Endocrine Abstracts

Introduction: Central congenital hypothyroidism (CCH), undetected by TSH-based NewbornScreening, occurs from TSH synthesis or secretion defects. An extremely rare (<1:100,000) cause concerns the recently described ImmunoGlobulinSuperFamily member 1 (IGSF1) gene, critical in TSH biosynthesis. These 2 infants highlight intriguing clinical features.

Case-1: Term male (BW 3.95 kg) with poor feeding and persistent jaundice (max bilirubin 362 umol/l) despite phototherapy, had mildly elevated TSH on Guthrie (11.4 mU/l). Repeat TFTs demonstrated low fT4 (6.8 pmol/l) with low/normal TSH (9.46 mU/l) suggesting possible central hypothyroidism. Examination showed small umbilical hernia and large testes for age (3 ml). Broader evaluation showed normal Synacthen (592 nmol/l), LH 5.8 IU/l, FSH 3.7 IU/l, although low prolactin (66 mIU/l). MRI was normal. Genetic analysis confirmed novel variant mis-sense IGSF1 mutation, c.3691 T>C, p.(1231R).

Case-2: Term male (BW 2.7 kg) with polyhydramnios and short limbs on antenatal scans. Clinical features at 10 weeks were roving nystagmus, short limbs, relative macrocephaly and large anterior fontanelle prompting skeletal dysplasia radiological and genetic investigations. Radiology identified only mild skeletal immaturity. Array CGH identified Xq26.2 1.02Mb deletion, encompassing FRMD7gene (associated with X-linked congenital nystagmus) and IGSF1gene (associated with central hypothyroidism). CGH array interpretation prompted TFTs: low-normal TSH 3.3 mIU/l with low FT4 8.4 pmol/l. Clinical features at 5 months included large anterior fontanelle, persistent posterior fontanelle, flat nasal bridge, moderate sized umbilical hernia, testes 2ml. Broader evaluation showed normal Synacthen (475 nmol/l), LH 1.0 IU/l, FSH 2.1 IU/l, prolactin 284 mIU/l. Thyroxine initiation achieved rapid fT4 normalisation and good developmental progress in both boys.

Conclusion: Biochemical screening will not detect Isolated TSH-deficiency. So, remembering subtle features aid early diagnosis to achieve good neurodevelopmental outcome: appreciation of inappropriately low-TSH and low-fT4 on jaundice screening and of subtle hypothyroidism with skeletal abnormalities. New rarer causes of Isolated TSH deficiency add extra unusual clinic-points: IGSF1 mutations cause an X-linked disorder with intriguing additional features of macro-orchidism (boys) and ovarian cysts (girls) and variable prolactin deficiency. A high index of suspicion for CCH in appropriate clinical settings along with timely therapeutic intervention (thyroxine replacement) can help prevent long term sequelae.