Endocrine Abstracts

JOINT2907

Introduction: Gonadal dysgenesis (GD) is the leading cause of disorders of sex development (DSDs) in Western societies. However, syndromic forms of GD are extremely rare and challenging to diagnose. We report a rare etiology of syndromic GD: IMAGE syndrome.

Case report: A newborn with a 46,XY karyotype, born to non-consanguineous parents, presented with a salt-wasting crisis at day 7 of life, associated with severe intrauterine growth retardation (IUGR) and a birth weight of 1760 g. Clinical examination revealed a dysmorphic syndrome characterized by scaphocephaly, midface hypoplasia, and external genital anomalies (Quigley stage II/Prader stage IV, distal hypospadias, micropenis, and left testicular ectopia). Hormonal investigations showed peripheral adrenal insufficiency (both glucocorticoid and mineralocorticoid deficiency), partial hypergonadotropic hypogonadism with normal AMH levels, and bilateral adrenal hypoplasia on abdominal CT scan. Genetic analysis did not identify any mutations in the implicated genes (NR0B1, NR5A1, HSD3B2, POR). At 3 years of age, severe growth failure (-3 SD) prompted a stimulation test, which revealed complete growth hormone deficiency (GH peak = 0.29 ng/ml), despite a normal pituitary MRI. The combination of IUGR, adrenal hypoplasia, genital anomalies, and GH deficiency strongly suggested the diagnosis of "Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies" (IMAGE) syndrome. Under hormone replacement therapy (hydrocortisone, fludrocortisone, and recombinant growth hormone), the evolution over 14 years was favorable: improved growth (-0.5 SD), spontaneous pubertal onset, no adrenal crisis, and good academic and social integration.

Discussion: IMAGe syndrome is a very rare condition caused by a mutation in the Cyclin-Dependent Kinase Inhibitor 1C (CDKN1C) gene. This ubiquitously expressed protein plays a fundamental role in the early stages of testicular development within the genital ridges. The clinical spectrum of IMAGe syndrome is broad and involves multiple organ systems. The dysmorphic syndrome includes facial and skeletal anomalies such as epiphyseal and metaphyseal dysplasia. Genital anomalies are generally mild, often limited to bilateral cryptorchidism and micropenis, as observed in our patient. Since CDKN1C is also expressed in the pituitary gland, IMAGe syndrome patients may present with varying degrees of pituitary hormone deficiencies, particularly affecting the somatotropic and gonadotropic axes. This could explain the complete GH deficiency and the moderately elevated gonadotropin levels observed in our patient.