Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

Impaired dentin mineralization, supernumerary teeth, hypoplastic mandibular condyles with long condylar necks, and a TRPS1 mutation.

Tricho-rhino-phalangeal syndrome type I, an autosomal dominant condition, is caused by heterozygous pathogenic variants in a zinc finger transcription factor, TRPS1, which has important roles in development of endochondral bones, teeth, and hair. Clinical manifestations of the patients include short stature, sparse, fine and slow-growing scalp hair, bulbous nose, supernumerary teeth, hip dysplasia, brachydactyly, and cone-shaped epiphyses of the phalangeal bones. OBJECTIVE: To clinically, radiographically, and molecular genetically investigate a patient with tricho-rhino-phalangeal syndrome type I. MATERIALS AND METHODS: Clinical and radiographic examination and mutation analysis of TRPS1 were performed. RESULTS: Clinical and radiographic examination indicated the patient had tricho-rhino-phalangeal syndrome type I. Sequencing of the TRPS1 gene revealed a heterozygous pathogenic variant (c.2762G>A; p.Arg921Gln). Oral examination showed supernumerary teeth, large dental pulp spaces, dental pulp stones, microdontia of the maxillary permanent lateral incisors, absence of the mandibular left second premolar and short root of the maxillary right second premolar, and hypoplastic mandibular condyles with long condylar necks. CONCLUSION: TRPS1 has an important function in regulating bone and dentin mineralization. Having large dental pulp spaces suggests that impaired dentin mineralization was the result of the TRPS1 pathogenic variant. This is the first patient with a TRPS1 pathogenic variant who had impaired dentin mineralization. This is also the third report showing the association between TRPS1 pathogenic variants and the presence of supernumerary teeth.

Recognizing and Managing Children with a Pediatric Cancer Predisposition Syndrome: A Guide for the Pediatrician.

It is estimated that at least 8% to 10% of children diagnosed with cancer have an inherited cancer predisposition syndrome. Pediatricians may be called upon to (1) identify children with symptoms suggestive of cancer that require further diagnostic testing, (2) identify children who should be referred to cancer genetics based on their personal and family histories, and (3) provide primary care to children who have an inherited cancer syndrome. This review article provides a list of clinical warning signs suggestive of childhood malignancy, discusses the personal and family history "red flags" suggestive of hereditary cancer, offers checklists to help identify patients who are candidates for cancer genetics evaluation, and describes features of the major pediatric cancer syndromes involving solid tumors and surveillance guidelines. This review aims to provide the pediatrician with the tools needed to recognize, refer, and help manage children at risk for pediatric cancer syndromes. [Pediatr Ann. 2018;47(5):e204-e216.].