Endocrine Abstracts

JOINT2293

Introduction: Growth hormone (GH) insensitivity (GHI) results from a spectrum of abnormalities in the action of GH, presenting clinically as either mild short stature with normal physical appearance or severe dysmorphic short stature. In Noonan syndrome (NS) variable GHI has been reported, especially in individuals with PTPN11 mutations. However, limited data are available on LZTR1 mutations.

Case report: A 1.8-year-old male patient was referred to our Pediatric Endocrinology Unit for growth failure. His length was 80.5 cm (-1.3 SDS), and height velocity was significantly reduced (-1.8 SDS). The patient was born at 38+2 weeks of gestation following a pregnancy complicated by polyhydramnios in the 3^rd trimester. Prenatal echocardiography revealed hypertrophy of the septum and right sections of the heart. At birth, his weight and length were adequate (3600 g and 53 cm, respectively). On the first day of life, he experienced a Sudden Unexpected Postnatal Collapse (SUPC). Postnatal cardiological evaluation confirmed hypertrophic cardiomyopathy with associated electrocardiographic abnormalities. Clinically, the patient exhibited features suggestive of RASopathy, therefore a genetic evaluation was performed. During the follow-up for growth failure, laboratory investigations revealed markedly reduced levels of IGFBP-3 (0.61 mg/L; range 1.20 - 3.30) and IGF-1 (13 ng/ml; range 18-156). Abdominal ultrasound was normal. Blood tests showed an increased INR (1.37, range 0.92-1.14) and reduced prothrombin time (64%, range 70-100). Cranial MRI was unremarkable. An arginine test was performed and revealed normal GH peak (14.60 ng/ml) with persistently significantly reduced IGF-1 and IGFBP-3 levels. Genetic analysis identified a heterozygous mutation in the LZTR1 gene (variant c.734G>A, p.Gly245Glu), classified as pathogenic and associated with NS.

Conclusions: This case confirms that some LZTR1 mutations can be associated with GHI. However, biallelic LTZR1 variants have been reported linked with GH deficiency (GHD). The molecular mechanisms causing GHI or GHD in LTZR1 remain unclear. An accurate auxological and biochemical evaluation is essential to distinguish these two conditions and establish a correct work-up and follow-up, as well as an adequate treatment strategy.