ABSTRACT
Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.
Subject(s)
Hypothalamic Diseases/drug therapy , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Disease Management , Humans , Hypothalamic Diseases/metabolism , Hypothalamic Diseases/pathology , Infant , Male , PrognosisABSTRACT
BACKGROUND: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. METHODS: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. RESULTS: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. CONCLUSIONS: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.
Subject(s)
Blepharoptosis/enzymology , Blepharoptosis/genetics , Carboxylic Ester Hydrolases/genetics , Dwarfism/enzymology , Dwarfism/genetics , Genetic Predisposition to Disease , Hypertrichosis/enzymology , Hypertrichosis/genetics , Intellectual Disability/enzymology , Intellectual Disability/genetics , Laurence-Moon Syndrome/enzymology , Laurence-Moon Syndrome/genetics , Retinitis Pigmentosa/enzymology , Retinitis Pigmentosa/genetics , Alleles , Amino Acid Sequence , Animals , Carboxylic Ester Hydrolases/chemistry , Central Nervous System/pathology , Developmental Disabilities/enzymology , Developmental Disabilities/genetics , Embryonic Development/genetics , Gene Expression Regulation, Developmental , Humans , Molecular Sequence Data , Mutation/genetics , Phenotype , Phospholipases/chemistry , Phospholipases/genetics , Protein Structure, Tertiary , Retina/pathology , Zebrafish/embryologyABSTRACT
PURPOSE: To assess the efficacy of cyclosporine 0.05% ophthalmic emulsion (Restasis; Allergan, Inc., Irvine, CA) in the treatment of contact lens wearers with dry eyes. METHODS: Contact lens wearers citing dry eye problems were identified through chart review. Participants were randomly assigned to a treatment group, receiving vials of cyclosporine 0.05% ophthalmic emulsion to use twice daily, or a placebo group, receiving vials of rewetting drops (Refresh Preservative Free Artificial Tears; Allergan, Inc.) to use twice daily. Corneal staining, tear film breakup time, and Schirmer test results were documented at baseline and after 3 months. Participants also completed questionnaires, the Ocular Surface Disease Index, and the National Eye Institute Refractive Error Quality of Life Instrument at baseline and after 3 months. RESULTS: For all parameters, including objective findings and subjective reporting of symptoms, there was no statistically significant difference between the treatment and placebo groups. CONCLUSIONS: This study did not detect a beneficial effect in using cyclosporine 0.05% ophthalmic emulsion over rewetting drops for contact lens wearers. This may be attributable to the small sample size. It is also possible that the mechanism of the dry eye state in contact lens wearers may be different from that of other dry eye states and thus make cyclosporine 0.05% ophthalmic emulsion an ineffective treatment.
