46,XY disorders of sex development and muscular dystrophy caused by Xp21 duplication: a case report and literature review

Introduction

Disorders of sex development (DSD) refer to a wide category of diseases with inconsistent chromosomal karyotype, gonadal phenotype, and gonadal anatomical structure. According to the chromosome karyotype, DSD is mainly categorized into 46,XY DSD, 46,XX DSD, and sex chromosome abnormal DSD (1). The incidence of 46,XY DSD is approximately 1/100,000 (2), with identified pathogenic genes such as SRY, WT1, DHH, SOX9, and NR0B1. Moreover, chromosomal abnormalities like deletions and duplications can lead to 46,XY DSD. Xp21 duplication, in particular, can cause a rare form of 46,XY complete or partial gonadal dysgenesis, often accompanied by multiple abnormalities, including muscular dystrophy, short stature, mental retardation, low ear position, thin upper lip, micrognathia, cleft palate, and syndactyly (3,4). Chromosome Xp21 region contains the NR0B1, GK, DMD, and IL1RAPL1 genes, which can lead to gonadal dysgenesis, adrenal dysgenesis, muscular dystrophy, glycerol phosphokinase deficiency and mental retardation. NR0B1, also known as DAX1, is located at Xp21. Duplication of the NR0B1 gene mainly affects the differentiation of 46,XY embryos into female gonads by inhibiting the expression of WT1, SF1, SOX9, SRY, and AMH genes. Testicular development gradually downregulates the effect of NR0B1, finally leading to the formation of female external genitalia or ambiguous external genitalia (4). Notably, gene deletion in the Xp21 region can lead to Xp21 contiguous gene deletion syndrome with coexisting gene defects. Clinical manifestations are associated with the affected genes, including glycerol kinase deficiency (GKD), adrenal hypoplasia congenita (AHC), Duchenne muscular dystrophy (DMD), retinitis pigmentosa (RP), chronic granulomatous disease (CGD), ornithine transcarbamylase deficiency (OTCD), etc. AHC, GKD, and DMD site defects are the most common (5).

We reported a patient with 46,XY complete gonadal dysplasia after birth, who exhibited muscular dystrophy and growth retardation at the age of 5 months. Genetic testing revealed a duplication of Xp21 with a size of approximately 7.79 Mb. This study expands the clinician’s understanding and diagnosis of 46,XY DSD due to Xp21 duplication. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-327/rc).

Case presentation

Data and methods

Case data

The proband, who was the firstborn in a non-consanguineous family, was delivered full-term without any complications following a normal pregnancy. His father, who was in good health, was 178 cm tall and weighed 80 kg. His mother, who was 156 cm tall and weighed 60 kg, had a regular menstrual cycle and experienced menarche at the normal age. She had a healthy pregnancy without any history of special medication, hypertension, hyperglycemia, hyperlipidemia, exposure to radioactive substances, or tobacco and alcohol use. The proband was supplemented with mixed feeding due to insufficient breast milk. There was no family history of genetic diseases, infertility, amenorrhea, abnormal spermatogenesis, or cryptorchidism. At birth, he was discovered to have abnormal external genitalia, with a karyotype of 46,XY being confirmed. At 5 months of age, the patient visited our clinic for abnormal sex differentiation.

On physical examination, his height was 60 cm [−3.06 standard deviation (SD)], his weight was 6.5 kg (−1.47 SD), and his head circumference was 41 cm (−1.50 SD). Skin pigmentation was not deepened, and normal muscle strength and tone were observed. He exhibited specific facial features, including a thin upper lip and low-set ears, along with delayed developmental milestones. At the age of five months, he displayed instability in head control. He presented with ambiguous external genitalia, characterized by a 0.5 cm penis, a urethral opening in the perineum, a split scrotum resembling labia majora, and testicles found in the inguinal region (Figure 1).

Figure 1 The characteristics of the external genitalia of the proband at the age of 5 months. Ambiguous external genitalia was observed in the proband, with a 0.5 cm penis, a urethral opening in the perineum, a split scrotum resembling labia majora, and testicles found in the inguinal region.

Supplementary examination: alanine aminotransferase (ALT): 294.0 U/L (reference range, 8–71 U/L); aspartate aminotransferase (AST): 299.0 U/L (reference range, 21–80 U/L); lactate dehydrogenase (LDH): 1,368 U/L (reference range, 170–450 U/L); creatine kinase (CK): 13,024 U/L (reference range, 50–310 U/L); creatine kinase MB (CKMB): 289.0 U/L (reference range, 0–25 U/L); triacylglycerol (TAG): 2.51 mmol/L (reference range, 0–1.7 mmol/L); high-density lipoprotein cholesterol (HDL-C): 2.02 mmol/L (reference range, 1.16–1.42 mmol/L); electrolytes and blood glucose levels are normal. Follicle stimulating hormone (FSH): 9.33 mIU/mL (reference range, 1.5–12.4 mIU/mL); luteinizing hormone (LH): 1.69 mIU/mL (reference range, 1.7–8.6 mIU/mL); estradiol (E): <18.35 pmol/L (reference range, 41.4–159 pmol/L); progesterone (P): 6.300 nmol/L (reference range, 0–0.474 nmol/L); testosterone (T): <0.087 nmol/L (reference range, <0.087–30.6 nmol/L); dihydrotestosterone (DHT): 130.26 pg/mL (reference range for males aged 1–9 years: 0.00–85.70 pg/mL); adrenocor ticotropic hormone (ACTH): 60.02 pg/mL (reference range, 0–46 pg/mL). Human chorionic gonadotropin stimulation test: T (after hcg): 0.529 nmol/L, DHT (after hcg): 199.99 pg/mL. Anti-mullerian hormone (AMH): 21.27 ng/mL (reference range, 1.45–18.77 ng/mL). Ultrasound of the inguinal scrotum: 8 mm by 4 mm circular low echo near the deep inguinal ring. Adrenal computed tomography (CT) results were normal, as well as echocardiography and abdominal ultrasound findings which showed no abnormalities in the liver, pancreas, or spleen. Electromyography indicated changes in active myogenic lesions, while the developmental screen test revealed motor, social, and adaptive intelligence levels equivalent to a 2-month-old, 4-month-old, and 4-month-old, respectively.

Genetic testing

Peripheral blood samples were collected from the patient and his parents for targeted next-generation sequencing (NGS). Genomic DNA was isolated from peripheral leukocytes using a DNA isolation kit (Tiangen, China) according to the manufacturer’s instructions (6). The DNA probes were designed to tile along the exon regions of the 325 genes associated with abnormal sex differentiation (Table S1). Sanger sequencing was performed to confirm the identified variants. Furthermore, the CMA method was utilized for copy number variation (CNV) detection, given the multiple systemic anomalies observed in the proband.

Relevant literature

“NR0B1 duplication/DAX1 duplication”, “46,XY disorder of sex development/46,XY DSD”, “Duchenne muscular dystrophy/DMD”, and “Xp duplication” were searched for in PubMed, CNKI (China National Knowledge Infrastructure), Wanfang Data Knowledge Service Platform and other databases from January 1978 to December 2023.

Results

Genetic analysis

The NGS revealed a duplication of approximately 5.72 Mb at Xp21.3p21.2 (25022786_30746859), encompassing 16 coding genes (MAGEB18, MAGEB6B, DCAF8L2, PPP4R3C, MAGEB10, DCAF8L1, IL1RAPL1, NR0B1, MAGEB1, MAGEB2, MAGEB3, MAGEB4, MAGEB5, MAGEB6, GK, and TASL). Notably, the DMD gene responsible for muscular dystrophy was not present in this region. Due to NGS being more focused on identifying single nucleotide variations and small insertions or deletions. Further analysis of CMA revealed that the proband had a duplication of Xp21.1p22.11 (23895951_31685946), spanning approximately 7.79 Mb and encompassing 30 protein-coding genes, including DMD (exons 53-79) and NR0B1 (Figure 2). The proband’s duplication of Xp21.1p22.11 (23895951_31685946) was classified as pathogenic, in accordance with the technical standards established by American College of Medical Genetics and Genomics (ACMG)/ClinGen in 2019 for the interpretation and reporting of constitutional copy-number variants (7). Furthermore, the proband also had a benign deletion of about 230 Kb on chromosome 6 p25.3, as classified by ACMG assessment. In order to further confirm the origin of the CNVs in the proband, a CMA analysis was performed on the mother. The results indicated that the mother also had the same Xp duplication, implying that the proband inherited the duplication from his mother. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the participant’s legal guardian for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 2 Result of the chromosomal microarray analysis in the proband. Microarray profile of the patient showing a hemizygous duplication of 7.79 Mb in the chromosome region Xp21 (red arrow).

Literature review

Including our study, a total of 26 related cases have been reported in domestic and foreign literature. Among these cases, 21 were clearly caused by Xp21 duplication and were classified as 46,XY DSD. The clinical and genetic characteristics of the proband and the cases reported in the relevant literature are shown in Table 1 (3,4,8-17).

Treatment and follow-up

The patient received a multidisciplinary consultation with the Endocrinology Department, Urology Department, Neurology Department, Rehabilitation Department, and Genetics Department. The patient presented with hypertrophic gonadotropic gonadal dysgenesis and poor testicular function. Further regular follow-up is required to evaluate penile development and testicular function. Currently, glucocorticoid treatment is temporarily withheld for young children, with administration typically commencing at the age of 4 years. Regular follow-up every 6 months is necessary to assess skeletal muscle function, bone and joint health, growth, development, and respiratory and digestive functions. Rehabilitation exercises should be implemented to prevent joint contractures and deformities. As a carrier, the mother of the proband has a 50% chance of transmitting the pathogenic gene to her offspring. Prenatal genetic diagnosis should be performed after the second pregnancy of the mother, at either 12 or 16 weeks of gestation to determine whether the fetus carries the same pathogenic mutation as the proband. At 1 year and 7 months old, the patient had low muscle strength. He could sit steadily and stand up with assistance, but he was unable to crawl or walk. Additionally, he was only able to utter a single sound and unintentionally pronounce ‘dad’ and ‘mom’.

Discussion

In this study, the patient presented with external genital dysplasia, and NGS revealed a copy number duplication of 5.72 Mb on Xp, a region containing 16 coding genes. Sex hormone testing showed that the child had hypertrophic gonadal dysgenesis, and the pathogenic gene associated with gonadal dysgenesis phenotype was the NR0B1 gene. The NR0B1 gene is located at Xp21 (30304206_30309390), with two exons and one intron, and encodes the DAX1 protein. The DAX1 protein is a nuclear receptor transcription factor, expressed in the adrenal glands, gonads, hypothalamus, and pituitary glands of the fetus. DAX1 is associated with the development and function of the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis (18). Duplication of the NR0B1 gene mainly causes abnormal sexual development in males. In contrast, loss of function mutation or deletion of NR0B1 can lead to adrenal hypoplasia and adrenal insufficiency among males, which manifests as hypogonadotropic hypogonadism or precocious puberty in adolescence (18,19). In 1978, German et al. (20) first proposed that the genes necessary for male testis development exist on the X chromosome. In 1994, Bardoni et al. (8) revealed dosage-sensitive sex reversal (DSS) on Xp21, a region of about 160 kb adjacent to the AHC site. In 2007, Smyk et al. (21) reported a case of 46,XY DSD with complete NR0B1 gene, but a 257 kb deletion in the upstream of the NR0B1 gene. The deletion affected the regulatory elements of DAX1 expression and increased the expression of DAX1 in the reproductive system. Therefore, in addition to dose sensitivity, abnormal development due to the NR0B1 gene mutations may also be influenced by positional sensitivity.

Including this case, 21 cases of 46,XY DSD caused by Xp21 duplication have been reported so far. Among these cases, 5 patients had testes, 11 patients had a uterus, and 3 patients had a uterus and ovary. The clinical manifestations of 46,XY DSD caused by Xp21 duplication are complex. Most cases (12/21) had complete gonadal dysgenesis, manifested as complete female vulva and striate glands. In addition, 6 out of 12 had gonadoblastoma and a small duplication on Xp. These patients sought medical attention due to amenorrhea during puberty (14,15). A small number of patients experienced the symptoms in infancy and suffered from poor quality of life. Most of them showed developmental delay or deformity and some of them died of autoimmune diseases (4). None of the patients had adrenal hypoplasia.

The maximum size of Xp repeat was 37.2 Mb (17), while its minimum size was 67.31 kb (16). A larger repeat size predicts a more complex clinical phenotype, and multi-system abnormalities. In addition to NR0B1, the smallest reported repeats contain MAGEB genes. However, in 2022, Meinel et al. (22) proposed that there were topological associated domains (TADs) on Xp21.2. The TAD of NR0B1 contains IL1RAPL1, MAGEB1, MAGEB2, MAGEB3, MAGEB4, and NR0B1 genes. The second nearby TAD contains TASL, GK, and TAB3 genes. The third TAD contains FTHL17 and DMD genes. Duplication (23), deletion (21), and translocation (24) of the NR0B1 locus can disrupt adjacent homologous TADs leading to 46,XY DSD development. Meinel et al. summarized and refined the pathogenesis of NR0B1 induced 46,XY DSD, enhancing our understanding of genome integrity significance in regulating and interacting sex-determining genes during gonadal development.

NR0B1 duplication does not affect 46,XX individuals. They have normal gonadal development and reproductive function. Studies suggested that this may be related to X-chromosome inactivation (25). Barbaro et al. (14) and Liu (3) investigated X chromosome inactivation in a family with Xp21 duplication. The former found that there was no strong selective methylation or obvious preferential inactivation of X chromosome carrying duplication. The latter study showed that 79% of the proband’s mother exhibited preferential inactivation of the NR0B1 gene on the X chromosome. However, the sample size of the current study is insufficient to draw definitive conclusions, necessitating further studies.

In this study, the preliminary genetic testing of the child showed that the pathogenic mutation region mainly included IL1RAPL1, GK, and NR0B1, which are associated with X-linked intellectual disability, GKD, AHC, and 46,XY reversal female. However, during the course of disease, the child exhibited marked motor development delay, elevated muscle enzymes and liver enzymes, high vigilance combined with muscular dystrophy, and electromyography showed myogenic damage. CMA confirmed that the child had a copy number duplication of about 7.79 Mb in Xp21.1p22.11, including the DMD gene.

DMD is an X-linked recessive hereditary disease (26) that mainly affects males and is typically characterized by symmetrical muscle weakness and muscular atrophy. The DMD gene is located at Xp21 (31097677_33339609), accounting for 1.5% of the total length of the X chromosome. It constitutes dystrophin (Dys), which is distributed in skeletal muscle and the myocardium and plays a key role in maintaining the integrity of muscle fibers and anti-stretching function (27). Mutations in the DMD gene mainly include deletions and duplications of exons, as well as point mutations and small insertions or deletions (28). In this study, the child had a duplication of exons 53-79 of the DMD gene. DMD has an insidious onset and progressive development. The majority of individuals experience loss of independent ambulation at the age of nearly 10 years, and succumb to cardiopulmonary failure by approximately 20 years of age. The prognosis of the patients is extremely poor, while a minority exhibit intellectual disability (5). Due to the particular location relationship between NR0B1 and DMD, the two are generally co-pathogenic in Xp21 contiguous gene deletion syndrome. In 1977, Mccabe et al. (29) first described a genetic syndrome characterized by psychomotor retardation, glyceroluria, epilepsy, muscular dystrophy, and osteoporosis. The syndrome is now known as complex GKD caused by contiguous Xp21 gene deletion. Apart from the GK gene deletion mutation, it commonly affects neighboring gene loci of the glycerol kinase gene locus, among which AHC-GKD-DMD is the most commonly affected gene. The clinical manifestations are associated with the deleted fragment (5,30).

So far, there are only two reported cases of 46,XY DSD caused by NR0B1 duplication on Xp21, similar to that of our patient (12,17). Except for genes with no repeated pathogenic reports, they exhibited large duplications on Xp21, including GK, NR0B1, and DMD, clinically characterized by abnormal sexual development, developmental delay, and muscular dystrophy. In this study, the patient had the smallest duplication. Could this be a new genetic syndrome, potentially classified as Xp21 contiguous gene duplication syndrome?

Conclusions

The phenotypic manifestations of individuals affected by Xp21 gene duplication are complex, involving multisystem abnormalities. Individuals with severe phenotypes not only present with sexual development issues but also experience growth retardation, potentially leading to fatality due to cardiac, pulmonary, or immunological complications (4,15). They may suffer from clinical challenges, such as gender selection, gonadectomy, and puberty initiation. Patients with DMD undergo a progressive deterioration in motor abilities and are susceptible to potentially fatal cardiorespiratory issues, resulting in a shortened lifespan. The introduction of novel therapies designed to promote low-level dystrophin expression or gene therapy may bring about positive outcomes for the majority of individuals diagnosed with DMD (31). Comprehensive multidisciplinary management is essential for patients with Xp21 duplication. In summary, this study described the clinical and genetic characteristics of a patient with Xp21 duplication, highlighting the importance of genetic testing and the potential benefits of early intervention and management.

Acknowledgments

The authors would like to express their gratitude to EditSprings (https://www.editsprings.cn) for the expert linguistic services provided.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-327/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-327/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-327/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the participant’s legal guardian for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Reyes AP, León NY, Frost ER, et al. Genetic control of typical and atypical sex development. Nat Rev Urol 2023;20:434-51. [Crossref] [PubMed]
2. Subspecialty Group of Endocrinologic, Hereditary and Metabolic Diseases, the Society of Pediatrics, Chinese Medical Association. Consensus statement on the diagnosis and endocrine treatment of children with disorder of sex development. Zhonghua Er Ke Za Zhi 2019;57:410-8. [Crossref] [PubMed]
3. Liu X. Clinic and Genetic Characteristics of 46, XY Sex Reversals in a Line with NROB1 Duplication. Xinxiang Medical University, 2021.
4. Sukumaran A, Desmangles JC, Gartner LA, et al. Duplication of dosage sensitive sex reversal area in a 46, XY patient with normal sex determining region of Y causing complete sex reversal. J Pediatr Endocrinol Metab 2013;26:775-9. [Crossref] [PubMed]
5. Pizza A, Picillo E, Onore ME, et al. Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: case report and review literature. Acta Myol 2023;42:24-30. [Crossref] [PubMed]
6. Zhou Q, Wang D, Wang C, et al. Clinical and Molecular Analysis of Four Patients With 11β-Hydroxylase Deficiency. Front Pediatr 2020;8:410. [Crossref] [PubMed]
7. Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 2020;22:245-57. [Crossref] [PubMed]
8. Bardoni B, Zanaria E, Guioli S, et al. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet 1994;7:497-501. [Crossref] [PubMed]
9. Gimelli G, Giglio S, Zuffardi O, et al. Gene dosage of the spermidine/spermine N(1)-acetyltransferase (SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD). Hum Genet 2002;111:235-41. [Crossref] [PubMed]
10. Barbaro M, Oscarson M, Schoumans J, et al. Isolated 46,XY gonadal dysgenesis in two sisters caused by a Xp21.2 interstitial duplication containing the DAX1 gene. J Clin Endocrinol Metab 2007;92:3305-13. [Crossref] [PubMed]
11. Barbaro M, Cicognani A, Balsamo A, et al. Gene dosage imbalances in patients with 46,XY gonadal DSD detected by an in-house-designed synthetic probe set for multiplex ligation-dependent probe amplification analysis. Clin Genet 2008;73:453-64. [Crossref] [PubMed]
12. Ledig S, Hiort O, Scherer G, et al. Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci. Hum Reprod 2010;25:2637-46. [Crossref] [PubMed]
13. White S, Ohnesorg T, Notini A, et al. Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One 2011;6:e17793. [Crossref] [PubMed]
14. Barbaro M, Cook J, Lagerstedt-Robinson K, et al. Multigeneration Inheritance through Fertile XX Carriers of an NR0B1 (DAX1) Locus Duplication in a Kindred of Females with Isolated XY Gonadal Dysgenesis. Int J Endocrinol 2012;2012:504904. [Crossref] [PubMed]
15. García-Acero M, Molina M, Moreno O, et al. Gene dosage of DAX-1, determining in sexual differentiation: duplication of DAX-1 in two sisters with gonadal dysgenesis. Mol Biol Rep 2019;46:2971-8. [Crossref] [PubMed]
16. Qin S, Wang X, Li Y. Genetic analysis of a 46,XY female with sex reversal due to duplication of NR0B1 gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2018;35:804-7. [Crossref] [PubMed]
17. Zhao Z, Li P, Song S, et al. Syndromic dysplasia caused by DAX1 gene duplication: a case report. Chinese Journal of Laboratory Diagnosis 2022;26:743-5.
18. Zheng W, Duan Y, Xia Y, et al. Clinical and genetic characteristics of 42 Chinese paediatric patients with X-linked adrenal hypoplasia congenita. Orphanet J Rare Dis 2023;18:126. [Crossref] [PubMed]
19. Zhang J, Chen Q, Guo S, et al. Pleomorphism of the HPG axis with NR0B1 gene mutation - a case report of longitudinal follow-up of a proband with central precocious puberty. J Pediatr Endocrinol Metab 2022;35:962-7. [Crossref] [PubMed]
20. German J, Simpson JL, Chaganti RS, et al. Genetically determined sex-reversal in 46,XY humans. Science 1978;202:53-6. [Crossref] [PubMed]
21. Smyk M, Berg JS, Pursley A, et al. Male-to-female sex reversal associated with an approximately 250 kb deletion upstream of NR0B1 (DAX1). Hum Genet 2007;122:63-70. [Crossref] [PubMed]
22. Meinel JA, Yumiceba V, Künstner A, et al. Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis. J Med Genet 2023;60:469-76. [Crossref] [PubMed]
23. Francese-Santos AP, Meinel JA, Piveta CSC, et al. A Novel Look at Dosage-Sensitive Sex Locus Xp21.2 in a Case of 46,XY Partial Gonadal Dysgenesis without NR0B1 Duplication. Int J Mol Sci 2022;24:494. [Crossref] [PubMed]
24. Rjiba K, Slimani W, Gaddas M, et al. Anomalies in Human Sex Determination: Usefulness of a Combined Cytogenetic Approach to Characterize an Additional Case with Xp Functional Disomy Associated with 46,XY Gonadal Dysgenesis. J Clin Res Pediatr Endocrinol 2023;15:25-34. [Crossref] [PubMed]
25. Werner JM, Hover J, Gillis J. Population variability in X-chromosome inactivation across 10 mammalian species. Nat Commun 2024;15:8991. [Crossref] [PubMed]
26. Shen J, Ding T, Sun X, et al. Comprehensive analysis of genomic complexity in the 5’ end coding region of the DMD gene in patients of exons 1-2 duplications based on long-read sequencing. BMC Genomics 2024;25:292. [Crossref] [PubMed]
27. Poyatos-García J, Soblechero-Martín P, Liquori A, et al. Deletion of exons 45 to 55 in the DMD gene: from the therapeutic perspective to the in vitro model. Skelet Muscle 2024;14:21. [Crossref] [PubMed]
28. Ma Y, Gui C, Shi M, et al. The cryptic complex rearrangements involving the DMD gene: etiologic clues about phenotypical differences revealed by optical genome mapping. Hum Genomics 2024;18:103. [Crossref] [PubMed]
29. Mccabe E, Guggenheim M, Fennessey P, et al. Glyceroiuria, psychomotor retardation, spasticity dystrophic myopathy, and osteoporosis in a sibship. Pediatr Res 1977;11:527.
30. Sadeghmousavi S, Shahkarami S, Rayzan E, et al. A 3-Year-Old Boy with an Xp21 Deletion Syndrome: A Case Report. Endocr Metab Immune Disord Drug Targets 2022;22:881-7. [Crossref] [PubMed]
31. Mendell JR, Muntoni F, McDonald CM, et al. AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial. Nat Med 2024; Epub ahead of print. [Crossref]