Objective:

To describe a rare pediatric presentation of dual neurogenetic diagnoses.

Background:

Phelan-McDermid syndrome (PMS) is an autosomal dominant condition associated with generalized hypotonia, intellectual disability with absent to severely delayed speech, and normal to advanced growth; caused by heterozygous deletions or other structural changes (e.g., ring chromosomes, unbalanced translocations) of the terminal end of chromosome 22q13.3 with involvement of SHANK3 or heterozygous pathogenic variants of SHANK3. Mitochondrial neurogastrointenstinal encephalomyopathy (MNGIE) is an autosomal recessive condition caused by thymidine phosphorylase deficiency leading to toxic nucleoside accumulation, and secondary mitochondrial damage, which manifest clinically as severe gastrointestinal dysmotility, cachexia, ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy.

Design/Methods:

Not applicable.

Results:

A 15-year-old female with PMS secondary to a ring chromosome 22, intellectual disability with absent speech, bilateral sensorineural hearing, progressive hypertonicity resulting in lower extremity contractures, severe failure to thrive, and weight loss refractory to enteral gastrostomy feeds initially presented for initiation of total parental nutrition. The extent of her growth delay and tone changes were atypical for the natural history of PMS, raising suspicion of a concomitant genetic condition. Neuroimaging revealed progressive white matter disease, mineralization of the basal ganglia and thalami, and inflammatory polyneuropathy. A subsequent expanded metabolic evaluation revealed elevated plasma thymidine and urine uracil, thymine, thymidine, and deoxyuridine, consistent with a biochemical diagnosis of MNGIE. Molecular testing confirmed a heterozygous TYMP gene deletion, consistent with her 22q13.3 microdeletion due to a ring chromosome, and a newly identified in trans missense pathogenic variant c.1040T>C (p.Leu347Pro). Her hospitalization was complicated by refeeding syndrome, multi-pathogen infections, respiratory failure, and death by multiorgan dysfunction.

Conclusions:

Atypical features of a primary neurogenetic condition should prompt investigation of a concomitant second genetic etiology, as earlier recognition of dual diagnoses can impact clinical management. Patients with terminal 22q13.3 deletions are at increased risk for various autosomal recessive conditions, including MNGIE.