Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.

Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.

Sclerocornea associated with the chromosome 22q11.2 deletion syndrome.

Reported ocular findings in the 22q11.2 deletion syndrome (which encompasses the phenotypes of DiGeorge, velocardiofacial, and Takao (conotruncal-anomaly-face) syndromes) have included posterior embryotoxon (prominent, anteriorly displaced Schwalbe's line at the corneal limbus or edge), retinal vascular tortuosity, eyelid hooding, strabismus, and astigmatism. We present seven 22q11.2 patients from multiple centers with sclerocornea, an eye finding previously unreported in the literature. Four boys and three girls were identified with sclerocornea, systemic DGS/VCFS findings, and fluorescence in situ hybridization (FISH)-confirmed microdeletion at chromosome 22q11.2. FISH diagnosis was perinatal in six patients but at 2 years of age in one child. Sclerocornea was bilateral in five patients. Findings included descemetocele (five eyes), microophthalmos (one eye), iridocorneal adhesions (one bilateral case), and severe anterior segment dysgenesis (one eye). Two patients underwent bilateral corneal transplantation; another two were scheduled for possible unilateral transplant. Sclerocornea is a static congenital condition in which the cornea is opaque and vascularized and resembles the sclera. The novel finding of sclerocornea suggests that a genetic locus at 22q11.2 may be involved in anterior segment embryogenesis. In most of our patients, the diagnostic process was underway, but in one patient 22q11.2 deletion was not suspected until after the child had already been undergoing treatment for sclerocornea for 2 years. Sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome. Ophthalmologists diagnosing sclerocornea in children with systemic findings suggestive of 22q11.2 deletion should ensure appropriate genetic referral.

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene.

Introduction/Methods Mutations in POLG1, the gene encoding mitochondrial polymerase gamma (Polγ), have been associated with a number of well-characterized phenotypes. In this study, we report two cases of patients with biallelic POLG1 mutations and stroke. We also performed a review of the literature and report on all clinical studies of patients with POLG1 mutations in which stroke was described in the phenotype. For each patient, genotype and phenotype are reported. Results Including our two patients, a total of 22 patients have been reported with POLG1 mutations and stroke. The average age of onset of stroke in these patients was 9 years with a range of 1-23 years. In cases where localization was reported, the occipital lobes were the primary location of the infarct. Mutations in the linker-linker or linker-polymerase domains were the most frequent genotype observed. Seizures (16/22) and hepatic dysfunction/failure (8/22) were the most commonly reported symptoms in the stroke cohort. Conclusion This article raises an underrecognized point that patients with POLG1 mutations may suffer a cerebrovascular accident at a young age. The most common location of the infarction is in the occipital lobe. The presentation may be similar to MELAS and can be misdiagnosed as a migrainous stroke.

Improving risk assessment in family medicine through the family history.

The family history is used as a screening tool to identify persons who may be at risk for a heritable disorder. Primary care providers sometimes do not thoroughly gather and document the family history. This pilot study was undertaken to determine whether having a genetic counselor on site at our family medicine clinic 2 days a week for 3 months would improve the quality of the family history field in patient records. We compared 7 elements in the family history field for patients seen before and after the genetic counselor was on site. Documentation of 1 of the 7 elements (major disease) improved significantly after the intervention period (P = .02). Changing provider behavior with regard to gathering and documenting family history of major disease may be facilitated by tools to help collect the family history and by using the increasing number of available genetic tests.

Mitochondrial mutation in a child with distal arthrogryposis.

A 15-year-old girl presented with stroke and was found to have a mitochondrial mutation MELAS T3271C. As an infant, she had required casting and surgery for clubbed feet as well as physical therapy for camptodactyly and adducted thumbs. Despite some residual deformities, psychomotor development was normal, but she was extremely small for her age with height, weight, and head circumference below the third centile. A younger brother had similar distal arthrogryposis, but normal height and weight and no history of stroke though he had been diagnosed with attention deficit. The parents and another brother were clinically normal. While the observation of MELAS in a child with distal arthrogryposis could be co-incidental, it raises concern about the possible role of mitochondrial myopathy or neuropathy in causation of distal arthrogryposis.