| Article Access Statistics|
| Viewed||663 |
| Printed||6 |
| Emailed||0 |
| PDF Downloaded||15 |
| Comments ||[Add] |
Click on image for details.
|LETTER TO EDITOR
|Year : 2021 | Volume
| Issue : 6 | Page : 1861-1862
CEDNIK Syndrome: Report of an Ultra-Rare Case from India
Vandana Bansal1, Vasundhara P Tamhankar2, Shilpa M Mithbawkar2, Parag M Tamhankar2
1 Department of Fetal Medicine, Surya Hospital, 101-102, Mangal Ashirwad, S.V. Road, Santacruz West, Mumbai, Maharashtra, India
2 Centre for Medical Genetics, Office 250/251, Ecstasy Business Park, JSD Road, Mulund West, Mumbai, Maharashtra, India
|Date of Submission||13-Sep-2019|
|Date of Decision||14-Nov-2019|
|Date of Acceptance||13-Jul-2020|
|Date of Web Publication||23-Dec-2021|
Dr. Parag M Tamhankar
Centre for Medical Genetics, Office 250/251, Ecstasy Business Park, JSD Road, Mulund West, Mumbai, Maharashtra - 400 081
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Bansal V, Tamhankar VP, Mithbawkar SM, Tamhankar PM. CEDNIK Syndrome: Report of an Ultra-Rare Case from India. Neurol India 2021;69:1861-2
CEDNIK or acronym standing for Cerebral dysgenesis, deafness, neuropathy, ichthyosis, and keratoderma is an autosomal recessive genetic syndrome due to mutation in SNAP29 (synaptosome associated protein 29) gene at locus 22q11.2. The gene encodes a SNARE (soluble N-ethylmaleimide-sensitive factor-attachment) protein (258 amino acid long) involved in vesicle fusion during Golgi transport of proteins. A 4-year-old girl child born of non-consanguineous Hindu parentage presented with global developmental delay and floppiness was referred for genetic evaluation. The child was born at term, birth history was uneventful. The child had not achieved any milestones such as head control, recognition of parents. The child had microcephaly (head circumference 45 cm, –3 SD), puffy eyelids, thick and arched eyebrows, roving eye movements, long face, tall forehead, bitemporal narrowing, broad nasal tip, prominent philtrum, tented upper lip, yellow, dysplastic teeth, large low set ears. Review of photographs from infancy showed that facial shape had changed from oval to an elongated rectangular with coarsening of features [Figure 1]. There was hypotonia with absent deep tendon reflexes. The child did not respond to sound or visual stimuli. There was lamellar ichthyosis (dry, thick skin with adherent scales) without erythema or desquamation. Nails were normal. Scalp hair was dry, sparse with frictional alopecia. There was no liver or spleen enlargement. The child had two healthy elder sisters (16 years and 13 years) and another affected brother (died at 5 years) and sister (died at 1.5 years). The maternal uncle had two children who were similarly affected (boy died at 8 months, girl died at 2.5 years).
|Figure 1: (a) Pedigree chart of family; (b) Photo around newborn period showing prominent eyebrows, broad nasal tip, long philtrum, tall forehead; (c) Photo around early infancy showing oval facies, deep set eyes, normal ears, normal jawline, prominent philtrum; (d and e) Photo at 4 years with long face, bi-temporal narrowing, thick arched eyebrows, puffy eyelids, broad nasal tip, large ears, shorter deep philtrum, tented upper lip, long jawline, prominent chin, sparse and dry hair, frictional alopecia; (f to i) Skin showing ichthyosis - adherent large scales over the knee, shin, lesser over dorsum of hand and feet, no desquamation, erythema and keratoderma. Written informed consent taken from the patient's family|
Click here to view
After next-generation sequencing (NGS) analysis for ~ 6000 genes the patient was identified to be homozygous for a frameshift mutation namely chr22:21235388dupA: c. 486dupA or p.S163Kfs*6 which is a known pathogenic mutation for CEDNIK syndrome. Capillary sequencing confirmed the variant in the family. The differential diagnosis of other neuro-ichthyotic syndromes namely Sjogren Larrson syndrome, Chanarin Dorfman syndrome, multiple sulfatase deficiency was ruled out in the patient clinically and by NGS test.,,
Till date, children in the age group infant to 13 years from eight unrelated families have been identified with CEDNIK syndrome since 2005, making it an ultra-rare syndrome. Neurological findings include primary brain malformation (pachygyria, polymicrogyria, cerebral demyelination, hypoplastic corpus callosum), visual impairment, retinal pigmented deposits, macular atrophy, optic disk hypoplasia, sensorineural deafness, and axonal and demyelinating neuropathy. Skin findings include ichthyosis and palmoplantar keratoderma.,,,,,
Sprecher identified two families, one with six cases and another with single case. All patients had mutation c. 223delG or p.V75sfs*28. Fuchs-Telem identified an infant from Kashmir with brittle coarse hair, micrognathia, and high-pitched cry and homozygosity for c. 486dupA mutation leading to truncated, mislocalized protein. McDonald-McGinn studied 17 patients with 22q11.2 deletion syndrome for mutations in SNAP29 gene. They identified two patients with CEDNIK disease. One infant had c. 388_389insA (p.T130fs) in SNAP29 gene (paternal inherited) along with a de novo 22q11.2 deletion (maternal allele) and another infant was heterozygous for c. 28_32delCCGTT (p.P10fs) in SNAP29 gene (maternal inherited) and de novo 22q11.2 deletion on the paternal allele. Ben-Salem identified another child with c. 223delG mutation, with collodion membrane at birth that gradually desquamated but left camptodactyly. Hsu described 10 years boy with homozygosity for c. 85C > T (p.Arg29Ter) with normal head circumference, progressive improvement in motor being able to pull to stand and use wheelchair and mental skills being able to communicate non-verbally. Poojary identified a 20-month-old child with homozygous c. 253C > T or p.Arg85Ter (exon 2) mutation and showed hyperkeratosis with acanthosis.
The patient was treated with emollient creams for ichthyosis and physiotherapy for hypotonia. The family was counseled about the recurrence risk of CEDNIK to be 25 percent in each of their pregnancy. Extended family screening was advised to detect at-risk members/carriers. During an ongoing pregnancy, fetus was found to be homozygous for mutation in SNAP29 gene at 14 weeks. The parents chose to discontinue the pregnancy.
In conclusion, CEDNIK is an ultra-rare genetic neuroichthyosis which is clinically recognizable and preventable by prenatal diagnosis and preimplantation genetic diagnosis. Recognition of facial phenotype in further cases will be essential for clinical phenotyping.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Rizzo WB. Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome. Expert Opin Orphan Drugs 2016;4:395-406.
Tamhankar PM, Iyer S, Sanghavi S, Khopkar U. Chanarin-Dorfman syndrome: Clinical report and novel mutation in ABHD5 gene. J Postgrad Med 2014;60:332-4.
] [Full text]
Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, et al
. Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C (alpha)-formylglycine generating enzyme. Cell 2003;113:435-44.
Sprecher E, Ishida-Yamamoto A, Mizrahi-Koren M, Rapaport D, Goldsher D, Indelman M, et al
. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet 2005;77:242-51.
Fuchs-Telem D, Stewart H, Rapaport D, Nousbeck J, Gat A, Gini M, et al
. CEDNIK syndrome results from loss-of-function mutations in SNAP29. Br J Dermatol 2011;164:610-6.
McDonald-McGinn DM, Fahiminiya S, Revil T, Nowakowska BA, Suhl J, Bailey A, et al
. Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS. J Med Genet 2013;50:80-90.
Ben-Salem S, Nara S, Al-Shamsi AM, Valle D, Ali BR, Al-Gazali L. New Arab family with cerebral dysgenesis, neuropathy, ichthyosis and keratoderma syndrome suggests a possible founder effect for the c. 223delG mutation. J Dermatol 2015;42:821-2.
Hsu T, Coughlin CC, Monaghan KG, Fiala E, McKinstry RC, Paciorkowski AR, et al
. CEDNIK: Phenotypic and molecular characterization of an additional patient and review of the Literature. Child Neurol Open 2017;4:2329048X17733214. doi: 10.1177/2329048X17733214
Poojary S, Shah KS, Bhalala KB, Hegde AU. CEDNIK syndrome in an Indian patient with a novel mutation of the SNAP29 gene. Pediatr Dermatol 2019;36:372-6.