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Let It Grow: Expanding the Phenotype of PPP3CA Mutations to Include Failure to Thrive

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
The protein phosphatase 3 catalytic subunit alpha (PPP3CA) gene encodes the alpha isoform of a subunit of calcineurin, which mediates calcium ion-dependent signal transduction and is a key regulator of synaptic vesicle recycling at nerve terminals. De novo variants in the PPP3CA gene have been reported in association with developmental delay, early-onset epilepsy, hypotonia, autistic features, and brain abnormalities. Heterozygous de novo variants located within the AI domain that are predicted to result in a gain of function, have been reported in a small number of individuals with craniofacial dysmorphism, cleft palate, arthrogryposis, short stature, and PPP3CA-related encephalopathy. To our knowledge, there are no reported cases of failure to thrive and this specific mutation.

Case Presentation
The proband is a 2-year-old full-term male with a history of poor weight gain, first noted at 3 months of age. Past medical history includes silent reflux, mild laryngomalacia, speech delay, and motor delay with delayed sitting and crawling, specifically. Denies seizures. Prenatal course and birth course were unremarkable. Birth weight 2.84 kg. His full sibling has ADHD and his mother has hypothyroidism. Physical exam was significant for a male appearing younger than the stated age with a thin build and triangular facies, non-verbal with delayed comprehension for age with truncal and axial hypotonia. Weight at the initial visit was 8.60 kg (0.12 percentile), length was 80 cm (14th percentile), and head circumference was 47 cm (22nd percentile).

Diagnostic Workup
Negative genetic testing included CMA, Fragile X, CFTR, and Methylation RRSS/ BWS. WES was positive for a De Novo Mutation in PPP3CA p.(Glu282Lys) (GAA>AAA): c.844 G>A in exon 7 of the PPP3CA gene- pathogenic-Autosomal dominant. (NM_000944.4). This mutation is consistent with neurodevelopmental disease with seizures.

Treatment and Management
Therapies including speech, physical, and occupational.

Discussion
This case implicates the importance of monitoring growth and development in children with De novo PP3CA mutations. In comparison with existing literature and similar cases, there is a documented case of failure to thrive along with developmental delay found to be associated with the PPP3CA mutation c.1417G>A (p.Ala473Thr). FTT has also been noted in PPP3CA mutations of the alpha subunit, but not the beta subunit, in mouse models.

Conclusion
To summarize, PPP3CA mutations are rare and are associated with developmental delays and seizures but failure to thrive has yet to be noted in this specific mutation. This clinical finding has been noted in PPP3CA mutation c.1417G>A (p.Ala473Thr) with developmental delay. Growth is a key component of development. Therefore, we propose that the phenotype of PPP3CA mutation be expanded to include failure to thrive, especially in those with developmental delays. Upcoming studies should aim to detail the relationships between genotypes and phenotypes with PPP3CA mutations, enhancing guidelines for diagnosis and treatment.

Agenda

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