Cretinism
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2] Omar Elshafei, MD[3] Synonyms and keywords: Congenital hypothyroidism; congenital iodine-deficiency syndrome; endemic cretinism; neurological cretinism; myxedematous cretinism; sporadic cretinism
Overview
Cretinism, more precisely termed congenital iodine-deficiency syndrome, is a severe and largely irreversible disorder of somatic growth and neurological development caused by deficient thyroid hormone action during fetal life and early infancy. Two distinct routes lead to the same clinical endpoint. The first is severe maternal and fetal iodine deficiency in an endemic goiter region, which produces endemic cretinism. The second is congenital hypothyroidism arising from an absent, ectopic, or hormonally defective thyroid gland in an iodine-sufficient population, historically called sporadic cretinism.
Endemic cretinism is classically divided into a neurological type, dominated by deaf-mutism, spastic diplegia, strabismus, and intellectual disability in a patient who is often clinically euthyroid, and a myxedematous type, dominated by persistent hypothyroidism, severe growth failure, and sexual immaturity. Mixed forms occur, and the two types are best understood as different expressions of a single fetal insult modified by the timing of the deficiency, by continuing postnatal thyroid failure, and by co-existing selenium deficiency and thiocyanate overload.
The central principle of the disease is timing. Thyroxine of maternal origin drives neuronal migration and cortical organization during the first half of gestation, before the fetal thyroid is functional. Damage sustained in that window cannot be reversed by later thyroid hormone replacement, which is why endemic cretinism is approached as a preventable rather than a treatable condition at the population level. Prevention rests on universal salt iodization and on correcting iodine status before conception rather than during pregnancy.
Sporadic cretinism, by contrast, is preventable at the individual level. Where newborn blood-spot screening exists, congenital hypothyroidism is detected within days of birth and treated with levothyroxine, and neurocognitive outcomes in adulthood are grossly normal. Where screening does not exist, and roughly seven in ten neonates worldwide are still born in such settings, the untreated natural history remains the classical picture of profound intellectual disability, disproportionate short stature, macroglossia, and umbilical hernia. The clinical priorities are therefore population iodine sufficiency, universal newborn screening, and prompt adequately dosed levothyroxine, with lifelong attention to growth, neurodevelopment, and hearing.
Historical Perspective
The association between endemic goiter and congenital neurological impairment was recognized in Alpine, Andean, and Himalayan valleys long before its cause was understood, and the traditional division of the syndrome into neurological and myxedematous forms dates from early twentieth-century field observations in the Chitral and Gilgit valleys.[1]
| Period | Development |
|---|---|
| 1917–1920 | Marine and Kimball conducted a controlled trial of sodium iodide prophylaxis in schoolgirls in Akron, Ohio. Goiter developed or worsened in 14% of untreated girls compared with 0.2% of treated girls, establishing that endemic goiter is preventable with iodine.[2] |
| 1922 | Iodized salt was introduced in the Appenzell region of Switzerland. Within a few years newborn goiter and most childhood goiter had disappeared, and no new infants were born with cretinism.[2] |
| 1966–1970 | A double-blind controlled trial of intramuscular iodized oil versus saline in the Western Highlands of Papua New Guinea demonstrated that endemic cretinism is caused by severe gestational iodine deficiency and can be prevented, but only when iodine is given before conception.[3] |
| 1970s | Newborn blood-spot screening programmes for congenital hypothyroidism were introduced, converting sporadic cretinism from an untreatable cause of intellectual disability into a preventable one.[4] |
| 1990 | Combined iodine and selenium deficiency was documented in the endemic-goiter belt of northern Zaire, providing the biochemical basis for the myxedematous phenotype of Central Africa.[5] |
| 1993 | WHO and UNICEF recommended universal salt iodization, the intervention that underpins the subsequent global decline in iodine deficiency disorders.[6] |
| 1994 | A prospective study in Xinjiang, China defined the window of fetal vulnerability, showing that iodine given in the first or second trimester, but not later, reduced neurological injury.[7] |
| 2017 | The first randomised placebo-controlled trial of iodine supplementation in mildly iodine-deficient pregnant women found no effect on child neurodevelopment, sharpening the distinction between severe and mild deficiency.[8] |
| 2019 | The Triac trial provided the first interventional evidence in MCT8 deficiency, a genetic thyroid hormone transporter defect that mimics cretinism.[9] |
| 2021–2026 | Consensus guidelines from ENDO-ERN, ESPE and ESE, the American Academy of Pediatrics, and the American Thyroid Association standardised screening, levothyroxine dosing, follow-up, and periconceptional iodine recommendations.[10][4][11] |
Classification
Cretinism is classified first by mechanism, endemic versus sporadic, and then within each group by phenotype or by anatomical and biochemical etiology.
Cretinism congenital thyroid hormone deficiency affecting the developing brain | |||||||||||||||||||||||||||||||
Endemic cretinism severe maternal and fetal iodine deficiency | Sporadic cretinism primary congenital hypothyroidism | ||||||||||||||||||||||||||||||
Myxedematous type persistent hypothyroidism, growth failure, thyroid atrophy or fibrosis | Thyroid dysgenesis agenesis, hypoplasia, ectopia | Dyshormonogenesis defective hormone biosynthesis in a structurally intact gland | |||||||||||||||||||||||||||||
Endemic Cretinism
| Feature | Neurological type | Myxedematous type |
|---|---|---|
| Predominant geography | Papua New Guinea, Himalayan and Andean endemias, Indonesia | Central Africa, notably the former Zaire; western China |
| Thyroid status at presentation | Usually clinically and biochemically euthyroid | Overt hypothyroidism, often profound |
| Neurological deficit | Deaf-mutism, spastic diplegia affecting legs more than arms, proximal rigidity, strabismus, intellectual disability, preserved cerebellar function | The same diffuse deficit is present, indicating a shared fetal insult |
| Growth and maturation | Stature usually preserved | Severe short stature, delayed bone age, sexual immaturity |
| Thyroid gland | Goiter common in the endemia | Atrophy and fibrosis; goiter often absent |
| Additional cofactors | Isolated severe iodine deficiency | Selenium deficiency and thiocyanate overload superimposed on iodine deficiency |
| Imaging | Minor non-localising changes on computed tomography | Basal ganglia calcification confined to those with severe hypothyroidism |
Detailed neurological examination of 104 cretins from a predominantly myxedematous endemia in western China and 35 from central Java showed the same neurological disorder in both types, with basal ganglia calcification on computed tomography in 15 of 50 subjects examined and present only in those with severe hypothyroidism. The differences between the two types are best explained by continuing postnatal thyroid hormone deficiency in the myxedematous form rather than by a different fetal mechanism.[1]
Sporadic Cretinism (Congenital Hypothyroidism)
| Axis | Categories |
|---|---|
| Level of the defect | Primary (thyroidal); central (pituitary or hypothalamic); peripheral (thyroid hormone transport, metabolism, or receptor defects) |
| Anatomy | Thyroid dysgenesis (agenesis, hypoplasia, ectopia) accounts for the majority of primary disease; dyshormonogenesis in a structurally normal or enlarged gland accounts for most of the remainder |
| Duration | Permanent versus transient, the latter typically associated with maternal antithyroid drugs, iodine excess or deficiency, prematurity, or monoallelic DUOX2 and DUOXA2 variants |
| Severity | Severe, moderate, or mild, graded by pretreatment free T4 and by thyroid morphology |
Pathophysiology
Thyroid Hormone and Fetal Brain Development
Thyroid hormone regulates neuronal proliferation and migration, dendrite and axon outgrowth, synaptogenesis, and myelination. The fetal thyroid does not secrete appreciable hormone until around the middle of the second trimester, so cortical development in the first half of gestation depends on transplacental transfer of maternal thyroxine, which is deiodinated to triiodothyronine within fetal brain tissue. Severe maternal iodine deficiency produces maternal hypothyroxinemia at precisely the stage when the developing cortex is most dependent on that supply, and the resulting disruption of neuronal migration is fixed by mid-gestation.[13][14]
Timing as the Determinant of Injury
The clinical importance of timing is established by two independent lines of trial evidence. In the Papua New Guinea trial, intramuscular iodized oil prevented cretinism only when given before conception; injection during an established pregnancy was ineffective.[3] In a severely iodine-deficient area of Xinjiang, iodine was administered systematically to children from birth to three years of age and to women at each trimester. The prevalence of moderate or severe neurological abnormality was 2 percent among the 120 infants whose mothers received iodine in the first or second trimester, compared with 9 percent among the 752 infants treated in the third trimester or after birth (P = 0.008).[7]
Modifying Cofactors
Selenium is required for the glutathione peroxidase system that detoxifies hydrogen peroxide generated during thyroid hormone synthesis, and for the deiodinases that activate thyroxine. In the northern Zaire endemic-goiter belt, serum selenium was seven times lower in 52 schoolchildren than in a non-deficient reference area and similarly low in 23 cretins, while erythrocyte glutathione peroxidase activity was five times lower in schoolchildren and two times lower in cretins (P = 0.004).[5] Unopposed hydrogen peroxide accumulation is thought to cause thyroid necrosis and fibrosis, generating the myxedematous phenotype. Importantly, selenium repletion in an iodine-deficient population can aggravate hypothyroidism by accelerating thyroxine metabolism, so selenium should not be given without concurrent iodine or thyroid hormone.[15] Dietary goitrogens, particularly thiocyanate derived from inadequately processed cassava, compete with iodide for uptake by the sodium-iodide symporter and aggravate deficiency.[14]
Mechanisms in Sporadic Disease
In primary congenital hypothyroidism the fetal brain is deprived of hormone principally after mid-gestation, because maternal thyroxine continues to reach the fetus until birth. This partial protection explains why an untreated infant may appear normal for the first weeks of life and why prompt postnatal replacement restores grossly normal neurocognitive outcomes, in sharp contrast to the fixed deficit of neurological cretinism.[4][12] Thyroid dysgenesis is usually sporadic and a molecular cause is identified in a minority of cases, whereas dyshormonogenesis is typically autosomal recessive, with TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4 and IYD among the recognised genes.[16]
Causes
| Category | Causes |
|---|---|
| Nutritional | Severe iodine deficiency in the maternal diet during the periconceptional period and first half of pregnancy; selenium deficiency; iron deficiency; thiocyanate overload from cassava and other goitrogens |
| Thyroid dysgenesis | Thyroid agenesis, hypoplasia, and ectopia; variants in TSHR, PAX8, NKX2-1, NKX2-5, FOXE1, GLIS3, JAG1, TUBB1 |
| Dyshormonogenesis | Variants in TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4 (Pendred syndrome), SLC26A7, IYD |
| Central hypothyroidism | Hypopituitarism, septo-optic dysplasia, TSHB, TRHR, IGSF1, TBL1X and IRS4 defects |
| Peripheral defects | MCT8 (SLC16A2) deficiency; SBP2 defects; resistance to thyroid hormone |
| Maternal and transient causes | Maternal antithyroid drugs; maternal TSH-receptor blocking antibodies; iodine excess from antiseptics or contrast media; iodine deficiency; prematurity and low birth weight |
Differentiating Cretinism from other Diseases
| Condition | Shared features | Distinguishing features |
|---|---|---|
| Down syndrome | Hypotonia, macroglossia, developmental delay, umbilical hernia, delayed dentition | Characteristic facies, single palmar crease, congenital heart disease, trisomy 21 on karyotype. Congenital and acquired hypothyroidism are more common in Down syndrome, so both may coexist and thyroid function must be tested rather than assumed |
| MCT8 deficiency (Allan-Herndon-Dudley syndrome) | Severe intellectual disability, hypotonia evolving to spasticity, impaired myelination | X-linked; elevated T3 with low free T4 and normal or mildly raised TSH; peripheral thyrotoxicosis with cerebral hypothyroidism; SLC16A2 variant[9] |
| Resistance to thyroid hormone | Goiter, developmental and attentional problems | Elevated free T4 and free T3 with non-suppressed TSH; usually autosomal dominant THRB variant |
| Pendred syndrome | Goiter, sensorineural deafness | Enlarged vestibular aqueduct on temporal bone imaging; usually euthyroid or mildly hypothyroid; SLC26A4 variant |
| Mucopolysaccharidosis (Hurler syndrome) | Coarse facies, macroglossia, umbilical hernia, short stature, developmental regression | Corneal clouding, hepatosplenomegaly, dysostosis multiplex, urinary glycosaminoglycans, normal thyroid function |
| Achondroplasia and other skeletal dysplasias | Disproportionate short stature | Normal intellect and normal thyroid function; characteristic radiographic and FGFR3 findings |
| Beckwith-Wiedemann syndrome | Macroglossia, umbilical hernia or omphalocele | Overgrowth rather than growth failure, hemihypertrophy, hypoglycemia, tumour predisposition |
| Prader-Willi syndrome | Neonatal hypotonia, poor feeding, developmental delay | Later hyperphagia and obesity, hypogonadism, characteristic methylation defect at 15q11-q13 |
| Cerebral palsy of other cause | Spastic diplegia, strabismus | Identifiable perinatal insult, asymmetric or evolving pattern, normal thyroid function, absent endemic exposure |
| Congenital infection (congenital rubella syndrome, cytomegalovirus) | Sensorineural deafness, intellectual disability, growth restriction | Chorioretinitis, cataract, hepatosplenomegaly, intracranial calcification in a periventricular distribution, positive serology or PCR |
| Rickets | Growth failure, delayed bone age, skeletal deformity | Metaphyseal fraying and cupping, hypophosphatemia or hypocalcemia, raised alkaline phosphatase, normal thyroid function |
| Transient hypothyroxinemia of prematurity | Low free T4 in the neonatal period | Normal or low TSH, spontaneous resolution, no thyroid structural abnormality |
Epidemiology and Demographics
Iodine Deficiency
Iodine deficiency remains the leading preventable cause of impaired brain development worldwide, although the global picture has transformed since universal salt iodization was adopted in 1993.[6] Salt iodization has been implemented in more than 120 countries and an estimated 71% of households worldwide have access to adequately iodized salt.[6] Contemporary national iodine status is tracked through median urinary iodine concentration surveys compiled in the Global Scorecard of Iodine Nutrition.[17] Overt endemic cretinism is now confined to residual pockets of severe deficiency, principally in mountainous and flood-leached inland regions of South Asia, Central and sub-Saharan Africa, and parts of Southeast Asia.[14]
Congenital Hypothyroidism
Primary congenital hypothyroidism is the most common neonatal endocrine disorder and the most common preventable cause of intellectual disability in populations where newborn screening operates.[16] The critical epidemiological gap is coverage rather than detection technology, since approximately 70 percent of neonates worldwide are born in countries that do not perform universal newborn screening.[4]
Demographics
| Variable | Pattern |
|---|---|
| Age | Endemic cretinism is established in utero and recognised in infancy or early childhood; sporadic disease is detected on day 2 to 3 of life where screening exists, and otherwise in the first months of life |
| Sex | Goiter and thyroid dysgenesis are more frequent in females; MCT8 deficiency affects males because it is X-linked |
| Geography | Endemic disease clusters in iodine-poor terrain; sporadic disease occurs worldwide and is independent of iodine status |
Risk Factors
- Residence in an area of severe iodine deficiency, particularly mountainous, inland, or repeatedly flooded terrain[13]
- Maternal iodine deficiency in the periconceptional period and first half of pregnancy, which is the modifiable exposure of greatest consequence[3][7]
- Coexisting selenium or iron deficiency and high dietary thiocyanate load from cassava[5][15]
- Absence of a household iodized salt supply or of a functioning salt iodization programme[6]
- Absence of a newborn screening programme for congenital hypothyroidism[4]
- Maternal thyroid disease, maternal antithyroid drug therapy, and maternal exposure to excess iodine including iodinated antiseptics and contrast agents[10]
- Preterm birth, low birth weight, and Down syndrome, each of which raises the risk of congenital or delayed-onset hypothyroidism and of a false-negative initial screen[4]
- Consanguinity and a family history of dyshormonogenesis or goitrous hypothyroidism[16]
Screening
Newborn Screening for Congenital Hypothyroidism
Newborn blood-spot screening should be performed in all infants. Screening earlier than 24 hours of life carries an increased risk of false-positive results because of the physiological neonatal TSH surge, and sampling between 24 and 72 hours after birth is recommended.[4] Prompt diagnosis leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood.[4] Screening strategies differ between programmes and include primary TSH measurement, primary T4 with reflex TSH, and combined approaches; a primary TSH strategy will not detect central hypothyroidism.[10]
Newborn blood-spot screening collected 24–72 hours after birth | |||||||||||||||||
Screening TSH within reference range no further action unless clinical signs are present | Elevated screening TSH urgent confirmatory serum TSH and free T4 | ||||||||||||||||
Congenital hypothyroidism confirmed start levothyroxine 10–15 mcg/kg daily without delay | |||||||||||||||||
Determine etiology by ultrasound ± scintigraphy re-evaluate at age 3 years if permanence is not established | |||||||||||||||||
Infants with clinical signs suggestive of hypothyroidism should have serum free T4 and TSH measured regardless of a normal screening result, because screening can fail through sampling, laboratory, or notification error, and because hypothyroidism can be acquired after the newborn screen.[4] Repeat screening is indicated in preterm and low-birth-weight infants, in multiple births, in infants admitted to neonatal intensive care, and in infants with Down syndrome.[10][4]
Population Screening for Iodine Deficiency
Population iodine status is monitored using median urinary iodine concentration, supplemented by goiter prevalence, thyroglobulin, and neonatal TSH distributions, the last of which may be elevated in iodine-deficient regions where congenital hypothyroidism screening is already in place.[11][17]
Natural History, Complications and Prognosis
Natural History
In endemic cretinism the injury is complete before birth. Affected infants show early motor delay, failure to acquire speech, and progressive appearance of spasticity and strabismus during the first two years, followed by a static deficit. In the myxedematous form, untreated postnatal hypothyroidism adds progressive growth failure, delayed bone age, and absent pubertal development.[1]
In untreated sporadic disease the newborn is often asymptomatic because of residual maternal thyroxine. Prolonged jaundice, feeding difficulty, constipation, hypothermia, a large posterior fontanelle, macroglossia, and umbilical hernia emerge over the first weeks, followed by progressive growth failure and irreversible loss of cognitive potential.[4]
Complications
- Permanent intellectual disability and impaired school performance
- Sensorineural deafness and speech failure
- Spastic diplegia, proximal rigidity, gait disorder, joint laxity and deformity
- Strabismus
- Disproportionate short stature, delayed bone age, and delayed or absent puberty in the myxedematous and untreated sporadic forms
- Goiter and, in iodine-deficient populations, later nodular thyroid disease and hyperthyroidism following abrupt iodine repletion[14]
- Increased stillbirth, neonatal mortality, and congenital anomaly rates in severely iodine-deficient populations[13]
Prognosis
Prognosis diverges sharply by mechanism. Fetal neurological injury from severe iodine deficiency is irreversible, and postnatal iodine or thyroid hormone does not restore lost cognitive function; the trial evidence supports prevention before conception rather than rescue during pregnancy.[3][7] By contrast, congenital hypothyroidism detected by newborn screening and treated early and adequately is compatible with grossly normal neurocognitive outcomes in adulthood.[4] Cohort and meta-analytic data indicate that initial levothyroxine doses below 10 mcg/kg are associated with a measurable IQ disadvantage in severe compared with mild disease, whereas high initial dosing achieves normal IQ without evidence of harm from transiently supranormal T4 in infancy.[18][19]
Diagnosis
History and Symptoms
The history should establish geographic and dietary iodine exposure, household salt iodization, maternal thyroid disease and drug exposure, consanguinity, and family history of goitrous hypothyroidism. In the neonate, prolonged jaundice, poor feeding, lethargy, constipation, hoarse cry, and hypothermia are the classical early symptoms; each may be absent, which is precisely why clinical recognition cannot substitute for biochemical screening.[4]
Physical Examination
Findings include a large posterior fontanelle, macroglossia, coarse facies, dry skin, umbilical hernia, hypotonia, and bradycardia in the sporadic form. In established endemic cretinism the examination shows deaf-mutism, proximal spastic rigidity affecting the lower limbs more than the upper, hyperreflexia, strabismus, primitive reflexes, and, in the myxedematous type, severe short stature with sexual immaturity.[1][4]
Laboratory Findings
| Test | Interpretation |
|---|---|
| Serum TSH and free T4 | Confirmatory test after an abnormal screen; interpreted against age-specific neonatal reference ranges. Elevated TSH with low free T4 indicates primary disease; low or inappropriately normal TSH with low free T4 suggests central disease |
| Thyroglobulin | Undetectable in agenesis and in thyroglobulin synthesis defects; elevated in dyshormonogenesis |
| Urinary iodine concentration | A population rather than individual index; used to characterise the iodine status of the community |
| Maternal TSH-receptor blocking antibodies | Indicated where transient disease or maternal autoimmune thyroid disease is suspected |
| Selenium and thiocyanate indices | Relevant in Central African and other endemias with a myxedematous phenotype |
| Genetic testing | Targeted panels or exome sequencing for dyshormonogenesis, syndromic dysgenesis, central hypothyroidism, and SLC16A2 |
Electrocardiogram
The electrocardiogram in untreated hypothyroid infants may show sinus bradycardia, low QRS voltage, and prolonged QT interval; low voltage should prompt evaluation for pericardial effusion. The electrocardiogram is not a diagnostic test for cretinism and should never delay confirmatory thyroid function testing.[10]
Chest X Ray
The chest x ray has no specific role. Cardiomegaly may reflect pericardial effusion in severe untreated hypothyroidism, and the study may be obtained where associated congenital heart disease is suspected.[10]
CT
Computed tomography of the brain in endemic cretinism is usually unremarkable apart from basal ganglia calcification, which was present in 15 of 50 subjects studied and was confined to those with severe hypothyroidism; the remaining changes were minor and did not localise the clinical deficit.[1]
MRI
Magnetic resonance imaging is preferred to computed tomography for assessing myelination and for excluding structural or midline anomalies in suspected central hypothyroidism, including pituitary hypoplasia and septo-optic dysplasia. Delayed myelination is characteristic of MCT8 deficiency and is an important differentiating finding.[12][9]
Echocardiography or Ultrasound
Thyroid ultrasound is the first-line imaging study for defining thyroid presence, size, and position and can be performed without interrupting treatment. Echocardiography is reserved for suspected pericardial effusion or associated congenital heart disease.[10]
Other Imaging Findings
Radionuclide scintigraphy using technetium-99m or iodine-123 distinguishes agenesis, ectopia, and a normally sited gland with dyshormonogenesis, and is most informative when performed within the first days of treatment. A knee radiograph showing an absent distal femoral epiphysis at term indicates intrauterine hypothyroidism and correlates with severity. Etiological imaging must never delay initiation of levothyroxine.[10][4]
Other Diagnostic Studies
Audiological assessment is mandatory because sensorineural deafness is a defining feature of neurological cretinism and is over-represented in congenital hypothyroidism. Formal developmental and neurocognitive assessment should be scheduled rather than left to opportunistic review.[10][1]
Treatment
Initial Management
When congenital hypothyroidism is diagnosed, correctly dosed levothyroxine should be started immediately, without waiting for etiological imaging or genetic results.[10] The recommended initial treatment is levothyroxine 10 to 15 mcg/kg daily given enterally.[4] Tablets should be crushed and given in a small volume of water or breast milk, and should not be co-administered with soy formula, iron, or calcium. In the established neurological cretin, by contrast, thyroid hormone does not reverse the fetal deficit; management is supportive and directed at hearing, mobility, communication, and, in the myxedematous form, correction of ongoing hypothyroidism.[1]
Medical Therapy
The goals of treatment are to maintain consistent euthyroidism, with a normal TSH and a free T4 in the upper half of the age-specific reference range during the first three years of life.[4] Higher initial dosing is supported by comparative outcome data. Children started on 10.1 to 15.0 mcg/kg daily had a mean IQ at four years of 98 ± 9 compared with 88 ± 13 for those started on 6.0 to 8.0 mcg/kg daily (P < 0.05), and IQ fell below 85 in 6 of 21 children (28%) in the intermediate-dose group but in none of the high-dose group (P = 0.03).[19] A subsequent cohort with meta-analysis found an IQ difference between severe and mild disease only when treatment began at a dose below 10 mcg/kg, and found no adverse cognitive effect of transiently supranormal T4 during infancy.[18] Frequent laboratory monitoring is required in the first years, with dose adjusted for weight gain and adherence.[10]
Procedural / Surgical Therapy
There is no surgical treatment for cretinism itself, and thyroidectomy has no role. Procedural care is directed at complications and comorbidity: hearing aids and, in selected children, cochlear implantation for sensorineural deafness; orthopaedic and rehabilitative management of spasticity, contracture, and joint deformity; and ophthalmological correction of strabismus. Surgery for a large obstructive goiter is occasionally required in dyshormonogenesis or in longstanding endemic goiter, but is not part of the management of the neurological syndrome.[10][1]
Long-Term Management
Follow-up should include regular thyroid function testing, growth and pubertal monitoring, attention to neurodevelopment and neurosensory function including hearing and vision, and education of the child and family about the condition.[10] Where permanence has not been established, for example in a normally sited gland or a mild biochemical phenotype, treatment should be re-evaluated at around three years of age, once the period of maximal brain dependence on thyroid hormone has passed. Every individual with congenital hypothyroidism is entitled to a planned transition of care from paediatric to adult services.[10]
Special Populations
| Population | Management considerations |
|---|---|
| Preterm and low-birth-weight infants | Delayed TSH rise and transient hypothyroxinemia are common; a single normal screen is insufficient and repeat screening is required[4][10] |
| Down syndrome | Higher prevalence of congenital and acquired hypothyroidism; systematic repeat testing rather than reliance on the initial screen[4] |
| Central hypothyroidism | Not detected by primary TSH screening; dosing and monitoring are guided by free T4 rather than TSH, and adrenal insufficiency must be excluded before starting levothyroxine[10] |
| Pregnancy and preconception | Adequate iodine intake should be secured before conception. Where subclinical hypothyroidism is identified, confirmatory repeat thyroid function testing is advised before committing to levothyroxine, since a substantial proportion of mild abnormalities normalise spontaneously[11] |
| MCT8 deficiency | Levothyroxine aggravates peripheral thyrotoxicosis and is inappropriate. The T3 analogue Triac ameliorates the peripheral thyrotoxicosis in an open-label phase 2 trial; effects on the neurocognitive phenotype remain under investigation[9] |
| Endemias with combined deficiency | Selenium must not be given without concurrent iodine or thyroid hormone, because isolated selenium repletion can aggravate hypothyroidism[15] |
Primary and Secondary Prevention
Primary prevention of endemic cretinism rests on universal salt iodization. All food-grade salt used in households and in food processing should be fortified with iodine, a strong WHO recommendation for populations in both stable and emergency settings.[6] Where salt iodization is not yet effective, iodized oil may be used, and the trial evidence indicates that it must be given before conception to prevent cretinism.[3] The severity gradient matters for policy. In severe deficiency, correction prevents cretinism and improves neurological outcome.[3][7] In mild-to-moderate deficiency the evidence is weaker and inconsistent: observational cohort data from the United Kingdom link low maternal iodine status to poorer verbal IQ and reading outcomes in childhood,[20] whereas a randomised placebo-controlled trial of 200 mcg iodine daily in 832 mildly iodine-deficient pregnant women, entering at a mean gestational age of 10.7 weeks with a median urinary iodine concentration of 131 mcg/L, found no effect on child neurodevelopment at 5 to 6 years.[8] A Cochrane review of eleven trials likewise found no clear evidence of benefit or harm on maternal or infant thyroid function or on child neurodevelopment.[21]
Secondary prevention consists of universal newborn screening with prompt confirmatory testing and immediate treatment, together with structured repeat screening in the higher-risk groups described above.[4][10]
Future or Investigational Therapies
Active areas of investigation include thyroid hormone analogues that do not require MCT8 for cellular entry, of which Triac is the most advanced,[9] expanded next-generation sequencing panels and analysis of oligogenic contributions to thyroid dysgenesis,[16] and refinement of newborn screening thresholds and algorithms to reduce false negatives in preterm infants without inflating recall rates.[10][4]
Case Studies
See also
de:Kretinismus fi:Kretinismi ur:فدامہ sv:Kretinism
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Halpern JP, Boyages SC, Maberly GF, Collins JK, Eastman CJ, Morris JG (1991). "The neurology of endemic cretinism. A study of two endemias". Brain. 114 (Pt 2): 825–841. doi:10.1093/brain/114.2.825. PMID 2043952.
- ↑ 2.0 2.1 Pearce EN, Zimmermann MB (2023). "The Prevention of Iodine Deficiency: A History". Thyroid. 33 (2): 143–149. doi:10.1089/thy.2022.0454.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Pharoah P, Buttfield IH, Hetzel BS (2012). "Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy". Int J Epidemiol. 41 (3): 589–592. doi:10.1093/ije/dys070. PMID 22586135.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 Rose SR, Wassner AJ, Wintergerst KA, Yayah-Jones NH, Hopkin RJ, Chuang J, Smith JR, Abell K, LaFranchi SH (2023). "Congenital Hypothyroidism: Screening and Management". Pediatrics. 151 (1): e2022060419. doi:10.1542/peds.2022-060419. PMID 36827523 Check
|pmid=value (help). - ↑ 5.0 5.1 5.2 Vanderpas JB, Contempré B, Duale NL, Goossens W, Bebe N, Thorpe R, Ntambue K, Dumont J, Thilly CH, Diplock AT (1990). "Iodine and selenium deficiency associated with cretinism in northern Zaire". Am J Clin Nutr. 52 (6): 1087–1093. doi:10.1093/ajcn/52.6.1087. PMID 2239787.
- ↑ 6.0 6.1 6.2 6.3 6.4 "Guideline: Fortification of Food-Grade Salt with Iodine for the Prevention and Control of Iodine Deficiency Disorders". World Health Organization. 2014. Retrieved 2026-08-14.
- ↑ 7.0 7.1 7.2 7.3 7.4 Cao XY, Jiang XM, Dou ZH, Rakeman MA, Zhang ML, O'Donnell K, Ma T, Amette K, DeLong N, DeLong GR (1994). "Timing of vulnerability of the brain to iodine deficiency in endemic cretinism". N Engl J Med. 331 (26): 1739–1744. doi:10.1056/NEJM199412293312603. PMID 7984194.
- ↑ 8.0 8.1 Gowachirapant S, Jaiswal N, Melse-Boonstra A, Galetti V, Stinca S, Mackenzie I, Thomas S, Thomas T, Winichagoon P, Srinivasan K, Zimmermann MB (2017). "Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial". Lancet Diabetes Endocrinol. 5 (11): 853–863. doi:10.1016/S2213-8587(17)30332-7. PMID 29030199.
- ↑ 9.0 9.1 9.2 9.3 9.4 Groeneweg S, Peeters RP, Moran C, Stoupa A, Auriol F, Tonduti D, Dica A, Paone L, Rozenkova K, Malikova J, van der Walt A, de Coo I, McGowan A, Lyons G, Aarsen FK, Barca D, Krude H, Craiu D, Chatterjee K, Visser TJ, Visser WE (2019). "Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial". Lancet Diabetes Endocrinol. 7 (9): 695–706. doi:10.1016/S2213-8587(19)30155-X. PMID 31377265. Vancouver style error: initials (help)
- ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17 10.18 10.19 10.20 van Trotsenburg P, Stoupa A, Léger J, Rohrer T, Peters C, Fugazzola L, Cassio A, Heinrichs C, Beauloye V, Pohlenz J, Rodien P, Coutant R, Szinnai G, Murray P, Bartés B, Luton D, Salerno M, de Sanctis L, Vigone M, Krude H, Persani L, Polak M (2021). "Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology". Thyroid. 31 (3): 387–419. doi:10.1089/thy.2020.0333. PMID 33272083 Check
|pmid=value (help). - ↑ 11.0 11.1 11.2 Korevaar T, Leung AM, Alexander EK, Bliddal S, Boelaert K, Brenta G, Chou R, Dhillon-Smith R, Dosiou C, Eaton JL, Guan H, Kilpatrick SJ, Lasserre BJ, Lee SY, Maraka S, Meister KD, Morris-Wiseman LF, Nguyen CT, Pearce EN, Shan Z (2026). "American Thyroid Association 2026 Guidelines for Thyroid Disease in Preconception, Pregnancy, and Postpartum". Thyroid. 36 (5): 481–544. doi:10.1177/10507256261445624. PMID 42219800 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ 12.0 12.1 12.2 12.3 12.4 Peters C, van Trotsenburg A, Schoenmakers N (2018). "DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives". Eur J Endocrinol. 179 (6): R297–R317. doi:10.1530/EJE-18-0383. PMID 30324792. Vancouver style error: initials (help)
- ↑ 13.0 13.1 13.2 Zimmermann MB, Jooste PL, Pandav CS (2008). "Iodine-deficiency disorders". Lancet. 372 (9645): 1251–1262. doi:10.1016/S0140-6736(08)61005-3. PMID 18676011.
- ↑ 14.0 14.1 14.2 14.3 14.4 Zimmermann MB, Boelaert K (2015). "Iodine deficiency and thyroid disorders". Lancet Diabetes Endocrinol. 3 (4): 286–295. doi:10.1016/S2213-8587(14)70225-6. PMID 25591468.
- ↑ 15.0 15.1 15.2 Vanderpas JB, Contempré B, Duale NL, Deckx H, Bebe N, Longombé AO, Thilly CH, Diplock AT, Dumont JE (1993). "Selenium deficiency mitigates hypothyroxinemia in iodine-deficient subjects". Am J Clin Nutr. 57 (2 Suppl): 271S–275S. doi:10.1093/ajcn/57.2.271S. PMID 8427203.
- ↑ 16.0 16.1 16.2 16.3 16.4 16.5 Stoupa A, Carré A, Polak M, Szinnai G, Schoenmakers N (2025). "Genetics of primary congenital hypothyroidism: three decades of discoveries and persisting etiological challenges". Eur Thyroid J. 14 (2): e240348. doi:10.1530/ETJ-24-0348.
- ↑ 17.0 17.1 "Global Scorecard of Iodine Nutrition". Iodine Global Network. 2025. Retrieved 2026-08-14.
- ↑ 18.0 18.1 Aleksander PE, Brückner-Spieler M, Stoehr AM, Lankes E, Kühnen P, Schnabel D, Ernert A, Stäblein W, Craig ME, Blankenstein O, Grüters A, Krude H (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. 103 (4): 1459–1469. doi:10.1210/jc.2017-01937. PMID 29325045.
- ↑ 19.0 19.1 Salerno M, Militerni R, Bravaccio C, Micillo M, Capalbo D, Di Maio S, Tenore A (2002). "Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism". Thyroid. 12 (1): 45–52. doi:10.1089/105072502753451968. PMID 11838730.
- ↑ Bath SC, Steer CD, Golding J, Emmett P, Rayman MP (2013). "Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC)". Lancet. 382 (9889): 331–337. doi:10.1016/S0140-6736(13)60436-5. PMID 23706508.
- ↑ Harding KB, Peña-Rosas JP, Webster AC, Yap C, Payne BA, Ota E, De-Regil LM (2017). "Iodine supplementation for women during the preconception, pregnancy and postpartum period". Cochrane Database Syst Rev. 3 (3): CD011761. doi:10.1002/14651858.CD011761.pub2. PMID 28260263. Vancouver style error: initials (help)