ESPE Abstracts

Introduction: Congenital disorders of glycosylation (CDG) are metabolic conditions resulting from defects in the glycosylation pathway. In addition to the primary neurological symptoms, other possible clinical findings may include distinctive coagulation abnormalities, as well as hepatic, gastrointestinal and, less frequently, hormonal disorders. The ALG1 gene defect is the third most prevalent CDG and compromises β-1,4 mannosyltransferase activity, which is critical for the initial steps in N-glycosylation. Only 73 cases of this entity have been reported.

Clinical Case: Two-year-old (y) twin siblings, born to non-consanguineous parents, were referred to the Endocrinology department due to abnormal thyroid function tests. Their medical history included neonatal hypoglycemia, early-onset epilepsy and developmental delay, hypertransaminasemia with normal liver function and no record of toxins or teratogens exposure. Initial tests ruled out infectious and metabolic diseases. Serologies, acyl carnitines and long-chain fatty acids were normal. MRI scans were normal. Physical examination showed facial dysmorphism, acquired microcephaly (-4 DS), growth impairment, accompanied by delayed bone age. Both of them had low stature: the boy´s height was -3.78 DS and his sister´s -2.58 DS. Subsequent monitoring, at 4y, revealed a probable pattern of growth hormone (GH) resistance, more notable in the female twin [GH 27 ng/ml, IGF1 26.1 ng/ml (-2.11 DS) and IGFBP3 2.52 mg/l (-0.41 DS)]. Since early evaluations, the male twin had central hypothyroidism: TSH 0.57 uUI/ml, total T4 1.81 ug/dl, free T4 0.65 ng/dl and T3 0.62 ng/ml, with low thyroid binding globulin (7.7 ug/ml) and negative antibodies, indicating peripheral alterations as well. His sister had a similar thyroid profile. Other assessments indicated central adrenal insufficiency, with cortisol values under 3 ug/dl and ACTH 21.6 pg/ml in the male and 12.8 pg/ml in the female twin. During follow-up, a severe factor XI deficiency with moderate factor VII and X deficiency and normal factor II was detected in the male twin. This finding, along with the rest of the clinical and biochemical features, suggested CDG and it was confirmed by Whole Exome Sequencing. Two ALG1 gene likely pathogenic variants were identified: c.773C4T (p.Ser258Leu) and c.826C>T (p.Arg276Trp). Segregation studies confirmed autosomal recessive inheritance.

Discussion: Although CDG is an infrequent condition with an initial neurological presentation, these cases reveal the likely underdiagnosed endocrine complications associated with this entity and highlight the importance of its evaluation. Early diagnosis could reduce further comorbidity and mortality in affected patients.