Cri-du-chat syndrome mimics Silver-Russell syndrome depending on the size of the deletion: a case report
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Silver-Russell Syndrome (SRS) is a rare growth-related genetic disorder mainly characterized by prenatal and postnatal growth failure. Although molecular causes are not clear in all cases, the most common mechanisms involved in SRS are loss of methylation on chromosome 11p15 (≈50%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (≈10%).
We present a girl with clinical suspicion of SRS (intrauterine and postnatal growth retardation, prominent forehead, triangular face, mild psychomotor delay, transient neonatal hypoglycemia, mild hypotonia and single umbilical artery). Methylation and copy number variations at chromosomes 11 and 7 were studied by methylation-specific multiplex ligation-dependent probe amplification and as no alterations were found, molecular karyotyping was performed. A deletion at 5p15.33p15.2 was identified (arr[GRCh37] 5p15.33p15.2(25942–11644643)× 1), similar to those found in patients with Cri-du-chat Syndrome (CdCS). CdCS is a genetic disease resulting from a deletion of variable size occurring on the short arm of chromosome 5 (5p-), whose main feature is a high-pitched mewing cry in infancy, accompanied by multiple congenital anomalies, intellectual disability, microcephaly and facial dysmorphism.
The absence of some CdCS features in the current patient could be due to the fact that in her case the critical regions responsible do not lie within the identified deletion. In fact, a literature review revealed a high degree of concordance between the clinical manifestations of the two syndromes.
KeywordsSilver-Russell syndrome Cri-du-chat syndrome aCGH Deletion
Deletion on the short arm of chromosome 5
Microarray-based Comparative Genomic Hybridization
Copy Number Variation
Differentially Methylated Region
Fluorescence In Situ Hybridization
IntraUterine Growth Retardation
Netchine-Harbison SRS Clinical Scoring System
PostNatal Growth Retardation
Maternal uniparental disomy for chromosome 7
Silver-Russel Syndrome (SRS, OMIM#180860) is a rare genetic imprinting disorder, initially described as an heterogeneous phenotype including intrauterine (IUGR) and postnatal growth retardation (PNGR) without catch-up growth, relative macrocephaly at birth, triangular face, body asymmetry, facial dysmorphic features and severe feeding difficulties [1, 2]. More recent case reports have led to the inclusion of low body mass index, hypoglycemia, motor and speech delay and psychosocial challenges as additional features (for a review, ). The incidence of the disease is not clear, reported estimates varying from 1/100,000 to 30/100,000 [3, 4]. Most cases of SRS are sporadic, with a low rate of familial cases that have been suggested to follow an autosomal dominant transmission pattern .
The wide variability of the clinical manifestations of SRS has led to the international recommendation to use the Netchine-Harbison SRS clinical scoring system (NH-CSS) , both for determining when SRS genetic testing should be run and when a clinical diagnosis of SRS should be given . Although studies have failed to determine the underlying molecular mechanism in some cases, approximately 50% of the clinically-diagnosed SRS patients present alterations at 11p15.5, mainly hypomethylation at H19/IGF2:IG-DMR, while 10% of them show maternal uniparental disomy of chromosome 7 (upd(7)mat) . In addition, there have been reports of a single maternally-transmitted CDKN1C activating mutation in five members of a four-generation family  and paternal IGF2 inactivating mutations in another family and four unrelated patients [8, 9, 10]. Further, sequence variants of two non-imprinted genes (HMGA2 and PLAG1) are also associated with SRS. Specifically, HMGA2 variants have been described in one family and two sporadic cases [11, 12] and PLAG1 mutations in a family and in one sporadic case . For the remaining 40% of SRS patients who are negative for these alterations, molecular karyotyping is advised [3, 13, 14]. Two recent reviews have compiled all the reported chromosomal regions involved in SRS-like cases and suggested that the most frequently affected is 12q14, followed by 1q21, 4p16.3, 15q26, 17p13.3 and 22q11 [9, 15].
The CARE guidelines were followed in reporting this case.
Molecular genetic studies
Genomic DNA was extracted from peripheral blood leukocytes using a commercial kit, following the manufacturer’s instructions (QiaAmp Blood Mini, Qiagen, Düren, Germany). Dosage and methylation analyses for chromosomes 11 and 7 were carried out by methylation-specific multiplex ligation-dependent probe amplification using the ME030-C3 and ME032-A1 kits, respectively (MRC-Holland, Amsterdam, The Netherlands) following the manufacturer’s recommendations. No alterations in methylation or copy number variations (CNV) were detected in either of these regions.
Fluorescence in situ hybridization (FISH) analyses were performed on metaphase cells and interphase nuclei using a Vysis CSF1R/D5S23, D5S721 FISH Probe Kit to confirm the presence of the deletion and its origin. The results showed one green signal (5p15) and two red signals (CSF1R probe) in the metaphases and nuclei of the index corresponding to a deletion of the 5p15 region (Additional file 1 Figure S1A, B), confirming the aCGH results. In accordance with the 2016 edition of the International System for Human Cytogenomic Nomenclature, the patient’s karyotype can be described as 46,XX,del(5)(p15.2).ish del(5)(p15.2)(D5S23-, D5S721-). The FISH pattern on chromosome 5 was normal in both parents (2G2R), confirming the de novo nature of the deletion (Additional file 1 Figure S1C-F).
Discussion and conclusions
Sometimes, clinical diagnosis of patients with syndromic manifestations is challenging due to either an absence of cardinal features or an overlap of characteristics between different disorders or a combination of both.
It is known that CdCS (OMIM#123450) is caused by deletions of heterogeneous size in the short arm of chromosome 5 . Even though it is considered a rare disease, CdCS is one of the most common chromosomal deletion syndromes with an incidence ranging from 1:15,000  to 1:50,000 live births . In more than 80% of cases, the deletion is found to be de novo  and its extension seems to be closely related to the presence of certain phenotypic features .
The main clinical features at birth are: plaintive high-pitched monochromatic cry similar to the mewing of a cat (95.9%), which disappears after the neonatal period; microcephaly (mean head circumference, 31.8 cm) and low weight (mean weight, 2614 g). Other notable characteristics are: rounded face (83.5%), broad nasal bridge (87.2%), hypertelorism (81.4%), epicanthal folds (90.2%), downslanting palpebral fissures (56.9%), low-set ears (69.8%), micrognathia (96.7%), abnormal dermatoglyphics (92%), hypotonia and down-turned corners of the mouth (81.0%) . CdCS patients also show severe psychomotor and intellectual disability, high palatal arch , speech delay, prenatal and postnatal growth delay, and low-set and/or poorly formed pinnae .
The majority of chromosome 5p deletions are associated with CdCS, but a del(5p) karyotype does not necessarily indicate CdCS [20, 23]. According to various different mapping studies using a strategy of “phenotype dissection”, some regions of the short arm of chromosome 5 have been associated with specific features which define certain aspects of the CdCS phenotype. Based on those studies, the critical factor responsible for the CdCS phenotype is considered to be the deletion located at 5p15.2, as haploinsufficiency of genes in this region is assumed to be associated with changes in facial features and severe mental retardation, as well as general CdCS features [19, 20, 22, 24]. Patients presenting the characteristic cat-like cry, the origin of the name of the syndrome, carry a deletion that includes a region proximal to 5p15.3 and distal to 5p15.2 [24, 25]. Different genes located within this region have been proposed to be responsible for the feature, namely, UBE2QL1/FLJ28076 (5p15.31) and MARCH6/TEB4 (5p15.2) . Surprisingly, the deletion of the patient we report encompasses both candidate genes, but she did not have the classical cry, just a high-pitched voice. Coincidentally, there is another CdCS case described in the literature in which the patient did not have high pitched cry but did have a high-pitched voice. He had a 5p15.2 deletion, similar to our patient, and they share other clinical characteristics such as growth delay, slightly small chin, hypotonia and speech delay .
The most distal part of 5p, the 5p15.3 band, has been reported to be related to speech delay . In that region, more precisely at 5p15.33, studies have located the SLC6A3 gene, which encodes an amine transporter responsible for dopamine reuptake. Curiously, an excess of dopamine has been associated with problems in speech due to its major role in fine motor movements and the fact that speech requires very accurate coordination of very diverse small muscles . The patient we describe has speech problems, probably because of a defect in the in the larynx with vocal fold atrophy. Notably, the SLC6A3 gene lies within the patient’s deletion, and that may explain the speech problems.
In addition, intellectual disability has been associated with a region at 5p15.2 , where the CTNND2 gene is located . This gene encodes a protein which plays a critical role in neural development, particularly in the formation and/or maintenance of dendritic spines and synapses . In the same cytogenetic band, there is another region which seems to be responsible for the facial dysmorphism [19, 22, 31]. Further, alterations in SEMA5A (5p15.31)  and CDH18 (5p14.3), CDH10 (5p14.2) and CDH9 (5p14.1)  also disrupt normal brain development; whereas autism spectrum and social communication disorders have been associated with the 5p14.1 cytogenetic band . Like many other cases and as described above, our patient has intellectual disability, not having achieved the milestones for her age. Even though CDH9, CDH10 and CDH18 genes are supposed to be involved in intellectual disability, they may be not so critical because they do not lie within the region of the patient’s deletion. On the contrary, CTNND2 and SEMA5A are in the deleted region and in consequence they may be responsible for this feature. On the other hand, autism is not one of the girl’s characteristics, perhaps due to the fact that the aforementioned region does not lie within the deletion. The CDH9 gene is located in the band related to autism, and hence, it could be responsible for this feature apart from intellectual disability.
Some of these phenotypic features are in common with those of SRS (Table 1). In fact, the patient we describe has four out of the six cardinal characteristics  of SRS and lacks other important features of CdCS (high pitched cry, rounded face). What is more, the syndromes share some cardinal features, making it difficult to reach an accurate clinical diagnosis when they are present in a patient. On the other hand, according to the recent reviews [9, 15], ours is the first report of a patient with SRS carrying a deletion at 5q. As suggested above, the reason for the absence of these cardinal CdCS features could be that the chromosomal regions involved in these signs are not deleted in our patient. Nevertheless, as previously suggested by other authors , it is important to underline the great variability in each feature as each individual trait is not caused by alterations in a single gene. Detailed molecular analysis of more patients with well-established clinical features is necessary to identify the role of the genes responsible for the CdCS.
In brief, overlapping clinical manifestations of different disorders can lead to a misdiagnosis that could be avoided with more detailed molecular testing. Specifically, deletions at 5p should be considered in clinical SRS patients with negative results for chromosome 11 and 7 alterations.
On the other hand, given the importance of correlating the deleted regions at 5p and the clinical features associated with CdCS, some chromosomal maps have been developed. Nevertheless, more molecular karyotyping studies would help identify precise genomic coordinates responsible for each feature of the syndrome.
We thank the patient and her parents for their participation in the study.
The costs of the publication and molecular analyses of this research were funded by grants from Instituto de Salud Carlos III (Institute of Health Carlos III) of the Spanish Ministry of Economy and Competitiveness, co-financed by the European Regional Development Fund (PI16/00073), the Department of Health of the Basque Government (GV2016111105; GV2017111040), and the University of the Basque Country UPV/EHU (PIF17/29).
Availability of data and materials
All data are available for the scientific community, including raw genetic data: requests should be sent directly to the corresponding author.
GPN conceived the project. AP designed the molecular approach. YV and JE-D performed the molecular studies of the syndromes. LG-N designed and carried out FISH analysis. GPN, AP, YV, JE-D and LG-N collaborated in the molecular analyses. IL, NG and BG participated in the recruitment, clinical information acquisition of the patient and parents and wrote the clinical description and discussion. YV and JE-D designed and wrote the first draft with molecular aspects in collaboration with LG-N. AP and GPN combined both clinical and molecular sections and prepared the first complete draft. All authors included modifications and suggestions to the initial version which were compiled by YV and GPN. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
All procedures followed met the ethical standards of the responsible committee. The present study was approved by the Basque ethics committee (PI2017018). Genetic analysis was performed after written informed consent from both parents.
Consent for publication
Consent to publish clinical data and photos of the patient was obtained from both parents of the minor.
The authors declare that they have no competing interests.
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