Congenital hypothyroidism

TOPIC: Congenital central hypothyroidism

Title: Role of the Thyrotropin-Releasing Hormone stimulation test in diagnosis of congenital central hypothyroidism in infants.

Authors: V an Tijn DA, de Vijlder JJM, & Vulsma T.

Reference: Journal of Clinical Endocrinology & Metabolism 93: 410-419, 2008



A shortage of thyroid hormone during prenatal life and the first years after birth results in a spectrum of neuropsychological disorders, depending on the duration and severity of the deficiency. In the case of congenital hypothyroidism of central origin (CH-C), the majority of patients have multiple pituitary hormone deficiencies (MPHD). This condition poses an additional threat to postnatal central nervous system development, primarily on account of neuroglycopenia due to ACTH/cortisol deficiency with or without additional GH deficiency. Therefore, in CH-C, rapid diagnosis is even more urgent than in congenital hypothyroidism of thyroidal origin.


In the assessment of hypothalamic-pituitary-thyroid function, the authors considered the pituitary response to intravenous administration of TRH (TRH test) pivotal. They evaluated the usefulness of the TRH test in a cohort of infants with neonatal congenital hypothyroidism screening results indicative of CH-C by analyzing the results within the framework of investigations of the anatomical and functional integrity of the hypothalamo-hypophyseal system. Design, Setting and


Dutch nationwide prospective study (1994'1996). Patients were included if neonatal CH screening results were indicative of CH-C and patients could be tested within 3 months of birth. Ten male and five female infants with CH-C, detected by neonatal screening, and six infants with false-positive screening results, nonthyroidal illness, or transient hypothyroidism, were included in the study.

Main Outcome Measures

Results of TRH tests, within the framework of extensive endocrinological examinations and cerebral magnetic resonance imaging, were measured.


All patients with type 3 TSH responses to TRH had MPHD, and the majority of patients (67%) with type 2 responses had isolated TSH deficiency.


The TRH test has a pivotal role in the diagnosis of TSH deficiency in young infants. Abnormal TRH test results, especially a type 3 response, urge immediate assessment of integral hypothalamic-pituitary function because the majority of patients have MPHD.


There is no doubt that newborn screening for congenital hypothyroidism (CH), begun over 30 years ago in Quebec and now conducted in most industrialized parts of the world, has been a resounding success. Although there continues to be some controversy as to whether subtle cognitive deficits persist in the most severely affected infants, all agree that the mental retardation due to primary congenital hypothyroidism has been eradicated with the advent of newborn screening and the timely initiation of postnatal therapy. Screening has also permitted the elucidation of the relative prevalence of the various etiologies of this heterogeneous disorder. Screening strategies vary, with some areas of the world (particularly the USA) performing a primary T4/backup TSH method; others (e.g., Europe, Australia, Japan parts of North America employing a primary TSH program, and a minority measuring both. Each approach has its advantages and limitations but both the primary T4/backup TSH and primary TSH methods appear to be similar in the initial screening goal of identifying babies with 'classical' primary congenital hypothyroidism. Whichever approach is employed, rarely babies are missed, due either to limitations in the screening strategy itself or to human error.

Since 1995 the Dutch program has initiated a novel multi-step screening strategy that includes, in addition to T4 and TSH, the measurement of thyroxine binding globulin (TBG) in the filter paper specimens with the lowest 5% of T4 values. The T4/TBG ratio is used as an indirect reflection of the free T4, which cannot be measured directly in dried blood spots. The group has shown that, for a relatively small incremental cost, this approach results in increased sensitivity and specificity in the detection of milder cases of primary CH that might otherwise be missed. An additional advantage is the identification of >90% of infants with central congenital hypothyroidism (CH-C), compared with only 30% with primary T4 screening and none with a primary TSH approach. The incidence of CH-C detected on screening was 1 in 21,000 for the years 1994-96 and 1 in 16/000 for the years 1995-2000, much higher than a recent estimate of 1 in 95,933 obtained in the US, and >80% of babies on subsequent testing had multiple pituitary hormone deficiencies. Given the high morbidity and mortality of congenital hypopituitarism, the availability of effective therapy, and an apparent frequency similar to that of phenylketonuria (1 in 18.000), the disorder for which neonatal screening began, the authors have convincingly argued that the goals of newborn thyroid screening should be extended to include the detection of babies with CH-C.

In the present study, the authors present the results of TRH testing in the original cohort of patients. Of 26 infants who fulfilled the screening criteria suggestive of CH-C, 5 were excluded from further analysis for various reasons and 6 turned out to have false-positive results. All 15 remaining infants had abnormal TSH responses to TRH when compared to adult normative values. Six patients had impaired release of TSH 'type 2 response'), and of this group only 4 had had additional pituitary hormonal deficiencies. In contrast, all 9 of the 9 patients whose response was characterized by a delayed peak ('type 3 response') had additional deficits. Although the authors conclude from these results that the TRH test therefore 'has a pivotal role in the diagnosis of TSH deficiency' a statistical analysis was not performed to determine whether this difference was significant. Furthermore, 5/6 of the infants with a type 2 response but only 1/8 patients with a type 3 response had a normal MRI, suggesting that in areas of the world such as the US where TRH is no longer available, brain imaging might provide a suitable alternative.

The present study is also at variance with a previous report of 5 infants with congenital hypopituitarism associated with an ectopic posterior pituitary gland (the predominant morphologic abnormality in this study) in which a type 2 response was characteristic of infants with more severe, not less severe hypopituitarism (Brown et al. JCEM 72:12-18, 1991). Clearly more numbers are needed before the utility of TRH testing in identifying infants at risk of multiple pituitary hormone deficiencies can be accepted. Summary and commentary prepared by Rosalind Brown (Related to Chapter 15 of TDM)

Word count: 1003 Last edited by Vicente Cano on June 18, 2011 at 10:39 pm