BackgroundPrimordial dwarfism is a state of extreme prenatal and postnatal growth deficiency, and is characterized by marked clinical and genetic heterogeneity.ResultsTwo presumably unrelated consanguineous families presented with an apparently novel form of primordial dwarfism in which severe growth deficiency is accompanied by distinct facial dysmorphism, brain malformation (microcephaly, agenesis of corpus callosum, and simplified gyration), and severe encephalopathy with seizures. Combined autozygome/exome analysis revealed a novel missense mutation in WDR4 as the likely causal variant. WDR4 is the human ortholog of the yeast Trm82, an essential component of the Trm8/Trm82 holoenzyme that effects a highly conserved and specific (m7G46) methylation of tRNA. The human mutation and the corresponding yeast mutation result in a significant reduction of m7G46 methylation of specific tRNA species, which provides a potential mechanism for primordial dwarfism associated with this lesion, since reduced m7G46 modification causes a growth deficiency phenotype in yeast.ConclusionOur study expands the number of biological pathways underlying primordial dwarfism and adds to a growing list of human diseases linked to abnormal tRNA modification.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0779-x) contains supplementary material, which is available to authorized users.

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is an extremely rare autosomal recessive disorder with distinctive clinical and neuroimaging findings. To date, only 17 patients from 9 unrelated families with BLC-PMG have been reported worldwide. Herein, we describe a series of 13 new patients derived from 10 unrelated Egyptian families. Patients presented at early life with the classic phenotype including severe microcephaly, failure to acquire developmental skills, growth failure and the distinguished calcification patterns involving the cortex, thalami, basal ganglia and pons. Additional features not reported before included calcification of the cerebellum (eight patients: 61.5%) and imperforate anus and undescended testis in a single patient. Molecular studies of the OCLN gene (NM_001205254) identified six distinct candidate mutations. Interestingly, the deletion mutation of the transmembrane domain in exons 3 and 4 (c.51-?_730-?del, p.Lys18_Glu243) was found in five unrelated families (50%), suggesting a founder mutation in our population. On the other hand, five novel truncating mutations (c.809delA (p.K270Rfs*62), c.858_861delTTAT (p.I286Mfs*45), c.1037+5G>C, c.1169C>G (p.S390*) and c.1180delG (p.E394Sfs*91)) were detected, each in one family. To our knowledge, this is the largest series of patients with BLC-PMG. Cerebellum calcification is an additional relevant finding in our series, thus expanding the neuroradiological phenotype of this syndrome.

Microcephalic Osteodysplastic Primordial Dwarfism type I (MOPDI) is an autosomal recessive disorder with poorly understood biology. It is characterized by profound prenatal and postnatal somatic growth failure, developmental brain malformations and by early death in infancy [Taybi and Linder, 1967;Majewski et al., 1982]. The longest survival among the previously reported cases was 12.75-year old boy [Nagy et al., 2012] who had compound heterozygous g.30G>A and g.111G>A mutations in RNU4ATAC. Another German girl with a homozygous g.55G>A mutation was described at the age of 9-year-old [Nagy et al., 2012]. Information in the medical literature regarding long survival of MOPDI patients is limited and the clinical phenotype with age has not yet been clearly characterized, making the diagnosis amongst older patients more challenging. We report on an 18-year-old male with late presentation of MOPDI caused by g.55G>A homozygous mutation in RNU4ATAC. He had a history of motor deterioration after an episode of encephalitis in addition to severe growth retardation.The patient was the 2nd child born to healthy consanguineous parents (first cousins) when the mother was 20 and the father was 31 years old. The other sib was normal. There is a family history of maternal uncle affected with neuropsychiatric disorder. The pregnancy was uneventful and he was delivered at 30 weeks of gestation with a birth weight 1,500 g and length 35.5 cm (both 3rd centile). He was admitted to neonatal intensive care unit for 12 days because of prematurity and growth retardation. Infancy was characterized by poor weight gain and delayed motor development. During infancy and early childhood, he had multiple episodes of infections, including recurrent otitis media. In addition to this history, the father provided us with a photographic picture of our proband when he was 1-year-old with a facial appearance of sparse hair, prominent eyes and nose and small mouth (Fig. 1).His motor milestones were delayed (head support at 12 months, sitting at 3 years, stood with support at 5 years and walked independently at 7 years). He was noted to have an unsteady gait that is accompanied by frequent falls. This was long-standing and progressive and followed by spasticity and contractures of the MS. 2016. Long-term survival in microcephalic osteodysplastic primordial dwarfism type I: Evaluation of an 18-year-old male with g.55G>A homozygous mutation in RNU4ATAC.Am J Med Genet Part A 170A:277-282.