Retinopathy in a Full-Term Infant with Cri-Du-Chat Syndrome

CASE REPORT

Retinopathy in a Full-Term Infant with Cri-du-Chat Syndrome

NISARG CHHAYA, MD; TINEKE CHAN, MD

37 39 EN ABSTRACT of cri-du-chat. Specifically, whole genome SNP microarray Cri-du-chat (CdC) is a 5p chromosomal deletion syn- analysis was performed in a CLIA-approved laboratory on drome. CdC has numerous systemic associations but the DNA isolated from whole blood of the patient. Analysis only a few ocular manifestations have been documented. identified a terminal, heterozygous deletion at 5p15.33p14.3 In this report we present novel ocular findings of periph- of 20.281 Mb as well as a contiguous heterozygous duplica- eral avascular retina and retinal hemorrhages in a full- tion of 1.593 Mb at 5p14.3 that affected 7 genes, including term female infant, born to non-consanguineous parents, partial copies of CDH18 and CDH12 (cadherin genes) at the who had clinical features of cri-du-chat syndrome and distal and proximal breakpoints. genetic confirmation. The retinal hemorrhages resolved. Follow-up systemic evaluation included an echocardio- However, the temporal avascular retina in our full-term gram which revealed a fenestrated patent foramen ovale patient remained. Further analysis of the 5p locus showed and a mildly dilated ascending aorta. MRI revealed enlarged 3 genes: CTNND2, SEMA5A and SLC6A18 that not only anterior fontanelle without ventriculomegaly. Laryngoscopy fit our patient’s external phenotype and ophthalmoscop- and renal ultrasound were unremarkable. Patient did not ic findings of retinal hemorrhages, but were also key in tolerate oral feeds and subsequently required the placement proper ocular development and neurogenesis, suggesting of a gastric tube on day-of-life 56. a genetic contribution by the short-arm of chromosome The patient was evaluated for screening eye exam at 41 5 to proper retinal maturation. Given these findings and weeks corrected age. On exam, both eyes had responses their association with cri-du-chat, special attention on appropriate for age; pupils were equal round and reactive, screening examinations should include a thorough eval- and intraocular pressures were soft to palpation. Pupils were uation of retinal vascularization in CdC patients, even in consistently resistant to topical mydriatics, as noted in pre- full-term neonates. vious reports.3 External examination revealed hypertelorism, KEYWORDS: cri-du-chat, retinal hemorrhages, a unilateral preauricular skin tag, epicanthal folds, and avascular retina down-slanting palpebral fissures. Handheld slit-lamp exam- ination was unremarkable. Dilated retinal examination of both eyes revealed an unremarkable posterior pole (Figure 1). However, evaluation of the peripheral retina revealed a

CASE REPORT After the mother underwent an Figure 1. Normal fundus photos of the Right (A) and Left (B) eyes uneventful cesarean delivery, a sin- gleton female infant weighing 7.1 lbs. was born at 39 weeks and 2 days gestational age. She was ad- mitted to the neonatal ICU for episodes of respiratory distress, stridor, desaturations and holding events, requiring NCPAP. Bedside scope revealed mild distal tracheo- malacia and grade I subglottic ste- nosis. Additional exam findings of a large anterior fontanelle, retrog- nathia, low resting heart rate and a meow-like cry prompted genetic analysis which revealed a diagnosis

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small avascular area in the far temporal periphery (zone III DISCUSSION in ICROP nomenclature) bilaterally. Overlying the avas- Cri-du-chat syndrome is a genetic condition resulting from cular retina were 10–12 scattered pinpoint hemorrhages a deletion of variable size occurring on the short arm of (Figure 2). By 44 weeks corrected gestational age, hemor- chromosome 5. The incidence ranges from 1:15,000 to rhages had resolved with persistence of avascular retina in 1:50,000 live-born infants.5 The main clinical features are zone III. Most recent fundus examination at 53 weeks cor- a high-pitched monochromatic cry, microcephaly, broad rected age showed the areas of temporal avascular retina had nasal bridge, epicanthal folds, micrognathia, abnormal der- improved slightly but had not completely resolved. matoglyphics, and severe psychomotor and mental impair- ments.1,2 Approximately 85% of cases Figure 2. Color photos of the far retinal periphery of the Right (A, C, E) and Left (B, D, F) eyes. are the result of a de novo partial Boxes highlight areas of peripheral dot-blot hemorrhages and avascular retina. deletion of the short arm of chromo- some 5 with 15% from translocation of 5p. 5p15.3 is the critical region for the monochromatic cry while 5p15.2 is associated with the systemic fea- tures.2 Numerous ophthalmic man- ifestations have been reported in the literature: exotropia, down-slanting palpebral fissures, epicanthal folds, hypertelorism, optic atrophy, reti- nal dysplasia and tortuous retinal blood vessels.3,4,5 Associations with Peter’s anomaly (5p15.33 deletion and 10q21.1 duplication) and Goldenhar syndrome (oculo-auriculo-vertebral spectrum; 5p14 locus) have also been reported in few reports.6,7,8 This case adds to the scant reports on a possible overlap of 5p15 in cri-du-chat with Goldenhar syndrome. Retinal vascular maturation in full- term infants is typically complete by gestational age 38–40 weeks. To our knowledge, our case is the first reported full-term infant with CdC to have an avascular retina and asso- ciated retinal hemorrhages. Although retinal hemorrhages eventually re- solved, even by gestational age 53 weeks, persistent areas of avascular retina were present. These findings, along with the previously docu- mented finding of retinal dysplasia by Hope et al,6 suggest that certain genes along the 5p14–15 locus may have a role in proper and timely ret- inal neurogenesis and angiogenesis. Our review of the genes along this patient’s 5p locus revealed 3 candi- dates that fit our patient’s external phenotype of Goldenhar-like features and ophthalmoscopic findings of reti- nal hemorrhages: CTNND2, an adhe- sive junction-associated protein of the

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beta-catenin superfamily, SEMA5A, an axonal membrane Authors protein, and SLC6A18, a specific transporter for neurotrans- Nisarg Chhaya, MD, PGY3, Division of Ophthalmology, Alpert mitters, amino acids, and osmolytes.9,10,11 Interestingly, Medical School of Brown University, Providence, RI. CTNND2 and SEMA5A are also important in appropriate Tineke Chan, MD, Division of Ophthalmology, Alpert Medical ocular development and neurogenesis, respectively.9,10 Given School of Brown University, Providence, RI. these findings and the possible association with CdC, a Disclaimer thorough evaluation of retinal vascularization/neurogenesis The views expressed herein are solely those of the authors. even in full-term neonates with cri-du-chat should be Financial Disclosures performed as part of their comprehensive assessment. None

References Correspondence Nisarg Chhaya, MD 1. Niebuhr E. The cri-du-chat syndrome: epidemiology, cytoge- netics, and clinical features. Hum Genet. 1978;44(3):227-275. Brown University doi:10.1007/BF00394291 1 Hoppin Street, Providence RI, 02908 2. Cerruti Mainardi P. cri-du-chat syndrome. Orphanet J Rare Dis. 617-851-1056 2006;1:33. Published 2006 Sep 5. doi:10.1186/1750-1172-1-33 [email protected] 3. Kitsiou-Tzeli S, Dellagrammaticas HD, Papas CB, Ladas ID, Bartsocas CS. Unusual ocular findings in an infant with cri-du- chat syndrome. J Med Genet. 1983;20(4):304-307. doi:10.1136/ jmg.20.4.304 4. Schechter RJ. Ocular findings in a newborn with cri-du-chat syndrome. Ann Ophthalmol. 1978;10(3):339-344. 5. Clark DI, Howard PJ, Patterson A. Ocular findings in a patient with deletion short arm chromosome 5 (cri-du-chat) and ring chromosome 14. Trans Ophthalmol Soc UK.1986;105 (Pt 6):723- 725. 6. Hope WC, Cordovez JA, Capasso JE, et al. Peters anomaly in cri- du-chat syndrome. J AAPOS. 2015;19(3):277-279. doi:10.1016/j. jaapos.2015.01.018 7. Choong YF, Watts P, Little E, Beck L. Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome? JAAPOS. 2003;7(3):226-227. doi:10.1016/s1091-8531(02)42019-8 8. Ala-Mello S, Siggberg L, Knuutila S, von Koskull H, Taskinen M, Peippo M. Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anom- aly. Am J Med Genet A. 2008;146A(19):2490-2494. doi:10.1002/ ajmg.a.32479 9. Database, GeneCards Human Gene. “CTNND2 Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?- gene=CTNND2. 10. Database, GeneCards Human Gene. “SEMA5A Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?- gene=SEMA5A. 11. Database, GeneCards Human Gene. “SLC6A18 Gene (Protein Coding).” GeneCards, www.genecards.org/cgi-bin/carddisp.pl?- gene=SLC6A18.

Acknowledgment Umadevi Tantravahi, PhD, Director, Division of Genetics, Depart- ment of Pathology, Women and Infants’ Hospital, Providence, RI.

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