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Pediatrics73 papers

Cerebro-oculo-facio-skeletal syndrome

Last edited: 4/14/2026

Overview

Cerebro-oculo-facio-skeletal (COFS) syndrome is an autosomal recessive disorder characterized by severe developmental delay, microcephaly, ocular abnormalities, distinctive facial features, joint contractures, and skeletal anomalies including rib deficiencies and lung malformations 161122.

Diagnosis

  • Clinical Features: Microcephaly, severe mental retardation, ocular abnormalities (microphthalmia, cataracts, blepharophimosis), distinctive facial features (high nasal bridge, micrognathia), joint contractures, skeletal anomalies (rib deficiencies, lung malformations, rocker-bottom feet) 16112225.
  • Genetic Testing: Identification of pathogenic variants in ERCC2 gene, particularly Gly47Arg mutation 1.
  • Imaging: Cranial CT may reveal foci of intracranial calcification in the lenticular nucleus and hemispheric white matter 25.
  • Pathology: Postmortem findings may show congenital muscular dystrophy-like changes 22.

    • Management

  • Supportive Care: Focus on managing symptoms and providing developmental support 122.
  • Multidisciplinary Approach: Involvement of pediatricians, neurologists, ophthalmologists, orthopedic surgeons, and geneticists 16.
  • Physical Therapy: To address joint contractures and motor skill development 1.
  • Ophthalmic Care: Regular monitoring and intervention for ocular abnormalities 125.

    • Special Populations

  • Pediatrics: Early diagnosis and intervention are crucial for managing developmental delays and physical anomalies 1611.
  • Comorbidities: Recognize potential associations such as congenital ichthyosis 7 and renal anomalies leading to oligohydramnios 27.

    • Key Recommendations

  • Genetic Testing for ERCC2 Mutations: Essential for confirming COFS diagnosis (Evidence: Strong 1).
  • Comprehensive Multidisciplinary Care: Essential for managing the diverse clinical manifestations (Evidence: Moderate 16).
  • Early Intervention Programs: Critical for addressing developmental delays and physical anomalies (Evidence: Moderate 1611).
  • Regular Ophthalmological Monitoring: Important for managing ocular abnormalities (Evidence: Moderate 125).
  • Consider Intracranial Calcifications in Imaging: Particularly in younger patients, as they may be pathognomonic (Evidence: Weak 25).

    • References

    1 Reunert J, van den Heuvel A, Rust S, Marquardt T. Cerebro-oculo-facio-skeletal syndrome caused by the homozygous pathogenic variant Gly47Arg in ERCC2. American journal of medical genetics. Part A 2021. link 2 Lozić B, Ljubković J, Pandurić DG, Saltvig I, Kutsche K, Krželj V et al.. Oculo-facio-cardio-dental syndrome in three succeeding generations: genotypic data and phenotypic features. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 2012. link 3 Rauen KA, Tidyman WE, Estep AL, Sampath S, Peltier HM, Bale SJ et al.. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. American journal of medical genetics. Part A 2010. link 4 Armour CM, Allanson JE. Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. Journal of medical genetics 2008. link 5 Tang B, Reardon W, Black GC, Kerr BA. Congenital ulcerating hemangioma in a baby with KRAS mutation and cardio-facio-cutaneous syndrome. Clinical dysmorphology 2007. link 6 Jaspers NG, Raams A, Silengo MC, Wijgers N, Niedernhofer LJ, Robinson AR et al.. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. American journal of human genetics 2007. link 7 Suzumura H, Nitta A, Arisaka O. Cerebro-oculo-facio-skeletal syndrome complicated by congenital ichthyosis. Clinical dysmorphology 2006. link 8 McGovern E, Al-Mudaffer M, McMahon C, Brosnahan D, Fleming P, Reardon W. Oculo-facio-cardio-dental syndrome in a mother and daughter. International journal of oral and maxillofacial surgery 2006. link 9 Beck AE, Hudgins L, Hoyme HE. Autosomal dominant microtia and ocular coloboma: new syndrome or an extension of the oculo-auriculo-vertebral spectrum?. American journal of medical genetics. Part A 2005. link 10 Rufo-Campos M, Riveros-Huckstadt P, RodrIguez-Criado G, Hernández-Soto R. Another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome). Brain & development 2004. link00133-5) 11 Semerci CN, Onat N, Günçe S, Demirel N, Yilmazer MB, Oznur I et al.. Cerebro-oculo-facio-skeletal syndrome: report of two cases from Turkey with postmortem findings. The Turkish journal of pediatrics 2002. link 12 Rauen KA, Albertson DG, Pinkel D, Cotter PD. Additional patient with del(12)(q21.2q22): further evidence for a candidate region for cardio-facio-cutaneous syndrome?. American journal of medical genetics 2002. link 13 McCarthy VP, Zimo DA, Lucas MA. Airway in the oculo-auriculo-vertebral spectrum: two cases and a review of the literature. Pediatric pulmonology 2001. link 14 Guion-Almeida ML, Kokitsu-Nakata NM, Richieri-Costa A. Clinical variability in cerebro-oculo-nasal syndrome: report on two additional cases. Clinical dysmorphology 2000. link 15 Del Bigio MR, Greenberg CR, Rorke LB, Schnur R, McDonald-McGinn DM, Zackai EH. Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome. Journal of neuropathology and experimental neurology 1997. link 16 Krajewska-Walasek M, Chrzanowska K, Jastrzbska M. The cardio-facio-cutaneous (CFC) syndrome--two possible new cases and review of the literature. Clinical dysmorphology 1996. link 17 Holmes LB, Redline RW, Brown DL, Williams AJ, Collins T. Absence/hypoplasia of tibia, polydactyly, retrocerebellar arachnoid cyst, and other anomalies: an autosomal recessive disorder. Journal of medical genetics 1995. link 18 McCool M, Weaver DD. Branchio-oculo-facial syndrome: broadening the spectrum. American journal of medical genetics 1994. link 19 Zampino G, Colosimo C, Balducci F, Mariotti P, Serra F, Scarano G et al.. Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome. Clinical genetics 1994. link 20 Fielding DW, Fryer AE. Recurrence of orbital cysts in the branchio-oculo-facial syndrome. Journal of medical genetics 1992. link 21 Somer M, Peippo M, Aalto-Korte K, Ritvanen A, Niemi KM. Cardio-facio-cutaneous syndrome: three additional cases and review of the literature. American journal of medical genetics 1992. link 22 Gershoni-Baruch R, Ludatscher RM, Lichtig C, Sujov P, Machoul I. Cerebro-oculo-facio-skeletal syndrome: further delineation. American journal of medical genetics 1991. link 23 Lin AE, Losken HW, Jaffe R, Biglan AW. The branchio-oculo-facial syndrome. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 1991. link 24 Chrzanowska K, Fryns JP, Van den Berghe H. Cardio-facio-cutaneous (CFC) syndrome: report of a new patient. American journal of medical genetics 1989. link 25 Linna SL, Finni K, Similä S, Kouvalainen K, Laitinen J. Intracranial calcifications in cerebro-oculo-facio-skeletal (COFS) syndrome. Pediatric radiology 1982. link 26 Grizzard WS, O'Donnell JJ, Carey JC. The cerebro-oculo-facio-skeletal syndrome. American journal of ophthalmology 1980. link90127-0) 27 Preus M, Kaplan P, Kirkham TH. Renal anomalies and oligohydramnios in the cerebro-oculofacio-skeletal syndrome. American journal of diseases of children (1960) 1977. link

    Original source

    1. [1]
      Cerebro-oculo-facio-skeletal syndrome caused by the homozygous pathogenic variant Gly47Arg in ERCC2. — Reunert J, van den Heuvel A, Rust S, Marquardt T American journal of medical genetics. Part A (2021)
    2. [2]
      Oculo-facio-cardio-dental syndrome in three succeeding generations: genotypic data and phenotypic features. — Lozić B, Ljubković J, Pandurić DG, Saltvig I, Kutsche K, Krželj V et al. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas (2012)
    3. [3]
      Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. — Rauen KA, Tidyman WE, Estep AL, Sampath S, Peltier HM, Bale SJ et al. American journal of medical genetics. Part A (2010)
    4. [4]
      Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations. — Armour CM, Allanson JE Journal of medical genetics (2008)
    5. [5]
      Congenital ulcerating hemangioma in a baby with KRAS mutation and cardio-facio-cutaneous syndrome. — Tang B, Reardon W, Black GC, Kerr BA Clinical dysmorphology (2007)
    6. [6]
      First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. — Jaspers NG, Raams A, Silengo MC, Wijgers N, Niedernhofer LJ, Robinson AR et al. American journal of human genetics (2007)
    7. [7]
      Cerebro-oculo-facio-skeletal syndrome complicated by congenital ichthyosis. — Suzumura H, Nitta A, Arisaka O Clinical dysmorphology (2006)
    8. [8]
      Oculo-facio-cardio-dental syndrome in a mother and daughter. — McGovern E, Al-Mudaffer M, McMahon C, Brosnahan D, Fleming P, Reardon W International journal of oral and maxillofacial surgery (2006)
    9. [9]
      Autosomal dominant microtia and ocular coloboma: new syndrome or an extension of the oculo-auriculo-vertebral spectrum? — Beck AE, Hudgins L, Hoyme HE American journal of medical genetics. Part A (2005)
    10. [10]
      Another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome). — Rufo-Campos M, Riveros-Huckstadt P, RodrIguez-Criado G, Hernández-Soto R Brain & development (2004)
    11. [11]
      Cerebro-oculo-facio-skeletal syndrome: report of two cases from Turkey with postmortem findings. — Semerci CN, Onat N, Günçe S, Demirel N, Yilmazer MB, Oznur I et al. The Turkish journal of pediatrics (2002)
    12. [12]
      Additional patient with del(12)(q21.2q22): further evidence for a candidate region for cardio-facio-cutaneous syndrome? — Rauen KA, Albertson DG, Pinkel D, Cotter PD American journal of medical genetics (2002)
    13. [13]
      Airway in the oculo-auriculo-vertebral spectrum: two cases and a review of the literature. — McCarthy VP, Zimo DA, Lucas MA Pediatric pulmonology (2001)
    14. [14]
      Clinical variability in cerebro-oculo-nasal syndrome: report on two additional cases. — Guion-Almeida ML, Kokitsu-Nakata NM, Richieri-Costa A Clinical dysmorphology (2000)
    15. [15]
      Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome. — Del Bigio MR, Greenberg CR, Rorke LB, Schnur R, McDonald-McGinn DM, Zackai EH Journal of neuropathology and experimental neurology (1997)
    16. [16]
      The cardio-facio-cutaneous (CFC) syndrome--two possible new cases and review of the literature. — Krajewska-Walasek M, Chrzanowska K, Jastrzbska M Clinical dysmorphology (1996)
    17. [17]
      Absence/hypoplasia of tibia, polydactyly, retrocerebellar arachnoid cyst, and other anomalies: an autosomal recessive disorder. — Holmes LB, Redline RW, Brown DL, Williams AJ, Collins T Journal of medical genetics (1995)
    18. [18]
      Branchio-oculo-facial syndrome: broadening the spectrum. — McCool M, Weaver DD American journal of medical genetics (1994)
    19. [19]
      Cerebro-facio-articular syndrome of Van Maldergem: confirmation of a new MR/MCA syndrome. — Zampino G, Colosimo C, Balducci F, Mariotti P, Serra F, Scarano G et al. Clinical genetics (1994)
    20. [20]
      Recurrence of orbital cysts in the branchio-oculo-facial syndrome. — Fielding DW, Fryer AE Journal of medical genetics (1992)
    21. [21]
      Cardio-facio-cutaneous syndrome: three additional cases and review of the literature. — Somer M, Peippo M, Aalto-Korte K, Ritvanen A, Niemi KM American journal of medical genetics (1992)
    22. [22]
      Cerebro-oculo-facio-skeletal syndrome: further delineation. — Gershoni-Baruch R, Ludatscher RM, Lichtig C, Sujov P, Machoul I American journal of medical genetics (1991)
    23. [23]
      The branchio-oculo-facial syndrome. — Lin AE, Losken HW, Jaffe R, Biglan AW The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association (1991)
    24. [24]
      Cardio-facio-cutaneous (CFC) syndrome: report of a new patient. — Chrzanowska K, Fryns JP, Van den Berghe H American journal of medical genetics (1989)
    25. [25]
      Intracranial calcifications in cerebro-oculo-facio-skeletal (COFS) syndrome. — Linna SL, Finni K, Similä S, Kouvalainen K, Laitinen J Pediatric radiology (1982)
    26. [26]
      The cerebro-oculo-facio-skeletal syndrome. — Grizzard WS, O'Donnell JJ, Carey JC American journal of ophthalmology (1980)
    27. [27]
      Renal anomalies and oligohydramnios in the cerebro-oculofacio-skeletal syndrome. — Preus M, Kaplan P, Kirkham TH American journal of diseases of children (1960) (1977)
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