Vrachnis et al. Mol Cytogenet (2021) 14:39 https://doi.org/10.1186/s13039-021-00557-y CASE REPORT Open Access Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search Nikolaos Vrachnis1,2,3* , Ioannis Papoulidis4, Dionysios Vrachnis5, Elisavet Siomou4, Nikolaos Antonakopoulos1,2, Stavroula Oikonomou6, Dimitrios Zygouris2, Nikolaos Loukas7, Zoi Iliodromiti8, Efterpi Pavlidou9, Loretta Thomaidis6 and Emmanouil Manolakos4 Abstract Background: The interstitial 6p22.3 deletions concern rare chromosomal events afecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways. Case presentation: We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes. Conclusions: Identifcation and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion. Keywords: 6p22.3 deletion, Syndrome, Developmental delay, Intellectual disability, Dysmorphism, Behavioral abnormalities, High-resolution microarray analysis Background dysmorphic features, and structural organ defects, as well Te interstitial deletion of chromosomal region 6p22.3 as intellectual disability. is a rare condition with variable phenotypic expression. We report herein a case of interstitial deletion of chro- To date, more than 30 children and adolescents with this mosome 6p investigated by array-CGH in a 2.8-year old deletion have been reported [1–11]. Interestingly, Col- boy with developmental delay, mild facial dysmorphism, mant et al. described an electively aborted fetus with and speech communication disorders. multiple abnormalities presenting the same deletion [12]. According to the size of the 6p22.3 deletion, which Case presentation usually varies between 1 and 10 MB [3, 4], the clinical Te patient was a 2.8-year old boy born to non-consan- manifestations may include behavioral abnormalities, guineous healthy parents after an uncomplicated full- term pregnancy. He is the third child of the family, the *Correspondence: [email protected] other two ofspring being a healthy 8-year old boy and 1 Third Department of Obstetrics and Gynecology, National a healthy 10-year old girl. He was born by cesarean sec- and Kapodistrian University of Athens, Medical School, Attikon Hospital, tion with birth weight 2.990 g (15th centile), length 50 cm Athens, GR, Greece Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Vrachnis et al. Mol Cytogenet (2021) 14:39 Page 2 of 9 (35th centile), and head circumference 34 cm (15th cen- High-resolution molecular karyotyping was performed tile). His perinatal history was uneventful. with an aCGH platform of 60,000 oligonucleotides (Agi- His motor milestones in infancy and toddlerhood are lent Technologies, Santa Clara, Cal., USA) at the age reported as normal, as he sat unsupported at the age of of 2 years and 8 months [ISCN formula: arr[GRCh37] 6 months and walked unaided at the age of 15 months. At 6p22.3 (15,794,379_18,277,334)x1dn]. DNA extracted the age of 13 months, bilateral cryptorchidism was surgi- from blood lymphocytes showed that the 6p deletion was cally corrected. a 2.5 Mb deletion of the distal short arm of chromosome Due to speech and language delay, he was referred at 6 with the proximal breakpoints between 15,794,379 bp the age of 2 years and 8 months for a full developmen- (last deleted oligo) and 15,793,879 bp (frst normal oligo), tal assessment. On physical examination, he was found to and the distal breakpoints between 18,291,461 bp (frst be a sociable child with mild dysmorphic facial and body normal oligo), and 18,277,334 bp (last deleted oligo) features, including frontal bossing, micrognathia, short (Fig. 1). thin nose, small deep-set eyes, small mouth with long Chromosome analysis with banding patterns, using fat philtrum, low-set ears with auricle abnormalities, GTG-banding techniques, was also carried out on stimu- widely spaced nipples, broad thumbs, and long tapering lated blood lymphocytes and analyzed at 550–600 band fngers. Developmental assessment showed that the child resolution. Cytogenetics revealed a normal karyotype. had good pretend play ability; however, verbal expres- Again, the parental karyotypes (blood lymphocytes) were sion was lacking, while his comprehension was limited to normal, as produced by using banding patterns. simple commands. His overall developmental level was equivalent to that of a healthy 15-month old child, which Discussion corresponds to low developmental quotient (DQ = 40). Deletions of 6p chromosome are a group of heterogene- On neurological examination, he showed global hypoto- ous chromosomal anomalies. Tere is variability in the nia of trunk and limbs without focal neurological signs. size and location of the breakpoints, resulting in diverse His height was 95 cm (50th centile), his weight was and overlapping clinical phenotypes, depending on the 15 kg (50th centile), and his head circumference was genes located in the deleted areas. Consequently, mak- 51 cm (30th centile). Laboratory investigation, including ing an accurate genotype–phenotype correlation is often audiological, visual, biochemical, metabolic, endocrine challenging. 6p deletions can involve either the distal or (thyroid, growth hormone, luteinizing hormone, follicle- the interstitial part of the short arm of chromosome 6. stimulating hormone, adrenocorticotropin hormone and Deletions involving the distal part of the short arm of prolactin), bone age, and kidney/liver and triplex ultra- chromosome 6 are relatively rare. Terminal deletions sound assessments were normal. Brain MRI (magnetic of 6p24-pter have been associated with developmen- resonance imaging) showed bilateral choroid plexus tal delay, brain malformations (including Dandy-Walker cysts, with a bigger cyst on the left and areas of increased malformation), anterior eye chamber abnormalities, signal intensity in periventricular white matter along the hearing loss, ear abnormalities, micrognathia, and heart lateral horns of both lateral ventricles and along the fron- defects. Patients with larger sized deletions of 6p23- tal horns, this probably related to late myelination. pter also present with microcephaly, genital anomalies, Fig. 1 Array-CGH analysis illustrating in depth the de novo interstitial microdeletion of approximately 2.5 Mb in size on the short arm of chromosome 6 at chromosomal band 6p22.3, chr6: 15,794,379 to 18,277,334, using build GRCh37 (hg19) Vrachnis et al. Mol Cytogenet (2021) 14:39 Page 3 of 9 language impairment, and delayed motor development DEK (DEK proto-oncogene), FAM8A1 (family with [11–18]. sequence similarity 8, member A1), GMPR (guanosine Interstitial deletions of 6p22-p24 have been reported monophosphate reductase gene), KDM1B (lysine dem- even less often. Our patient had an interstitial deletion ethylase 1B), KIF13A (kinesin family member 13A gene), of about 2.5 Mb in chromosomal band 6p22.3. Some of MYLIP (myosin regulatory light chain interacting protein the aforementioned reports concern deletions with dif- gene), NHLRC1 (NHL repeat containing E3 ubiquitin ferent breakpoints which do not overlap with our case, protein lipase 1 gene), NUP153 (nucleoporin 153 gene), thus exhibiting a diferent phenotype. For example, there RMB24 (RNA binding motif protein 24 gene), STMND1 is a report of four patients with a 6p22.3 deletion located (stathmin domain containing 1 gene), and TPMT (thio- more proximally in comparison with our case. Tree of purine S-methyltransferase gene) (Table 1). them had mesomelic dysplasia and the fourth (who had In the literature, there are several reports of 6p22.3 a larger deletion) had developmental delay without skel- deletions which overlap with the deleted region of our etal anomalies [19]. Ladinsky et al. also reported a patient patient. Our search on the PUBMED database revealed with skeletal abnormalities (lower extremity hemimelia 19 cases, while the DECIPHER database revealed 18 with mesomelic shortening), facial dysmorphisms, sen- cases. Some of these patients were genetically investi- sorineural hearing