Although neonatal screening has dramatically improved the prognosis for children affected by CH, this does not necessarily imply that early and appropriate l-T4 replacement therapy results in the same health outcomes of unaffected children.

In a large cohort of 361 children from the UK national register of children with CH detected by neonatal screening, Tillotson et al. [8] reported a normal IQ at the age of 5 years. However, compared to controls, IQs were 10.3 points lower in patients with severe CH as defined by low serum T4 at diagnosis (T4 < 24.8 nmol/L) [8]. Similar results were reported by Rovet et al., who observed an IQ 8 points lower in children with CH with respect to their unaffected siblings at the age of 6 years [9]. Salerno et al. reported subnormal IQ in 13 out of 40 patients with CH aged 12 years as compared to their sibs, with lower IQ scores being associated with lower serum T4 concentrations at diagnosis and poor treatment compliance during follow-up [10]. In 49 young adults with CH aged 20 years, although within normal range, IQs were found to be 9 points lower than their siblings (total IQ 102.4 vs 111.4) [11]. Moreover, Kempers et al. reported a mean IQ 10 points lower (IQ 91.3 vs 101.3) in adult patients with severe CH (initial T4 < 30 nmol/L) compared with mildly affected patients (T4 ≥ 60 nmol/L) [12].

Because most children exhibiting subtle neurocognitive impairment started treatment with relatively low doses of l-T4, in the 1990s CH treatment guidelines were revised to recommend an increase of l-T4 starting dose from 6–8 to 10–15 mcg/kg per day in order to faster normalize circulating thyroid hormone and reduce the postnatal period of TH insufficiency [13, 14].

Indeed, high-dose l-T4 treatment (10–15 mcg/kg per day) resulted in a rapid normalization of thyroid hormone levels, within the first 2 weeks after therapy initiation, and in a better intellectual outcome [15–22].

In 44 CH children evaluated at a mean age of 8 years, high-dose l-T4 treatment followed by a rapid postnatal normalization of thyroid function resulted in IQ scores similar to their siblings. Moreover, the proportion of lower IQ (i.e., <85) was similar in both groups (27 % in CH children vs 26 % in their siblings) [22].

However, despite optimized treatment regimens improving neurodevelopmental outcomes, some children with CH are still reported as having subtle cognitive deficits. Indeed, Dimitropulos et al. evaluated intellectual outcome at a median age of 14 years in 63 children with CH treated early and with high l- T4 dose and reported an IQ within normal range but almost 10 points lower than controls, with patients with athyreosis being more severely affected [23]. These deficits may reflect a prenatal brain injury due to thyroid hormone insufficiency in utero not completely reverted by postnatal treatment. Even though transplacental supply of maternal T4 may protect fetal brain from severe neurological impairment, it may not be sufficient to protect from severe fetal hypothyroidism [24].

In conclusion, neurodevelopmental outcome in CH patients is affected by several factors such as severity of CH at diagnosis, etiology, delayed bone maturation at diagnosis, delayed age at initiation of replacement l-T4 therapy, low initial l-T4 dose, later time of thyroid function normalization, poor compliance to treatment, and sociodemographic factors [10, 11, 18, 19, 25–31].

Although allowing better neurocognitive outcome, high-dose l-T4 therapy may lead to an increased risk of supraphysiological free T4 (fT4) levels, which have been associated with attention and behavioral problems in childhood [29]. Indeed, in the study by Alvarez et al., the number of episodes of overtreatment during the first 6 months was a stronger predictor of alertness deficit during the school age than the initial l-T4 dose and the etiology of CH [32].

Recently, Bongers-Sckokking et al. found that the episodes of overtreatment during the first 2 years of therapy were associated with a lower IQ at the age of 11 years in comparison to CH patients with no episodes of overtreatment [33].

Therefore, beyond l-T4 starting therapy, a further concern involves optimal testing frequency. The American Academy of Pediatrics recommends to assess thyroid function 2 and 4 weeks after the start of therapy, then 1–2 monthly till 6 months of age, 3–4 monthly from 6 months to 3 years, and every 6–12 months till the end of growth [34]. However, better outcomes may be achieved with more frequent tests in order to prevent iatrogenic hyperthyroidism [35, 36].

Moreover, different l-T4 initial doses and thyroid hormone monitoring based on etiology of CH have been suggested as a possible strategy to avoid prolonged period of supraphysiological FT4 levels. Indeed, children with athyreosis would require higher and more frequent monitoring [37]. Using a different initial dose strategy according to the etiology of CH, Mathai et al. [36] reported a rapid normalization of thyroid function without prolonged secondary hyperthyroidism. Thus, they recommend starting CH treatment with high but variable l-T4 doses based on etiology, in conjunction with close monitoring of thyroid function [36].

Several studies on children and adults with CH detected by neonatal screening reported decreased motor skills with fine motor and balance function impairment with respect to controls, more pronounced in children with severe CH at diagnosis [38–40]. Indeed, children with athyreosis aged 7–14 years performed significantly worse in motor functioning than children with thyroid dysgenesis, despite early and high-dose l-T4 treatment [30]. However, data are still controversial; indeed, Albert et al. recently observed that early and high-dose treatment, followed by a rapid postnatal normalization of thyroid function, resulted in visual perception and motor coordination similar between children with CH at a mean age of 9 years and their siblings [22].

TH plays a role in cochlear and auditory function development.

Mild hearing impairment and abnormal auditory brainstem-evoked potential tracings have been reported in children with CH [41, 42].

A recent questionnaire-based report from France has shown a higher prevalence of sensorineural hearing loss as well as conductive deficits in young adults with CH (particularly those with a severe form) with respect to the general population. Hearing loss in CH children is mostly bilateral, mild to moderate, and in some cases requires hearing aids [43–46].

Therefore, early and regular evaluation of hearing acuity through childhood should be considered in patients with CH to avoid substantial adverse effects on speech development, school performance, and social interactions that may occur in case of undiagnosed hearing impairment [47].

Children with CH may display behavioral problems such as inattention, distractibility, hyperactivity, and restlessness [48–50]. Introversion and motor clumsiness have also been described, particularly in those with thyroid agenesis [51]. Even suboptimal initial treatment has been associated with attention problems and aggression [21]. Attention deficits were also associated with late normalization of TH after treatment initiation as well as with higher circulating fT4 levels at the time of testing [52, 53].

Even young adults with CH, aged 20 years, exhibited increased scores on anxiety and somatic complaint subscales [54]. They also experienced difficulties in arithmetic, and a greater percentage of them, particularly those who received lower l-T4 starting dose, did not finish high school [11].

Schooling aspects are strictly related to neurodevelopmental outcomes, and many authors focused on educational performances in children with CH with contrasting results [50, 54–56]. Generalized learning disorders have been reported in up to 20 % of CH children [57]. These children were particularly defective in symbol copy, geometric copy, phrase repetition, and spontaneous writing.

In young adults with CH born up to 1988, educational attainment was associated with CH severity and treatment adequacy [45]. Moreover, initially low l-T4 dosage (below vs ≥7 mcg/kg/day), absence of near normalization of thyroid hormone levels after 15 days of treatment, and poor compliance to the treatment throughout childhood were associated with an increased risk of school delay [58].

Primary school age seems to be the period of life when CH children are more likely to develop behavioral problems, thus at this age special attention should be paid to parental worries and anxiety [59].

During the last decade, the mechanisms involved in memory processes have been extensively studied in children with CH. It is well known that the hippocampus, which is essential for learning and memory, starts to develop early in gestation and early maternal hypothyroidism affects offspring hippocampal development and memory. TH is a modulator of memory processes through mechanisms which are still not completely understood [60–62]. Animal models of gestational hypothyroidism have shown that the rodent hippocampus is particularly vulnerable to TH loss from early gestation to the end of infancy [4, 63, 64].

Children born from women diagnosed with hypothyroidism prior or during pregnancy exhibited significantly smaller right and left hippocampal volumes on magnetic resonance imaging (MRI) despite l-T4 treatment. Moreover, the hippocampal volumes were negatively correlated with maternal third-trimester TSH levels and positively correlated with third-trimester fT4 [65]. Even later in life, children and adolescents with CH exhibited poorer recall on memory tasks compared to controls (although in the average range for population norms) and an increased number of everyday memory problems correlated with hippocampal volumes. Moreover, on functional MRI, adolescents with CH showed increased magnitude of hippocampal activation which was also correlated with the severity of the hypothyroidism early in life [65, 66]. These findings suggest that perinatal deprivation of TH has long-standing effects on hippocampal function and may account for memory problems experienced by adolescents with CH. Thus, despite newborn screening and prompt treatment, early TH deficiency seems to have long-lasting effects on the hippocampus and its relationship to memory functioning [65, 66].

Besides the neurocognitive outcomes, other aspects of social and everyday life such as emotions, self-esteem, and quality of life (QoL) have been extensively assessed in children with CH. The results of these studies are difficult to interpret considering the multitude of factors influencing these psychological components even in healthy people. Moreover, the existence of a chronic disease per se, regardless of its severity, may represent a risk factor for psychological disorders such as anxiety, depression, affective problems, and aggressive behavior [67, 68].

Patients growing up with CH, diagnosed by neonatal screening, are more often at risk for health-related QoL impairment, lower self-esteem, and delayed developmental milestones on the domain of social development. In addition, the cognitive and motor problems of CH patients, when present, may also affect their social life, self-esteem, and emotional functioning [69]. Consequently, the focus during follow-up should shift to school performances, social-emotional functioning, and supporting the patients.

Studies on QoL and living conditions in adolescents and young adults with CH detected on newborn screening yielded contrasting results [45, 70].

Compared with their peers, fewer CH patients attained secondary or tertiary education, the highest socioeconomic category, or were in full-time employment, which seemed to be mainly dependent on a greater CH severity at diagnosis, a worse treatment adequacy, and the presence of associated chronic conditions. . However, from a public health standpoint, the subtle impairment reported seemed to have just a little impact since most patients were well integrated into society, in education, or had at least some employment [45].

How much of the emotional aspects and QoL of these patients depends on specific factors related to CH (i.e., severity of neonatal CH, etiology, timing and dose of treatment, monitoring of thyroid function, parental attitude, etc.) or on the fact of living with a chronic condition remains to be further defined. However, the improvement in the management of children with CH during the last years, with early, high-dose l-T4 treatment, and close monitoring of thyroid function will probably result in better outcomes in the majority of affected patients.

Psychomotor development and school progression should be periodically monitored in all children with CH, particularly in those with severe CH at diagnosis, athyreosis, and poor control during the first year. Hearing tests and screening for visual processing problems and speech delay are recommended prior to entering school. Adherence to treatment should also be regularly and carefully monitored [71].