9q22.3 MICRODELETION IN A FEMALE CHILD WITH GLOBAL DEVELOPMENTAL DELAY AND PHYSICAL ANOMALIES: A CASE REPORT

9q22.3 MICRODELETION IN A FEMALE CHILD WITH GLOBAL DEVELOPMENTAL DELAY AND PHYSICAL ANOMALIES: A CASE REPORT | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 1 May 2025 V1 Latest version Share on 9q22.3 MICRODELETION IN A FEMALE CHILD WITH GLOBAL DEVELOPMENTAL DELAY AND PHYSICAL ANOMALIES: A CASE REPORT Authors : Ashok Paudel 0009-0006-5367-7738 , Janak Pathak , Mandeep Yadav 0000-0002-2132-8094 [email protected] , and Bina Prajapati Manandhar Authors Info & Affiliations https://doi.org/10.22541/au.174608475.54966517/v1 295 views 129 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Abstract Introduction The 9q22.3 microdeletion syndrome is a rare chromosomal disorder associated with developmental delays, congenital anomalies, and phenotypic overlap with Gorlin syndrome. Clinical variability complicates diagnosis, necessitating advanced genetic testing. Case Report A 13-month-old female presented with global developmental delay, macrocephaly (>97th percentile), and dysmorphic features, including frontal bossing, flat TITLE: 9q22.3 MICRODELETION IN A FEMALE CHILD WITH GLOBAL DEVELOPMENTAL DELAY AND PHYSICAL ANOMALIES: A CASE REPORT Dr. Ashok Paudel 1 ,Dr. Janak Pathak 2 ,Dr. Mandeep Kumar Yadav* 3 , Dr. Bina Prajapati 4. Affiliations: ¹ Department of Pediatrics, Kanti Children’s Hospital, Maharajgunj, Kathmandu, Nepal ² Department of Pediatrics, Kanti Children’s Hospital, Maharajgunj, Kathmandu, Nepal ³ Department of Pediatrics, Kanti Children’s Hospital, Maharajgunj, Kathmandu, Nepal ⁴ Department of Pediatrics, Kanti Children’s Hospital, Maharajgunj, Kathmandu, Nepal *Corresponding author: Dr. Mandeep Kumar Yadav Email: [email protected] Introduction The 9q22.3 microdeletion syndrome is a rare chromosomal disorder associated with developmental delays, congenital anomalies, and phenotypic overlap with Gorlin syndrome. Clinical variability complicates diagnosis, necessitating advanced genetic testing. Case Report A 13-month-old female presented with global developmental delay, macrocephaly (>97th percentile), and dysmorphic features, including frontal bossing, flat nasal bridge, left-hand polydactyly, toe overcrowding, and a café-au-lait spot. Motor delays (head control at 7.5 months, independent sitting at 13 months) contrasted with emerging bisyllabic speech. Brain MRI showed reduced white matter and a thin corpus callosum. Whole exome sequencing identified a heterozygous 7,280.56 KB deletion at 9q22.31-q22.33 (de novo origin). Confirmatory testing was unavailable due to resource constraints. Discussion This case broadens the phenotypic spectrum of the syndrome by introducing features such as toe overcrowding and café-au-lait spots. The absence of classic Gorlin syndrome characteristics, along with the lack of overgrowth traits, highlights the gene-specific variability in this condition. The patient’s speech development, which differs from the typical delays seen in similar cases, further emphasizes the heterogeneity of the syndrome. Additionally, the overlap with PTCH1 mutations points to the importance of ongoing tumor surveillance. Finally, the limitations in available resources underscore the diagnostic challenges faced in low-resource settings. backend=biber, style=alphabetic, sorting=ynt ]biblatex Conclusion Comprehensive genetic testing is vital for children with developmental delays and dysmorphic features, as it aids in accurate diagnosis and the identification of novel findings. These discoveries enhance diagnostic precision and inform personalized interventions, which, when coupled with multidisciplinary care, improve overall outcomes. Global disparities in genetic diagnostics highlight the need for greater accessibility to testing. Early diagnosis enables timely interventions and supports informed family planning. KEYWORDS : 9q22.3 microdeletion, chromosome 9, developmental delay, congenital anomalies, chromosome deletion syndrome INTRODUCTION: The 9q22.3 microdeletion is a chromosomal alteration where a small segment of the long (q) arm of chromosome 9 is missing in each cell. Individuals with this condition lack at least 352 kilobases (kb) in the q22.3 region, the smallest known deletion causing associated symptoms, with the largest reported being 20.5 megabases (Mb). The symptoms include delayed development, intellectual disability, certain physical abnormalities, and features of a genetic condition called Gorlin syndrome/NBCNS (Nevoid Basal Cell Carcinoma Syndrome). (1) Chromosome 9q22.31-q22.33 deletions are relatively rare and the specific clinical presentation can vary significantly based on the exact genes involved in the deletion. Here we present a case of 13 months old female with global developmental delay and physical anomalies with a contiguous heterozygous deletion of size (≈7280.56 KB) on chromosome 9 (9q22.31-q22.33). CASE REPORT: History : A female child was born at 38+5 weeks of gestation to a 29-year-old mother (G2P1A1) and a 29-year-old father, by a non-consanguineous marriage. The mother’s first pregnancy ended in a spontaneous abortion at 91 days. During this pregnancy, an antenatal ultrasound at 6 months revealed a unilateral lateral ventricle prominence of 9 mm. The pregnancy was further complicated by chronic cervicitis, leading to an elective lower segment cesarean section (LSCS) due to cervical incompetence. The baby had a delayed cry after birth but did not require resuscitation. At birth, she weighed 3750 grams (87th percentile) and had a head circumference of 37 cm (>97th percentile).The neonatal period was marked by a 12-day Neonatal Intensive Care Unit (NICU) stay due to neonatal sepsis but meningitis was ruled out. At 2 months of age, she was hospitalized again for 12 days due to aspiration pneumonia and was discharged from the hospital after appropriate management. She was vaccinated appropriately as per the national immunization protocol. Developmentally, her motor milestones were delayed. At 4 months, her parents noticed she could not hold her head which persisted until she was 7.5 months old. Although she eventually achieved neck control, she could not sit with support. By 9 months, she was able to roll over completely, reach and grasp objects, and produce monosyllabic sounds. During her last visit to the outpatient department at our center at the age of 13 months, she could sit without support for a few seconds, had a unidextrous reach, could transfer objects, wave bye-bye, and speak bisyllabic words. Physical Examination: On physical examination the clinical picture included macrocephaly, frontal bossing, flat nasal bridge, epicanthal folds, a high arched palate, a midline cleft, a long philtrum, left-hand polydactyly, overcrowding of toes, and a café-au-lait spot on the anterior abdominal wall. (Figure 1) During anthropometric examination, the patient’s weight was 3750 grams at birth, which was above the 85 th percentile. By 13 months of age, her weight had reached 10 kilograms, exceeding the 75th percentile. Her head circumference measured 37 cm at birth, placing her above the 97 th percentile. At 4 months, her head circumference was 42 cm, at the 86th percentile, and has remained above the 97 th percentile since the 11 th month. Her length at 1 month was 54 cm, placing her at the 56 th percentile, and has been above the 97 th percentile since the 11 th month (Figure 2). Investigations : During different hospital visits, a series of investigations were conducted. At 1 month of age, an electroencephalogram (EEG) was performed and returned normal results. A Brain Magnetic Resonance Imaging (MRI) at 4 months showed reduced white matter volume in the centrum semiovale, a relatively thin corpus callosum, and prominent lateral ventricles, suggesting a possible early prenatal brain insult. Basic blood investigations were essentially normal. Given the clinical findings, chromosomal analysis was performed, revealing a normal karyotype with no deletions or duplications. Subsequent whole exome sequencing and whole mitochondrial genome sequencing identified a heterozygous deletion of approximately 7280.56 KB on chromosome 9 (region 9q22.31-q22.33). No significant single nucleotide variants (SNVs) or insertions/deletions (Indels) were detected, nor were there any significant clinically relevant variants in the mitochondrial genome. To confirm the Copy Number Variant (CNV) detected, further testing via Multiplex Ligation-dependent Probe Amplification (MLPA), microarray, or Polymerase Chain Reaction (PCR) was recommended due to the lower specificity of the Next-Generation Sequencing (NGS)-based assay for large deletions/duplications. However, due to resource limitations, we were unable to perform these additional tests. Figure 1 Photographs of the patient at age 9 months. Note the epicanthic fold and Flat nasal bridge (a), Large Head Size (b), Crowding of toes (c) and Polydactyly (d) Source: World Health Organization. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Methods and development. Geneva, WHO, 2006.” Figure 2 : Anthropometric recording of the patient at different ages. (a) Length/Height (b) Weight for age (c) Head circumference for age MANAGEMENT AND FOLLOW UP : The patient is being managed conservatively through a multidisciplinary approach that includes active participation from her family. Regular follow-up visits are conducted to facilitate appropriate screenings and assessments to anticipate potential complications. We are closely monitoring her growth, developmental milestones, and conducting regular behavioral assessments. She is under consistent follow-up with a physiotherapist to address the potential needs for physical, occupational, and speech therapies to support her developmental progress. Additionally, age-appropriate nutritional supplements are provided to meet her dietary requirements. DISCUSSIONS: This case report details a female child presenting with significant developmental delays, macrocephaly, and several dysmorphic features, alongside a notable chromosomal abnormality. The identified heterozygous deletion on chromosome 9 (region 9q22.31-q22.33) aligns with several reported features in the literature, providing a genetic basis for the clinical presentation. The physical examination of our patient revealed several dysmorphic features, including macrocephaly, frontal bossing, flat nasal bridge, epicanthal folds, high arched palate, midline cleft, long philtrum, left-hand polydactyly, and a café-au-lait spot, along with overcrowding of the toes. These findings suggest a syndromic presentation, consistent with those reported in the literature (2, 3, 4). Despite these findings, our case lacks features such as metopic craniosynostosis, hydrocephalus (3), rib and vertebral anomalies (3, 4), trigonocephaly (5), hypotonia (3, 5) and ocular abnormalities (6) described in other reports. Notably, overcrowding of the toes and café-au-lait spots have not been reported previously in association with this syndrome. Our patient’s unique presentation, including overcrowding of the toes and café-au-lait spots, suggests that the phenotypic spectrum of 9q22.3 microdeletion syndrome may be broader than currently understood. Further research is needed to elucidate these genotype-phenotype correlations and develop targeted therapeutic strategies. The developmental milestones of the patient were notably delayed, particularly in motor skills. By 9 months, she could roll over and grasp objects, but head hold was not achieved until 7.5 months, and she could not sit with support. These motor delays are significant, aligning with studies where 37.5% of the population displayed motor delays, and 62.5% had global developmental delays, with a cumulative prevalence of 61.3% for global developmental delay. (3) Conversely, our patient could produce monosyllabic sounds by 9 months and bisyllabic words by 13 months, contrasting with the absence of speech delays reported in the study but aligning with the cumulative prevalence of global developmental delay in this study (3) and other reported cases.(4,6) The 9q22.3 microdeletion can occur de novo or be inherited in an autosomal dominant pattern, sometimes from an asymptomatic parent with a balanced translocation.(5) Both the parents of our patient are healthy and doesn’t exhibit any physical features in contrast to the report of familial constitutional deletion (7) and both are cognitively normal, similar to the cognitively normal father of a two mentally retarded female siblings, all with a 5.3 Mb deletion in the 9q22.2-q22.32 region indicating a familial constitutional deletion.(7) A study described overgrowth syndrome with 9q22.3 microdeletion, including macrosomia and increased length at birth. (5) On the other hand, our patient does not exhibit characteristic findings such as trigonocephaly, overgrowth, small mouth, and hypotonia observed in the two presented cases even though macrocephaly is still present.(5) Most of the literature involving 9q interistitial deletion involves the Gorlin syndrome. Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome (NBCCS) or basal cell nevus syndrome (BCNS), is a genetic disorder linked to the PTCH1 gene on chromosome 9q22.32. The diagnosis of Gorlin syndrome can be established by meeting either two major criteria and one minor criterion or one major criterion and three minor criteria. The major criteria include lamellar calcification of the falx, jaw keratocysts, palmar or plantar pits, multiple basal cell carcinomas (more than five in a lifetime or at least one before the age of 30), and having a first-degree relative with Gorlin syndrome. The minor criteria include childhood medulloblastomas, lympho-mesenteric or pleural cysts, macrocephaly, cleft lip or palate, vertebral or rib anomalies, preaxial or postaxial polydactyly, ovarian or cardiac fibromas, and ocular anomalies. (8) Our case did not meet the diagnostic criteria for Gorlin syndrome, despite the involvement of 9q22.32. Nonetheless, given that numerous features of BCNS have age-dependent penetrance, with a median onset age of 25 years, diagnosing BCNS based solely on clinical criteria can be challenging, particularly in early childhood. (9) Given the challenges in diagnosing 9q22.3 microdeletion syndrome, especially in early childhood, comprehensive genetic evaluations are essential. Early diagnosis can facilitate timely interventions, such as physical, occupational, and speech therapy, to support the patient’s development. Regular follow-up with a multidisciplinary team is crucial for monitoring and managing the diverse clinical symptoms and to detect any potential development of the various benign and malignant tumors associated with the syndrome. In conclusion, the diagnosis of the 9q22.31-q22.33 chromosomal deletion in our patient highlights the critical need for comprehensive genetic evaluations and coordinated multidisciplinary care. Confirmatory testing using alternate methods such as MLPA (Multiplex Ligation-dependent Probe Amplification), microarray, or PCR is recommended to validate the chromosomal deletion. Due to resource limitations, we were unable to perform these additional tests, which represents a significant limitation in our case. Genetic testing in family members should be pursued to better understand the inheritance patterns and provide more personalized genetic counseling. This will help the family comprehend the implications of these genetic findings and make informed decisions about future pregnancies and health management. Regular follow-up with a multidisciplinary team, including neurologists, developmental pediatricians, and geneticists, is essential to monitor and manage developmental delays and other clinical symptoms associated with this chromosomal deletion. Future research should aim to further delineate the phenotypic spectrum associated with 9q22.31-q22.33 deletions and explore potential therapeutic interventions to improve patient outcomes. KEY CLINICAL MESSAGE (KCM): Diagnosis of the 9q22.31-q22.33 chromosomal deletion in our patient underscores the need for thorough genetic evaluations and multidisciplinary care in pediatric patients with developmental delays and anomalies, aiding families in understanding genetic implications and making informed decisions about future pregnancies and health management. backend=biber, style=alphabetic, sorting=ynt ]biblatex CONFLICT OF INTEREST None AUTHOR CONTRIBUTIONS All authors contributed equally to this work. Dr. Ashok Paudel: Conceptualization; Writing – Original Draft; Writing – Review & Editing Dr. Janak Pathak: Conceptualization; Writing – Original Draft; Writing – Review & Editing Dr. Mandeep Kumar Yadav: Conceptualization; Writing – Original Draft; Writing – Review & Editing Dr. Bina Prajapati: Supervision ACKNOWLEDGEMENTS We would like to extend our heartfelt thanks to all the team members of Kanti Children’s Hospital, Maharjgunj,Kathmandu, Nepal for their invaluable support and guidance. CONSENT Written informed consent was obtained from the patient’s guardians for the publication of this case report and any accompanying images. A copy of the written consent from the patient for publication is available for review by the Editor-in-Chief of this journal on request. REFERENCES: 1. Imaizumi K. [Chromosome 9]. Ryoikibetsu Shokogun Shirizu. 2001;(33):403-6. Japanese. PMID: 11462491. [PubMed ] 2. Yamamoto K, Yoshihashi H, Furuya N, Adachi M, Ito S, Tanaka Y, Masuno M, Chiyo H, Kurosawa K. Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature. Congenit Anom (Kyoto). 2009 Mar;49(1):8-14. doi: 10.1111/j.1741-4520.2008.00212.x. PMID: 19243411. [PubMed | Full Text | DOI] 3. Muller EA, Aradhya S, Atkin JF, Carmany EP, Elliott AM, Chudley AE, Clark RD, Everman DB, Garner S, Hall BD, Herman GE, Kivuva E, Ramanathan S, Stevenson DA, Stockton DW, Hudgins L. Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay. Am J Med Genet A. 2012 Feb;158A(2):391-9. doi: 10.1002/ajmg.a.34216. Epub 2011 Dec 21. PMID: 22190277. [PubMed | Full Text | DOI] 4. Olivieri C, Maraschio P, Caselli D, Martini C, Beluffi G, Maserati E, Danesino C. Interstitial deletion of chromosome 9, int del(9)(9q22.31-q31.2), including the genes causing multiple basal cell nevus syndrome and Robinow/brachydactyly 1 syndrome. Eur J Pediatr. 2003 Feb;162(2):100-3. doi: 10.1007/s00431-002-1116-4. Epub 2002 Dec 10. PMID: 12548386. [PubMed | Full Text | DOI] 5. Redon R, Baujat G, Sanlaville D, Le Merrer M, Vekemans M, Munnich A, Carter NP, Cormier-Daire V, Colleaux L. Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome. Eur J Hum Genet. 2006 Jun;14(6):759-67. doi: 10.1038/sj.ejhg.5201613. PMID: 16570072. [PubMed | Full Text | DOI] 6. Keselman D, Singh R, Cohen N, Fefer Z. De Novo Interstitial Deletion of 9q in a Pediatric Patient With Global Developmental Delay. Child Neurol Open. 2019 May 7;6:2329048X19844920. doi: 10.1177/2329048X19844920. PMID: 31106228; PMCID: PMC6506918. [PubMed | Full Text | DOI] 7. Siggberg L, Peippo M, Sipponen M, Miikkulainen T, Shimojima K, Yamamoto T, Ignatius J, Knuutila S. 9q22 Deletion–first familial case. Orphanet J Rare Dis. 2011 Jun 22;6:45. doi: 10.1186/1750-1172-6-45. PMID: 21693067; PMCID: PMC3135502. [PubMed | Full Text | DOI] 8. Evans DG. Nevoid Basal Cell Carcinoma Syndrome. 2002 Jun 20 [updated 2024 Feb 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301330. [PubMed | Full Text ] 9. Cowan R, Hoban P, Kelsey A, Birch JM, Gattamaneni R, Evans DG. The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br J Cancer. 1997;76(2):141-5. doi: 10.1038/bjc.1997.354. PMID: 9231911; PMCID: PMC2223943. [PubMed | Full Text | DOI] Supplementary Material File (figures.docx) Download 2.05 MB Information & Authors Information Version history V1 Version 1 01 May 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords genetics and genomics paediatrics and adolescent medicine Authors Affiliations Ashok Paudel 0009-0006-5367-7738 Kanti Children's Hospital View all articles by this author Janak Pathak Kanti Children's Hospital View all articles by this author Mandeep Yadav 0000-0002-2132-8094 [email protected] Kanti Children's Hospital View all articles by this author Bina Prajapati Manandhar Kanti Children's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 295 views 129 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Ashok Paudel, Janak Pathak, Mandeep Yadav, et al. 9q22.3 MICRODELETION IN A FEMALE CHILD WITH GLOBAL DEVELOPMENTAL DELAY AND PHYSICAL ANOMALIES: A CASE REPORT. Authorea . 01 May 2025. 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