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Department of Pediatric Endocrinology (D.A.v.T., J.J.M.d.V., T.V.), Emma Children’s Hospital AMC, Academic Medical Center, University of Amsterdam, NL-1100 DE Amsterdam, The Netherlands; Department of Radiology (B.V.), Academic Medical Center, University of Amsterdam, NL-1100 DE Amsterdam, The Netherlands; and Department of Social Pediatrics and Child and Youth Health Care (P.H.V.), The Netherlands Organization for Applied Scientific Research (TNO) Prevention and Health, NL-2301 CE Leiden, The Netherlands
Address all correspondence and requests for reprints to: David A. van Tijn, M.D., Department of Pediatric Endocrinology, Emma Children’s Hospital AMC, Academic Medical Center, G2-133, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: tijn1{at}planet.nl.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Despite the severity of hormonal dysfunction, congenital disorders of the hypothalamo-hypophyseal system are seldom diagnosed in early infancy. In contrast to a TSH-based screening program, a T4-based neonatal screening for congenital hypothyroidism (CH) is suited in principle for early detection of cases of CH of central origin (CH-C) (13), thus disorders of the hypothalamo-hypophyseal system. Unawareness of the vital risks and ignorance of the possibilities to identify these patients by neonatal screening (13) have hampered the development of diagnostic protocols apt to detect this life-threatening entity of CH.
In 1995, after a 1-yr trial period, the Dutch neonatal CH-screening program, based on initial T4 and consecutive TSH determination, was extended with a determination of T4 binding globulin (TBG) (14). A pilot study had indicated that this addition, besides reduction of the number of false-positive screening results, could improve detection of CH-C (15). Therefore, for a period of 2 yr, all children with screening results indicative of CH-C were enrolled in a nationwide prospective study to determine whether the neonatal CH screening protocol extended with TBG determinations improves early detection of CH-C and to assess the extent of pituitary hormone deficiency among the identified CH-C patients. Of all patients detected by neonatal screening, the integrity of the hypothalamo-hypophyseal system was investigated following a standardized protocol of endocrine function testing and neuroradiologic imaging. We report the major results after 5 yr of follow-up of the cohort of 19 patients with permanent CH-C, detected by neonatal screening.
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Patients and Methods |
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The neonatal CH screening procedure was based on determination of T4 in dried blood spots obtained by heel puncture 5–7 d after birth and consecutive TSH determination of those samples in the lowest 20% of T4 concentrations and TBG of those samples in the lowest 5% of T4 concentrations (Fig. 1
). The ratio between the T4 and TBG concentrations was used as a measure of the free circulating T4 concentration. In a pilot study, the cut-off value for the T4 to TBG ratio was estimated at 8.5 (15). To prevent delayed diagnosis of the most severe cases, children with TSH concentrations more than or equal to 50 µU/ml (50 mU/liter) plasma and/or T4 SD scores (T4-SDS) less than or equal to –3.0 were directly referred to a pediatrician. Children with borderline TSH [20–50 µU/ml plasma (20–50 mU/liter)], and/or borderline T4-SDS (–1.6 to –2.9), and/or T4 to TBG ratio less than 8.5 underwent a second heel puncture. When the result was abnormal or again borderline, the child was referred to a pediatrician. The screening result was considered indicative of CH-C if T4-SDS and/or T4 to TBG ratio was abnormal, with accompanying heel stick TSH less than 20 µU/ml (20 mU/liter) plasma.
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The study design is depicted in Fig. 1
. The subjects were participants in a Dutch nationwide prospective study, running from April 1, 1994, to April 1, 1996. Infants with neonatal CH-screening results indicative of CH-C and subsequent plasma free T4 concentrations below the beforehand estimated cut-off of 0.93 ng/dl (12 pmol/liter) (16) and plasma TSH concentrations less than 15 µU/ml were enrolled. A diagnosis of CH-C was assessed by a TRH test. Anterior pituitary function was assessed primarily by stimulation tests. TRH and CRH tests took place on consecutive days as soon as the alleged CH-C patient was referred; T4 supplementation was installed immediately after TRH test results had proven CH-C. Arginine and GnRH tests were performed at the age of 3 months, when euthyroid status had been accomplished by T4 supplementation, using the opportunity provided by the postnatal surge of gonadotropins and sex steroids to evaluate gonadotropin function (17, 18). Also, in most patients, MRI of the cerebrum was performed around the age of 3 months, to assess the anatomical integrity of the hypothalamo-hypophyseal system. In 2001, all cases were reevaluated for revised diagnoses, additional morbidity, growth, and treatment data. The study protocol was approved by the Dutch Pediatric Endocrine Society and by the Medical Ethics Committees of the participating centers. Parental informed consent was obtained in all cases.
Investigation of the thyrotropic hormone axis
Plasma TSH was measured before and 15, 30, 45, 60, 120, and 180 min after iv administration of TRH (10 µg·kg–1). An adequate TSH response to TRH (type 0) was defined by a peak concentration exceeding 15 µU/ml (19, 20, 21) and return to baseline within 3 h (19, 22). In response to TRH, CH-C patients either show diminished (type 2), or slightly delayed but excessive increase and delayed decrease of the TSH plasma concentration (type 3) (19, 20).
Investigation of the ACTH axis
Plasma ACTH and cortisol were measured before and 5, 10, 15, 30, 45, 60, 120, and 150 min after iv administration of CRH (1 µg·kg–1). An adequate response was defined by an ACTH peak concentration exceeding 80 pg/ml or four times baseline level and a cortisol peak concentration exceeding 18 µg/dl (500 nmol/liter) or 7 µg/dl (200 nmol/liter) over baseline level (23). In selected cases, a short ACTH test was performed (see Table 2). An adequate response to ACTH was defined by a cortisol peak concentration exceeding 18 µg/dl (500 nmol/liter) or 7 µg/dl (200 nmol/liter) over baseline level (24, 25). Of all patients, multiple random plasma cortisol samples were taken. Concentrations exceeding 18 µg/dl (500 nmol/liter) were considered adequate (23).
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Plasma GH was measured before and 30, 45, 60, 75, 90, 120, and 180 min after iv administration of arginine (500 mg·kg–1). A GH concentration exceeding 10 ng/ml (20 mU/liter) was considered an adequate response (26). Function test results were complemented by baseline plasma IGF-I and IGF binding protein 3 (IGFBP-3) determinations (27).
Investigation of the gonadotropic hormone axis
Plasma LH and FSH were measured before and 15, 30, 45, 60, and 120 min after iv administration of GnRH (10 µg·kg–1). An adequate response was defined by peak concentrations of LH exceeding 3 mU/ml and FSH exceeding 6 mU/ml in girls, 3 mU/ml in boys (28).
Investigation of posterior pituitary function
In all patients, plasma sodium and potassium concentrations and diuresis rate were determined.
MRI
To evaluate pituitary morphology, MRI studies were performed under general anesthesia, in most patients using a 1.5 Tesla Siemens Magnetom (Siemens, Munich, Germany). Transversal (5 mm), sagittal (3 mm), and coronal (3 mm) T1-weighted spin-echo images were obtained. In the transversal plane, proton density as well as T2-weighted turbo-spin echo sequences were used also. In addition, a T1-weighted 3D series (MPRage) was taken.
Assays
TSH was measured by immunochemiluminometric assay (ICMA; Behring, Amsterdam, The Netherlands). T4, T3, and rT3 were measured by in-house RIA methods (AMC, Amsterdam, The Netherlands). Free T4 was measured by a two step RIA assay (SPAC fT4 Fraktion; Byk-Sangtek Diagnostica, Dietzenbach, Germany). TBG was measured by RIA (Eiken Chemical Co., Tokyo, Japan). ACTH was measured by ICMA (Nichols Institute, Wychen, The Netherlands). Cortisol was measured by fluorescence polarization immunoassay (TDx; Abbott, Amstelveen, The Netherlands). LH and FSH were measured by ICMA (Amerlite; Amersham Biosciences, Little Chalfont, UK). 17-ß-Estradiol was measured by RIA (estradiol-2; Sorin Biomedica, Saluggia, Italy). Testosterone was measured by RIA (Coat-a-Count, Diagnostic Products Corp., Los Angeles, CA). GH was measured by RIA (Spectria/Orion, Turku, Finland). IGF-I and IGFBP-3 were measured by RIA (in-house assays Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands).
Statistical analysis
SPSS 10.1 (SPSS, Inc., Chicago, IL) was used for statistical computations. All reported P values are two-sided.
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Results |
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Of 385,000 infants screened during the study period, 26 met with the inclusion criteria. Perinatal characteristics and endocrine test results of these subjects are summarized in Tables 1, 2, and 3.
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p22. He died of cardiorespiratory insufficiency before further endocrine tests could be performed.
One infant (patient no. 19), born to a mother with previously unnoticed Graves’ disease, had abnormal TRH test results at the age of 17 d [TSH peak concentration of 4.4 µU/ml (4.4 mU/liter)]. By then, his free T4 concentration had already increased to a near normal concentration of 0.91 ng/dl (11.7 pmol/liter) without medical intervention. Spontaneous restoration of thyroid function was awaited. From the age of 5 wk until the age of 13 months, TSH and free T4 concentrations in plasma were within the normal range. A TRH test at the age of 13 months demonstrated normal TSH secretion (Fig. 2A) [TSH peak concentration, 26.4 µU/ml (26.4 mU/liter)]. Consequently, he was diagnosed with transient CH-C (29).
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. At follow-up, none of the surviving false-positive subjects have developed signs or symptoms of hypopituitarism. Among these subjects with false-positive screening results, the age of inclusion ranged from 14–93 d (median 44 d).
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Neonatal CH screening took place 5–15 d after birth (median 6 d), except for patient no. 11, who was screened at the age of 130 d, after he had moved from India to The Netherlands. The patients’ TSH concentrations in dried heel puncture blood spots ranged from below detection level to 7 µU/ml plasma, T4 concentrations ranged from 0.6–11.3 µg/dl (8–145 nmol/liter), and TBG concentrations ranged from 9.9–31.8 µg/dl (183–589 nmol/liter). All patients except nos. 8 and 19 had T4 to TBG ratios below the cut-off level of 8.5, previously indicated for discrimination of CH-C patients from false-positives in the screening population (15). Patients 8 and 19 were referred on the basis of low screening T4-SDS and consecutive plasma free T4 concentrations less than 0.93 ng/dl (12 pmol/liter) and plasma TSH concentrations less than 15 µU/ml (15 mU/liter; Table 1).
Investigation of the thyrotropic hormone axis
All infants with baseline plasma free T4 concentrations less than 0.93 ng/dl (12 pmol/liter) exhibited type 2 (n = 9) or type 3 (n = 9) responses to TRH (Fig. 2, B and C). The cut-off level for diminished (type 2) TSH response could be estimated at 14 µU/ml (14 mU/liter; Table 2). The patients’ type 2 and type 3 responses, expressed as area under the curve, were significantly different (P = 0.001 for type 2; P = 0.013 for type 3 by the Mann-Whitney U test) from the responses of subjects 21–26, who exhibited type 0 responses (Fig. 2D).
Investigation of the ACTH axis
Nine of 19 patients tested (47%) were found to be deficient, whereas eight had clearly adequate results and two (patients 10 and 13) had borderline results and were given cortisol-supplementation for 1 and 2 yr, respectively. After discontinuation of supplementation, they had normal adrenocorticotropic function, as evidenced by a normal circadian cortisol rhythm.
Of the nine patients found deficient, four showed impaired response of both ACTH and cortisol to CRH. Another three patients (nos. 2, 18, and 20) showed adequate ACTH response, but impaired cortisol response. ACTH tests in two of the latter infants resulted in impaired cortisol response accordingly. Two patients were considered too small (no. 12) or too ill (no. 3) to undergo a CRH test, for which a relatively large amount of blood is required. Instead, ACTH tests were performed. The results of random plasma cortisol samples taken in all subjects were in accordance with the function test results (Table 3).
Investigation of the somatotropic hormone axis
After 5 yr of follow-up, 12 of 18 (67%) patients with permanent CH-C alive [from the initial 20 patients, one (no. 1) had died, and one (no. 19) had transient CH-C] have shown retarded growth. Arginine tests, performed at the age of 3 months when euthyroid status had been accomplished by T4 supplementation, were abnormal in 10 of those infants and normal in all infants with normal growth (Table 3). Two infants (nos. 8 and 13) with normal arginine test results showed growth retardation around the age of 2.5 yr. Both had repeated GH stimulation tests that yielded severely impaired GH release after stimulation with arginine, GHRH (no. 8) and clonidine (no. 13), respectively. Baseline growth factors were measured at the age of 3 months. Significant differences between children with normal vs. retarded growth (exclusive of subjects 8 and 13) were observed in arginine test results (P = 0.001 by the Mann-Whitney U test) as well as baseline plasma concentrations of IGF-I and IGFBP-3 at age 3 months (P = 0.001 and P = 0.011, respectively).
Investigation of the gonadotropic hormone axis
Six of 15 patients tested (40%) did not reach plasma peak concentrations of LH exceeding 3 mU/ml (3 U/liter) and FSH exceeding 6 mU/ml (6 U/liter; girls) or 3 mU/ml (3 U/liter; boys) after infusion of GnRH. Two of those had hypogenitalism. All six hypogonadotropic patients had baseline morning plasma concentrations of testosterone (boys) less than 0.6 ng/ml (2 nmol/liter) or 17-ß-estradiol (girls) less than 11 pg/ml (40 pmol/liter) at age 3 months. One patient (no. 6) who was not subjected to a GnRH test did have an abnormally low baseline plasma testosterone concentration (Table 3).
Investigation of posterior pituitary function
None of the subjects studied had symptoms indicating disturbance of posterior pituitary function.
MRI of the brain
Nine of 17 patients (53%) who underwent MRI had a small anterior pituitary lobe, located in the sella turcica, invisible or very thin pituitary stalk, and ectopic posterior pituitary lobe, located at the median eminence in the floor of the third ventricle (Fig. 3). Six patients had cerebral malformations, such as agenesis of the corpus callosum and bilateral periventricular nodular heterotopia and/or hydrocephalus. All patients with posterior pituitary ectopia had multiple pituitary hormone deficiency (Table 3).
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Discussion |
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Initial estimates of the prevalence of CH-C among live born children in the United States and Canada ranged from 1:110,000 to 1:29,000 (33, 34, 35). In a similar retrospective study of the 1981–1989 screening population in The Netherlands, we estimated a prevalence of 1:26,000 (36). Three fourths of these children turned out to have multiple pituitary hormone deficiency. Delayed detection and incomplete diagnosis of the hormonal deficiencies in question resulted in significant morbidity such as severe hypoglycemia and neonatal hepatitis and a mortality rate as high as 14% (36). Because all deficient hormones can readily be supplemented, timely diagnosis significantly improves the outcome (37). The prevalence of 1:20,263 live born neonates (95% confidence interval, 1:12,976 to 1:33,654), as estimated in the present study, is higher than previously reported (33, 34, 35, 36), presumably due to the fact that this is the first representative and unbiased cohort, efficiently detected. In a recent evaluation of the 1995–2000 period, we estimated a prevalence of 1:16,404 (95% confidence interval, 1:13,174 to 1:21,173) at an estimated detection rate of 91.6% (38). Because it is unlikely that the prevalence of CH-C in The Netherlands is significantly different from that in North America, we presume that in prior studies (33, 34, 35, 36) both the mildest and the most severe cases have been missed, similar to the situation in 21
-hydroxylase deficiency in the prescreening era (39, 40).
An anticipated Achilles’ heel of our study is the fact that normal values for endocrine function tests for this specific age group are largely unavailable. However, it turned out that patients with CH-C could be discriminated very well from the infants with false-positive screening results on the basis of their TRH test results. Further evidence was acquired from the fact that the majority of CH-C patients (78%) had multiple pituitary hormone deficiency and 53% had a pituitary malformation as visualized by MRI. All patients had baseline plasma free T4 concentrations less than 0.93 ng/dl (12 pmol/liter) at referral.
TRH tests of CH-C patients show either diminished (type 2) (19, 20, 21), or slightly delayed but excessive increase and delayed decrease of the TSH plasma concentration (type 3) (19, 20). Generally, type 2 responses are considered to reflect disturbance at the pituitary level, whereas type 3 responses reflect disturbance at the hypothalamic level. Accordingly, the clinical pictures associated with these responses are termed secondary/pituitary and tertiary/hypothalamic hypothyroidism. Remarkably, seven of the nine patients with the pituitary malformation posterior pituitary ectopia (Table 3) exhibit type 3 responses. Apparently, not the disturbance of the pituitary itself, but instead the disturbance of the interrelation between hypothalamus and (anterior) pituitary gland causes the pituitary deficiency.
Consequently, our study confirms other reports (41, 42, 43) that the distinction of secondary and tertiary hypothyroidism is improper. Therefore, we recommend the use of the term "congenital hypothyroidism of central origin" (CH-C) for neonates with apparent TSH deficiency (44) and congenital disorders of the hypothalamo-hypophyseal system to cover multiple pituitary hormone deficiency.
Forty-seven percent of the CH-C patients had evidence of glucocorticoid deficiency. Remarkable was our observation that three patients exhibited substantial rise of plasma ACTH but not cortisol concentrations in response to CRH. This phenomenon, indicative of adrenocortical hypoplasia as a result of long-time insufficient stimulation by ACTH, has not been described before.
Sixty-seven percent of the CH-C patients had evidence of GH deficiency, as shown by growth retardation and catch-up growth after installment of GH treatment. Two of these patients had normal test results at the age of 3 months. They showed retarded growth in the third year of life and at repeated testing proved severely GH deficient.
Gonadal function cannot be definitively assessed at this age. However, we speculated that the temporary activity of the gonadotropic axis in infancy (17, 18) would enable function testing at the age of 3 months. It will take another decade to validate the results, but GnRH test results and baseline testosterone and 17ß-estradiol concentrations clearly divided the study population into two groups. Nine of 15 infants tested had results comparable to those in Tanner stages 2–4. Six infants (40%) had baseline (morning) plasma concentrations of testosterone less than 0.6 ng/ml (2 nmol/liter) or 17-ß-estradiol less than 11 pg/ml (40 pmol/liter) and did not reach LH concentrations above 3 mU/ml (3 U/liter) and FSH concentrations above 6 mU/ml (6 U/liter; girls) or 3 mU/ml (3 U/liter; boys) after infusion of GnRH.
None of the patients had symptoms indicating disturbance of posterior pituitary function neonatally or at follow-up. However, partial diabetes insipidus cannot be ruled out, because it has been shown that, even in the absence of polyuria, polydipsia, or nocturnal enuresis, the vasopressin response to osmolar stimuli might very well be subnormal in patients with (congenital) hypopituitarism and posterior pituitary ectopia, suggesting damage in the hypothalamic vasopressin secreting centers (45).
The MRI studies performed in 17 of the patients revealed nine cases (53%) of posterior pituitary ectopia, a pituitary malformation often associated with multiple pituitary hormone deficiency (5, 46, 47). All of these infants had deficiencies of one or more pituitary hormones besides TSH. In fact, the emergence of a second deficiency of anterior pituitary function was predicted by the finding of posterior pituitary ectopia in patient no. 8, who initially had TSH deficiency only.
In conclusion, our data indicate that infants with permanent CH-C, making up 13.5% of all permanent CH patients, can be detected very well in a T4-based neonatal CH screening program, extended with TSH and TBG determinations. The majority of patients detected have multiple pituitary hormone deficiency, a life-threatening disorder. Therefore, neonatal screening should be followed by assessment of the integrity of the hypothalamo-hypophyseal system without delay. In this respect, the protocol here presented proved feasible and effective. CH-C warrants early detection and timely treatment, and thus putative reduction of mortality and severe morbidity, such as neuroglycopenia and consequent irreversible damage to the central nervous system. The estimated prevalence and the severity of pituitary dysfunction of this treatable disorder call for explicit attention for this entity of CH in neonatal screening programs worldwide.
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Acknowledgments |
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Footnotes |
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First Published Online March 22, 2005
Abbreviations: CH, Congenital hypothyroidism; CH-C, CH of central origin; ICMA, immunochemiluminometric assay; IGFBP-3, IGF binding protein 3; MRI, magnetic resonance imaging; TBG, T4 binding globulin; T4-SDS, T4 SD score.
Received December 13, 2004.
Accepted March 10, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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0.8 SD below the mean), the TSH concentration was measured in the same sample. Of those samples in the lowest 5% of T4 concentrations (i.e. 
