Identification of a novel IGSF1 variant in two Malaysian male siblings with central hypothyroidism and macroorchidism

Immunoglobulin superfamily member 1 (IGSF1) mutation is the commonest cause of mild to moderate isolated central congenital hypothyroidism and has an X-linked recessive inheritance, primarily affecting males. Other notable clinical features are macro-orchidism with delayed pubertal testosterone rise, large birth weight, increased body mass index, low prolactin andtransient growth hormone deficiency. Two male siblings with central hypothyroidism were found to have a novel IGSF1 c.3467T>A variant that was likely pathogenic based on the family segregation study. The proband, aged 3 years, presented at 18 days old with prolonged jaundice while his 16-year-old brother was only shown to have central hypothyroidism after the genetic analysis result of the proband was known. Both siblings were obese, had large birth weights, macro-orchidism and low prolactin. The proband’s brother had intellectual disability while the proband had normal development. This case study highlights the importance of evaluation for IGSF1 variants in patients with unexplained central hypothyroidism, especially when accompanied by X-linked inheritance and macro-orchidism. Family segregation analysis will facilitate detection of other affected family members or carriers who may also benefit from thyroxine treatment.

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