Full case: A 19-year-old boy with Down syndrome and progressive loss of communication?

The Case

A 19-year-old boy with a history of trisomy 21 with multiple congenital anomalies, including esophageal atresia with tracheoesophageal fistula, diaphragmatic hernia, and duodenal stenosis status post repair in the neonatal period, asthma, obstructive sleep apnea, and hyperthyroidism resulting in total thyroidectomy and iatrogenic hypothyroidism presented with 6 months of behavioral and cognitive changes. He developed a loss of verbal communication, episodic unresponsiveness, head bowing, shut eyes, persistent drooling, fatigue with daytime somnolence, weight loss, and abdominal pain.

He was referred to the gastrointestinal specialist to rule out esophageal strictures that might be contributing to the persistent drooling. He was started on a trial of a proton pump inhibitor (PPI). He had difficulty taking his PPI and was given a trial of famotidine. His drooling improved but did not dissipate, and his other symptoms persisted. His parents described him as now only opening his eyes when eating, walking, or watching television. He had no ocular motor dysfunction on physical exam. He also had loss of verbal communication, whereas previously he was speaking 25 words. He had a new inability to carry out ADLs such as using the restroom and eating. His parents denied vomiting, diarrhea, and photophobia.

He was started on fluoxetine due to suspected underlying depression. Three weeks later, he began laughing and having improved head control, seeking others, and showing affection to his parents and siblings again but did not show improvement in his verbal communication. Thyroid levels, hemoglobin A1c, complete blood count (CBC), comprehensive metabolic panel (CMP), C-reactive protein (CRP), prothrombin (PT), international normalized ratio (INR), and a celiac panel were all within normal limits, with gamma-glutamyl transferase (GGT) notably elevated at 78 U/L. Kidney, ureter, and bladder (KUB) X-ray demonstrated retained food in the stomach, with an esophagram showing an impacted food bolus at the level of the proximal intrathoracic esophagus.

The patient was then admitted, and an esophagogastroduodenoscopy (EGD) was done, revealing distal esophageal erosions with biopsy-proven active gastritis. During the same admission, neurology was consulted for a video-electroencephalography (VEEG), and a lumbar puncture (LP) was performed, yielding normal findings. The patient was restarted on his PPI regimen plus carafate with additional instructions to continue famotidine and repeat endoscopy in 2-3 months. Additional imaging included magnetic resonance imaging (MRI) of the brain, which revealed blooming within the basal ganglia and the cerebral peduncles suggestive of iron deposition and supratentorial white matter signal abnormalities (Figure).

Diagnosis: Down Syndrome Regression Disorder (DSRD)

Discussion

DSRD is an uncommon and likely underreported condition affecting individuals living with DS in late adolescence, regardless of their level of intellectual disability. The majority of cases develop between ages 10 to 30 years, with a female predominance of 64%.^1,2 Symptoms are broad and often include language disturbances; loss of autonomy and daily living skills such as dressing, toileting, and eating; behavioral changes such as depression, psychosis, and catatonia; executive dysfunction affecting memory, attention, and processing speed; and motor abnormalities causing abnormal movements, stereotypies, perseveration, and extrapyramidal symptoms.² While DSRD must be on the differential, it is a diagnosis of exclusion as various etiologies, including major depressive disorder, seizure disorders, thyroid abnormalities, infectious or autoimmune encephalitis, and structural brain abnormalities, must first be ruled out. Of note, this case presentation had unremarkable thyroid studies, VEEG, and LP results but showed significant abnormal brain MRI findings.

Early recognition and intervention play a pivotal role in preventing progression of regressive symptoms and in improving overall patient outcomes. While the precise etiology of DSRD is unknown, various studies have focused on investigating abnormalities in neuroimaging and CSF analysis. One case series found that the imaging revealed abnormal iron accumulation in the basal ganglia, which was similar to our patient.³ A retrospective, multi-center, case-control study revealed that neuroimaging was abnormal in 22% (16/72) of cases, showing punctate T2 signal abnormalities and basal ganglia calcification. CSF was abnormal in 17% (9/72) of cases, including pleocytosis, elevated protein, elevated IgG index, and oligoclonal bands.⁴ These abnormalities have shown potential in being predictive of responsiveness to immunotherapy, and response rates have been reported as high at 80% (Santoro 2024 diagnostic). Although various therapeutic approaches have been explored, the ideal treatment is not yet clear as the mechanism of DSRD is not fully understood.

There has been increasing awareness surrounding the potential for an autoimmune mechanism. DS patients are predisposed to chronic inflammatory states, making it possible that DSRD is caused by an underlying autoimmune pathogenesis.¹ Studies have shown that intravenous immunoglobulin (IVIG) has been effective in improving symptoms in DSRD patients, with an 88% response rate in all 72 patients and a 92% response rate in patients with a neurodiagnostic abnormality compared to a 36% and 42% response rate from steroids alone, respectively.⁴ Additional awareness has been increasing surrounding the use of electroconvulsive therapy (ECT) for DSRD. A recent case study found that, after trials of IVIG and ECT, the patient had a small, unsustained response to IVIG alone for less than 3 months and a rapid, sustained response to ECT once it was introduced for more than 6 months with maintenance ECT.⁵ Further literature has shown similar responses to ECT, but it is difficult to generalize these findings due to the number of reported cases.⁶ More recently, the usage of lorazepam has been shown to be of significant benefit. A study comparing lorazepam (n=85) vs IVIG (n=68) vs no treatment (n=59) revealed that lorazepam and IVIG outperformed no therapy (p < 0.001), with IVIG showing additional benefit over lorazepam for patients with lumbar puncture, neurodiagnostic study, and serum cytokine or MRI abnormalities.⁷

References

1. Santoro JD, Jafarpour S, Keehan L, et al. Diagnostic abnormalities, disease severity and immunotherapy responsiveness in individuals with Down syndrome regression disorder. Sci Rep. 2024;14(1). doi:10.1038/s41598-024-81819-8

2. Bonne S, Iftimovici A, Mircher C, et al. Down syndrome regression disorder, a case series: clinical characterization and therapeutic approaches. Front Neurosci. 2023;17. doi:10.3389/fnins.2023.1126973

3. Gregory A, Wilson JL, Hogarth P, Hayflick SJ. Abnormal brain iron accumulation is a rare finding in Down syndrome regression disorder. Pediatr Neurol. 2023;138:1-4. doi:10.1016/j.pediatrneurol.2022.09.002

4. Santoro JD, Partridge R, Tanna R, et al. Evidence of neuroinflammation and immunotherapy responsiveness in individuals with Down syndrome regression disorder. J Neurodev Disord. 2022;14(1). doi:10.1186/s11689-022-09446-w

5. Connors MH, Sachdev PS, Colebatch JG, Taylor MS, Trollor J, Mohan A. Case report: Down syndrome regression disorder, catatonia, and psychiatric and immunomodulatory interventions. Front Psychiatry. 2024;15. doi:10.3389/fpsyt.2024.1416736

6. Kelley BJ, Bailey KJ, Hubregsen JJ. Clinical response to electroconvulsive therapy in a young adult with Down syndrome regression disorder. J ECT. 2024;41(2). doi:10.1097/yct.0000000000001093

7. Santoro JD, Jafarpour S, Rezvan PH, et al. A comparative effectiveness study of lorazepam or IVIG versus no treatment for Down syndrome regression disorder. Neurol Ther. 2026;15(3):1099-1120. doi:10.1007/s40120-026-00906-2