PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

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

The Development of Abstract Word Meanings

Extensive research has shown that children’s early words are learned through sensorimotor experience. Thus, early-acquired words tend to have more concrete meanings. Abstract word meanings tend to be learned later but less is known about their acquisition. We collected meaning-specific concreteness ratings and examined their relationship with age-of-acquisition. Earlier-acquired meanings were rated as more concrete while later-acquired meanings as more abstract, particularly for words typically considered to be concrete. The results suggest that sensorimotor experiences are important to early-acquired word meanings, and other experiences (e.g., linguistic) are important to later-acquired meanings, consistent with a multi-representational view of lexical semantics

Early outcomes of pyrolytic carbon hemiarthroplasty for the treatment of trapezial-metacarpal arthritis

PURPOSE: Pyrolytic carbon implants have been successfully used in the treatment of osteoarthritis of the metacarpophalangeal and proximal interphalangeal joints. Recently, pyrolytic carbon hemiarthroplasties have been proposed for the treatment of osteoarthritis of the trapezial-metacarpal (TM) joint of the thumb. We wished to review our short-term outcomes for this device in the treatment of TM arthritis. METHODS: Fifty-four arthritic TM joints in 49 patients, with a mean age of 59 years, were treated with use of a pyrolytic carbon hemiarthroplasty procedure. Underlying diagnoses included osteoarthritis in 44 thumbs, rheumatoid arthritis in 8 thumbs, psoriatic arthritis in 1 thumb, and juvenile rheumatoid arthritis in 1 thumb. The patients were followed up clinically as well as radiologically for an average of 22 months postoperatively. RESULTS: The overall 22-month survival rate excluding scaphotrapezio-trapezoidal joint arthritis was 80% according to a Kaplan-Meier analysis. Ten metacarpal subluxations were observed. Seven of these cases were salvaged by increasing the depth of the trapezial cup. A total of 15 reoperations were required in this cohort. No complications were seen in the patients with inflammatory arthritis. Thirty-five patients were pain free at the latest follow-up, and 6 reported mild to occasional pain with repetitive activities. The overall satisfaction rate was 40 of 49 patients (81%). Grip strength recovered to 86% of that of the contralateral side. Apposition key and opposition pinch strength improved to 92% and 95%, respectively, of those of the contralateral hand. CONCLUSIONS: Pyrolytic carbon thumb arthroplasty may prove to be an acceptable option for the treatment of TM, although a high complication rate was observed in this early cohort, with many cases of subluxation attributed to the creation of a too shallow trapezial cup. Further comparative studies are warranted. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I

<i>PIK3CA</i>-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of &lt;i&gt;PIK3CA&lt;/i&gt; 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 &lt;i&gt;PIK3CA&lt;/i&gt; mutations in 60 individuals. Several other individuals ( &lt;i&gt;n&lt;/i&gt; = 12) were identified separately to have mutations in &lt;i&gt;PIK3CA&lt;/i&gt; by clinical targeted-panel testing ( &lt;i&gt;n&lt;/i&gt; = 6), whole-exome sequencing ( &lt;i&gt;n&lt;/i&gt; = 5), or Sanger sequencing ( &lt;i&gt;n&lt;/i&gt; = 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 &lt;i&gt;PIK3CA&lt;/i&gt; mutations were novel. We also identified constitutional &lt;i&gt;PIK3CA&lt;/i&gt; mutations in 10 patients. Our molecular data, combined with review of the literature, show that &lt;i&gt;PIK3CA&lt;/i&gt; -related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features(1-5). We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism

Stress in Parents of Children With Genetically Determined Leukoencephalopathies: A Pilot Study.

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