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Recent advances in central congenital hypothyroidism.

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Schoenmakers, Nadia  ORCID logo
Alatzoglou, Kyriaki S 
Chatterjee, V Krishna 
Dattani, Mehul T 


Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.



central hypothyroidism, congenital hypothyroidism, hypopituitarism, thyrotropin releasing hormone, Congenital Hypothyroidism, Humans, Infant, Newborn, Pituitary Gland, Pituitary Hormones

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J Endocrinol

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Wellcome Trust (095564/Z/11/Z)
Wellcome Trust (100585/Z/12/Z)
Medical Research Council (MC_UU_12012/5/B)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)
This work was supported by funding from the Wellcome Trust (Grant 100585/Z/12/Z, to N.S., Grant 095564/Z/11/Z, to K.C.)