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Cited by 21Thyroid Disorders and TreatmentsMetabolism and Genetic DisordersPituitary Gland Disorders and Treatments

Cognitive and Motor Outcome in Patients with Early-Detected Central Congenital Hypothyroidism Compared with Siblings

Open access
Naafs, Jolanda C, Marchal, Jan Pieter, Fliers, Eric, Verkerk, Paul H, Luijten, Michiel A J, Boelen, Anita, van Trotsenburg, A S Paul, Zwaveling-Soonawala, Nitash·2021·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa901PMC PMC7947775
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Abstract

Context: Early treatment of primary congenital hypothyroidism (CH) prevents irreversible brain damage. Contrary to primary CH, outcome studies on central CH are scarce. Most patients with central CH have multiple pituitary hormone deficiencies (MPHD); these patients are also at risk for neonatal hypoglycemia. Objective: To assess cognitive and motor outcome in patients with early-treated central CH detected by the Dutch neonatal screening. Methods: In this cross-sectional study, primary outcome full-scale intelligence quotient (FSIQ) was measured in patients with MPHD and patients with isolated central CH born between January 1, 1995, and January 1, 2015, with siblings as controls. Secondary outcomes were intelligence test subscales and motor function. Linear mixed models were used to compare both patient groups and siblings, followed by post hoc tests in case of significant differences. Results: Eighty-seven patients (52 MPHD; 35 isolated central CH) and 52 siblings were included. Estimated marginal means for FSIQ were 90.7 (95% CI 86.4-95.0) in patients with MPHD and 98.2 (95% CI 93.0-103.5) in patients with isolated central CH. While patients with MPHD scored lower FSIQs than siblings (mean difference –7.9 points, 95% CI –13.4 to –2.5; P = .002), patients with isolated central CH did not. Processing speed was lower in both patient groups than in siblings (mean differences –10.5 and –10.3 points). Motor difficulties occurred significantly more often in patients (33%) versus siblings (5%; P = .004). Conclusion: In early-treated central CH, FSIQ is comparable with siblings in patients with isolated central CH, while patients with MPHD have a significantly lower FSIQ. This may be explained by disease-specific consequences of MPHD, such as neonatal hypoglycemia and more severe hypothyroidism.

AI snapshot

Written from the paper’s full text.

TL;DR

In this Dutch nationwide cross-sectional cohort, early-treated isolated central congenital hypothyroidism was associated with normal full-scale IQ compared with siblings, whereas patients with multiple pituitary hormone deficiencies had significantly lower FSIQ. Both patient groups showed lower processing speed and more motor difficulties than siblings.

Key findings

  • Among 87 patients (52 MPHD; 35 isolated central CH) and 52 siblings, estimated marginal mean FSIQ was 90.7 (95% CI 86.4–95.0) in MPHD, 98.2 (95% CI 93.0–103.5) in isolated central CH, and 98.6 (95% CI 94.5–102.8) in siblings. MPHD patients scored 7.9 points lower than siblings (95% CI –13.4 to –2.5; P = .002), while isolated central CH patients did not differ significantly from siblings.
  • Processing speed was lower in both patient groups than in siblings, with mean differences of –10.5 points for MPHD and –10.3 points for isolated central CH.
  • Motor difficulties on the MABC-2 checklist occurred in 33% of patients versus 5% of siblings (P = .004); delayed motor development requiring physical therapy was present in 34% of patients versus 19% of siblings (P = .03).
  • An FSIQ <70 was found in 8 patients (9%) and no sibling controls (P = .04).

Methods

  • Cross-sectional study of patients with central CH detected by Dutch neonatal screening, born January 1, 1995, to January 1, 2015; patients were recruited through treating physicians, and each included patient had an unaffected sibling control where available.
  • Cognitive assessment used age-appropriate Dutch Wechsler scales (WPPSI-III-NL, WISC-III-NL, WAIS-IV-NL); motor outcome used the MABC-2 checklist and parent/medical-chart data on motor milestones and physical therapy.
  • Linear mixed models with a random intercept for family compared endocrine status groups (MPHD, isolated central CH, healthy siblings), followed by post hoc Tukey tests; pretreatment and assessment-time FT4 were added to FSIQ models.

Limitations

  • The paper states that the MABC-2 checklist was suitable only for part of the patients, yielding a relatively small motor-outcome group, and that a checklist is less reliable than objective motor assessment; it also states that excluding syndromic patients leaves cognitive outcome in syndromic patients unexplored.
  • The paper states that the study cannot answer whether neonatal screening for central CH prevents cognitive impairment, because late-detected patients were not studied.
  • Evident from the text: assessors were not formally blinded to disease status, and 35 eligible patients declined participation, which may introduce selection bias despite the nationwide cohort.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/clinem/dgaa901

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 48 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In a recent systematic review, sufficiently large studies on cognitive outcome in patients with central congenital hypothyroidism are lacking.

    “In a recent systematic review, we showed that sufficiently large studies on cognitive outcome in patients with central CH are lacking (14).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Naafs, 2020, Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data, Eur J Endocrinol. source

      The passages available from our copy identify the paper as a systematic review of cognitive outcome in congenital central hypothyroidism, but contain no findings about the size of existing studies. Searches for the claimed lack of sufficiently large studies and for small sample sizes found no passage addressing that conclusion. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
  • Premisecitation

    Clinical detection of central congenital hypothyroidism usually occurs far beyond the neonatal period.

    “clinical detection usually occurs far beyond the neonatal period (8-10).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Zwaveling-Soonawala, 2015, The severity of congenital hypothyroidism of central origin should not be underestimated, J Clin Endocrinol Metab source

      The Discussion (page not available) reports a cohort of 34 children with late-diagnosed central congenital hypothyroidism, supporting that clinical diagnosis can be delayed. It does not give their ages at diagnosis or establish that detection usually occurs far beyond the neonatal period. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [9] Nebesio, 2010, Newborn screening results in children with central hypothyroidism, J Pediatr. source
    • cites [10] Cavarzere, 2014, Diagnostic pitfalls in the assessment of congenital hypopituitarism, J Endocrinol Invest. source
  • Premisecitation

    Multiple pituitary hormone deficiencies are present in the majority of patients with central congenital hypothyroidism.

    “MPHD are present in the majority of patients with central CH (7).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] van Tijn, 2005, Neonatal detection of congenital hypothyroidism of central origin, J Clin Endocrinol Metab. source
  • Premisecitation

    Patients with multiple pituitary hormone deficiencies are at risk for severe hypoglycemia and thus for brain damage and cognitive impairment.

    “With these hormone deficiencies, patients with MPHD are at risk for severe hypoglycemia and thus for brain damage and cognitive impairment (12, 13).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [12] Harding, 2017, An emerging evidence base for the management of neonatal hypoglycaemia, Early Hum Dev. source

      The Outcomes section states that severe, persistent hypoglycaemia can cause brain injury in newborns and discusses possible later neurocognitive impairment. It does not identify patients with multiple pituitary hormone deficiencies as a group at risk for hypoglycaemia, so the claim's MPHD-specific part is unsupported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [13] McKinlay, 2017, Association of neonatal glycemia with neurodevelopmental outcomes at 4.5 years, JAMA Pediatr. source
  • Premisecitation

    More than half of patients with central congenital hypothyroidism have moderate to severe hypothyroidism.

    “more than half of patients with central CH have moderate to severe hypothyroidism”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Zwaveling-Soonawala, 2015, The severity of congenital hypothyroidism of central origin should not be underestimated, J Clin Endocrinol Metab source
    • cites [9] Nebesio, 2010, Newborn screening results in children with central hypothyroidism, J Pediatr. source
    • cites [10] Cavarzere, 2014, Diagnostic pitfalls in the assessment of congenital hypopituitarism, J Endocrinol Invest. source
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 26
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Motor Assessment Battery for Children-2 checklist was developed to screen 5- to 13-year-old children in primary education for motor difficulties.

    “Parents were asked to complete the Motor Assessment Battery for Children-2 (MABC-2) checklist, developed to screen 5- to 13-year-old children in primary education for motor difficulties (19).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Schoemaker, 2003, Psychometric properties of the movement assessment battery for children-checklist as a screening instrument for children with a developmental co-ordination disorder, Br J Educ Psychol. source

      The Background (p. 2) says the M-ABC Checklist was developed to screen children for movement difficulties in schools. But the instrument described is the original M-ABC Checklist, not the MABC-2 checklist; the paper describes its items as covering children aged 4–12, not 5–13 (p. 3). (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Carriers of TBL1X or IRS4 variants are reported to have lower plasma free thyroxine concentrations, and it remains unclear whether this represents disease or reflects an altered individual set point.

    “This is because carriers are reported to have lower plasma FT4 concentrations, and it remains unclear whether this represents disease or reflects an altered individual “set point” (16).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Heinen, 2016, Mutations in TBL1X are associated with central hypothyroidism, J Clin Endocrinol Metab. source

      The Results report lower plasma FT4 concentrations in adults with TBL1X mutations than in controls. The Discussion questions whether the lower concentrations cause hypothyroidism in target tissues and considers individual FT4 set points. These passages support the claim for TBL1X carriers, but not its extension to IRS4 carriers; no page numbers were available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In those studies, full-scale intelligence quotients were shifted towards lower values, with 10% of patients having an FSIQ below 70.

    “FSIQs were shifted towards lower values with 10% of patients having an FSIQ <70 (below –2 SD in the general population)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Naafs, 2020, Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data, Eur J Endocrinol. source

  • May combine two claims.

    Premisecitation

    The included studies were small, heterogeneous, and possibly suffered from selection bias, so results should be interpreted with caution.

    “but the included studies were small, heterogeneous, and possibly suffered from selection bias, so that results should be interpreted with caution (14).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Naafs, 2020, Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data, Eur J Endocrinol. source

      The indexed Abstract passage is a publication record, not a discussion of the included studies. Searches for small studies, heterogeneity, selection bias, and limitations found no passage addressing those points, so the claimed caution cannot be verified from our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a previous study of patients with early-detected central congenital hypothyroidism, the diagnosis was seldom made based on clinical signs, even though 66% had been hospitalized in the first week of life.

    “we found that the diagnosis was seldom made based on clinical signs, even though 66% of these patients had been hospitalized in the first week of life (11).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Naafs, 2020, Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening, Eur J Endocrinol. source

      The Results and Early signs and symptoms sections report that 61 of 92 patients (66%) were hospitalized before screening results were known, but only three were diagnosed on clinical grounds during those admissions. Our copy does not establish that all 61 hospitalizations occurred in the first week of life. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Isolated central congenital hypothyroidism is associated with X-linked genes.

    “A male predominance was seen among patients; this was not unexpected since isolated central CH is associated with X-linked genes (16, 22).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [16] Heinen, 2016, Mutations in TBL1X are associated with central hypothyroidism, J Clin Endocrinol Metab. source
    • cites [22] Heinen, 2018, Mutations in IRS4 are associated with central hypothyroidism, J Med Genet. source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    The z-test for partially paired samples was used because the MABC-2 checklist is validated for ages 5 to 13 only, rendering a partially paired sample.

    “Proportions of abnormal MABC-2 scores were compared using the z-test for partially paired samples, as the MABC-2 checklist is validated for ages 5 to 13 only, thus rendering a partially paired sample (20).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Derrick, 2015, Test statistics for comparing two proportions with partially overlapping samples, J Appl Quant Methods

      The Introduction (page not provided) describes comparing proportions when samples contain both paired and unpaired observations, and the Additional information section recommends a z-statistic for that setting. The paper does not address the MABC-2 checklist, its validated age range, or whether that age range made the citing study's samples partially paired. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The majority of early-treated patients with primary congenital hypothyroidism now obtain normal or near-normal IQ scores.

    “the majority of early-treated patients now obtain normal or near-normal IQ scores (2, 3).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] Aleksander, 2018, Mean high-dose l-thyroxine treatment is efficient and safe to achieve a normal IQ in young adult patients with congenital hypothyroidism, J Clin Endocrinol Metab. source
    • cites [3] Albert, 2013, Neurodevelopmental and body composition outcomes in children with congenital hypothyroidism treated with high-dose initial replacement and close monitoring, J Clin Endocrinol Metab. source

  • May combine two claims.

    Premisecitation

    In a previous study, 96% of patients with multiple pituitary hormone deficiencies had growth hormone deficiency and 88% had central adrenal insufficiency.

    “In our previous study 96% of patients with MPHD had growth hormone deficiency, and 88% had central adrenal insufficiency (11).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Naafs, 2020, Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening, Eur J Endocrinol. source

      The Discussion reports that 96% of MPHD patients had growth hormone deficiency. It reports ACTH deficiency—the relevant measure for central adrenal insufficiency—in 49 of 57 MPHD patients (86%), not 88%. The paper’s 88% figure refers to patients hospitalized before neonatal screening results became known. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The systematic review identified 6 studies measuring full-scale intelligence quotient, including 30 patients in total (27/30 with multiple pituitary hormone deficiencies).

    “We identified 6 studies that measured full-scale intelligence quotient (FSIQ), including 30 patients in total (27/30 MPHD).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Naafs, 2020, Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data, Eur J Endocrinol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A lower processing speed has also been reported in patients with early-detected primary congenital hypothyroidism, although not consistently.

    “A lower processing speed has also been reported in patients with early-detected primary CH, although not consistently (2, 31).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [2] Aleksander, 2018, Mean high-dose l-thyroxine treatment is efficient and safe to achieve a normal IQ in young adult patients with congenital hypothyroidism, J Clin Endocrinol Metab. source
    • cites [31] Pardo Campos, 2017, Cognitive profiles of patients with early detected and treated congenital hypothyroidism, Arch Argent Pediatr. source

      The Results report lower processing speed in children whose congenital hypothyroidism was diagnosed and treated before 30 days of age, compared with children without it. The cited paper does not establish the sentence’s additional qualification that this finding has been reported inconsistently. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Joustra et al. examined executive functioning and memory, but not FSIQ, in 15 adult patients with IGSF1 deficiency syndrome; patients performed worse than controls on executive functioning tasks, while their memory function was normal.

    “In addition, Joustra et al. examined executive functioning and memory, but not FSIQ, in 15 adult patients with IGSF1 deficiency syndrome. Patients performed worse than controls on executive functioning tasks, while their memory function was normal (29).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Joustra, 2016, Mild deficits in attentional control in patients with the IGSF1 deficiency syndrome, Clin Endocrinol (Oxf). source

  • May combine two claims.

    Premisecitation

    So far, FSIQ has only been reported in a few patients with isolated central congenital hypothyroidism; in the authors' previous systematic review, patients with isolated central congenital hypothyroidism were underrepresented.

    “So far, FSIQ has only been reported in a few patients with isolated central CH; in our previous systematic review patients with isolated central CH were underrepresented, highlighting the need for further studies on cognitive outcome in this condition (14, 28).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] Naafs, 2020, Cognitive outcome in congenital central hypothyroidism: a systematic review with meta-analysis of individual patient data, Eur J Endocrinol. source
    • cites [28] Karges, 2004, Compound heterozygous and homozygous mutations of the TSHbeta gene as a cause of congenital central hypothyroidism in Europe, Horm Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In general, cognitive outcomes are normal in patients with early-treated mild or moderate primary congenital hypothyroidism, while developmental problems may occur in patients with severe primary congenital hypothyroidism despite early treatment.

    “In general, cognitive outcomes are normal in patients with early-treated mild or moderate primary CH while developmental problems may occur in patients with severe primary CH, despite early treatment (2, 3, 6, 24).”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [2] Aleksander, 2018, Mean high-dose l-thyroxine treatment is efficient and safe to achieve a normal IQ in young adult patients with congenital hypothyroidism, J Clin Endocrinol Metab. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [3] Albert, 2013, Neurodevelopmental and body composition outcomes in children with congenital hypothyroidism treated with high-dose initial replacement and close monitoring, J Clin Endocrinol Metab. source
    • cites [6] Léger, 2014, European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism, Horm Res Paediatr. source
    • cites [24] Kempers, 2006, Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening, J Clin Endocrinol Metab source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    A male predominance was seen among patients.

    “A male predominance was seen among patients; this was not unexpected since isolated central CH is associated with X-linked genes (16, 22).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Free thyroxine concentration was within target range in 80 patients (92%), above the upper limit of the reference interval in 5 patients, and below the lower limit in 2 patients.

    “FT4 concentration was within target range in 80 patients (92%), above the upper limit of the reference interval in 5 patients (23-25.9 pmol/L) and below the lower limit in 2 patients (8.4 and 10 pmol/L).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Motor difficulties, as indicated by the MABC-2 checklist, were present more often in patients with central congenital hypothyroidism than in siblings (P = .004).

    “Motor difficulties were seen more often in patients than in siblings (P = .004).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.

  • May combine two claims.

    Findingown data

    In patients with central congenital hypothyroidism, an FSIQ <70 (< -2 SD) was seen in 8 patients (9%), but no sibling controls (P = .04).

    “Eight patients (9%), but no sibling controls, had an FSIQ <70, <–2 SD in the general population (P = .04).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.

  • May combine two claims.

    Findingown data

    In patients with early-treated isolated central congenital hypothyroidism, verbal IQ and performance IQ were similar to siblings.

    “FSIQ, verbal IQ, and performance IQ in patients with early-treated isolated central CH were similar to siblings.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A weak positive correlation between pretreatment free thyroxine and full-scale intelligence quotient was found (r = 0.22; P = .04).

    “If assessed outside of the model, a weak positive correlation between pretreatment FT4 and FSIQ was found (r = 0.22; P = .04).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    The milestone of walking independently was reached significantly later by patients with central congenital hypothyroidism than by siblings.

    “Milestone “walking independently” was reached significantly later by patients than siblings; this age difference was mainly caused by the difference between patients with MPHD and siblings (Table 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.
    • Rests on an assumption: Missing motor milestone data are missing at random, so available motor milestone data are representative.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    FSIQ and additional subscales did not differ between patients with and without a participating sibling (data not shown).

    “FSIQ and additional subscales did not differ between patients with and without a participating sibling (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Processing speed is significantly lower in both isolated central congenital hypothyroidism and multiple pituitary hormone deficiency patients compared with siblings, with similar differences of about 10.3 and 10.5 points lower, respectively.

    “Processing speed was significantly lower in both patient groups when compared with siblings, with a similar difference in patients with MPHD and patients with isolated central CH, scoring on average 10.5 and 10.3 points lower than siblings (Table 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Genetic etiology was identified in 27 of 35 patients with isolated central congenital hypothyroidism.

    “which includes the genetic etiology of isolated central CH for 27 out of 35 cases (15 IGSF1, 5 IRS4, 5 TBL1X, 1 TRHR, 1 TSHB).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The included patients are representative of all patients with early-detected central congenital hypothyroidism in the Netherlands.

  • May combine two claims.

    Findingown data

    Mean full-scale intelligence quotient was 93.8 ± 17.9 in all patients with central congenital hypothyroidism and 99.2 ± 14.0 in siblings.

    “Mean FSIQ was 93.8 ± 17.9 in all patients with central CH and 99.2 ± 14.0 in siblings (Fig. 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The included sibling controls were unaffected by central congenital hypothyroidism or other conditions that affect cognitive or motor outcome.
    • Rests on an assumption: The different Dutch Wechsler intelligence scales used across age groups yield comparable full-scale intelligence quotient scores.

  • May combine two claims.

    Findingown data

    Based on pretreatment FT4 concentration, 69% of patients with multiple pituitary hormone deficiencies had moderate to severe hypothyroidism, compared with 37% of patients with isolated central congenital hypothyroidism.

    “Based on the pretreatment FT4 concentration 69% of patients with MPHD had moderate to severe hypothyroidism, opposed to only 37% of patients with isolated central CH.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pretreatment FT4 concentration categories (moderate to severe versus mild) reflect the severity of hypothyroidism.

  • May combine two claims.

    Findingnone given

    Almost all patients with multiple pituitary hormone deficiencies had pituitary stalk interruption syndrome, creating a homogeneous group of patients, and almost all patients with isolated central congenital hypothyroidism had a genetically confirmed diagnosis.

    “Almost all patients with MPHD had PSIS, creating a homogeneous group of patients, and almost all patients with isolated central CH had a genetically confirmed diagnosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Only 6 out of 9 patients with multiple pituitary hormone deficiencies in special education had a participating sibling.

    “Only 6 out of 9 patients with MPHD in special education had a participating sibling; pairwise analysis showed no significant difference between patients and siblings (P = .68).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.

  • May combine two claims.

    Findingown data

    The MABC-2 checklist indicated motor difficulties in 5 patients with isolated central congenital hypothyroidism (33%), 8 patients with multiple pituitary hormone deficiencies (33%), and 1 sibling (5%).

    “The MABC-2 checklist was completed for 39 patients (24 MPHD, 15 isolated central CH) and 21 siblings, and indicated motor difficulties in 5 patients with isolated central CH (33%), 8 MPHD patients (33%), and 1 sibling (5%).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Siblings are an ideal control group for patients with central congenital hypothyroidism.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    By using a sibling control group, confounding factors shared by patients and siblings were controlled for.

    “By using a sibling control group, confounding factors shared by patients and siblings were controlled for.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Since all tests yielded age-specific norm scores, age was not added to the model.

    “Since all tests yielded age-specific norm scores, age was not added to the model.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    When a participant underwent a Wechsler test within the previous 12 months (n = 4), the first score was obtained rather than retesting, to prevent an inflated score due to a practice effect.

    “When a participant underwent a Wechsler test within the previous 12 months (n = 4), the first score was obtained rather than retesting, to prevent an inflated score due to a practice effect (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Sirois, 2002, Quantifying practice effects in longitudinal research with the WISC-R and WAIS-R: a study of children and adolescents with hemophilia and male siblings without hemophilia, J Pediatr Psychol. source

  • May combine two claims.

    Premisecitation

    The Dutch neonatal screening program since 1995 uses a 3-step approach with T4 measurement first, TSH measurement in the lowest 20% of T4 concentrations, and TBG measurement in the lowest 5%.

    “Since 1995, the Dutch neonatal screening program has consisted of a 3-step approach, with T4 measurement as the first step in all neonates, TSH measurement in the lowest 20% of T4 concentrations, and thyroxine-binding globulin (TBG) measurement in the lowest 5%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Lanting, 2005, Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program, Pediatrics. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Assessors were not formally blinded for participants' disease status.

    “Although assessors were not involved in clinical care for the patients, they were not formally blinded for the participants’ disease status: participants were not asked to conceal their disease status but were also not encouraged to talk about it.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    A linear mixed model accounts for the fact that patient and sibling data are not independent, and facilitates the use of data from all patients, regardless of the presence of an eligible sibling.

    “A linear mixed model accounts for the fact that patient and sibling data are not independent, and facilitates the use of data from all patients, regardless of the presence of an eligible sibling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The end date ensured patients would be at least 3 years old, which is considered the youngest age to reliably conduct the selected intelligence tests.

    “The end date ensured patients would be ≥3 years old, which is considered the youngest age to reliably conduct the selected intelligence tests (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Baron, 2012, Assessment of intelligence in the preschool period, Neuropsychol Rev source

  • May combine two claims.

    Interpretationown data

    In early-treated central congenital hypothyroidism, full-scale intelligence quotient is comparable with siblings in patients with isolated central congenital hypothyroidism, while patients with multiple pituitary hormone deficiencies have a significantly lower full-scale intelligence quotient.

    “In early-treated central CH, FSIQ is comparable with siblings in patients with isolated central CH, while patients with MPHD have a significantly lower FSIQ.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The included patients are representative of all patients with early-detected central congenital hypothyroidism in the Netherlands.
    • Rests on an assumption: Lack of formal blinding of assessors did not materially bias the cognitive assessments.
    • Rests on an assumption: The included sibling controls were unaffected by central congenital hypothyroidism or other conditions that affect cognitive or motor outcome.
    • Rests on an assumption: The different Dutch Wechsler intelligence scales used across age groups yield comparable full-scale intelligence quotient scores.

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    The use of a checklist is considered less reliable than an objective motor assessment.

    “In addition, the use of a checklist is considered less reliable than an objective motor assessment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Early postnatal hypothyroidism affects cerebellar development, and this mechanism is thought to be the origin of motor deficits in primary congenital hypothyroidism.

    “Early postnatal hypothyroidism affects cerebellar development, and this mechanism is thought to be the origin of motor deficits in primary CH (32).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Zoeller, 2004, Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings, J Neuroendocrinol. source

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    It is likely that neonatal screening prevents prolonged thyroid hormone shortage and its consequences on brain development.

    “It remains unknown what these outcomes would be without neonatal detection, but it is likely that neonatal screening prevents prolonged thyroid hormone shortage and its consequences on brain development.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    By using a nationwide cohort, selection bias was minimized compared to a single center study.

    “By using a nationwide cohort, selection bias was minimized compared to a single center study, and the included siblings represent an ideal control group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The checklist used to assess motor outcome was only suitable for a part of the patients, leading to a relatively small group for whom motor outcome could be reported.

    “A limitation of our study was that the checklist used to assess motor outcome was only suitable for a part of the patients. This led to a relatively small group for whom motor outcome could be reported.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    The exclusion of syndromic patients from cognitive testing creates a more homogeneous patient group and rules out syndromes as a cause of cognitive impairment, but leaves cognitive outcome in syndromic patients unexplored.

    “The exclusion of syndromic patients from cognitive testing can be considered both a strength and a limitation. While this creates a more homogeneous patient group, and rules out syndromes as a cause of cognitive impairment, it leaves cognitive outcome in syndromic patients unexplored.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The exclusion of syndromic patients from cognitive testing does not bias the cognitive results for the non-syndromic population.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study presents cognitive testing results of the largest group of patients with central congenital hypothyroidism studied to date.

    “We present cognitive testing results of the largest group of patients with central CH studied to date.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    To date, central congenital hypothyroidism is the only pituitary hormone deficiency accessible for neonatal screening, which can be performed cost-effectively.

    “To date, central CH is the only pituitary hormone deficiency accessible for neonatal screening, which can be performed cost-effectively (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Lanting, 2005, Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program, Pediatrics. source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    In patients with multiple pituitary hormone deficiencies, early diagnosis prevents the consequences of additional pituitary hormone deficiencies, such as ongoing hypoglycemia, and thus aggravation of cognitive impairment.

    “In patients with MPHD, early diagnosis also prevents the consequences of additional pituitary hormone deficiencies, such as ongoing hypoglycemia, and thus aggravation of cognitive impairment.”
    Quote in the paperNot a substantial claim
46 of 46

  • The paper relies on this without support.

    The included patients are representative of all patients with early-detected central congenital hypothyroidism in the Netherlands.

    “From the nationwide database, 133 patients with central CH were identified, of whom 7 were excluded because of a severe syndrome (11). Of the remaining patients, 3 had emigrated, 1 was untraceable, and 35 declined participation in the cognitive assessment, yielding 87 patients and 52 siblings, originating from 84 families.”

  • The paper relies on this without support.

    Lack of formal blinding of assessors did not materially bias the cognitive assessments.

    “Although assessors were not involved in clinical care for the patients, they were not formally blinded for the participants’ disease status: participants were not asked to conceal their disease status but were also not encouraged to talk about it.”

  • The paper relies on this without support.

    The included sibling controls were unaffected by central congenital hypothyroidism or other conditions that affect cognitive or motor outcome.

    “For each included patient 1 unaffected sibling of at least 3 years old, sharing both biological parents with the patient, was included as control.”

  • The paper relies on this without support.

    The Dutch neonatal screening program detects all or nearly all central congenital hypothyroidism cases in the Netherlands.

    “All patients with central CH detected by neonatal screening in The Netherlands are registered in a national database maintained by the Netherlands Organization for Applied Scientific Research.”

  • The paper relies on this without support.

    The different Dutch Wechsler intelligence scales used across age groups yield comparable full-scale intelligence quotient scores.

    “We used the most recent Dutch Wechsler scales available at the start of the study: the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III-NL) for participants <6 years, the Wechsler Intelligence Scale for Children (WISC-III-NL) for participants 6 to 16.9 years old, and the Wechsler Adult Intelligence Scale (WAIS-IV-NL) for participants ≥17 years.”

  • The paper relies on this without support.

    Siblings are an ideal control group for patients with central congenital hypothyroidism.

    “and the included siblings represent an ideal control group.”

  • The paper relies on this without support.

    Pretreatment FT4 concentration categories (moderate to severe versus mild) reflect the severity of hypothyroidism.

    “Based on the pretreatment FT4 concentration 69% of patients with MPHD had moderate to severe hypothyroidism, opposed to only 37% of patients with isolated central CH.”

  • The paper relies on this without support.

    Missing motor milestone data are missing at random, so available motor milestone data are representative.

    “Because not all parents could remember when motor milestones were reached, data on motor milestones are not available for all patients.”

  • The paper relies on this without support.

    The exclusion of syndromic patients from cognitive testing does not bias the cognitive results for the non-syndromic population.

    “The exclusion of syndromic patients from cognitive testing can be considered both a strength and a limitation.”
9 of 9

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting upper confidence limit for the MPHD-isolated CH IQ difference

    Minor

    The prose reports the upper limit of the 95% confidence interval as 0.01, while Table 4 reports 0.02 for the same comparison.

1 of 1

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Authors
Naafs, J. C., Marchal, J. P., Fliers, E., Verkerk, P. H., Luijten, M. A. J., Boelen, A., van Trotsenburg, A. S. P., & Zwaveling-Soonawala, N.
Affiliations
  • Emma Kinderziekenhuis (NL)
  • Amsterdam University Medical Centers (NL)
  • Netherlands Organisation for Applied Scientific Research (NL)
  • Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, department of Pediatric Endocrinology, Amsterdam, The Netherlands
Corresponding author
Naafs, Jolanda C
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-12-03
Volume
106
Issue
3
Pages
e1231-e1239
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgaa901
PMC
PMC7947775
OpenAlex
W3108258316
Semantic Scholar
0b4e95dad01f36942f218bd6ddbc011ec69d00fa
Cited by
21
References
34
Citations by year
2026: 3 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 4
FWCI
1.27
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (acceptedVersion, cc-by)
  • TNO Repository (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
Pfizer (WI219179)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
multiple pituitary hormone deficiency, early treatment, full-scale intelligence quotient, cognitive outcomes, motor function, neonatal hypoglycemia, processing speed, sibling comparison, newborn screening
MeSH terms
Motor Disorders, Adolescent, Child, Child, Preschool, Cognition, Cognition Disorders, Congenital Hypothyroidism, Cross-Sectional Studies, Female, Humans, Infant, Newborn, Intelligence Tests, Male, Motor Activity, Netherlands, Prognosis, Retrospective Studies, Thyroxine, Neonatal Screening, Treatment Outcome, Hormone Replacement Therapy, Siblings, Early Diagnosis, Early Medical Intervention

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

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