibrosis

Joubert Syndrome and Related Disorder

References

  1. 1 2 3 4 5 6 Doherty, D.; Parisi, M. A.; Finn, L. S.; Gunay-Aygun, M.; Al-Mateen, M.; Bates, D.; Clericuzio, C.; Demir, H.; Dorschner, M. (2010-01-01). "Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)". Journal of Medical Genetics. 47 (1): 8–21. doi:10.1136/jmg.2009.067249. ISSN 1468-6244. PMC 3501959Freely accessible. PMID 19574260.
  2. 1 2 Kumar, S (1996). "Renal insufficiency is a component of COACH syndrome". Am J Med Genet. 61 (2): 122–6. doi:10.1002/(SICI)1096-8628(19960111)61:2<122::AID-AJMG3>3.0.CO;2-Z. PMID 8669436.
  3. 1 2 Verloes, A (1989). "Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis". Am J Med Genet. 32 (2): 227–32. doi:10.1002/ajmg.1320320217. PMID 2929661.
  4. ↑ Wiesner, GL (1992). "Familial cerebellar ataxia and hepatic fibrosis--a variant of COACH syndrome with biliary ductal proliferation". Am. J. Hum. Genet. Suppl. 51: A110.
  5. ↑ Lewis, SM (1994). "Joubert syndrome with congenital hepatic fibrosis: an entity in the spectrum of oculo-encephalo-hepato-renal disorders". Am J Med Genet. 52 (4): 419–26. doi:10.1002/ajmg.1320520406. PMID 7538263.
  6. ↑ Gentile, M (1996). "COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation". Am J Med Genet. 64 (3): 514–20. doi:10.1002/(SICI)1096-8628(19960823)64:3<514::AID-AJMG13>3.0.CO;2-O. PMID 8862632.
  7. ↑ Satran, D.; Pierpont, M. E.; Dobyns, W. B. (1999-10-29). "Cerebello-oculo-renal syndromes including Arima, Senior-Löken and COACH syndromes: more than just variants of Joubert syndrome". American Journal of Medical Genetics. 86 (5): 459–469. doi:10.1002/(sici)1096-8628(19991029)86:5<459::aid-ajmg12>3.3.co;2-3. ISSN 0148-7299. PMID 10508989.
  8. ↑ Coppola, G.; Vajro, P.; De Virgiliis, S.; Ciccimarra, E.; Boccone, L.; Pascotto, A. (2002-08-01). "Cerebellar vermis defect, oligophrenia, congenital ataxia, and hepatic fibrocirrhosis without coloboma and renal abnormalities: report of three cases". Neuropediatrics. 33 (4): 180–185. doi:10.1055/s-2002-34492. ISSN 0174-304X. PMID 12368986.
  9. ↑ Brancati, Francesco; Iannicelli, Miriam; Travaglini, Lorena; Mazzotta, Annalisa; Bertini, Enrico; Boltshauser, Eugen; D'Arrigo, Stefano; Emma, Francesco; Fazzi, Elisa (2009-02-01). "MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement". Human Mutation. 30 (2): E432–442. doi:10.1002/humu.20924. ISSN 1098-1004. PMC 2635428Freely accessible. PMID 19058225.
  10. 1 2 Mitsui, Fukiko; Aikata, Hiroshi; Azakami, Takahiro; Katamura, Yoshio; Kimura, Takashi; Kawaoka, Tomokazu; Saneto, Hiromi; Takaki, Shintaro; Hiraga, Nobuhiko (2009-03-01). "The first Japanese case of COACH syndrome". Hepatology Research. 39 (3): 318–323. doi:10.1111/j.1872-034X.2008.00445.x. ISSN 1386-6346. PMID 19261004.
  11. ↑ Kirchner, Gabriele I.; Wagner, Siegfried; Flemming, Peer; Bleck, Joerg S.; Gebel, Michael; Schedel, Ingolf; Schüler, Andreas; Galanski, Michael; Manns, Michael P. (2002-10-01). "COACH syndrome associated with multifocal liver tumors". The American Journal of Gastroenterology. 97 (10): 2664–2669. doi:10.1111/j.1572-0241.2002.06051.x. ISSN 0002-9270. PMID 12385458.
  12. ↑ Foell, Dirk; August, Christian; Frosch, Michael; Harms, Erik; Zimmer, Klaus-Peter (2002-09-01). "Early detection of severe cholestatic hepatopathy in COACH syndrome". American Journal of Medical Genetics. 111 (4): 429–434. doi:10.1002/ajmg.10614. ISSN 0148-7299. PMID 12210305.
  13. ↑ Maria, B. L.; Quisling, R. G.; Rosainz, L. C.; Yachnis, A. T.; Gitten, J.; Dede, D.; Fennell, E. (1999-06-01). "Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance". Journal of Child Neurology. 14 (6): 368–376. doi:10.1177/088307389901400605. ISSN 0883-0738. PMID 10385844.
  14. ↑ Saraiva, JM (1992). "Joubert syndrome: a review". Am J Med Genet. 43 (4): 726–31. doi:10.1002/ajmg.1320430415. PMID 1341417.
  15. 1 2 Steinlin, M (1997). "Follow-up in children with Joubert syndrome". Neuropediatrics. 28 (4): 204–11. doi:10.1055/s-2007-973701. PMID 9309710.
  16. ↑ Maria, B. L.; Boltshauser, E.; Palmer, S. C.; Tran, T. X. (1999-09-01). "Clinical features and revised diagnostic criteria in Joubert syndrome". Journal of Child Neurology. 14 (9): 583–590; discussion 590–591. doi:10.1177/088307389901400906. ISSN 0883-0738. PMID 10488903.
  17. ↑ Foell, D (2002). "Early detection of severe cholestatic hepatopathy in COACH syndrome". Am J Med Genet. 111 (4): 429–34. doi:10.1002/ajmg.10614. PMID 12210305.
  18. ↑ Uemura, Tadahiro; Sanchez, Edmund Q.; Ikegami, Toru; Watkins, David; Narasimhan, Gomathy; McKenna, Greg J.; Chinnakotla, Srinath; Dawson, Sherfield; Randall, Henry B. (2005-12-01). "Successful combined liver and kidney transplant for COACH syndrome and 5-yr follow-up". Clinical Transplantation. 19 (6): 717–720. doi:10.1111/j.1399-0012.2005.00409.x. ISSN 0902-0063. PMID 16313315.
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