Dwarfism in Tibetan Terrier dogs with an LHX3 mutation

Canine pituitary dwarfism in German Shepherd and related dog breeds has been reported to be associated with a 7-bp deletion mutation in intron 5 of the LHX3 gene. This mutation is transmitted as an autosomal recessive trait that results in dwarf dogs with significantly smaller stature and abnormal haircoat, and potentially early death. Phenotypically, affected adult dogs are proportionally dwarfs. These dwarfs also have a soft, woolly puppy coat that fails to transition into the typical adult hair coat, and marked hair loss occurs in some dogs. We report a similar manifestation of dwarfism in Tibetan Terriers with the same LHX3 mutation. Dwarf Tibetan Terrier puppies were born physically normal but failed to gain weight or to grow at the same rate as their normal littermates. The 7-bp deletion mutation of the LHX3 gene was identified in both alleles of 3 Tibetan Terrier dwarfs from 3 litters, which were biologically related. All parents of these dogs are carriers, confirming transmission of dwarfism in an autosomal recessive manner. Recognition and detection of this mutation will help in guiding future breeding plans to eventually eliminate this trait from Tibetan Terriers.

MITOL dysfunction causes dwarfism with anterior pituitary hypoplasia

In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.

Economic and social aspects of pituitary dwarfism treatment with recombinant growth hormone

Rationale. Pituitary dwarfism is an orphan disease requiring pathogenetic treatment. The domestic literature lacks studies devoted to the medical and economic effectiveness of treatment for growth hormone deficiency (GHD) using recombinant growth hormone (rGH) drugs. Aim. To analyze the cost effectiveness of rGH therapy in GHD children in the Russian Federation under the Program «7 High-Cost Nosologies». Material and methods. We analyzed data of 50 GHD children living in 4 regions of the Russian Federation and receiving rGH therapy under the Program «7 High-Cost Nosologies». We evaluated the amount of drug consumption and the economic component: the cost of treatment and monitoring for ≥ 6 years. The incremental cost was calculated as the difference between a program providing a GHD child with rGH treatment and monitoring and an alternative program providing a GHD child with financial and social assistance and medical examination. Results. The median cost of treatment of a single child with rGH at a dose of 0.033 mg/kg/day was 437.5 thousand rubles or 8.12 thousand US dollars for the entire analyzed period (mean, 6.95 years). The median cost of treatment per child per year was 63.6 thousand rubles/year or 1.09 thousand USD/year. Given the cost of treatment and monitoring, the integrated management of one patient cost 68.4 thousand rubles per year (470.7 thousand rubles for 6.95 years), on average, with monitoring accounting for 7.05%. The total cost of all benefits and examinations for one disabled child was 178.97 thousand rubles per year or 1,243.86 thousand rubles for 6.95 years (medical examinations accounted for 1.2%). Upon calculating the cost difference between the program providing a GHD child with treatment and monitoring and the alternative program when a GHD child was not provided with treatment, but received appropriate disability payments and medical examination, the incremental cost amounted to 110.6 thousand rubles per child per year (773.18 thousand rubles for 6.95 years). Conclusion. The study demonstrates that treatment of GHD children under Program «7 High-Cost Nosologies» is cost-effective for both the patient and society and the state in general. For example, the incremental cost between the two programs is 110.6 thousand rubles for a year or 773.18 thousand rubles for 6.95 years. The study results indicate the importance of thorough analysis of the effects and costs in assessing the effectiveness of medical programs, especially in the case of orphan diseases.