Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285), c.247_250del (p.Asn83Hisfs4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

BackgroundImmunocompromised patients are at high risk for morbidity and mortality due to respiratory syncytial virus (RSV) infection. Increasingly, pediatric patients with malignancy or undergoing transplantation are managed primarily as outpatients. Data regarding the clinical presentation and outcomes of RSV in the outpatient pediatric immunocompromised population are limited.MethodsWe performed a retrospective cohort study of children with hematologic malignancy or hematopoietic or solid organ transplant with laboratory‐confirmed RSV infection diagnosed as outpatients at an academic medical center between 2008 and 2013.ResultsOf 54 patients with RSV detected while outpatients, 15 (28%) were hospitalized, 7 (13%) received ribavirin, and one (2%) received intravenous immunoglobulin. One (2%) patient was critically ill, but there were no deaths due to RSV infection. Fever (P < 0·01) was associated with increased risk of hospitalization.ConclusionsMost immunocompromised children with RSV detected while outpatients did not require hospitalization or receive antiviral treatment. Potential studies of RSV therapies should consider inclusion of patients in an ambulatory setting.

Since the United States Food and Drug Administration’s approval of over-the-counter levonorgestrel emergency contraception, access to this time-sensitive medication has improved. However, multiple barriers, including the cost of the medication and pharmacy availability, still exist. The objective of this study was to determine the over-the-counter availability of levonorgestrel emergency contraception in pharmacies on Oahu, Hawaii. We conducted a cross-sectional population-based study using in-person simulated patient encounters at all pharmacies on Oahu. Out of 109 chain pharmacies and 13 independent pharmacies, 102 (84%) pharmacies had levonorgestrel emergency contraception available over the counter. Of pharmacies in which it was available, 12.7% required an employee to unlock the medication, 37.3% required the medication to be unlocked at the register, 29.4% were packaged in a large plastic box, and 3.9% were packaged in a blister pack. Levonorgestrel emergency contraception is widely available as an over-the-counter medication in pharmacies on Oahu, yet there are packaging and display practices that make it less accessible. Many of these practices could be improved with pharmacy education or changes in store policies. Systems-based interventions are needed to improve the access to levonorgestrel emergency contraception as an over-the-counter medication.