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Diagnosis of Congenital Central Hypothyroidism in Infants« Back to Volume 24, Issue 2, November 2008 - Table of Contents In the Netherlands, since 1995, a primary thyroxin (T4) determination with supplemental thyroid-stimulating hormone (TSH) and T4-binding globulin (TBG) measurements have been used as a routine screening protocol for congenital hypothyroidism. This screening approach was developed as congenital hypothyroidism of central origin (CH-C)—often complicated by hypoglycemia due to growth hormone deficiency and/or ACTH deficiency—poses an additional threat to the central nervous system development. The authors considered that a rapid diagnosis is critical in this population. The neonatal CH screening program was therefore adapted to improve detection of TSH deficiency. Indeed in a recent evaluation of the nationwide prospective screening program from 1995-2000 an increase of 1/16404 of CH-C was demonstrated with a detection rate of 91.6%. From these data CH-C—formerly considered as a rare entity—would make up 13.5% of all cases of permanent CH detected in a 6-year study period. The results of this showed that the TRH test plays a pivotal role in young infants. Infants with neonatal screening results indicative of CH-C and subsequent free T4 <0.93 ng/dL and TSH <15 µU/mL were enrolled in the study; 26 out of 385,042 neonates met the criteria and were tested within 3 months of birth. A TRH test was performed on 21 subjects; 6 of these children were found to have false-positive screening results. The remaining 15 infants were found to have CH-C during a 5-year follow-up. In this group cortisol deficiency was present in 9 cases, GHD in 10 cases, and gonadotropins deficiency in 6 subjects. TRH tests were interpreted by plotting results at several times after TRH administration. On the basis of former studies an adequate TSH response to TRH was characterized by a peak concentration greater than 15µU/mL and a return to baseline within 3 hours. In response to TRH, patients showed either diminished increase (type 2 response) or slightly delayed but excessive increase and delayed decrease of plasma TSH (type 3 response). All patients with type 3 TSH response had multiple pituitary hormone deficiencies (MPHD), whereas the majority of patients (67%) with type 2 response—which reflects an impaired TSH secretion—had isolated TSH deficiency. In 12 of 15 infants, the screening test provided the first indication of CH-C. The most frequently encountered problems were pathological neonatal jaundice (40%), hypoglycemia (33%), and persistent vomiting (20%). Fourteen children underwent MRI of the brain, 8 had posterior pituitary ectopia (PPE). All of these patients had MPHD. The TRH test, in spite of the difficulties in establishing the pattern of a normal response in relation to age, appears to be crucial in the diagnosis of CH-C. It allows immediate assessment of the hypothalamic-pituitary function, and therefore rapid and appropriate treatment may be given. This appears to be particularly relevant for the group of infants screened in the early neonatal period as presenting at the typical TSH response: first increased and thereafter with a delayed return to normal. Editor’s CommentA frequently used strategy for the diagnosis of CH is to first measure T4 in all samples, followed by TSH measurement for samples with low T4 values. Several North American states use this strategy. In the Netherlands, the latter approach was extended with the determination of TBG levels for the lowest 5% of T4 values. The T4 /TBG ratio serves as an indirect measure of the free T4 concentration (which cannot be determined directly in dried blood spots). In contrast to most screening programs, in which TSH levels are determined for the lowest 10% of T4 readings, TSH levels are measured for the lowest 20% of T4 values. In this way, the Dutch screening program provides unique information about the prevalence of CH-C.1 Such an approach cannot be performed in countries that have based neonatal screening on blood TSH values. However the merit of the Dutch group had been to adapt the neonatal CH screening in order to be able to detect CH-C. They have shown an unexpectedly rather high frequency of central hypothyroidism at birth. From a clinical point of view the issue is important as many of these children are at risk for neuropsychological disorders and appropriate diagnosis would have been missed or delayed. Congenital hypothyroidism can often be diagnosed on a set of clinical symptoms without TRH testing; however it is frequently delayed if midline defects are not present. In patients with an abnormal newborn screen suggestive of CH-C, in whom a TRH test cannot be administered, treatment with thyroid supplementation should be considered throughout the infancy until the diagnosis is established later in life. In this interesting study the abnormal neonatal screen was the first sign in over 90% of the identified cases with MPHD. It appears that the TRH stimulation test may aid in differentiating CH-C from other diseases in a context of newborn screening with low false-positive rates.2 Raphaël Rappaport, MD References - (linked to
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Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
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