Using next-generation sequencing for the diagnosis of rare disorders: a family with retinitis pigmentosa and skeletal abnormalities.

Linkage analysis with subsequent candidate gene sequencing is typically used to diagnose novel inherited syndromes. It is now possible to expedite diagnosis through the sequencing of all coding regions of the genome (the exome) or full genomes. We sequenced the exomes of four members of a family presenting with spondylo-epiphyseal dysplasia and retinitis pigmentosa and identified a six-base-pair (6-bp) deletion in GNPTG, the gene implicated in mucolipidosis type IIIγ. The diagnosis was confirmed by biochemical studies and both broadens the mucolipidosis type III phenotype and demonstrates the clinical utility of next-generation sequencing to diagnose rare genetic diseases.

Pediatric trigger thumb in identical twins: congenital or acquired?

Pediatric trigger thumb is an uncommon condition with a calculated incidence of 3 per 1000 live births or less. Some reports have suggested a congenital etiology while others could not find a single case of pediatric trigger thumb at birth. This article reports the occurrence of bilateral trigger thumbs in identical twins, age 3 years and 9 months, affecting their thumbs to similar extents, which may suggest a congenital etiology.Congenital etiology for trigger thumb has been proposed for many reasons: occurrence in infants, occurrence in twins, occasional bilaterality, possible presence of triggering at birth, and absence of history of trauma. The occurrence of pediatric trigger thumb in twins has been reported 3 times in the literature; all reported cases were bilateral, as in our case.The mean age at presentation of pediatric trigger thumb is 2 years. The thumb is usually held in a fixed flexion position (mimicking a fracture). Examination usually reveals a palpable nodule in the flexor pollicis longus tendon at the metacarpal joint. This is an important clinical sign. Triggering in children, however, is rare. Macroscopically, there is a nodular thickening of the tendon itself. Pathological changes can be found in the tendon, tendon sheath, or both. A specimen taken from one of the nodules in our case showed degenerative changes while those from both pulleys were normal.Pediatric trigger thumb responds predictably to A1 pulley release, preferably before age 4 years, although milder cases may resolve spontaneously.

Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.

Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical and genetic heterogeneity. Fifteen unrelated ARVC families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from a genetically isolated population. Identification of key recombination events reduced the disease region to a 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C-->T, S358L), was carried on all recombinant ARVD5 ancestral haplotypes from affected subjects and not found in population controls. The mutation occurs in a highly conserved transmembrane domain of TMEM43 and is predicted to be deleterious. Clinical outcomes in 257 affected and 151 unaffected subjects were compared, and penetrance was determined. We concluded that ARVC at locus ARVD5 is a lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8, 95% CI 1.3-10.9). Heart failure was a late manifestation in survivors. Although little is known about the function of the TMEM43 gene, it contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.

A case of fatal aconitine poisoning by Monkshood ingestion.

Accidental aconitine poisoning is extremely rare in North America. This report describes the confirmation of a case of accidental aconitine poisoning using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The case involved a 25-year-old man who died suddenly following a recreational outing with friends where he consumed a number of wild berries and plants including one that was later identified as Monkshood (Aconitum napellus). Postmortem blood and urine samples were available for analysis. All routine urine and blood toxicology screens were negative. The LC-MS/MS method allowed sensitive quantification of aconitine, the main toxin in A. napellus, and showed 3.6 and 149 microg/L in blood and urine, respectively. These concentrations were similar to that reported in other aconitine-related deaths. This case illustrates the dangers of consuming unidentified plants, and documents concentrations of aconitine in blood and urine in a fatal case of A. napallus-related poisoning.

Corpora amylacea in a leiomyoma of soft tissue.

A case of myxoid leiomyoma of deep soft tissue is described. The patient was a 42-year-old woman who presented with menorrhagia, and an ischiorectal mass was identified. A total hysterectomy was performed, and the mass was removed. On gross examination, the mass was 6cm x 5cm x 4cm and had a mucoid cut surface. Histologic examination revealed a myxoid leiomyoma with abundant intracellular corpora amylacea (CA). An infarcted leiomyoma was present in the hysterectomy specimen. The patient remains well, with no evidence of recurrence 3 years after surgery. Leiomyomas of deep soft tissue are rare, and, to our knowledge, none have been described containing CA.

Subungual metastasis from a rectal primary: case report and review of the literature.

BACKGROUND: Subungual metastases from colorectal cancer are unusual and have mainly been reported in patients with lung, genitourinary, and breast cancer. OBJECTIVE: We present the case of a 72-year-old man with rectal adenocarcinoma and a subungual metastasis to the left thumb 5 years later. METHODS: A case report and a brief review of the literature of subungual metastases are given. RESULTS: The thumb was amputated and the patient died 6 months later with extensive metastatic disease. CONCLUSION: Metastatic carcinoma should be considered in the differential diagnosis of persistent subungual masses, particularly in patients with a history of cancer. The prognosis with such lesions is generally poor.

Acute carpal tunnel syndrome due to filarial infection.

A case of acute carpal tunnel syndrome (CTS) due to filarial infection is reported in a resident of Newfoundland, Canada. The patient presented with classical symptoms and signs of acute CTS and a filarial worm was identified in synovial tissue removed during surgery that was morphologically consistent with the genus Brugia. Antifilarial antibodies were present in serum. Surgical removal of the infected tissue, without administration of antifilarial drugs, proved adequate in eradicating the infection and a subsequent serum sample was negative for antifilarial antibodies. The patient remains asymptomatic more than two years after surgery. This case is unusual in its clinical presentation and geographic location.