ESPE Abstracts (2019) 92 P3-269

IGSF1 Mutation: Treatment in the Absence of Symptoms?

Sarah Castets1, Julia Vergier1, Alice Godefroy2, Alexandru Saveanu1, Patrick Collignon3, Thierry Brue1, Rachel Reynaud1

1AP-HM, Centre de Référence des Maladies rares d'origine hypophysaire HYPO, Marseille, France. 2Hôpital Saint Joseph, Marseille, France. 3Hôpital Sainte Musse, Toulon, France

Introduction: Congenital central hypothyroidism is a rare pathology, whose molecular origin has been identified more frequently since discovery of the role of IGSF1. The natural evolution of central hypothyroidism in patients with mutations is not well known however.

Case report: A male infant born at term with a normal birth weight received thyroid function tests in the neonatal period because of symptoms of brain-lung-thyroid syndrome (generalized hypotonia, hyaline membrane disease). The tests in fact revealed isolated central hypothyroidism (TSH, 3.8 mIU/L; T3, 1.56 pmol/L; T4, 6.2 pmol/L) with normal hypothalamic-pituitary MRI results. The patient had another episode of severe acute respiratory distress, and developed asthma. Endocrinological follow-up confirmed the isolated and persistent nature of TSH deficiency. NGS analysis revealed a c.2485dup variant of IGSF1 (X-linked inheritance). Family investigations were performed. Tests revealed central hypothyroidism for both brothers. The elder brother (6 years old) has normal growth and psychomotor development and is completely asymptomatic. The younger brother (9 months of age) is asymptomatic but overweight. Thyroid tests were performed at day 3 of life for the younger brother because of family history. They revealed a low T3 level (3.5 pmol/l) and subnormal T4 level (11.4 pmol/l). No treatment was initiated. At 9 months of age, the T3 level had normalised (5.6 pmol/l) but the T4 level had decreased (8.2 pmol/l). At this stage, L-thyroxine treatment was initiated for both brothers, despite the absence of symptoms.

Discussion: This genetic variant has never been described in the literature but is considered pathological. The diagnosis, which would have eluded neonatal screening in France, was made because of the initial clinical presentation with respiratory distress, but these symptoms have not been reported for IGSF1 mutations. The absence of symptoms in spite of clear central hypothyroidism has been described in the families of other index cases, and points towards the probable presence of compensating mechanisms, such as a possible increase in deiodinase levels, which would maintain a sufficient concentration of T3. This case highlights the variability of T3 and T4 levels in the absence of treatment in children, with a possible worsening of central hypothyroidism over time, suggesting that genetic testing in the family is essential to confirm diagnosis.

Conclusion: Prospective follow-up of this family should shed light on the natural history of central hypothyroidism and provide arguments for or against initiating treatment in the absence of symptoms.

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