A homozygous Y443C variant in the RNPC3 is associated with severe syndromic congenital hypopituitarism and diffuse brain atrophy

Abstract

Biallelic RNPC3 variants have been reported in a few patients with growth hormone deficiency, either in isolation or in association with central hypothyroidism, congenital cataract, neuropathy, developmental delay/intellectual disability, hypogonadism, and pituitary hypoplasia. To describe a new patient with syndromic congenital hypopituitarism and diffuse brain atrophy due to RNPC3 mutations and to compare her clinical and molecular characteristics and pituitary functions with previously published patients. A 20-year-old female presented with severe growth, neuromotor, and developmental delay. Her weight, height, and head circumference were 5135 gr (À25.81 SDS), 68 cm (À16.17 SDS), and 34 cm (À17.03 SDS), respectively. She was prepubertal, and had dysmorphic facies, contractures, and spasticity in the extremities, and severe truncal hypotonia. There were no radiological signs of a skeletal dysplasia. The bone age was extremely delayed at 2 years. Investigation of pituitary function revealed growth hormone, prolactin, and thyroid-stimulating hormone deficiencies. Whole-exome sequencing revealed a novel homozygous missense (c.1328A > G; Y443C) variant in RNPC3. Cranial MRI revealed a hypoplastic anterior pituitary with diffuse cerebral and cerebellar atrophy. The Y443C variant in RNPC3 associated with syndromic congenital hypopituitarism and abnormal brain development. This report extends the RNPC3-related hypopituitarism phenotype with a severe neurodegenerative presentation.

A <i>Novel RNPC3</i> Gene Variant Expands the Phenotype in Patients with Congenital Hypopituitarism and Neuropathy

“…Although polyneuropathy has already been reported in the 4 patients with RNPC3 variants reported by Akin et al, this study mainly focused on the mechanism of POI [4]. In the subsequent study by Bezen et al [9], due to the death of their case, they could not confirm polyneuropathy by ENMG. However, they suggested their patient having polyneuropathy owing to the suggestive clinical findings.…”

“…Patient 1 had pituitary hypoplasia, while patient 2 had not. Further pituitary MRI controls could reveal hypoplasia in this case, suggesting hypoplasia developing during the course [2, 4, 9].…”

“…Polyneuropathy was detected in the homozygous and compound heterozygous variants respectively; p.(L483F), p.([P474T]; [R502*]), and p.([P474T]; [P474Lfs*10]) [4]. Very recently, the homozygous p.(Y443C) variant was also suggested to cause polyneuropathy, according to clinical data, in addition to CH and diffuse brain atrophy [9]. Hence, it is difficult to define the pathophysiology of neuropathy in the RNPC3 -related CH with this limited knowledge.…”

“…RNPC3 is variably expressed throughout the human body, including the pituitary gland, hypothalamus, and ovary [4]. In human brain sections, RNPC3 expression was demonstrated from highest to lowest expression profile; cerebral cortex, white matter, cerebellum, amygdala, basal ganglia, hippocampal formation, thalamus, hypothalamus, medulla oblongata, pons, midbrain, spinal cord [8,9]. In this study, we aimed to evaluate the clinical and molecular characteristics of two siblings with CH and neuropathy and define the differences between the previously reported cases to expand the phenotypic attributes of RNPC3related CH.…”

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance

“…The variant was predicted deleterious with a CADD score of 16.94. Interestingly, a recent article describes a patient with severe growth delay, and anatomic brain anomalies including an enlargement of the peri-cerebral spaces, in which the same RNPC3 variant was identified [ 59 ] The tyrosine residue is a well-conserved amino acid in the RNA recognition motif 2 (RRM2) involved in the binding of RNPC3 to small nuclear RNAs. Indeed, RNPC3 gene encodes for a component the pre-mRNA splicing machinery, the minor (U12-dependent) spliceosome complexes, reported to target around 700–800 genes [ 60 ].…”