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Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

In October 2016, Seattle Children's Hospital notified the Washington State Department of Health (DOH) and CDC of a cluster of acute onset of limb weakness in children aged ≤14 years. All patients had distinctive spinal lesions largely restricted to gray matter detected by magnetic resonance imaging (MRI), consistent with acute flaccid myelitis (AFM). On November 3, DOH issued a health advisory to local health jurisdictions requesting that health care providers report similar cases. By January 24, 2017, DOH and CDC had confirmed 10 cases of AFM and excluded two suspected cases among residents of Washington during September-November 2016. Upper respiratory tract, stool, rectal, serum, buccal, and cerebrospinal fluid (CSF) specimens were tested for multiple pathogens. Hypothesis-generating interviews were conducted with patients or their parents to determine commonalities between cases. No common etiology or source of exposure was identified. Polymerase chain reaction (PCR) testing detected enterovirus D68 (EV-D68) in nasopharyngeal swabs of two patients, one of whom also tested positive for adenovirus by PCR, and detected enterovirus A71 (EV-A71) in the stool of a third patient. Mycoplasma spp. immunoglobulin M (IgM) titer was elevated in two patients, but both had upper respiratory swabs that tested negative for Mycoplasma spp. by PCR. Clinicians should maintain vigilance for AFM and report cases as soon as possible to state or local health departments.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals ( n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing ( n = 6), whole-exome sequencing ( n = 5), or Sanger sequencing ( n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA -related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

Microdeletions of 1q41q42 have recently been classified as a syndrome. Features include significant developmental delay and characteristic dysmorphic features as well as cleft palate, clubfeet, seizures, and short stature in some individuals, with a clinical diagnosis of Fryns syndrome in two individuals with congenital diaphragmatic hernia at the severe end of the spectrum. The gene DISP1, which is involved in sonic hedgehog signaling, has been proposed as a candidate for the midline defects in this syndrome. We undertook a genotype-phenotype analysis of seven previously unreported individuals with deletions of 1q41q42 that range from 777 kb to 6.87 Mb. Three of the individuals in our cohort do not display the major features of the syndrome and have more proximal deletions that only overlap with the previously described 1q41q42 smallest region of overlap (SRO) at DISP1. One individual with several features of the syndrome has a more distal deletion that excludes DISP1. The three remaining individuals have larger deletions that include the entire SRO and demonstrate features of the microdeletion syndrome. Confounding genotype-phenotype correlations, one of the small deletions involving DISP1 was inherited from a phenotypically normal parent. DISP1 haploinsufficiency may not be solely responsible for the major features of 1q41q42 microdeletion syndrome, and other genes in the SRO likely play a role in the phenotype. Additionally, some features present in a minority of individuals, such as Pelger-Huët anomaly, may be attributed to deletions of genes outside of the SRO., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Tracheal agenesis is a rare malformation of the lower respiratory tract. Investigation of a patient with multiple congenital anomalies and tracheal agenesis prompted a review of the literature which uncovered 42 previously published cases, most of whom had other defects. The presence in our patient of a tracheal abnormality in association with radial hypoplasia, single umbilical artery, tetralogy of Fallot, and left hydroureter initially suggested presence of the VACTERL association. However, numerical classification of malformation patterns in the reported patients with tracheal agenesis and in a series of patients with tracheoesophageal fistula and other components of the VACTERL association suggests that tracheal agenesis does not occur in the VACTERL association and may be part of another pattern of malformations which includes laryngeal atresia, complex congenital heart anomalies, radial ray defects, and duodenal atresia.