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A Middle-aged Woman With Severe Scoliosis and Encephalopathy

Educational Objective
Based on this clinical scenario and the accompanying image, understand how to arrive at a correct diagnosis.
1 Credit CME

A 42-year-old woman presented with clinical features of microcephaly, short stature, intellectual disability, severe degree of scoliosis, gait abnormality, and encephalopathy (Figure, A and B). She was born in 1973 at 38th week of gestation followed by a normal delivery (weight, 3.15 kg and head circumference, 42 cm) to nonconsanguineous parents. The head size was normal at birth, and no other abnormalities were seen during her infancy. At age 2 years, her parents noticed that she had delayed motor and language milestones. She experienced a progressive developmental delay such as reduction of head growth, loss of acquired communication, and loss of motor functions between ages 9 and 12 years. The severity of scoliosis increased with age, and she became a wheelchair user at age 18 years. She was referred to us at age 40 years with the characteristic features of growth deceleration (height, 142 cm; weight, 22 kg; body mass index, 11 [calculated as weight in kilograms divided by height in meters squared]), apraxia, left-sided hemiplegia, spasticity, sleep apnea, constipation, osteoporosis, hypoalgesia, and repetitive hand tapping (Video). Blood reports showed anemia (hemoglobin level of 9.1 g/dL; to convert to grams per liter, multiply by 10) and low levels of high-density lipoprotein cholesterol (47 mg/dL; to convert to millimoles per liter, multiply by 0.0259). There was no history of autistic behavior, vision or hearing impairments, or epilepsy. The electrocardiogram showed sinus rhythm with T wave inversion (V3-V6), and echocardiography showed mild cardiomegaly. The brain magnetic resonance imaging studies showed a diffuse reduction in the corpus callosum involving splenium and enlarged right ventricle, resulting in cerebral lateral ventricular asymmetry (Figure, C).

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C. Rett syndrome

Diagnosing neurodevelopmental disorders at middle age is crucial. Chromosomal analysis using GTG banding revealed a normal karyotype for the patient (46, XX), and her mother’s karyotype analysis revealed a highly skewed pattern of the X chromosome (85:15) by using the X-chromosomal inactivation analysis. Because there is no fragile site seen in the X-chromosome of the patient, we excluded fragile X syndrome. Turner syndrome (45, XO) was debarred as the patient had a normal ovarian function with 2 X-chromosomes. The patient had fulfilled all the 4 main criteria and 5 of 11 supportive criteria of Rett syndrome (RTT).1 Although the clinical features are overlapped with cerebral palsy, sequencing results confirmed the known pathogenic mutation of MECP2 gene variant c.316C>T; R106W (reference sequence: NM_004992.3) causing RTT.

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Article Information

Corresponding Author: Balachandar Vellingiri, MSc, MPhil, PhD, Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Maruthamalai Road, Coimbatore, Tamil Nadu 641046, India (dr.gomathimohan@gmail.com).

Published Online: November 16, 2020. doi:10.1001/jamaneurol.2020.4270

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by University Grants Commission: National Fellowship for Scheduled Caste Candidates Ms Mohan Gomathi, UGC–RGNF SRF (award F1-17.1/2017-18/RGNF-2017-18-SC-TAM-35724 /(SA-III/Website) 02/08/2017) and was supported by grants from the Science and Engineering Research Board Early Career Research Award funded by the Government of India, New Delhi (Grant ECR/2016/ 001688).

Additional Contributions: We thank the patient and her family members for granting permission to publish this information. We thank Dr S. Velmurugan, MBBS, CCT-Paediatrics, Hope Child Neuro Centre, R. S. Puram, Coimbatore, India, for directing us to perform clinical and radiological diagnosis for the patient. We acknowledge the department of Human Genetics and Molecular Biology, Bharathiar University, for providing necessary infrastructure facilities, ethical approval, and technical assistance to conduct this article.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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