Mosaic IL6ST variant inducing constitutive GP130 cytokine receptor signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy.

Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through Janus kinase signal transducers and activators of transcription pathway (JAK/STAT) activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186_Tyr190del variant present constitutively. Tyr186_Tyr190del was found by exome sequencing and was shown to be de novo (absent in proband's parents and siblings) and mosaic (present in approximately 15-40% of cells depending on the tissue studied-blood, urine sediment, hair bulbs and buccal swab). Functional studies were performed in the Epstein-Barr virus-immortalized patient's B cell lymphoblastoid cell line, which carried the variant in approximately 95% of the cells. Western blot showed that the patient's cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3, which is indicative of IL6-independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1, we speculate that these drugs may be effective in the treatment of our patient's condition.

Moderate congenital adrenal hyperplasia in two girls diagnosed by newborn screening.

INTRODUCTION: Congenital adrenal hyperplasia (CAH) before the introducing a newborn screening was initially diagnosed based on clinical symptoms or positive family history and thereafter confirmed hormonal profiles. PATIENTS' REPORT: We present two female newborns with atypical screening results born shortly after the introduction of neonatal screening for congenital adrenal hyperplasia in the Wielkopolska region. Female patients 1 and 2 were both born at term and discharged from neonatal departments without any suspicion of disease. After performing complete neonatal screening for CAH, girls were admitted to the endocrine department for further investigations. In both cases, the girls did not exhibit characteristic symptoms of the disease. Using the Synacthen test, we observed an insufficient increase in cortisol and an abnormal increase in 17-OHP concentrations. The 24-hour urinary steroid profile analyzed by GC-MS confirmed the diagnosis. In both cases, treatment with hydrocortisone and fludrocortisone was initiated. Genetic evaluation confirmed mutations in the CYP21A2 gene. DISCUSSION AND CONCLUSION: Newborn screening for CAH is useful for revealing a moderate form of CAH and indicates the need to start treatment in cases without typical signs of disease to prevent further virilization and the generation of a GnRH-independent precocious puberty. For nonobvious screening results, clinical information, including any data on virilization, is extremely helpful. Therefore, a careful assessment of newborns' genitalia in neonatal departments is important. The screening laboratory should be informed about any abnormalities to perform a complete screening immediately decreasing significantly the time between taking the paper sample and the final diagnosis.

PAPP-A2 a new key regulator of growth.

Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this is still one of the most common causes of reports to the endocrine clinic and hospitalisation in the endocrine department. A properly functioning growth hormone/insulin-like growth factor (GH/IGF) axis is one of the most important factors in proper growth. A lot of genetic defects in this axis lead to syndromes marked by impaired growth, like Laron syndrome, muta-tions in the STAT5B, insulin-like growth factor 1 (IGF1), and insulin-like growth factor 1 receptor (IGF1R) and mutations in the acid labile subunit (ALS). Two proteases important for the proper functioning of the GH/IGF axis: pregnancy-associated plasma protein-A (PAPP-A) and pregnancy-associated plasma protein-A2 (PAPP-A2), have been described. The first description of the new syndrome of growth failure associated with mutation in the PAPP-A2 gene was given by Andrew Dauber et al. This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth.