Endocrine Abstracts

Introduction: Biallelic mutations in the TSHB gene are a recognized cause of isolated congenital central hypothyroidism (CH), with autosomal recessive inheritance. In countries where neonatal CH screening relies on detection of an elevated TSH, such cases are missed, with the potential for delayed diagnosis and subsequent developmental impairment.

Case: A female infant presented aged 8 weeks with prolonged jaundice, poor weight gain, constipation, sleepiness and poor feeding. She exhibited coarse facial features and a prominent tongue, in addition to hypotonia, cool peripheries and an umbilical hernia. Biochemistry revealed profound central hypothyroidism (TSH 3.06 mU/l, free T₄ <3.89 pmol/l), with a flat response to TRH testing, but otherwise preserved pituitary function. Thyroxine treatment was initiated; however, aged 7 years, she has residual mild motor delay.

Genetic analyses in the Proband revealed a homozygous, previously reported TSHB mutation (c.373delT, p. Cys125Valfs*10), however, despite paternal heterozygosity for 373delT, the mother exhibited only WT TSHB sequence. Haplotype analysis delineated a 251kb region with loss of heterozygosity at 1p13.2, including the TSHB, TSPAN2 and SYCP1 genes, and an informative SNP 4.4 kb proximal to TSHB (rs1321108), confirmed uniparental (paternal) inheritance (A/A), since no maternal allele (G/G) was inherited. This suggested either maternal deletion of one TSHB allele, or paternal, uniparental isodisomy as the likely genetic basis.

Conclusions: Published literature is devoid of UK or Irish cases with TSHB defects. Our patient, from Dublin, exhibits a novel genetic mechanism (paternal TSHB mutation and absent maternal allele), and characteristic clinical features. Her motor delay probably reflects delayed treatment, since central hypothyroidism is missed on CH screening in the UK and Ireland. This observation supports inclusion of T4 measurement in the CH screening programme.