Short Stature due to Bioinactive Growth Hormone (Kowarski Syndrome)

Bioinactive growth hormone (BGH) is a structurally abnormal, biologically inactive, but immunoreactive form of growth hormone encoded by pathogenic growth hormone 1 gene variants. The underlying cause of the defective physiology is decreased BGH binding affinity to both growth hormone binding proteins and growth hormone receptors (GHRs). GHR cannot dimerize when it is in a quiescent state because BGH cannot activate it. Nondimerized GHR is unable to activate intracytoplasmic signaling pathway molecules such as Janus kinase 2 and signal transducer and activator of transcription, which initiate insulin-like growth factor-1 (IGF-1) transcription. IGF-1 cannot therefore be synthesized and IGF-1 levels in the circulation decrease. In contrast to children with growth hormone insensitivity, children with short stature due to BGH, known as Kowarski syndrome, exhibit an outstanding linear growth response to recombinant growth hormone therapy. For a number of reasons, differential diagnosis presents some difficulties. Similar diseases caused by genetic abnormalities that cause short stature range in severity from minor to severe clinical spectrum. Furthermore, some patients with Kowarski syndrome have previously been diagnosed with familial short stature, constitutional delayed puberty, and idiopathic short stature. This paper aims to review the particular clinical and laboratory findings of BGH. This study collected clinical and laboratory data from KS cases reported in the literature. This review reports that KS cases have lower SDSs for height and IGF-1 compared to growth hormone deficiency. The diversity of genetic defects underlying Kowarski syndrome (KS) will provide new insights into growth hormone insensitivity. As the availability of genetic analysis, including functional investigations expands, researchers will identify new underlying genetic pathways.