X-Linked Myotubular Myopathy and Duchenne Muscular Dystrophy in a Preterm Infant: A Rare Combination Uma Varma, MRCPCH,a Devdeep Mukherjee, DCH, MRCPCH,b Imelda Hughes, FRCP,a Chitra Sethuraman, MD, FRCPath,a Susan Kamupira, MRCPCHb

Disorders of central and peripheral nervous system should be considered in abstract floppy infants with ventilator dependence. Workup for neuromuscular disorders should be undertaken in infants with hypotonia, weakness, contractures, feeding difficulties, or failed attempts at extubation. We present the case of a preterm infant with hypotonia and ventilator dependence where despite a positive result, further investigations were undertaken because of lack of clinical correlation. The infant had a rare combination of 2 neuromuscular conditions: X-linked myotubular myopathy and Duchenne muscular dystrophy. One was the reason for immediate clinical manifestation and the other influenced the prognosis and decision-making in determining aRoyal Manchester Children’s Hospital, Manchester, United reorientation of care. This case demonstrates the value of interpretation of Kingdom; and bSaint Mary’s Hospital, Manchester, United a positive result that did not explain the clinical picture and warranted Kingdom consideration of further diagnosis. This case also emphasizes the importance Drs Varma and Mukherjee collected the information of discussions with family about the prognosis of 2 conditions that influenced and drafted the initial manuscript; Drs Hughes and decision making. Kamupira identified the case; Dr Sethuraman contributed to the valuable histopathology information and provided the images; and all authors reviewed and revised the document and approved the final manuscript as submitted. Congenital myopathies are a group of a male infant diagnosed with XLMTM DOI: https://doi.org/10.1542/peds.2018-2879 heterogeneous rare neuromuscular and DMD, which constitute Accepted for publication Feb 13, 2020 disorders with distinct a combination of a rare and a more common muscle disorder. Address correspondence to Uma Varma, MRCPCH, histopathological features of rods, Department of Paediatric Neurology, Royal cores, central nuclei, and fiber-type Manchester Children’s Hospital, Oxford Rd, disproportion.1 X-linked myotubular Manchester M33 9WL, United Kingdom. CASE REPORT myopathy (XLMTM) is a type of E-mail: [email protected] congenital myopathy with incidence of This male infant was born prematurely PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1:50 000 live male births caused by to a primigravida mother at 31 weeks’ 1098-4275). mutation in the MTM1 gene.2 The gestation by cesarean delivery under Copyright © 2020 by the American Academy of Pediatrics presentations vary in severity, ranging general anesthesia because of placental FINANCIAL DISCLOSURE: from fatal forms in infancy to milder abruption and antepartum hemorrhage. The authors have indicated they have no financial relationships relevant to this 3 The pregnancy was uneventful and phenotypes surviving until adulthood. article to disclose. Duchenne muscular dystrophy (DMD) there was no history of fl FUNDING: No external funding. is an X-linked genetic disorder that polyhydramnios. The infant was oppy at birth and showed no respiratory POTENTIAL CONFLICT OF INTEREST: The authors have affects 1 in 3600 to 6000 live male fl effort but had a good heart rate. He was indicated they have no potential con icts of interest births.4 Most patients present with to disclose. intubated and given surfactant with delayed motor milestones and a provisional diagnosis of respiratory progressive motor difficulties with To cite: distress syndrome. Varma U, Mukherjee D, Hughes I, et al. additional respiratory, cardiac X-Linked Myotubular Myopathy and Duchenne complications, and death in the second Despite minimal ventilation Muscular Dystrophy in a Preterm Infant: A Rare Combination. Pediatrics. 2020;146(3):e20182879 or third decade. We present the case of requirements, the infant continued to

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 3, September 2020:e20182879 CASE REPORT have poor respiratory effort and failed several attempts at extubation and trials of noninvasive ventilation. Direct laryngotracheal bronchoscopy did not reveal any airway abnormalities. The infant remained hypotonic with a paucity of limb movements. He had facial weakness and poor gag and suck reflexes. His fl fi deep tendon re exes were dif cult to FIGURE 3 elicit. He was also noted to have FIGURE 2 Immunohistochemical stain for dystrophin re- bilateral undescended testes. He vealing a negative reaction. Hematoxylin and eosin stain revealing trans- developed bilateral chylothorax at versely oriented muscle fibers with centrally 3 weeks of age, which resolved with placed nuclei. low long-chain triglyceride, high- undertaken by the medical teams and medium–chain triglyceride parents for reorientation of care, and formula milk. placed nuclei in the majority of the the infant died at 2½ months of age. myofibers (Fig 2). This picture was Both parents had genetic Investigations were initiated to highly suggestive of a congenital investigations that revealed that the determine the cause. Creatine kinase centronuclear myopathy. In addition, mother was a carrier for MTM1 but was 228 U/L. An MRI of the brain and immunohistochemistry revealed not DMD. The father had no spine revealed no evidence of hypoxic a complete loss of dystrophin abnormalities detected. ischemic injury or other congenital expression with an absence of structural abnormalities. Metabolic staining in dystrophin 1, 2, 3 to rod C investigation results were negative. and N terminus (Fig 3). Electron DISCUSSION Microarray analysis revealed Xp21.1 fi microscopy revealed bers with Disorders of central and peripheral deletion (dystrophin deletion) with central nuclei, some with central nervous system should be considered loss of exons 46 to 52 out-of-frame glycogen, and also revealed in floppy infants with ventilator deletion indicative of DMD. However, proliferation of transverse tubules dependence. An underlying this was not suspected to be the fi (Fig 4). Genetic tests con rmed neuromuscular disorder should be cause of his neonatal hypotonia and XLMTM. The mutation was considered when there is evidence of ventilator dependence. A c.1189dupT p.Tyr397fs and results in hypotonia, weakness, feeding and pyridostigmine trial pending results a premature termination of the MTM1 swallowing difficulties, contractures, of acetylcholine receptor and muscle- protein and is predicted to be or multiple failed attempts at specific tyrosine kinase antibodies pathogenic. extubation. revealed no significant response and the results were negative (Fig 1). Test The patient’s parents were counseled Hypotonia of the neonatal period can results for SMN gene and myotonic extensively regarding the 2 genetic be a result of central causes such as dystrophy were negative. An open conditions in the infant that would chromosomal disorders, hypoxic muscle biopsy histology done at 39 significantly affect his quality of life. injury, metabolic disorders, or weeks’ corrected age revealed After several multidisciplinary team diffusely abnormal and centrally meetings, a joint decision was

FIGURE 1 FIGURE 4 Time line of investigations. CK, creatine kinase; CMV cytomegalovirus; DLTB, direct laryngotracheal Electron microscopy image revealing fibers bronchoscopy; ECHO echocardiogram; MusK, muscle specific tyrosine kinase; SMA, spinal muscular with central glycogen accumulation and elec- atrophy; TFT, thyroid function test. tron dense tubules.

Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 VARMA et al because of peripheral neuromuscular A muscle biopsy was undertaken at Although the need for 24-hour disorders. A detailed family history, 54 days of life and 39 weeks’ invasive ventilatory support is maternal history, and examination corrected gestation. Skeletal muscle uncommon in most congenital might reveal a diagnosis such as development occurs throughout the myopathies, XLMTM is an exception, myotonic dystrophy or myasthenia period of embryogenesis. Dystrophin and decisions on long-term gravis. Antenatal history of is expressed in the sarcolemma of ventilation have to be discussed in polyhydramnios and reduced fetal most myotubes by 9 weeks’ gestation. detail with the family.11 In our movements might be suggestive of Marked changes occur in the patient, this discussion was crucial a peripheral disorder. A structure and organization of muscle because of the accompanying comprehensive birth history is cells from 16 to 22 weeks and diagnosis of DMD, which is essential because prematurity and the muscles look organized with a condition with progressive condition of the infant at birth can fascicules of grouped fibers from 24 muscular dystrophy. fl ’ 8 in uence the differential diagnosis. weeks gestation. The muscle biopsy This case demonstrates how despite Clinical examination can reveal signs specimen was suggestive of getting a positive result with the such as facial dysmorphism, facial centronuclear myopathy and the lack microarray, further tests had to be weakness, tongue fasciculations, and of dystrophin expression also was in done because of a lack of correlation a pattern of weakness, which would keeping with the Xp21 mutation. between the result and the clinical help in formulating differential To our knowledge, this is the first picture. This case also reflects diagnosis. case report of an individual with sensitive discussions with the family a diagnosis of XLMTM and DMD. Both on how the care of the infant could be Investigations for congenital conditions are X linked but on oriented and emphasizes the myopathies, congenital muscular different loci, with the former on importance of genetic counseling. We dystrophies, congenital myasthenic Xq28 and the latter on Xp21. Both have described an unusual and rare syndromes, metabolic myopathies, conditions are different in their combination of 2 X-linked muscle spinal muscular atrophy, and Prader- pathogenesis and in the way they conditions in the same patient. Willi syndrome should be affect the muscles; this is evident in considered.5 their natural history and ABBREVIATIONS Congenital myopathies are histopathology. Congenital myopathy considered after investigating for the genes mostly encode protein DMD: Duchenne muscular other more common conditions.6 components of the sarcomere and dystrophy Genetic testing without muscle biopsy proteins involving calcium signaling XLMTM: X-linked myotubular is undertaken only in special with faulty gene causing ineffective myopathy circumstances such as a severely ill muscle contraction. Muscle dystrophy infant or in withdrawal of care.6 genes mostly code for components of Creatine kinase, metabolic tests, muscle membrane and extracellular matrix with faulty gene resulting in acetylcholine receptor and muscle- REFERENCES dystrophic muscle.6 specific kinase antibodies, tests for 1. Colombo I, Scoto M, Manzur AY, et al. SMN1 mutation, myotonic dystrophy, In XLMTM, the infants present early Congenital myopathies: natural history and Prader-Willi syndrome were in life with hypotonia, generalized of a large pediatric cohort. Neurology. normal in our case. MRI of the brain weakness, and significant respiratory 2015;84(1):28–35 did not reveal any evidence of fi insuf ciency needing ventilator 2. Amburgey K, Tsuchiya E, de Chastonay hypoxia or structural abnormality. support as we saw in our patient. S, et al. A natural history study of Although the microarray had picked More than half die of respiratory X-linked myotubular myopathy. up a significant diagnosis of DMD, it failure in the first year of life. In Neurology. 2017;89(13):1355–1364 could not explain the clinical picture a recent, large multicenter study by 9 3. Abath Neto O, Silva MRE, de Araújo in this infant. Antenatal and early Beggs et al, 90% needed respiratory Martins C, et al. A study of a cohort of detection of mutation is possible in support at birth, nearly half of the X-linked myotubular myopathy at the families with a history of DMD. Most patients required 24-hour ventilator clinical, histologic, and genetic levels. cases are picked up after concerns of support, and 60% needed Pediatr Neurol. 2016;58:107–112 fi motor dif culties at a later age. The tracheostomy, thus making it a severe 4. Bushby K, Finkel R, Birnkrant DJ, et al; mean age of diagnosis of DMD in form of congenital myopathy. There DMD Care Considerations Working a 10-year retrospective study from are case reports suggestive of Group. Diagnosis and management of a tertiary neuromuscular center in chylothorax in XLMTM, but there is Duchenne muscular dystrophy, part 1: United Kingdom was 4.3 years.7 no definite explanation for this.10 diagnosis, and pharmacological and

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 146, number 3, September 2020 3 psychosocial management. Lancet of Duchenne muscular dystrophy: Vol 113. Amsterdam, Netherlands: Neurol. 2010;9(1):77–93 a retrospective case note review. Elsevier; 2013:1299–1310 5. North KN, Wang CH, Clarke N, et al; Arch Dis Child. 2014;99(12): 9. Beggs AH, Byrne BJ, De Chastonay S, International Standard of Care 1074–1077 et al. A multicenter, retrospective Committee for Congenital Myopathies. 8. Romero NB, Mezmezian M, medical record review of X-linked Approach to the diagnosis of congenital Fidzianska A. Main Steps of myotubular myopathy: the RECENSUS Neuromuscul Disord Muscle Nerve – myopathies. . 2014; Skeletal Muscle Development study. . 2018;57(4):550 560 24(2):97–116 in the Human: Morphological 10. Smets K. X-linked myotubular myopathy 6. North KN. Clinical approach to the Analysis and Ultrastructural and chylothorax. Neuromuscul Disord. diagnosis of congenital myopathies. Chaarcterstics of Developing 2008;18(2):183–184 Semin Pediatr Neurol. 2011;18(4): Human Muscle. In: Dulac O, 11. Wang CH, Dowling JJ, North K, et al. – 216 220 Lassonde M, Sarnat HB, eds. Consensus statement on standard of 7. van Ruiten HJA, Straub V, Bushby K, Handbook of Clinical Neurology: care for congenital myopathies. J Child Guglieri M. Improving recognition Pediatric Neurology Part III, vol. Neurol. 2012;27(3):363–382

Downloaded from www.aappublications.org/news by guest on September 27, 2021 4 VARMA et al X-Linked Myotubular Myopathy and Duchenne Muscular Dystrophy in a Preterm Infant: A Rare Combination Uma Varma, Devdeep Mukherjee, Imelda Hughes, Chitra Sethuraman and Susan Kamupira Pediatrics originally published online August 21, 2020;

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Downloaded from www.aappublications.org/news by guest on September 27, 2021 X-Linked Myotubular Myopathy and Duchenne Muscular Dystrophy in a Preterm Infant: A Rare Combination Uma Varma, Devdeep Mukherjee, Imelda Hughes, Chitra Sethuraman and Susan Kamupira Pediatrics originally published online August 21, 2020;

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