Clinical Endocrinology (2003) 59, 230–236 230 © 2003 Blackwell Publishing Ltd Blackwell Publishing Ltd. Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during L-thyroxine replacement Laura Fugazzola*, Luca Persani*§, Deborah Mannavola*, Eugenio Reschini†, Guia Vannucchi*, Giovanna Weber‡ and Paolo Beck-Peccoz* *Institute of Endocrine Sciences and †Department of Nuclear Medicine, University of Milan, Ospedale Maggiore IRCCS and §Istituto Auxologico Italiano IRCCS, and ‡Department of Pediatrics, Scientific Institute H.S. Raffaele, Milan, Italy (Received 20 January 2003; returned for revision 16 February 2003; finally revised 18 February 2003; accepted 9 April 2003) Summary OBJECTIVE The differential diagnosis of congenital hypothyroidism (CH) is aimed to distinguish transitory from permanent forms, to optimize L-thyroxine (L-T4) therapy to replacement or TSH-suppressive regimens, and to reach accurate definition of the clinical and biochemical phenotype for subsequent genetic inves- tigations and counselling. Therefore, L-T4 therapy is presently withdrawn in most instances and investiga- tions are performed in a disturbing hypothyroid state. DESIGN The availability of recombinant human TSH (rhTSH) prompted us to assess its efficacy in the differential diagnosis of CH during L-T4 therapy. PATIENTS AND MEASUREMENTS Eight adult patients with permanent CH remained on L-thyroxine and under- went a new protocol for rhTSH (Thyrogen ® ) testing with injections [4 μg/kg/day intramuscularly (i.m.)] at days 1, 2 and 3. At day 3, 123 I was administered and uptake obtained after 2 and 24 h. Serum TSH and thy- roglobulin (Tg) levels were measured at days 1–4. Neck ultrasound was carried out in all cases. RESULTS Serum TSH reached levels > 20 mU/l at day 2 and remained above 30 mU/l on days 3 and 4. Stim- ulation of Tg levels was seen in five patients with peak at day 4. Lingual thyroid was documented at scinti- graphy (TS) in three Tg-responsive patients who were previously diagnosed as having thyroid agenesia. In one patient with dyshormonogenesis and high Tg, TS con- firmed the presence of goitre with positive perchlorate test. TS was negative in the remaining four cases. All tests indicated complete agenesia in one, whereas a minimal Tg response was marker of nearly complete agenesia in another. The last two TS-negative patients had hypoplastic glands at ultrasound, and refractoriness to TSH stimulation was confirmed by absent Tg response. CONCLUSIONS We report the first application of rhTSH for differential diagnosis of patients with permanent CH, avoiding the undesirable transient hypothyroidism consequent to L-T4 withdrawal. The data obtained led to the change of the diagnosis at presentation in 4/8 patients and to a more accurate description of the clin- ical picture in all patients. The proposed protocol has been proved to cause Tg increases even in the pres- ence of small amounts of responsive thyroid cells. The rhTSH testing led to the desired disease characteriza- tion, thus allowing specific management and targeted genetic analyses. Congenital hypothyroidism (CH) affects one out of 3000– 4000 newborns (Fisher, 1991; American Academy of Paediatrics & American Thyroid Association, 1993; Toublanc, 1999; Foley, 2000). In about 80% of the cases with permanent CH, the cause is a developmental defect of the thyroid gland (dysgenesia), including partial or complete absence of thyroid tissue (hemi- agenesia or agenesia), arrested migration of the embryonic thyroid cells (ectopia) and thyroid hypoplasia. The remaining cases are due to functional thyroid cell defects, including impaired responsiveness to TSH stimulation (resistance to TSH) or defects in iodide transport or in the enzymatic steps leading to thyroid hormone biosynthesis (dyshormonogenesis; Devos et al., 1999; DeVijlder & Vulsma, 2000; Foley, 2000). The differential diagnosis between different forms of CH is principally aimed to distinguish transitory (mainly due to iodide contamination or transplacental passage of blocking agents) from permanent CH (Fisher, 1991; American Academy of Paediatrics & American Thyroid Association, 1993; Toublanc, 1999; Foley, 2000), in order to avoid unnecessary treatment and psychosocial problems due to continuous monitoring. Other indications for Correspondence: Paolo Beck-Peccoz, MD, Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore IRCCS, Via F. Sforza, 35–20122 Milan, Italy. Tel: +39 02 50320607; Fax: +39 02 50320605. E-mail: paolo.beckpeccoz@unimi.it