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Congenital Cataracts, Facial Dysmorphism, and Neuropathy Syndrome: Additional Clinical Features
Pediatric Neurology xxx (2016) e1ee2
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Correspondence
Congenital Cataracts, Facial Dysmorphism, and Neuropathy Syndrome: Additional Clinical Features To the Editor Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) syndrome is an autosomal recessive disorder identified in patients of Roma ancestry. It is caused by the c.863þ389C>T founder mutation in the CTDP1 gene encoding FCP1, a putative transcriptional factor that controls proliferation and development and regulates transcription of heat shockeinduced genes.1-3 Additional features of the syndrome include cognitive impairment, cerebellar dysfunction, short stature, hypogonadotropic hypogonadism, decreased mineral bone density, secondary skeletal deformities, and parainfectious rhabdomyolysis.1 Recently a patient with CCFDN syndrome with choreoathetosis as a prominent clinic finding was reported.4 We describe two siblings with CCFDN syndrome with pronounced intrafamilial variability and additional clinical findings that expand the clinical phenotype. The index patient is a five-year-old girl with congenital cataracts, microcephaly, facial dysmorphism, and thoracic scoliosis. She is cognitively impaired and manifests mild dystonic posturing, ataxia, and signs of peripheral neuropathy (thenar hypotrophy, pes cavus, weakness, and areflexia). Neurophysiological studies were consistent with sensorimotor demyelinating neuropathy with features of axonal loss. Family history is significant for a deceased older brother who had congenital cataracts, developmental delay, failure-to-thrive, acquired microcephaly, and a parainfectious myoglobinuria episode at age 2.5 years. He experienced cardiorespiratory collapse during a febrile illness at age three years. A severe dilated cardiomyopathy was detected. Viral studies were negative. His condition deteriorated and he died six days later. An urgent muscle biopsy before his demise showed small group atrophy, consistent with a neurogenic process, and nonspecific myopathic changes (increased fiber diameter variability and mild endomysial fibrosis). Molecular analysis from peripheral blood of Patient 1 and from the muscle biopsy in Patient
Funding source: None. Financial disclosures: None of the authors have any financial relationships relevant to the article to disclose. Conflicts of interest: None of the authors have any conflicts of interest to disclose. 0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2016.11.001
2 disclosed homozygosity for the founder mutation c.863þ389C>T in the CDTP1 gene. The clinical manifestations of these siblings are indicative of intrafamilial variability and a broader spectrum of clinical manifestations in CCFDN syndrome; in particular, cardiomyopathy has not been previously reported. Expression of CTDP1 in cardiac myocytes and the role of FCP1 in regulating the effective transcription of heat shockeinduced genes suggest that cardiac involvement is related to CTDP1 dysfunction.3,5 Heat shock proteins play a role in the response to environmental stresses and are involved in cardiac and skeletal muscle development and differentiation.6 Dysregulation of heat shock protein expression has been implicated in congenital cataracts, myopathies, peripheral neuropathies, cardiomyopathy, and multisystemic disorders.7 We speculate that rhabdomyolysis and cardiologic decompensation in the setting of febrile illnesses might be the result of impaired heat shock response in CCFDN syndrome. Involvement of the central nervous system also occurs in CCFDN syndrome, mainly manifesting as cognitive impairment and cerebellar ataxia. A possible progressive course manifesting as cerebral atrophy has been described in adult patients.8 Deceleration of head growth has not been previously reported in CCFDN syndrome. We hypothesize that acquired microcephaly in the deceased brother was indicative of an earlier progressive course of the disease. In summary, cardiomyopathy and acquired microcephaly may be additional features of the spectrum of CCFDN. Impaired heat shock response may be involved in the pathogenesis of rhabdomyolysis and cardiomyopathy induced by febrile illness.
References 1. Kalaydjieva L, Chamova T. Congenital cataracts, facial dysmorphism, and neuropathy. GeneReviews 2010 [updated 2014]. 2. Schauer T, Tombácz I, Ciurciu A, Komonyi O, Boros IM. Misregulated RNA Pol II C-terminal domain phosphorylation results in apoptosis. Cell Mol Life Sci. 2009;66:909-918. 3. Fuda NJ, Buckley MS, Wei W, et al. Fcp1 dephosphorylation of the RNA polymerase II C-terminal domain is required for efficient transcription of heat shock genes. Mol Cell Biol. 2012;32: 3428-3437.
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Correspondence / Pediatric Neurology xxx (2016) e1ee2
4. Mosquera-Gorostidi A, Aguilera-Albesa S, Yoldi-Petri ME. Congenital cataract with facial dysmorphism and neuropathy: key clinical features. Pediatr Neurol. 2016;58:116-117. 5. Available at: http://www.proteinatlas.org/ENSG00000060069-CTDP1/ tissue. Accessed September 10, 2016. ska-Magiera M, Jab1on ska J, Saczko J, Kulbacka J, 6. Dubin Jagla T, Daczewska M. Contribution of small heat shock proteins to muscle development and function. FEBS Lett. 2014;588: 517-530. 7. Kakkar V, Meister-Broekema M, Minoia M, Carra S, Kampinga HH. Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech. 2014;7: 421-434. 8. Chamova T, Zlatareva D, Raycheva M, Bichev S, Kalaydjieva L, Tournev I. Cognitive impairment and brain imaging characteristics of patients with congenital cataracts, facial dysmorphism, neuropathy syndrome. Behav Neurol. 2015;2015:639539.
Evanthia A. Makrygianni, MD First Department of Pediatrics National and Kapodistrian University of Athens Medical School Aghia Sophia Children’s Hospital Athens, Greece E-mail address: [email protected] George K. Papadimas, MD, PhD Department of Neurology National and Kapodistrian University of Athens Medical School
Aeginition Hospital Athens, Greece George Vartzelis, MD, PhD Second Department of Pediatrics National and Kapodistrian University of Athens School of Medicine P. & A. Kyriakou Children’s Hospital Athens, Greece Maria Georgala, MD Department of Clinical Neurophysiology Metropolitan Hospital Athens, Greece Maria Tzetis, PhD Myrto Poulou, PhD Sophia Kitsiou-Tzeli, MD, PhD Department of Medical Genetics National and Kapodistrian University of Athens Medical School Athens, Greece Roser Pons, MD, PhD First Department of Pediatrics National and Kapodistrian University of Athens Medical School Aghia Sophia Children’s Hospital Athens, Greece
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Correspondence
Congenital Cataracts, Facial Dysmorphism, and Neuropathy Syndrome: Additional Clinical Features To the Editor Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) syndrome is an autosomal recessive disorder identified in patients of Roma ancestry. It is caused by the c.863þ389C>T founder mutation in the CTDP1 gene encoding FCP1, a putative transcriptional factor that controls proliferation and development and regulates transcription of heat shockeinduced genes.1-3 Additional features of the syndrome include cognitive impairment, cerebellar dysfunction, short stature, hypogonadotropic hypogonadism, decreased mineral bone density, secondary skeletal deformities, and parainfectious rhabdomyolysis.1 Recently a patient with CCFDN syndrome with choreoathetosis as a prominent clinic finding was reported.4 We describe two siblings with CCFDN syndrome with pronounced intrafamilial variability and additional clinical findings that expand the clinical phenotype. The index patient is a five-year-old girl with congenital cataracts, microcephaly, facial dysmorphism, and thoracic scoliosis. She is cognitively impaired and manifests mild dystonic posturing, ataxia, and signs of peripheral neuropathy (thenar hypotrophy, pes cavus, weakness, and areflexia). Neurophysiological studies were consistent with sensorimotor demyelinating neuropathy with features of axonal loss. Family history is significant for a deceased older brother who had congenital cataracts, developmental delay, failure-to-thrive, acquired microcephaly, and a parainfectious myoglobinuria episode at age 2.5 years. He experienced cardiorespiratory collapse during a febrile illness at age three years. A severe dilated cardiomyopathy was detected. Viral studies were negative. His condition deteriorated and he died six days later. An urgent muscle biopsy before his demise showed small group atrophy, consistent with a neurogenic process, and nonspecific myopathic changes (increased fiber diameter variability and mild endomysial fibrosis). Molecular analysis from peripheral blood of Patient 1 and from the muscle biopsy in Patient
Funding source: None. Financial disclosures: None of the authors have any financial relationships relevant to the article to disclose. Conflicts of interest: None of the authors have any conflicts of interest to disclose. 0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2016.11.001
2 disclosed homozygosity for the founder mutation c.863þ389C>T in the CDTP1 gene. The clinical manifestations of these siblings are indicative of intrafamilial variability and a broader spectrum of clinical manifestations in CCFDN syndrome; in particular, cardiomyopathy has not been previously reported. Expression of CTDP1 in cardiac myocytes and the role of FCP1 in regulating the effective transcription of heat shockeinduced genes suggest that cardiac involvement is related to CTDP1 dysfunction.3,5 Heat shock proteins play a role in the response to environmental stresses and are involved in cardiac and skeletal muscle development and differentiation.6 Dysregulation of heat shock protein expression has been implicated in congenital cataracts, myopathies, peripheral neuropathies, cardiomyopathy, and multisystemic disorders.7 We speculate that rhabdomyolysis and cardiologic decompensation in the setting of febrile illnesses might be the result of impaired heat shock response in CCFDN syndrome. Involvement of the central nervous system also occurs in CCFDN syndrome, mainly manifesting as cognitive impairment and cerebellar ataxia. A possible progressive course manifesting as cerebral atrophy has been described in adult patients.8 Deceleration of head growth has not been previously reported in CCFDN syndrome. We hypothesize that acquired microcephaly in the deceased brother was indicative of an earlier progressive course of the disease. In summary, cardiomyopathy and acquired microcephaly may be additional features of the spectrum of CCFDN. Impaired heat shock response may be involved in the pathogenesis of rhabdomyolysis and cardiomyopathy induced by febrile illness.
References 1. Kalaydjieva L, Chamova T. Congenital cataracts, facial dysmorphism, and neuropathy. GeneReviews 2010 [updated 2014]. 2. Schauer T, Tombácz I, Ciurciu A, Komonyi O, Boros IM. Misregulated RNA Pol II C-terminal domain phosphorylation results in apoptosis. Cell Mol Life Sci. 2009;66:909-918. 3. Fuda NJ, Buckley MS, Wei W, et al. Fcp1 dephosphorylation of the RNA polymerase II C-terminal domain is required for efficient transcription of heat shock genes. Mol Cell Biol. 2012;32: 3428-3437.
e2
Correspondence / Pediatric Neurology xxx (2016) e1ee2
4. Mosquera-Gorostidi A, Aguilera-Albesa S, Yoldi-Petri ME. Congenital cataract with facial dysmorphism and neuropathy: key clinical features. Pediatr Neurol. 2016;58:116-117. 5. Available at: http://www.proteinatlas.org/ENSG00000060069-CTDP1/ tissue. Accessed September 10, 2016. ska-Magiera M, Jab1on ska J, Saczko J, Kulbacka J, 6. Dubin Jagla T, Daczewska M. Contribution of small heat shock proteins to muscle development and function. FEBS Lett. 2014;588: 517-530. 7. Kakkar V, Meister-Broekema M, Minoia M, Carra S, Kampinga HH. Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis Model Mech. 2014;7: 421-434. 8. Chamova T, Zlatareva D, Raycheva M, Bichev S, Kalaydjieva L, Tournev I. Cognitive impairment and brain imaging characteristics of patients with congenital cataracts, facial dysmorphism, neuropathy syndrome. Behav Neurol. 2015;2015:639539.
Evanthia A. Makrygianni, MD First Department of Pediatrics National and Kapodistrian University of Athens Medical School Aghia Sophia Children’s Hospital Athens, Greece E-mail address: [email protected] George K. Papadimas, MD, PhD Department of Neurology National and Kapodistrian University of Athens Medical School
Aeginition Hospital Athens, Greece George Vartzelis, MD, PhD Second Department of Pediatrics National and Kapodistrian University of Athens School of Medicine P. & A. Kyriakou Children’s Hospital Athens, Greece Maria Georgala, MD Department of Clinical Neurophysiology Metropolitan Hospital Athens, Greece Maria Tzetis, PhD Myrto Poulou, PhD Sophia Kitsiou-Tzeli, MD, PhD Department of Medical Genetics National and Kapodistrian University of Athens Medical School Athens, Greece Roser Pons, MD, PhD First Department of Pediatrics National and Kapodistrian University of Athens Medical School Aghia Sophia Children’s Hospital Athens, Greece