ESPE Abstracts

Introduction: PMM2-CDG is the most common congenital disorder of glycosylation (CDG). Since glycoproteins are involved in every endocrine axis, PMM2-CDG patients have a high risk of developing endocrinopathies.

Case report: We describe two 12 years-old female PMM2-CDG patients with severe short stature and no clinical sign of puberty. One patient showed low serum levels of insulin-like growth factor-1 (IGF-1) and IGF binding protein 3 (IGF-BP-3), associated to normal somatotropic response to the stimulation test and delayed bone age. The other patient had normal IGF-1 and IGF-BP-3 serum levels, deficient somatotropic response to the stimulation test and slightly delayed bone age. Both patients had hypergonadotropic hypogonadism with increased levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and very low levels of 17-beta-estradiol and anti-mullerian hormone (AMH). Abdominal ultrasound showed infantile uterus and small ovaries. Thyroid function, adrenal function, prolactin, glucidic and lipidic metabolism were normal in both patients.

Discussion: Short stature and hypergonadotropic hypogonadism were the main endocrine manifestations observed in our PMM2-CDG patients. Significant postnatal growth decline and final short stature are reported in PMM2-CDG and can be associated with low serum levels of IGF-1 and IGF-BP-3, as shown in one of our patients. Recent literature describes that abnormal glycosylation prevents correct processing of IGF-1 and its receptor (IGF-1R) impairing the GH-IGF1 signalling pathway. Puberal abnormalities, such as delayed, incomplete, or absent puberty, can also be part of the PMM2-CDG phenotype, especially in females. A dysfunction in the FSH cascade seems to be the main cause of hypergonadotropic hypogonadism since glycosylation is required to allow high binding affinity between FSH and its receptor (FSH-R). They did not show signs of other endocrinopathies related to PMM2-CDG, including thyroid abnormalities (high thyrotropin and low thyroxin-binding globulin are common findings while hypothyroidism is infrequent), hypoglycemia and hyperinsulinemia, adrenal insufficiency, hyperprolactinemia and hypolipidemia.

Conclusion: Endocrinopathies are frequently part of the clinical phenotype of PMM2-CDG, therefore the pediatric endocrinologist is an important figure for both diagnosis and subsequent management of this disorder. In presence of multiple endocrinological abnormalities, particularly severe short stature and absence of puberty, differential diagnosis should include PMM2-CDG. The involvement of the endocrine system in CDGs should be further investigated in light of recent discoveries on the biochemical mechanisms underlying CDGs and of the new treatments available in the field of pediatric endocrinology.