ABSTRACT
We describe a case of a pregnancy complicated by early onset asymmetric growth restriction with anhydramnios with termination occurring at 21 weeks. Fetal autopsy showed demineralization of bones and renal tubular dysgenesis. Placental pathology showed features of massive perivillous fibrin deposition and chronic histiocytic intervillositis. We review prior documentation of this association and briefly discuss potential pathogenesis.
Subject(s)
Bone Diseases, Metabolic/diagnosis , Fetal Growth Retardation/diagnosis , Kidney Tubules, Proximal/abnormalities , Placenta Diseases/diagnosis , Urogenital Abnormalities/diagnosis , Abortion, Eugenic , Adult , Bone Diseases, Metabolic/pathology , Female , Fetal Growth Retardation/pathology , Humans , Kidney Tubules, Proximal/pathology , Male , Placenta Diseases/pathology , Pregnancy , Syndrome , Urogenital Abnormalities/pathologyABSTRACT
Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.
Subject(s)
Cleidocranial Dysplasia/genetics , Ectodermal Dysplasia/genetics , Limb Deformities, Congenital/genetics , Membrane Proteins/genetics , Micrognathism/genetics , Mutation , Alleles , Cells, Cultured , Cleidocranial Dysplasia/diagnosis , Ectodermal Dysplasia/diagnosis , Female , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Infant, Newborn , Inositol/metabolism , Intracellular Signaling Peptides and Proteins , Limb Deformities, Congenital/diagnosis , Membrane Proteins/metabolism , Micrognathism/diagnosis , Phenotype , Phthalimides/pharmacology , Quinolines/pharmacology , Vacuoles/metabolismABSTRACT
In 1981, Currarino et al described a triad of findings that consist of partial sacral dysgenesis, presacral mass (anterior meningocele, enteric cyst, or presacral teratoma) and anorectal malformation. Currarino syndrome exhibits variable expressivity and the clinical presentation tends to vary with the age of the subject such as spinal anomaly detected in the fetus, imperforate anus in the newborn, and intractable constipation or neurologic symptoms in the infant and older child. At any age, meningitis can be the presenting symptom and imaging is required for proper investigation. Meningitis, sepsis, urinary tract infections, and, rarely, malignant transformation of a teratoma are serious potential complications. This pictorial review describes the imaging findings, clinical history, surgical interventions, and genetic background in 5 children with this syndrome who presented in our hospital in the interval of 1 year.
