Original articles

Volume XLII, n. 1 - March 2023

Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: case report and review literature

Authors

Key words: Xp21 contiguous gene deletion syndrome, CGDS, DMD, GKD, NR0B1, IL1RAPL1
Publication Date: 2022-03-31

Abstract

The contiguous gene deletion syndromes (CGDS) are rare genomic disorders resulting from the deletion of large segments of DNA, manifested as the concurrence of apparently unrelated clinical features. A typical example of CGDS is Xp21 contiguous gene deletion syndrome that involves GK and its neigh-boring genes (usually DMD and NR0B1) and results in a complex phenotype, which is related to the size of deletion and involved genes. Development delay and intellectual disability are almost a constant feature of patients with CGDS. We report the case of a boy with Duchenne muscular dystrophy (DMD) and glycerol kinase deficiency (GKD) as part of the contiguous gene deletion syndrome Xp2.1, in association with intellectual disability (ID) in whom multiplex ligation-dependent probe amplification (MLPA) test first identified a hemizygous deletion involving the entire dystrophin gene. Subsequently, the array CGH study identified a maternally inherited hemizygous deletion of the Xp21.2-Xp21.1 region of approximately 3.7Mb that included both DMD and GK genes confirming the diagnosis of Xp21 CGDS. Moreover, we report a review of the cases published in the literature over the last 20 years, for which a better description of the genes involved in the syndrome was available. Intellectual disability does not appear as a constant feature of the syndrome, reiterating the concept that complex GKD syndrome results from small deletions that affect closely related but separate loci for DMD, GK and adrenal hypoplasia, rather than a single large deletion including all genes. This case highlights the importance of more in-depth genetic investigations in presence of apparently unrelated clinical findings, allowing an accurate diagnosis of contiguous gene deletion syndromes.

Introduction

Human glycerol kinase deficiency (GKD) with hyperglycerolemia and glyceroluria, alone or in association with psychomotor retardation, spasticity, dystrophic myopathy and osteoporosis, was first described in 1977 1,2. In the subsequent decade, many reports appeared in which the disease was associated with additional phenotypes such as congenital adrenal hypoplasia (ACH), chronic granulomatous disease (CGD), retinitis pigmentosa (RP), McLeod syndrome and/or severe mental retardation, and the disease was named as complex glycerol kinase deficiency (cGKD) 3-8.

In 1985, both X-linked glycerol kinase and X-linked adrenal hypoplasia were mapped to the short arm of the X chromosome, on the region Xp2.1 9; the cause of cGKD was attributed to the deletion of the X chromosome 10,11 and the molecular-genetic evidence provided by Franke et al. in 1987 12. In 90s the term “contiguous gene deletion syndrome” (CGDS, OMIM 300679) was used to indicate rare genomic disorders that result from the deletion of large segments of DNA that involve multiple adjacent gene loci on a specific chromosome 13-29. They present as the concurrence of apparently unrelated clinical features, each due to the single gene involved.

Xp2.1 contiguous gene deletion syndrome is due to the partial deletion of the Xp2.1 region 13-29. Depending on the size of the deletion, other genes responsible for multiple distinct diseases may be involved. Among them, NR0B1 causing adrenal hypoplasia congenita (AHC), GK causing glycerol kinase deficiency (GCD) and DMD causing Duchenne muscular dystrophy are the genes most frequently involved. However, the loci for Aland Island eye disease 27,28, chronic granulomatous disease 7, McLeod phenotype 7, retinitis pigmentosa 7, ornithine transcarbamylase deficiency, CFAP47 (cilia- and flagella-associated protein 47), CYBB (gp91), XK (Kell antigen), RPGR (retinitis pigmentosa GTPase regulator) 26 have also been reported.

As CGDS first description involved GK (OMIM 300474) and the neighboring genes NR0B1 (OMIM 300473) and DMD (OMIM 300377), it was also called complex glycerol kinase deficiency (cGKD), characterized by hyperglycerolemia and glyceroluria associated with signs and symptoms of congenital adrenal hypoplasia (AHC) and/or Duchenne muscular dystrophy (DMD) 5,7,11,12,19,21-24.

Glycerol kinase deficiency (GKD) is a rare X-linked recessive metabolic disorder1,4,30 for which three clinical types are described, based on the age onset of the symptoms: infantile, juvenile and adult form 17. The clinical findings may vary and include metabolic crisis during starvation, hypoglycemia, seizures, growth restriction, and developmental delay. Childhood GKD, the most common form, may show a more complex clinical presentation, depending on the genes involved along with GK 14-16,25. Juvenile or symptomatic GKD and adult or asymptomatic GKD are instead isolated forms. The clinical features of the former consist in vomiting, acidemia and central nervous system deterioration, including stupor and coma while the latter is detected incidentally with pseudo-hypertriglyceridemia 17.

X-linked AHC, caused by deletion of NR0B1 gene, is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH) 31. Adrenal insufficiency has acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty 31-33.

Duchenne Muscular Dystrophy (DMD) is the most frequent and more severe muscular dystrophy in children. The age of onset is between 3 and 5 years, with delay in the motor skills 34. Since adolescence, both heart and respiratory muscles are involved in the dystrophic process with evolution towards severe dilated cardiomyopathy and respiratory failure 35-37. In the vast majority of cases, the patient’s mental abilities remain unaffected, though the presence of mental retardation or attentional/autism spectrum disorders has been reported in some studies in up to 30% of patients 38,39, especially in those with deletions located at the 3’ of DMD gene. Creatine kinase can increase up to 100 times the upper normal limit 40.

Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include both IL1RAPL1 and DMD genes 41-43. IL1RAPL1 gene deletions are often associated with intellectual disability (ID) and, sometimes, autistic spectrum disorder 42-43. Female carriers of the syndrome may present symptoms related to the specific phenotypes. Two girls have been reported with developmental delay and myopathy, without adrenal dysfunction, due to an Xp21 deletion involving DMD, GK, NR0B1, and IL1RAPL1 genes 44. Usually, the diagnosis is based on clinical and biochemical findings, and confirmed by genetic analysis.

We report the case of a boy with Duchenne muscular dystrophy (DMD) and glycerol kinase deficiency (GKD) as part of the contiguous gene deletion syndrome Xp2.1. Intellectual disability (ID) was also present. Moreover, we report a review of the cases published in the literature in the last 20 years, for which a better description of the genes involved in the syndrome was available.

Case report

The proband is the only child of non-consanguineous parents with no relevant family history. The pregnancy was complicated by threatened miscarriage during the first trimester. He was born prematurely, at 38 weeks by elective caesarean section and showed a birth weight, length and head circumference of 3200 g (25-50th centile), 51 cm (50-75th centile) and 34.5 cm (50th centile), respectively; the Apgar score was 8 at 1 minute, and 9 at 5 minutes. He presented cyanosis and respiratory distress at birth and a delay in the acquisition of physiological motor milestones: at 7 months, he was still unable to hold his head and to sit up unassisted.

At 10 months the child was addressed to the Pediatric Neurology Unit of the Santobono-Pausilipon Children’s Hospital due to global developmental delay associated with high blood transaminases levels. The neurological examination revealed diffuse hypotonia, in particular in the upper and lower limb muscles. The laboratory tests confirmed the elevation of transaminases, CK and lactato-dehydrogenase. Electromyography disclosed a myopathic pattern, while muscle biopsy evidenced a dystrophic pattern with absence of dystrophin staining on immunohistochemistry. Brain MRI showed cerebral periventricular white matter’s abnormalities, likely related to immaturity and altered myelination. The detection of hyperCKemia, up to 40 times the upper normal limit, guided the diagnosis of DMD, for which genetic analysis of DMD gene was requested. The analysis performed by MLPA technique evidenced the deletion of the entire DMD gene.

At the age of 13 months, the child was sent to the Cardiomyology and Medical Genetics of the Luigi Vanvitelli University Hospital for taking care. Physical examination revealed diffuse hypotonia; the child was able to maintain the sitting position, but not to move from supine to sitting position nor to maintain upright position.ECG and echocardiogram were normal. The neuropsychiatric evaluation revealed an IQ score of 25 (< 1st centile), leading to the diagnosis of severe ID. The laboratory findings showed CK: 14576 U/L (normal range: 60-190 U/L); lactate dehydrogenase (LDH): 1742 U/L (normal range: 240-480 U/L); aspartate aminotransferase (AST): 248 U/L (normal range: 5-32 U/L); alanine aminotransferase (ALT): 334 U/L (normal range: 5-33 U/L) and triglycerides 405 mg/dl (normal range: 20-175 mg/dl). The high concentration of serum triglycerides without turbid appearance of the serum sample led to the suspicion of pseudo-hypertriglyceridemia. The patient’s urinary glycerol excretion analysed by using gas chromatography-mass spectrometry, was 1082 mM/Mcreatine (normal range: < 1 mM/Mcreat), confirming the suspicion of a CGDS.

After informed consent of parents, an array CGH was performed on the proband and their mother, previously identified as a DMD gene carrier. The informed consent is a routine part of clinical testing at Luigi Vanvitelli University Hospital. The consent encompasses testing as well as collecting and using individuals’ clinical data for research or publication purposes. The array CGH study identified an approximately 3.7 Mb maternally inherited hemizygous microdeletion of the Xp21.2-Xp21.1 region that included DMD and GK genes, consistent with the diagnosis of Xp21 contiguous gene deletion syndrome.The patient started therapy with deflazacort, antioxidants and ACE inhibitors; low-fat diet, physical and speech therapy were recommended. Since then, he did periodic checks every six months and acquired autonomous walking at the age of 4.11. At last observation, at the age of 8.5, he presented waddling gait, lumbar hyperlordosis, mild scoliosis, bilateral Achilles tendon contractures, positive Gowers’ sign; moreover, he was unable to run and needed support in standing up from the chair and climbing and descending steps. Cardiac investigation remained normal until 8 years, when myocardial fibrosis of the left ventricular posterior wall was noted at the ECG. He still speaks a few words. Triglycerides remained elevated (two times the upper normal limit).

Discussion

The most common combination of the Xp21 contiguous gene deletion syndrome is the lack of DMD, GK and/or NR0B1 genes (complex GKD). AHC, due to deletions of NR0B1 gene, is usually the first condition to appear in the cGKD with symptoms of adrenal insufficiency 14-16.

The lack of DMD and GK genes only represents a minority of cases, affecting less than 5% of patients of complex GKD 4-7,15-16. The diagnostic suspicion of the infantile form of GKD can be in presence of complete deletion of the DMD gene together with the incidental finding of increased serum triglyceride levels, and confirmed by array CGH study.

Elevated serum triglyceride levels and glyceroluria are caused by the deficiency of glycerol kinase, the enzyme responsible for the phosphorylation of glycerol resulting from the breakdown of triglycerides leading to accumulation of glycerol in the blood 24. Hyperglycerolaemia can lead to hypoglycemia and osmotic dehydration 45.

The Xp21 contiguous gene deletion syndrome is often difficult to diagnose in its early stage because of different clinical characteristics attributable to the single-gene involved in the deletion 45,46. The physicians should consider the Xp21 contiguous gene deletion syndrome in infants with dystrophinopathy and pseudo-hypertriglyceridemia.

Global developmental delay and intellectual disability often occur with GCDS. Table I lists the fourteen cases of the syndrome presenting with the DMD phenotype and published since the 2000s. In almost all the reported cases the sequencing of genes involved in the Xp21 region, spanned distally the DMD gene and included GK (3 documented cases), NR0B1 (3 cases) and IL1RAPL1 (3 cases)genes (Fig. 1). The deletions of the DMD locus were all located in the distal part of the gene after exon 44 (1 case) and after exon 62 (2 cases). DMD patients who present these mutations generally are at higher risk of developing cognitive or other /signs of interest of the CNS 38,39. A decrease in full-scale intelligence quotient (FSIQ < 70) has been reported in about 30% of DMD patients compared with the population’s mean, while a severe impairment with a FSIQ < 50 in approximately 3.0% 38. Zhang et al. showed that nearly all patients with deletions involving DAX1, but not DMD, had mental retardation if IL1RAPL1 (interleukin-1 receptor accessory protein-like gene 1) gene was deleted 41. IL1RAPL1 is highly expressed in the postnatal brain, specifically in hippocampus, suggesting a specialized role in memory and learning abilities. However, despite such extensive deletions, cases who do not present the phenotypic manifestations associated with the lack of the related genes have been reported in the literature. For example, in the patient described by Seltzer et al. in 1989 8, the specific activity and kinetics of muscle GK were normal, but the subcellular distribution of muscle GK was altered; on the contrary liver GK had less than 10% of normal activity and showed markedly altered kinetics, suggesting that muscle and liver GK are genetically distinct. Based on these findings, they suggested that complex GKD syndrome results from small deletions that affect closely related but separate loci for DMD, GK and adrenal hypoplasia, rather than a single large deletion including all genes 9. In our patient, in which the deletion is limited to the Xp21 region including DMD and GK loci, we retain that the clinical picture of a severe intellectual disability can be the result of multiple concurrent causes, such as the complete deletion of DMD gene, prematurity and brain suffering due to neonatal respiratory distress.

In conclusion, determining the extent of the deletion by an appropriate molecular analysis has relevant implications on establishing the appropriate medical management that demands the need for a multidisciplinary team approach. Making the exact diagnosis is also useful in the identification of the female carriers and in the genetic counselling. The case here reported highlights the importance of more in-depth genetic investigations in presence of apparently unrelated clinical findings, allowing an accurate diagnosis of contiguous gene deletion syndromes.

Acknowledgements

We are grateful to the patient’s family for collaboration.

Conflict of interest statement

The Authors declare no conflict of interest.

Funding

The study did not receive any fund.

Authors’ contributions

AP: formal analysis and writing the original draft; EP, MEO: formal analysis and preparation of the figure; MS, LPa: clinical evaluation; VN: data curation and validation; LP: conceptualization, methodology, supervision, writing - original draft, writing - review & editing.

Ethical consideration

The study was conducted according to the rules of the Helsinki declaration. As indicated in the text the informed consent was achieved at the time of hospitalization. The consent encompasses genetic testing as well as collecting and using individuals’ clinical data for research or publication purposes.

Figures and tables

Figure 1. Array 4x180K CGH analysis. The values of the positive or negative Log2 ratio (Y-axis) for each probe in this specific chromosome range (Xaxis) are represented by blue and red dots. The red bar corresponds to the deletion of about 3.7 Mb (hg19:ChrX:30615032-34345109), detected with 261 probes in our proband and his carrier mother. The wide deleted region includes the GK and DMD genes. Array CGH profiles shows: the hemizygous deletion in the proband (A) and the heterozygous deletion in his carrier mother (B)

Figure 2. Gene map of region Xp21 on human X chromosome. The black box corresponds to the Xp21 contiguous gene deletion syndrome region, which includes twenty-three genes. The deletion identified in our proband can be visualized in the red box, which involves a region of 3.7 Mb (chrX:30,623,289-34,345,080) and encompasses DMD and GK genes. OMIM genes are in bold.

Patient’s number Involved Genes (centromere-telomere direction) Deletion Size Age at clinical presentation Symptoms Metabolic Laboratory findings CK values in U/L Reference
1 DMD; other genes were not investigated n.r. 19 days Dehydration; intermitting vomiting; developmental delay; global weakness; calf hypertrophy; reflexes absent, ID ↓natraemia,17-OH-progesterone ↑ kalaemia, triglycerides, urinary glycerol 2.507 Ramanjam V. et al., 2010
2 DMD; other genes were not investigated n. r. prenatal Hypotonia; waddling gait; difficulty in climbing stairs, ID ↓17-OH-progesterone ↑ triglycerides, urinary glycerol 5.307 Ramanjam V. et al., 2010yes
3 DMD (exons 62-66), GK, NR0B1 n. r. 42 months Nausea; vomiting, global development delay; unable to walk, go upstairs, run fast; Gower’s sign; calf hypertrophy, ID ↓natraemia,cortisol, cholesterol, apolipoprotein-B, HDL- ↑ kalaemia, LDH, ALT, triglycerides, α-OH-butyratedehydrogenase 5.798 Ma H. et al., 2004
4 DMD, GK n. r. 4 months Failure to thrive; global developmental delay; axial hypotonia; distal hypertonia, ID ↑ LDH, ALT, AST, triglycerides, urinary glycerol 10.818 Jamroz E. et al.,2010
5 DMD, GK 3.7Mb 7 months Global development delay; hypotonia; unable to walk, to go upstairs, to sit, ID ↑ LDH, ALT, AST, triglycerides, urinary glycerol 14.576 Present Case
6 DMD (exons 45-79), GK n. r. 36 days failure to thrive; global developmental delay; difficulty in walking, getting up from the seated position; Gower’s sign; calf hypertrophy ↓natraemia, glycaemia, cortisol, aldosteron; 17-OH-progesterone ↑ kalaemia, ACTH, renin, triglycerides, urinary glycerol 12.395 Rathnasiri A. et al.,2021
7 DMD, GK, NR0B1 n. r. 11 days salt loss with lethargy; vomiting; metabolic acidosis; progressive muscle weakness, ID ↓natraemia, glycemia; ↑ kalaemia, triglycerides, serum and urinary glycerol n.r. Pantoja-Martines J. et al., 2007
8 DMD, GK, NR0B1 n. r. 48 days Hypotonia, growth retardation, vomiting, dark skin ↓natraemia,17-OH-progesterone ↑ kalaemia, ALT, AST, triglycerides, α-OH-butyratedehydrogenase urinary, glycerol 1.586 Tao N. et al., 2002
9 DMD, GK, NR0B1 3.88Mb 18 days Weight <3rd percentile; dehydration; dysmorphic facial features ↓natraemia, glycemia; ↑ kalaemia, triglycerides, urinary glycerol; α-OH-butyrate; LDH, ALT,AST 1.586 Korkut S. et al., 2016
10 DMD (partial), GK, NR0B1, IL1RAPL1 (part) n. r. 36 days Difficulty to feed, vomiting, weight loss, hypotonia, dehydration ↓natraemia, glycemia; ↑ kalaemia, triglycerides, urinary glycerol 5.758 Korkut S. et al., 2016
11 DMD, GK, NR0B1, IL1RAPL1 n. r. 7 months Global developmental delay; pronounced axial hypotonia, ID ↑ triglycerides, serum and urinary glycerol 12.829 Sanz-Ruiz I. et al., 2009
12 DMD (exons 62-79), GK, NR0B1, IL1RAPL1 n. r. 1 month Generalized hypotonia; inadequate breast-feeding; failure to thrive; decreased skin turgor; sitting with support ↓natraemia; ↑ kalaemia, ALT, AST, triglycerides, LDH 7.019 Sevim U. et al., 2011
13 IL1RAPL1, MAGEB1-4, ROB,CXorf2, GM, AP3K71P,FTHL1, DMD, FAM47A, TMEM47, FAM47B 5.8Mb data not available Liu L. et al., 2021
14 DMD, GK, CFAP47, CYBB, XK,RPGR 7.5Mb 19 days Macrosomia, neonatal sepsis; liver and lung abscesses ↑ ALT, AST, triglycerides 1.115 Bi S. et al., 2023
Table I. Age of onset, initial clinical presentation and genetic information in reported cases with CGDS involving DMD, GK, NR0B1 and IL1RAPL1 genes.

References

  1. McCabe E, Fennessey P, Guggenheim M. Human glycerol kinase deficiency with hyperglycerolemia and glyceroluria. Biochem Biophys Res Commun. 1977;78:1327-1333. doi:https://doi.org/10.1016/0006-291x(77)91437-1
  2. Yoshimoto M, Takayanagi T, Nagayoshi T. Case of adrenal insufficiency, nonspecific myopathy, psychomotor retardation and glyceroluria--glycerol kinase deficiency?. No To Hattatsu. 1984;16:328-329.
  3. Guggenheim M, McCabe E, Roig M. Glycerol kinase deficiency with neuromuscular, skeletal and adrenal abnormalities. Ann Neurol. 1980;7:441-9. doi:https://doi.org/10.1002/ana.410070509
  4. McCabe ER: Human glycerol kinase deficiency: an inborn error of compartmental metabolism. Biochem Med. 1983;30:215-30. doi:https://doi.org/10.1016/0006-2944(83)90088-1
  5. Renier W, Nabben F, Hustinx T. Congenital adrenal hypoplasia, progressive muscular dystrophy, and severe mental retardation, in association with glycerol kinase deficiency, in male sib. Clin Gen. 1983;24:243-251. doi:https://doi.org/10.1111/j.1399-0004.1983.tb00078.x
  6. Seltzer W. Firminger H, Kleiri J, et al: Adrenal dysfunction in glycerol kinase deficiency. Biochem Med. 1985;33:189-199. doi:https://doi.org/10.1016/0006-2944(85)90027-4
  7. Francke U, Ochs H, de Martinville B. Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet. 1985;37:250-267.
  8. Seltzer W, Angelini C, Dhariwal G. Muscle glycerol kinase in Duchenne dystrophy and glycerol kinase deficiency. Muscle Nerve. 1989;12:307-313. doi:https://doi.org/10.1002/mus.880120409
  9. Bartley J, Patil S, Goshal R. X-linked glycerol kinase and X-linked adrenal hypoplasia maps on Xp21. Am J Hum Genet. 1985;37.
  10. Wieringa B, Huatinx T, Scheres J. Complex glycerol kinase deficiency syndrome explained as X-chromosomal deletion. Clin Genet. 1985;27:522-523. doi:https://doi.org/10.1111/j.1399-0004.1985.tb00244.x
  11. Clarke A, Roberts S, Thomas N. Duchenne muscular dystrophy with adrenal insufficiency and glycerol kinase deficiency: high resolution cytogenetic analysis with molecular, biochemical, and clinical studies. J Med Genet. 1986;23:501-508. doi:https://doi.org/10.1136/jmg.23.6.501
  12. Francke U, Harper J, Darras B. Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: molecular genetic evidence for deletions. Am Hum Genet. 1987;40:212-227. doi:https://doi.org/10.1111/j.1399-0004.1985.tb00244.x
  13. McCabe E, Towbin J, van den Engh G. Xp21 contiguous gene syndromes: deletion quantitation with bivariate flow karyotyping allows mapping of patient breakpoints. Am J Hum Genet. 1992;51:1277-1285.
  14. Ma H, Jiang J, Wang Y. Gene deletion analysis of a Chinese boy with Xp21 contiguous gene deletion syndrome. Chin Med J (Engl). 2004;117:789-791.
  15. Duat-Rodríguez A, Gutiérrez-Solana L, García-Peñas J. Contiguous gene deletion syndrome in Xp21. Rev Neurol. 2010;50.
  16. Stanczak C, Chen Z, Zhang Y. Deletion mapping in Xp21 for patients with complex glycerol kinase deficiency using SNP mapping arrays. Hum Mutat. 2007;28:235-242. doi:https://doi.org/10.1002/humu.20424
  17. Sevim U, Fatma D, Ihsan E. A neonate with contiguous deletion syndrome in XP21. J Pediatr Endocrinol Metab. 2011;24:1095-1098. doi:https://doi.org/10.1515/jpem.2011.350
  18. Sanz-Ruiz I, Bretón-Martínez J, Del Castillo-Villaescusa C. Contiguous gene deletion syndrome in Xp21: an unusual form of presentation]. Rev Neurol. 2009;49:472-474.
  19. Amato A. Duchenne muscular dystrophy and glycerol kinase deficiency: a rare contiguous gene syndrome. J Clin Neuromuscul Dis. 2000;1. doi:https://doi.org/10.1097/00131402-200006000-00006
  20. Liu L, Wang L, Jiao Z. Diagnosis of a patient with adjacent gene deletion syndrome with DMD complete deletion type of Duchenne muscular dystrophy. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021;38:869-872. doi:https://doi.org/10.3760/cma.j.cn511374-20200324-00196
  21. Cole D, Clarke L, Riddell D. Congenital adrenal hypoplasia, Duchenne muscular dystrophy, and glycerol kinase deficiency: importance of laboratory investigations in delineating a contiguous gene deletion syndrome. Clin Chem. 1994;40:2099-2103.
  22. Casado de Frías E, Ruibal FJ, Bueno LG. Syndrome of contiguous gene deletions in Xp-21 (deficiency of the glycerol-kinase complex). The association of Duchenne muscular dystrophy, glycerol kinase deficiency and congenital suprarenal hypoplasia]. An Esp Pediatr. 1997;47:639-6342.
  23. Pantoja-Martínez J, Martínez-Castellano F, Tarazona-Casany I. Contiguous gene deletion syndrome in Xp21: the association between glycerol kinase deficiency, congenital suprarenal hypoplasia and Duchenne’s muscular dystrophy. Rev Neurol. 2007;44:606-609.
  24. Rathnasiri A, Senarathne U, Arunath V. A rare co-occurrence of Duchenne muscular dystrophy, congenital adrenal hypoplasia and glycerol kinase deficiency due to Xp21 contiguous gene deletion syndrome: case report. BMC Endocr Disord. 2021;21. doi:https://doi.org/10.1186/s12902-021-00876-6
  25. Jamroz E, Paprocka J, Popowska E. Xp21.2 contiguous gene syndrome due to deletion involving glycerol kinase and Duchenne muscular dystrophy loci. Neurol India. 2010;58:670-671. doi:https://doi.org/10.4103/0028-3886.68690
  26. Bi S, Dai L, Jiang L. Chronic granulomatous disease associated with Duchenne muscular dystrophy caused by Xp21.1 contiguous gene deletion syndrome: Case report and literature review. Front Genet. 2023;13. doi:https://doi.org/10.3389/fgene.2022.970204
  27. Weleber R, Pillers D, Powell B. Aland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21. Similarity to incomplete congenital stationary night blindness. Arch Ophthalmol. 1989;107:1170-1179. doi:https://doi.org/10.1001/archopht.1989.01070020236032
  28. Pillers D, Towbin J, Chamberlain J. Deletion mapping of Aland Island eye disease to Xp21 between DXS67 (B24) and Duchenne muscular dystrophy. Am J Hum Genet. 1990;47:795-801.
  29. Sadeghmousavi S, Shahkarami S, Rayzan E. A 3-Year-old boy with an Xp21 Deletion Syndrome: a case report. Endocr Metab Immune Disord Drug Targets. 2022;22:881-887. doi:https://doi.org/10.2174/1871530322666220201143656
  30. Ribeiro A, Pinto S, Ayres-Pereira I. Deficiencia de glicerolcinasa: una causa metabolica de retraso global del desarrollo [Glycerol kinase deficiency: a metabolic cause of global developmental delay]. Rev Neurol. 2019;68:179-180.
  31. Cox P. Congenital adrenal hypoplasia. Proc R Soc Med. 1962;55:981-982.
  32. Fichna M, Zurawek M, Gut P. Adrenal hypoplasia congenita - an uncommon reason of primary adrenal insufficiency. Ann Endocrinol (Paris). 2010;71:309-313. doi:https://doi.org/10.1016/j.ando.2010.04.003
  33. Al Amer A, Al Rubaya K, Alzahrani A. Adrenal hypoplasia congenita in identical twins. Saudi Med J. 2019;40:87-92. doi:https://doi.org/10.15537/smj.2019.1.23337
  34. Thangarajh M. The Dystrophinopathies. Continuum (Minneap Minn). 2019;25:1619-1639. doi:https://doi.org/10.1212/CON.0000000000000791
  35. Nigro G, Comi L, Politano L. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol. 1990;26:271-277. doi:https://doi.org/10.1016/0167-5273(90)90082-g
  36. Nigro G, Comi L, Politano L. Myology. (Engel A, Franzini-Armstrong C, eds.). McGraw-Hill; 2004.
  37. LoMauro A, Romei M, Gandossini S. Evolution of respiratory function in Duchenne muscular dystrophy from childhood to adulthood. Eur Respir J. 2018;51. doi:https://doi.org/10.1183/13993003.01418-2017
  38. Banihani R, Smile S, Yoon G. Cognitive and Neurobehavioral Profile in Boys with Duchenne Muscular Dystrophy. J Child Neurol. 2015;30:1472-1482. doi:https://doi.org/10.1177/0883073815570154
  39. Mohamadian M, Rastegar M, Pasamanesh N. Clinical and Molecular Spectrum of Muscular Dystrophies (MDs) with Intellectual Disability (ID): a Comprehensive Overview. J Mol Neurosci. 2022;72:9-23. doi:https://doi.org/10.1007/s12031-021-01933-4
  40. Kiessling W, Beckmann R. Serum levels of myoglobin and creatine kinase in Duchenne muscular dystrophy. Klin Wochenschr. 1981;59:347-348. doi:https://doi.org/10.1007/BF01525003
  41. Zhang Y, Huang B, Niakan K. IL1RAPL1 is associated with mental retardation in patients with complex glycerol kinase deficiency who have deletions extending telomeric of DAX1. Hum Mutat. 2004;24. doi:https://doi.org/10.1002/humu.9269
  42. McAvoy S, Ganapathiraju S, Perez D. DMD and IL1RAPL1: two large adjacent genes localized within a common fragile site (FRAXC) have reduced expression in cultured brain tumors. Cytogenet Genome Res. 2007;119:196-203. doi:https://doi.org/10.1159/000112061
  43. Wikiera B, Jakubiak A, Zimowski J. Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion). Pediatr Endocrinol Diabetes Metab. 2012;18:153-157.
  44. Heide S, Afenjar A, Edery P. Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature. Eur J Med Genet. 2015;58:341-345. doi:https://doi.org/10.1016/j.ejmg.2015.04.003
  45. Ramanjam V, Delport S, Wilmshurst J. The diagnostic difficulties of complex glycerol kinase deficiency. J Child Neurol. 2010;25:1269-1271. doi:https://doi.org/10.1177/0883073809357240
  46. Tao N, Liu X, Chen Y. Delayed diagnosis of complex glycerol kinase deficiency in a Chinese male infant: a case report. BMC Pediatr. 2022;22. doi:https://doi.org/10.1186/s12887-022-03568-9

Downloads

Authors

Antonella Pizza* - Medical Genetics and Cardiomyology, Department of Precision Medicine, University Hospital and University of Campania ´Luigi Vanvitelli´, Naples, Italy; * These authors contributed equally to the study

Esther Picillo* - Medical Genetics and Cardiomyology, Department of Precision Medicine, University Hospital and University of Campania ´Luigi Vanvitelli´, Naples, Italy

Maria Elena Onore - Medical Genetics and Cardiomyology, Department of Precision Medicine, University Hospital and University of Campania ´Luigi Vanvitelli´, Naples, Italy

Marianna Scutifero - Medical Genetics and Cardiomyology, Department of Precision Medicine, University Hospital and University of Campania ´Luigi Vanvitelli´, Naples, Italy

Luigia Passamano - Medical Genetics and Cardiomyology, Department of Precision Medicine, University Hospital and University of Campania ´Luigi Vanvitelli´, Naples, Italy

Vincenzo Nigro - Medical Genetics and Cardiomyology, Department of Precision Medicine, University Hospital and University of Campania ´Luigi Vanvitelli´, Naples, Italy;  Telethon Institute of Genetics and Medicine, Pozzuoli, Italy

Luisa Politano - Cardiomyology and Medical Genetics, University Hospital and University of Campania ´Luigi Vanvitelli, Naples, Italy https://orcid.org/0000-0002-0925-7158

How to Cite
Pizza*, A., Picillo*, E., Onore, M. E., Scutifero, M., Passamano, L., Nigro, V., & Politano, L. (2022). Xp21 contiguous gene deletion syndrome presenting as Duchenne muscular dystrophy and glycerol kinase deficiency associated with intellectual disability: case report and review literature. Acta Myologica, 42(1). https://doi.org/10.36185/2532-1900-246
  • Abstract viewed - 983 times
  • PDF downloaded - 467 times