By: Ekaterina Kouzmina

The past centuries brought an enormous change in the ways that people live and work. One of the great changes was seen in the field of medicine both in terms of treating diseases and disorders as well as evaluating and describing new ones. The topic of neurodevelopmental disorders was of great interest as people worried about the “degeneration” of the human race(1). Therefore, the children with mental abnormalities were studied and described. Certain types of disorders were discovered and studied much earlier than others: Fetal Alcohol Syndrome was already studied at the end of 19th century(1) while the Asperger Syndrome was described in the middle of 20th century(2). In contrast, the neurodevelopmental disorder that will be described below has a much longer history.

Cretinism is classified as an iodine deficiency disorder, which may also be associated with hypothyroidism. Thyroid hormones and regulation of iodine are strongly intertwined, making this disorder have several possible causes: iodine deficiency or thyroid gland dysfunction in the pregnant mother or in the newborn child (whose CNS is still developing)(4). Thyroid hormones are very important for the normal development of the central nervous system and the disruption of this hormonal system leads to both mental and physical defects in affected individuals(3,4).

The first historical mentions of cretinism as a mental disorder were from 13th century Europe, while the first association between the characteristic mental retardation and the link to hypothyroidism was noted in the 16th century(5). 19th century was marked by research of this disorder and its connection to goiters as well as the thyroid gland insufficiency(3,5). Diagnostics started with basic clinical observations, but 20th century brought more precise methods including radionuclide labelling and various screening procedures(5).

Currently this disorder is more common in the developing countries due to the low iodine in the diet, which leads to thyroid gland dysfunction. Yet recent researches find certain genetic predisposition and implicate several genes (such as DEHAL1 gene mutations)(4). Such mutations can be found through studies of pedigrees of families with histories of thyroid gland diseases (goiters and hypothyroidism). Different model organisms have also been used in order to test the genes of interest and effects of environmental factors. Another important area of research in the cretinism disorder is early assessment and action in cases where possibility of abnormality is observed. Pregnant women in the “risk” population are being tested in order to determine the optimal way of assessing the chance of thyroid gland failure and therefore introduction of preventive measures to avoid affect on the fetus(6).


Cretinism is associated with both hypothyroidism (low levels of thyroid hormones) and iodine deficiency, but it has two subtypes depending on the type of association. The effects can be seen as early as a few weeks after birth (in case of the mother being iodine deficient or having a dysfunctional thyroid gland during pregnancy) o
Neurological cretinism (adapted from Zimmermann, M.B. (2011))
r during childhood (in case of the child being iodine deficient or developing thyroid gland problems after birth)

Neurological cretinism

This type of cretinism is associated with severe iodine deficiency and is more prevalent in countries with low iodine in the diet(3). This is also the most common type of cretinism world-wide(7). It is marked by severe mental retardation, such as strained performance on simple tasks, as well as certain physical abnormalities that include: deafness and mutism, squinting, impaired volitional control over limbs, which may evolve into symmetrical lower limb paralysis, such as diplegia(3,8). Goiters and thyroid gland dysfunction may be present in this type of cretinism, but they are not necessary for the identification(3).
Hypothyroid cretinism (adapted from Chen, Z. P., Hetzel, B. S. (2010))

Hypothyroid cretinism

This type of cretinism is associated with severe hypothyroidism, which was caused by iodine deficiency(3). It is marked by mental retardation (which is less severe than in neurological cretinism) as well as physical abnormalities that differ from neurological type: stunted growth (dwarfism and retarded maturation – such as incomplete facial maturation), thick skin, and delayed reflexes(3). Individuals in this category are also common to have heart abnormalities such as low voltage QRS complexes, which in literature have been associated with cardiomyopathy and loss viable heart tissue(9). In contrast to the neurological cretins, these individuals usually have severe hypothyroidism(7).


Causes and Treatments

Changes in the fetal brain

Thyroid hormones and iodine are strongly intertwined, and although the two different cretinism types are more associated with a deficiency in one of them (neurological cretinism) or both (hypothyroid cretinism), the levels of both factors should be considered, especially the timing of their demand in neurodevelopment. Neurological cretinism is the result of
Human development and timing of factors leading to certain disorder types (adapted from Bernal, J. (2007))
affected early gestation, while hypothyroid cretinism is the result of affected later gestation, which leads to the differences in symptoms(8).

Several studies were able to look at the physical brain changes in adult cretins (affected children who grew up) and fetuses in comparison to unaffected individuals. Non-invasive imaging techniques, such as CT scans and MRIs, were able to detect cortical degeneration in the form of atrophied cerebral cortex and pons, enlargement of lateral ventricles, as well as a large number of cortical sulci in the grown up cretins from the Andean region(10). In contrast, a similar study from China showed mostly normal structures except for increased intensity of the T1-weighted MRI in the region of basal ganglia, in particular – globus pallidus and substantia nigra(10). Meanwhile, the study, which looked at spontaneously aborted fetuses due to iodine deficiency in Chinese women, showed the delayed development of cortical masses in terms of decreased brain weight and delayed differentiation of cortical layers, and abnormal allocation of certain types of brain cells upon the completion of layer differentiation(10).

Thyroid hormones

Comparison of hands of unaffected individual (left) and individual with cretinism disorder, which manifests dwarfism (right). (Adapted from Brown, P. (2012))
There are several different thyroid hormones, but it has been noted that maternal T4 (thyroxine) was able to predict the fetal thyroid hormonal levels better than, for example, T3 (triiodothyronine)
(8). Once a woman gets pregnant, she must produce enough hormones for herself and for the developing fetus. During the first trimester, also marked as Stage 1, the mother has a large increase in the T4 production, which in return inhibits TSH (thyroid stimulating hormone)(8). T4 is produced by the thyroid gland, while 80% of T3 is produced from T4 by enzymatic modification using type 2 deiodinase (D2), which is expressed in certain types of glial cells, such as astrocytes(7,8,11). Thyroid hormones are hydrophobic, meaning that they are not very soluble in aqueous environment, which requires them to bind to plasma transport proteins in order to be delivered to the target tissue. Once the hormone is transported to the right place, it enters the cell using ATP dependent mechanisms such as the monocarboxylate transporter-8 (MCT8) or organic anion transporter protein family (e.g. OATP1c1)(8). Once inside the cell, in case of neurodevelopment – the neuron, T3 hormone (which is the active form of thyroid hormone, unlike T4) binds to the thyroid nuclear receptors and activates transcription of certain genes. These receptors may also function without the lygand (thyroid hormone) interacting with corepressors and preventing gene transcription, in which case they are called aporeceptors(11). Another function of these hormones is to regulate signal transduction by communication with ion channels and activation of signalling cascades (e.g. mitogen-activated protein kinase (MAPK) cascade), which includes phosphorylation(8,11). One of the interactions of thyroid hormones includes the insulin-like growth factor (IGF), which regulates the actions of the growth hormone (GH)(8). Low levels of thyroid hormone in hypothyroid cretinism lead to lower levels of IGF and subsequently low levels of GH, which results in dwarfism.

Role of thyroid hormones in development

Stages of human development and levels of thyroid hormones (adapted from Williams, G. R. (2008))
hormones are very important in the correct development of both the central nervous system as well as the peripheral nervous system due to their regulation of the processes such as neurogenesis, formation of neuronal communicating units (dendrites and synapses), and axonal myelination(8). This development can be divided into three stages during which thyroid hormones are required in order to produce normal phenotype. Inadequate levels of the hormone during specific stages would lead to the defects that are characteristic to cretinism.

Stage 1 starts at about 16-20 weeks after conception and the fetus is very dependent on the maternal thyroid hormone as the fetal level of organ maturation has not yet reached the stage of independent production. This period is marked by the processes of neuronal proliferation and migration(8). Stage 2 begins at the point when the fetal thyroid gland starts to function (at the onset of second trimester) and lasts the remainder of pregnancy(7,8). This period is marked by more neuronal migration, neurogenesis, as well as the building of connections between the neurons: axonal growth, dendritic expansion, and synaptogenesis(8). This is also the stage when glial cells mature and axonal myelination takes place, which leads to malformed connections and axonal insulation if the regulatory thyroid hormones are scarce. Stage 3 occurs right after birth and from this point all the thyroid hormones are fully supplied by the newborn child(8). This stage is marked by continued migration, such as of granule cell to hippocampus and pyramidal cells to the cortex(8). Therefore, these processes would be affected if the newborn themselves is subjected to low levels of iodine or develops thyroid gland dysfunction.

Importance of iodine in thyroid hormone synthesis (adapted from Trinity University:


Iodine is a critical component in production of thyroid hormones by the thyroid gland, but it is also very important for overall development (severe iodine deficiency during fetal development may result in abortion or stillbirth).

Iodine deficiency has adverse effects on adults including impairment of mental capabilities, lowered work productivity, and goiters, but the most severe effects are felt by pregnant women(7). The reason for this is that the requirements for iodine in pregnant women may be as high as 1.5 times or more than in other individuals due to the following factors: there is a rise in production of thyroid hormones that requires iodine; iodine, similarly to thyroid hormones, is transferred to the fetus; and there is a rise in renal clearance(7).

Mild iodine deficiency triggers a certain adaptive response in individuals, which is marked by increased production of T3 hormone in order to maintain euthyroidism(10). If this is triggered in a pregnant woman, she is sharing less iodine with the fetus (due to her iodine deficiency), but can maintain the right level of thyroid hormones in her body. The fetus on the other hand does not have such a response and becomes hypothyroid due to insufficient amount of iodine (which affects fetal hormonal production starting at Stage 2) and hormones received from the mother(10).

Problems during pregnancy and their treatment

Iodine deficiency

Iodine deficiency during pregnancy leads to the impairments, described in the previous sections. Severity of the impairment depends on the extent of iodine deficiency, the temporal aspect of the deficiency, and whether treatment was administered and when.

Iodine deficiency can be tested by measuring urinary iodine concentration. The normal concentration is considered to be 135-155 µg/L during pregnancy and it is sustained by a daily iodine intake of 220-250 µg(7). Since this amount is not always available from ordinary diet, there have been a number of intervention projects to prevent the associated disorders.
Iodized salt (retrieved from

Some of the common intervention projects include salt iodization, iodization of irrigation water, and direct supplementation of pregnant women. A good example of salt iodization program is the implementation of a national law by the Kyrgyz Government in 2001 that forbade the use of non-iodized salt and favoured an alternative of potassium iodate (25-55 mg iodine/kg salt)(12). Iodization of irrigation water project was performed in the Xinjiang Province in China in order to provide higher iodine levels to the rural areas(13). This was an important step forward as it constituted a rise in level of iodine in plants (crops and ones consumed by domestic animals), domestic animals and their products (e.g. chicken eggs) and therefore human population, who consumed both crops and animal products(13). Pregnant women, who are at risk of developing iodine deficiency or a thyroid gland dysfunction have to get the iodine supplementation (if they were not on supplementation beforehand) or increased supplementation, which would continue during breastfeeding due to continued high demand for iodine during that time period (the demand may be even higher than during pregnancy)(10). This supplementation may come through iodized salt (most common) or iodized oil(7).

It is very important to catch the iodine deficiency at its early stage, as correct supplementation reduces the adverse effects (if caught early enough, the fetus has a good chance for normal development). Supplementation can also ameliorate the prognosis of the fetus that started developing in severe iodine deficiency conditions. Studies found that iodine supplementation through iodized oil facilitated increase in birth weights, decrease in the chance of microcephaly and neonatal death, and a rise in the average IQ compared with those children who were born before the supplementation program started(7). It was also noted that supplementation improved growth of the children, which is believed to be connected to the thyroid hormone interaction with GH.

Maternal hypothyroidism

Iodine deficiency is a known problem that is being dealt with by salt supplementation. In contrast, malfunctioning thyroid gland is more difficult to identify as the symptoms do not come right away and are not explicitly noticeable in cases of mild thyroid insufficiency(6). If maternal thyroid gland fails to produce enough thyroid hormones, that has an adverse effect on the developing fetus. Therefore it is important to screen the women in the “risk” population (those who have a predisposition to thyroid gland dysfunction) in order to determine their thyroid gland status. The timing of screening plays an important role as on one hand it is desirable to detect the problem as early as possible to begin treatment, but on the other hand early screening would miss thyroid underfunction that could start later in pregnancy.
Maternal hypothyroidism (retrieved from

The common methods of screening look at combination of hormones to determine their overall body levels and their levels relative to each other. Some of the combinations may include TSH and FT4 (F stands for “free”); TSH, FT4, and FT3; TSH, FT4, and TT3 (total T3)(14).

The study performed by Moleti et al. found that pregnant women in the “risk” population developed overt hypothyroidism earlier in gestation (peak between 5 and 12 weeks after conception and up to 26 weeks after conception), while the development of isolated hypothyroidism occurred throughout gestation (peaking at 20-26 weeks after conception). Isolated hypothyroidism is defined as having a normal level of free T4, while overt hypothyroidism is defined as having a decreased level of free T4(15). Therefore, screening helps to identify whether there is a problem with the thyroid function and whether the fetus is at risk, but it is difficult to determine the best time for the screening.

Since iodine deficiency is the main reason for hypothyroidism, iodine supplementation is advised, especially for women in the “risk” populations, who are thinking about getting pregnant, as they need to have sufficient iodine amount for normal fetal development. A more expensive way of treating hypothyroidism would be the supplementation of T4 itself, which can then be converted to T3. This way of treatment is currently used to treat pregnant European women with overt hypothyroidism, supplementing various doses of L-T4 ranging from 25-50 µg to 200 µg daily(14).

Genetic Mutations

Cretinism is mostly a result of the intrauterine (low levels of iodine and thyroid hormones from mother) and extrauterine (mother subjected to iodine deficiency) environments. Yet, individual cases showed abnormalities in receptors: TSH or thyroid hormone receptors, enzymes: NADPH oxidases(important in thyroid hormone synthesis), and transporters: MCT8, which could have a genetic basis(5). These cases were presented as a couple of different reports, making it impossible to make a link and generalize them to the whole population of affected individuals.

Nevertheless is seems that there could be a particular marker that could account for more than a couple of cases. A mutation in DEHAL1 gene was found in several different families, leading the individuals with mutations in both copies of the gene to some kind of thyroid disorder(4). The gene was found to be coding for iodotyrosine dehalogenase, which plays a role iodine regulation in thyroid gland(4). Unfortunately the current screening techniques have a high chance of missing such mutation in which case it gets passed on to the progeny in the autosomal recessive form(4).

Pedigrees of two families carrying DEHAL1 mutation (adapted from Moreno, J. C., Visser, T. C. (2010))

Animal Models

Environmental manipulations

Animal models are very useful in terms of the ability to subject them to conditions, which are similar to the ones triggering human
Lamb whose mother was subjected to iodine deficiency (top) and control (bottom) at 140 days of gestation (adapted from Chen, Z. P. (2010))
disease, and to test prevention measures as well as various treatments. Environmental manipulations for cretinism disorder involve subjecting pregnant test animals to either iodine deficiency or other conditions that would affect the function of their thyroid gland (such as administration of anti-thyroid drugs)
(16). Such studies have been performed in rodents (rats) and mammals (marmosets, lambs)(3,10). The results from all these studies were very similar to each other and to the deficiencies seen in affected humans. The affected newborn animals had reduced body and brain weight, showed physical abnormalities (skull and limb development), as well as strongly decreased hair growth. All these species showed a distinct underdevelopment of cerebellum(3).

Genetic manipulations

Genetic manipulations are common in mice as there are many different strands available and they are relatively easy to breed and manipulate (in comparison to larger animals). These genetic manipulations help to simulate potential genetic mutations that may lead to hypothyroidism or cretinism.

Studies looked at gene mutations far “up-stream” of the thyroid gland, such as knocking out neuroD2, which is involved in brain development and has direct effect on the hypothalamic-pituitary-thyroid axis. Although, the effects of such knock-outs are much more severe than ordinary hypothyroidism, thyroxine supplementation was able to ameliorate this condition(17). Other studies looked at the altered levels of phosphorylation in different brain areas such as hippocampus, knocked-out transporters (MCT8), thyroid hormone receptor deletions (although it was found that deleting the receptors had a less adverse effect than decreasing hormone levels), as well as thyroid receptor knock-ins (study of cerebellum showed that increase in number of receptors does not ameliorate condition of thyroid hormone resistant individuals), as well as other genetic manipulations(8,11,16,18,19).

Homo floresiensis

Is it a new species or did the archeologists find the remains of ancient individuals affected by cretinism? Did the story of cretinism start much earlier than 13th century?
Comparison of Homo floresiensis (a) and modern cretin (b, c) skulls. One of the visible differences is the mandibular malformation and overbite in cretins, which is not present in H. floresiensis (adapted from Brown, P. (2012))

Comparison of skulls: Homo floresiensis (left), modern human (right) (adapted from Brown, P. (2012))

The human remains that date back to at least 15,000 years ago were found on the island of Flores (Indonesia) in 2003(20). They were a subject of a big debate as they had a number of characteristics that are attributable to modern humans (in particular to those affected by cretinism), but at the same time they had a number of characteristics that are absent in modern humans. The studies of limbs showed distinctive primitive features, which included different rotational angles, bone width/length ratios(20). Certain values, such as upper/lower limb lengths ratio, decreased height, and certain skull features were very similar in modern cretins and H. Floresiensis(20).

The “Cretinism hypothesis” has been quite popular in the past years, but the most recent view was proposed by Brown (2012), who performed a number of tests and compared the modern cretins to the mysterious remains. The conclusion was that Homo floresiensis was indeed a different species. This conclusion was based on comparing modern cretins and the discovered remains based on brain sizes, skull features (facial bone morphology, structure of sinuses and pituitary fossa), thickness and structure of bones and ratios of their lengths(21).


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