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 Table of Contents  
Year : 2020  |  Volume : 7  |  Issue : 2  |  Page : 101-104

Distal interstitial 1p36 deletion syndrome in a case of global developmental delay with multiple congenital malformations

1 Department of Pediatrics, MGM Medical College, Aurangabad, Maharashtra, India
2 Department of Pediatric Neurology, MGM Medical College and Research, Aurangabad, Maharashtra, India

Date of Submission24-May-2020
Date of Acceptance24-May-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Dr. Suvarna Magar
Department of Pediatrics, MGM Medical College, N-6, CIDCO, Aurangabad 431002, Maharashtra.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mgmj.MGMJ_44_20

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We report a 1-year-old girl child with a global developmental delay with multiple congenital malformations who presented with the abnormalities including postnatal growth failure, feeding difficulties, seizures, developmental delay, cardiovascular malformations, microcephaly, vertebral segmental defects in the cervical region, Hirschsprung disease, corpus callosal hypoplasia, bilateral fifth finger clinodactyly, and dysmorphic features, including the frontal and parietal bossing, posteriorly rotated ears, hypertelorism, straight eyebrows, and a prominent, upturned broad nose with a long philtrum were noticed. Owing to global developmental delay and multiple congenital malformations, the first-line diagnostic test considered was chromosomal microarray, and it revealed a pathogenic copy number variation in chromosome 1, short arm, 7.3Mb deletion from segment 1p36.32 to 1p36.22. It is a descriptive study undertaken for clinical characteristics and diagnostic evaluation in a girl with global developmental and multiple congenital malformations. The phenotypic features described in our patient could be matched with the genotype on microarray evaluation and were comparable with various studies recorded in literature.

Keywords: 1p36 microdeletion syndrome, chromosomal microarray, congenital malformations

How to cite this article:
Magar S, Engade M, Bhartiya S, Tamrakar A. Distal interstitial 1p36 deletion syndrome in a case of global developmental delay with multiple congenital malformations. MGM J Med Sci 2020;7:101-4

How to cite this URL:
Magar S, Engade M, Bhartiya S, Tamrakar A. Distal interstitial 1p36 deletion syndrome in a case of global developmental delay with multiple congenital malformations. MGM J Med Sci [serial online] 2020 [cited 2020 Jul 9];7:101-4. Available from: http://www.mgmjms.com/text.asp?2020/7/2/101/287171

  Introduction Top

Over the past decade, molecular genetic analyses have undergone tremendous advances and refinement of several chromosomal regions involved in congenital malformations, intellectual disability, and autism have led to well-established syndromes. Here, we report a case of a 1-year old girl child with global developmental delay and multiple congenital malformations with dysmorphism diagnosed with chromosome 1p36 deletion following chromosomal microarray (CMA) technique. CMA was preferred over karyotype for diagnostic purposes as per American Academy of Medical Genetics (ACMG) guidelines,[1] because of advantages such as far better yield than karyotype, cost-effectiveness, and possible diagnosis in one visit, which is very important as a negative result discourages further follow-up for additional genetic testing. CMA also allows exact delineation of chromosomal segment loss and counseling based on genotype–phenotype correlation based on the CMA findings.

  Case report Top

The patient was born to non-consanguineous parents. The baby was born vaginally at 36 weeks of gestation with a birth weight of 2000g. She was kept in the neonatal intensive care unit (NICU) for 5 days for low-birth-weight care. The parents visited genetic outpatient department (OPD) at the age of 6 months in view of developmental delay and other health-related problems in the child. None of the milestones were achieved as a child. The child had constipation from birth, and barium enema revealed a dilated transverse colon and descending colon suggestive of Hirschsprung disease. The two-dimensional (2D) echo was suggestive of moderate-sized patent ductus arteriosus. The child also had a posterior vaginal wall prolapse tag, and the excision of the tag was done at 3 months of age. X-rays of the spine revealed vertebral segmentation defects in the cervical region. Magnetic resonance imaging (MRI) of the brain revealed corpus callosal hypoplasia. On physical examination at 6 months of age, the anthropometric measures were as follows: weight—2.9kg (below third percentile), length—54cm (below third percentile), and head circumference—34cm (below third percentile). She had dysmorphic facial characteristics including microcephaly, a prominent forehead, deep-set eyes with epicanthic fold, straight eyebrows, micrognathia, and a bilateral fifth finger clinodactyly. At 11 months of age, she achieved head holding and started recognizing her mother. At this age, her weight increased to 5.7kg, and facial features included hirsutism, one upturned broad nasal tip with long philtrum, and straight and bushy eyebrows [Figure 1]. Considering multiple congenital malformations with global developmental delay, a CMA test was done, and it revealed a 1p36 deletion syndrome. The patient was directed to rehabilitation, and she required surgical references. A systematic long-term clinical follow-up was planned. Owing to multiple congenital malformations, CMA was considered as the first test for diagnosis.[1] CMA detects submicroscopic deletions and duplications because of higher resolution than karyotype.
Figure 1: Phenotypic features in the patient reveal hirsutism, straight bushy eyebrows, picanthal folds, long philtrum, upturned nasal tip, low set ears, and so on

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  Materials and methods Top

CMA was considered as per recommendation.[1] The microarray consisted of a total of 315,608 features covering control, copy number (CN), and single nucleotide polymorphism (SNP) probes. There is a total of 18K CN and 148K SNP probes uniformly spaced over the genome. The minimum resolution for detection is approximately 1 MB for losses and approximately 2 MB for gains. Genomic DNA was digested with Nsp1 and then ligated by the Nsp1 adapter followed by polymerase chain reaction (PCR) amplification. Amplified PCR products were labeled with biotin and hybridized overnight onto the array. The array was washed using a fluidic station and then scanned on an Affymetrix GeneChip scanner. The data file generated was analyzed using a chromosome analysis suite. The analysis is based on the human reference genome.

  Results Top

A loss of 7.3Mb was observed on chromosome 1, spanning from 1p36.32 to 1p36.22 region. It had 89 genes in the deleted segment. The karyotype of the child was asked to exclude the possibility of unbalanced chromosomal rearrangements after the CMA report was received. Karyotyping of both parents was also advised to look for complex balanced chromosomal arrangements in parents but they could not follow-up later for karyotype testing. The risk of recurrence could be higher in carrier parents than normal parents. Genetic counseling was provided based on findings of microdeletion and its correlation to phenotypic features. Counseling about recurrence risk in future pregnancies could not be done as karyotypes of children and parents were not available.

CMA was considered as the first diagnostic test for the presentation of global developmental delay and multiple congenital malformations because of advantages such as far better yield than karyotype, cost-effectiveness, and possible diagnosis in one visit, which is very important, as negative result discourages further follow-up for additional genetic testing. It also allows exact delineation of chromosomal segment loss and counseling based on genotype–phenotype correlation based on the CMA findings.

  Discussion Top

Monosomy 1p36 is the most common terminal deletion in human beings, responsible for approximately 1% of all cases of idiopathic mental retardation.[2] The patients with 1p36 microdeletion syndrome have facial and developmental characteristics such that one can make a gestalt diagnosis. Microcephaly, straight eyebrows, epicanthal folds, deeply set eyes, wide and depressed nasal bridge, large and late closing anterior fontanel, prominent forehead, midface hypoplasia, long philtrum, pointed chin, and posteriorly rotated low-set ears constitute the typical craniofacial abnormalities of the syndrome.[3],[4] Our patient had many of the characteristics described in the literature. The largest case series of 60 cases by Battaglia et al.[2] has mentioned most of the phenotypic features, and we compared the phenotypes present in our patients with those described in this study [Table 1]. We also compared the phenotypic features in the case series by Kang et al.,[5] and case reports by Kang et al.[6] and Nicoulaz et al.,[7] and this review enabled us to recognize the pattern of congenital malformations for the diagnosis of this syndrome in the absence of karyotype.
Table 1: Comparison of the phenotypic features and the phenotypes present in patients

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We tried to find out genotype–phenotype correlation for this deletion. Genes, which may contribute to developmental delay and structural malformations of brain, include CAMTA1 and TP73, which are part of this microdeletion.[8] Genes, which may contribute to cardiovascular malformations associated with 1p36 region, include DVL, SKI, RERE, PDPN, SPEN, CLCNKA, ECE1, HSPG2, LUZP1, and WASPF2;[9] of these genes, RERE gene is present in the region deleted. Haploinsufficiency of RERE might be sufficient to cause many of the structural malformations associated with proximal 1p36 deletions.[10] Deletions of different sizes have been shown to express similar phenotypes in review by Rocha et al.[8] The final aspect of the syndrome is governed by more complex causes than a simple contiguous gene deletion,[11] such as the effect of the position of one or more genes, genetic and/or environmental factors that may aggravate or mitigate the phenotype, and CN variations or other genetic mutations other than 1p36.

The management of a patient diagnosed with 1p36 deletion syndrome should include regular measurement of growth parameters and nutrition, evaluation for cardiac, renal, and skeletal abnormalities, and early intervention for intellectual disability. Appropriate surgical treatment for cardiac, skeletal, genitourinary, and gastrointestinal, cerebral structural malformations, and antiepileptic drugs for seizures are needed.

  Conclusion Top

Our findings of CMA report for a case of multiple congenital malformations and global developmental delay revealed distal interstitial 1p36 deletion syndrome. The phenotypic features described in our patient could be matched with the genotype on microarray evaluation and were comparable with various studies in literature.

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.


I thank the patient’s parents who helped us with their child’s genetic testing.

Financial support and sponsorship

This study was supported by MGMIHS.

Conflicts of interest

There are no conflicts of interest.

  References Top

Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86:749-64.  Back to cited text no. 1
Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L, McDonald-McGinn D, et al. Further delineation of deletion 1p36 syndrome in 60 patients: A recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics 2008;121:404-10.  Back to cited text no. 2
Jones KL. 1p36 deletion syndrome. In: Jones KL, Jones MC, del Campo M, editors. Smith’s recognizable patterns of human malformation. 7th ed. Philadelphia, PA: Elsevier Saunders; 2013. p. 84-5.  Back to cited text no. 3
Battaglia A. p 36 Deletion Syndrome – ARCHIVED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2008 Feb 1 [Updated 2013 Jun 6]. In: Adam MP, Ardinger HH, Pagon RA, et al, editors.GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.  Back to cited text no. 4
Kang SH, Scheffer A, Ou Z, Li J, Scaglia F, Belmont J, et al. Identification of proximal 1p36 deletions using array-CGH: A possible new syndrome. Clin Genet 2007;72:329-38.  Back to cited text no. 5
Kang DS, Shin E, Yu J. 1p36 deletion syndrome confirmed by fluorescence in situ hybridization and array-comparative genomic hybridization analysis. Korean J Pediatr 2016;59(Suppl 1):S14-8.  Back to cited text no. 6
Nicoulaz A, Rubi F, Lieder L, Wolf R, Goeggel-Simonetti B, Steinlin M, et al. Contiguous ~16Mb 1p36 deletion: Dominant features of classical distal 1p36 monosomy with haplo-lethality. Am J Med Genet Part A 2011;155:1964-8.  Back to cited text no. 7
Rocha CF, Vasques RB, Santos SR, Paiva CL. Mini-review: Monosomy1p36 syndrome: Reviewing the correlation between deletion sizes and phenotypes. Genet Mol Res 2016;15:1-7.  Back to cited text no. 8
Zaveri HP, Beck TF, Hernández-García A, Shelly KE, Montgomery T, van Haeringen A, et al. Identification of critical regions and candidate genes for cardiovascular malformations and cardiomyopathy associated with deletions of chromosome 1p36. PLoS One 2014;9: e85600.  Back to cited text no. 9
Fregeau B, Kim BJ, Hernández-García A, Jordan VK, Cho MT, Schnur RE, et al. De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions. Am J Hum Genet 2016;98:963-70.  Back to cited text no. 10
Õiglane-Shlik E, Puusepp S, Talvik I, Vaher U, Rein R, Tammur P, et al. Monosomy1p36-A multifaceted and still enigmatic syndrome: Four clinically diverse cases with shared white matter abnormalities. Eur J Paediatr Neurol 2014;18:338-46.  Back to cited text no. 11


  [Figure 1]

  [Table 1]


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