Primary hepatic Mycobacterium tuberculosis complex infection with terminal dissemination in a pig-tailed macaque (Macaca nemestrina).

An adult, female, pig-tailed macaque (Macaca nemestrina) of Indonesian origin presented with profound weight loss, anemia (PCV, 29%; normal, 36% to 45%), hypoalbuminemia (1.0 g/dL; normal, 3.5 to 5.2 g/dL), elevated alkaline phosphatase (1990 U/L; normal, 26 to 98 U/L), and an elevated erythrocyte sedimentation rate (75 mm/h; normal, less than 20 mm/h). Abdominal ultrasonography demonstrated an enlarged liver with hyperechoic areas. Euthanasia was performed. Grossly, the liver had multifocal, effacing, white masses throughout and was enlarged with rounded edges. There were 2, small nodules in the right lung lobes. Histologically, the hepatic masses were densely fibrous-encapsulated granulomas with vast central necrosis. The lung nodules also were maturing granulomas, and one kidney and one atrium had small, early granulomas. Fite acid-fast stains of liver and lung revealed very few acid-fast bacilli. PCR analysis of paraffin-embedded liver identified Mycobacterium tuberculosis complex. Culture of the liver was negative twice. This macaque had 16 negative intradermal tuberculin skin tests over the course of 6 y. We hypothesize that the animal arrived with a latent hepatic or enteric infection that later recrudesced and disseminated. Primary hepatic mycobacteriosis is not a typical presentation of tuberculosis in macaques. Negative tuberculin skin tests can be seen with latent infections and extrapulmonary tuberculosis such as Pott disease. This case underscores the problems associated with current surveillance procedures and the risks associated with latent mycobacterial infections in macaques.

ABCA12 is the major harlequin ichthyosis gene.

Harlequin ichthyosis (HI) is the most severe form of autosomal-recessive, congenital ichthyosis. Affected infants have markedly impaired barrier function and are more susceptible to infection. Abnormalities in the localization of epidermal lipids as well as abnormal lamellar granule formation are features of HI skin. Previously, we and others have shown that mutations in the ABCA12 gene encoding an adenosine triphosphate-binding cassette (ABC) transporter underlie the skin disease HI. In this study, we have sequenced the ABCA12 gene in an additional 14 patients and show that all contain mutations, with the majority being either nonsense substitution or frameshift mutations. Eleven HI patients had bi-allelic ABCA12 mutations, whereas in the remaining three HI patients in this study, ABCA12 mutations were detected on only one allele by sequencing. In addition, the one patient from the previous study where no sequence mutations were detected was screened for heterozygous deletions. A combination of oligonucleotide arrays, multiplex PCR analysis and single-nucleotide polymorphism genotyping revealed a heterozygous intragenic deletion in exon 8. These mutation data establish ABCA12 as the major HI gene.

Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis.

Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.