Untreated Congenital Hypothyroidism Research Articles

Screening T4 and TSH in Early Detection of Congenital Hypothyroidism in Newborns: What’s the Dilemma?

Untreated congenital hypothyroidism (CH) leads to intellectual disability. Newborn screening (NBS) for CH should be done on all infants. Prompt diagnosis by NBS leads to early and adequate treatment outcomes in very normal neurocognitive outcomes in adulthood. Newborn screening (NBS) for congenital hypothyroidism (CH) is one of the major achievements in preventive medicine. Most neonates born with CH have a normal appearance and no detectable physical signs. Blood spot thyroid stimulating hormone (TSH), thyroxine (T4), or both can be used for CH screening. The latter is more sensitive but not cost-effective, so screening by TSH or T4 is used in various programs worldwide. TSH screening is more specific in the diagnosis of CH. T4 screening is more sensitive in detecting newborns with rare hypothalamic-pituitary-hypothyroidism, but it’s less specific with a high frequency of false positives especially in low birth weight and premature infants. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis and accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Doctors need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism appear (such as large posterior fontanelles, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid hormone and free thyroxine is indicated, regardless of NBS results. So all these babies should be treated as having CH during the first 3 years of life, taking into account the risk of mental retardation. Re-evaluation after 3 years is required in such patients.

Homozygous Mutations in Thyroid Peroxidase (TPO) in Hypothyroidism with Intellectual Disability, Developmental Delay, and Hearing and Ocular Anomalies in Two Families: Severe Manifestation of Untreated TPO-deficiency Poses a Diagnostic Dilemma.

Intellectual disability (ID) involves compromised intellectual, learning and cognitive skills, and behavioral capabilities with reduced psychomotor skills. One of the preventable causes of ID is congenital hypothyroidism (CH), which may be due to biallelic mutations in thyroid peroxidase (TPO). In low- and middle-income countries with no newborn screening programs, CH poses a great risk of ID and long-term morbidity. We report two large Pakistani families with a total of 16 patients afflicted with CH. Detailed clinical and behavioral assessments, SNP-based homozygosity mapping, linkage analysis, and exome sequencing were performed. Initially, affected individuals were referred as suffering ID (in 11 of 16 patients) and developmental delay (in 14). Secondary/associated features were verbal apraxia (in 13), goiter (in 12), short stature (in 11), limb hypotonia (in 14), no pubertal onset (five of 10 of age ≥14 years), high myopia (in eight), muscle cramps (in six), and in some, variable microcephaly and enuresis/encopresis, fits, chronic fatigue, and other behavioral symptoms, which are not characteristics of CH. Molecular genetic analyses led to the discovery of homozygous variants in TPO: novel missense variant c.719A>G (p.Asp240Gly) in family 1 and rare c.2315A>G (p.Tyr772Cys) in family 2. In low-resource countries where neonatal screening programs do not include a CH test, the burden of neurodevelopmental disorders is likely to be increased due to untreated CH. Secondly, in the background of the high prevalence of recessive disorders due to high parental consanguinity, the severe manifestation of TPO-deficiency mimics a wide range of neurological and other presentations posing a diagnostic dilemma.

Effects of untreated congenital hypothyroidism

Effects of untreated congenital hypothyroidism

A Severely Neglected Paediatric Case: Congenital Hypothyroidism

Introduction: Congenital hypothyroidism is a common endocrinal disorder of newborn. Early diagnosis and management is essential to prevent the irreversible complication of congenital hypothyroidism. So, widespread implementation of newborn screening for this condition is very important [1]. Case report: A 14- year- old boy presented with short stature, chronic constipation, intellectual disability and delayed puberty as a result of untreated congenital hypothyroidism. Conclusion: This case shows the importance of early diagnosis and management of congenital hypothyroidism by routine newborn screening and adequate replacement therapy.

Outcomes of lowered newborn screening thresholds for congenital hypothyroidism.

Newborn screening (NBS) has largely eliminated the physical and neurodevelopmental effects of untreated congenital hypothyroidism (CH). Many countries, including Australia, have progressively lowered NBS bloodspot thyroid-stimulating hormone (b-TSH) thresholds. The impact of these changes is still unclear. To evaluate the performance of CH NBS following the reduction of b-TSH thresholds in New South Wales (NSW) and the Australian Capital Territory (ACT), Australia, from 15 to 8 mIU/L, and to determine the clinical outcomes of cases detected by these thresholds. NBS data of 346 849 infants born in NSW/ACT, Australia from 1 November, 2016-1 March, 2020 inclusive were analysed. A clinical audit was conducted on infants with a preliminary diagnosis of CH born between 1 January, 2016-1 December, 2020 inclusive. The lowered b-TSH threshold (≥8 mIU/L, ~99.5th centile) detected 1668 infants (0.48%), representing an eight-fold increase in recall rate, of whom 212 of 1668 (12.7%) commenced thyroxine treatment. Of these 212 infants, 62 (29.2%) (including eight cases with a preliminary diagnosis of thyroid dysgenesis) had an initial b-TSH 8-14.9 mIU/L. The positive predictive value for a preliminary diagnosis of CH decreased from 74.3% to 12.8% with the lowered threshold. Proportionally, more pre-term infants received a preliminary CH diagnosis on screening with the lower threshold (16.1% of 62) than with the higher threshold (8.0% of 150). Clinically relevant CH was detected using the lowered threshold, albeit at the cost of an eight-fold increase in recall rate. Further clinical and economic studies are required to determine whether benefits of lowered screening thresholds outweigh potential harms from false-positive results on infants, their families and NBS programs.

Optimizing Growth: The Case for Iodine.

Iodine is an essential micronutrient and component of thyroid hormone. An adequate dietary iodine intake is critical to maintain and promote normal growth and development, especially during vulnerable life stages such as pregnancy and early infancy. The role of iodine in cognitive development is supported by numerous interventional and observational studies, and when iodine intake is too low, somatic growth is also impaired. This can be clearly seen in cases of untreated congenital hypothyroidism related to severe iodine deficiency, which is characterized, in part, by a short stature. Nevertheless, the impact of a less severe iodine deficiency on growth, whether in utero or postnatal, is unclear. Robust studies examining the relationship between iodine and growth are rarely feasible, including the aspect of examining the effect of a single micronutrient on a process that is reliant on multiple nutrients for optimal success. Conversely, excessive iodine intake can affect thyroid function and the secretion of optimal thyroid hormone levels; however, whether this affects growth has not been examined. This narrative review outlines the mechanisms by which iodine contributes to the growth process from conception onwards, supported by evidence from human studies. It emphasizes the need for adequate iodine public health policies and their robust monitoring and surveillance, to ensure coverage for all population groups, particularly those at life stages vulnerable for growth. Finally, it summarizes the other micronutrients important to consider alongside iodine when seeking to assess the impact of iodine on somatic growth.

Congenital Hypothyroidism: Screening and Management.

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Congenital Hypothyroidism: Screening and Management.

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS. The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

A retrospective study of thyroid hormone in Pediatrics: relationships with growth hormone correlation with effects of diabetes in Riyadh, Saudi Arabia

Background: Inadequate Thyroid Hormone at birth in newborns is known as Congenital Hypothyroidism (CH) and it has a critical role in their growth and brain development. As a result, untreated CH and abnormal GH/IGF1 levels can lead to failure to thrive, osteoporosis, and Diabetic Retinopathies, among other problems. This retrospective study examines the chances of developing growthhormone disruption and Diabetes Mellitus in patients diagnosed with Congenital Hypothyroidism at the Security Forces Hospital in Riyadh, Saudi Arabia. Methodology: A retrospective chart review of growth hormone deficient (GHD) patients was done at the security force hospital in Riyadh, Saudi Arabia. The data was collected from the medical records of the patients. The study included all patients with growth hormone deficiency (GHD) who had complete clinical, diagnostic and treatment data. Result: At the beginning of the research, 287 growth hormone-deficient (GHD) children ranging in age from 1 to 15 years old were evaluated for diabetes. A total of 151 (52.6%) of the 287 patients got levothyroxine therapy, while the remaining 136 (47.4%) did not (control group). Because the p-value <0.05 (t(149) = 1.165, p = 0.246), the mean difference in blood sugar level changes is not statistically significant (t(149) = 1.165, p = 0.246). Conclusion: We found that levothyroxine therapy has no discernible effect on blood sugar level fluctuations in males and females. Key words: Growth hormone deficiency, Kingdom of Saudi Arabia, Diabetes.

Identification of Primary Congenital Hypothyroidism Based on Two Newborn Screens - Utah, 2010-2016.

Newborn screening for primary congenital hypothyroidism is part of the U.S. Recommended Uniform Screening Panel (1,2). Untreated congenital hypothyroidism can result in cognitive impairment and growth complications (decreased height/length). Initial newborn screening for congenital hypothyroidism is typically performed 24-48 hours after birth. Fourteen states, including Utah, perform a routine second screen at approximately 2 weeks of age.* During 2010-2016, a total of 359,432 infants in Utah were screened for congenital hypothyroidism, and 130 cases were diagnosed; among these, 98 had an abnormal first screen, and 25 had an abnormal second screen (seven infants were excluded because of missing data). A retrospective examination of Utah's screening data indicated that 20% of congenital hypothyroidism cases could not have been efficiently identified by a single screen alone. This study highlights the utility of a two-screen process and demonstrates that differential cutoff values for the first and second screens could optimize both screening sensitivity and specificity.

Maternal thyroid hormone is required for parvalbumin neurone development in the anterior hypothalamic area.

Thyroid hormone (TH) is crucial for brain development and function. This becomes most evident in untreated congenital hypothyroidism, leading to irreversible mental retardation. Likewise, maternal hypothyroxinaemia, a lack of TH during pregnancy, is associated with neurological dysfunction in the offspring, such as autism and reduced intellectual capacity. In the brain, TH acts mainly through TH receptor α1 (TRα1). Consequently, mice heterozygous for a dominant-negative mutation in TRα1 display profound neuroanatomical abnormalities including deranged development of parvalbumin neurones. However, the exact timing and orchestration of TH signalling during parvalbumin neurone development remains elusive. In the present study, we dissect the development of parvalbumin neurones in the anterior hypothalamic area (AHA) in male mice using different mouse models with impaired pre- and postnatal TH signalling in combination with bromodeoxyuridine birth dating and immunohistochemistry. Our data reveal that hypothalamic parvalbumin neurones are born at embryonic day 12 and are first detected in the AHA at postnatal day 8, reaching their full population number at P13. Interestingly, they do not require TH postnatally because their development is not impaired in mice with impaired TH signalling after birth. By contrast, however, these neurones crucially depend on TH through TRα1 signalling in the second half of pregnancy, when the hormone is almost exclusively provided by the mother. For the first time, our findings directly link a maternal hormone to a neuroanatomical substrate in the foetal brain, and underline the importance of proper TH signalling during pregnancy for offspring mental health. Given the role of hypothalamic parvalbumin neurones in the central control of blood pressure, the present study advocates the inclusion of cardiovascular parameters in the current discussion on possible TH substitution in maternal hypothyroxinaemia.

Development of the thyroid gland

Thyroid hormones are crucial for organismal development and homeostasis. In humans, untreated congenital hypothyroidism due to thyroid agenesis inevitably leads to cretinism, which comprises irreversible brain dysfunction and dwarfism. Elucidating how the thyroid gland - the only source of thyroid hormones in the body - develops is thus key for understanding and treating thyroid dysgenesis, and for generating thyroid cells in vitro that might be used for cell-based therapies. Here, we review the principal mechanisms involved in thyroid organogenesis and functional differentiation, highlighting how the thyroid forerunner evolved from the endostyle in protochordates to the endocrine gland found in vertebrates. New findings on the specification and fate decisions of thyroid progenitors, and the morphogenesis of precursor cells into hormone-producing follicular units, are also discussed.

In vivo Functional Consequences of Human THRA Variants Expressed in the Zebrafish.

Heterozygous mutations in the thyroid hormone receptor alpha (THRA) gene cause resistance to thyroid hormone alpha (RTHα), a disease characterized by variable manifestations reminiscent of untreated congenital hypothyroidism but a raised triiodothyronine/thyroxine ratio and normal thyrotropin levels. It was recently described that zebrafish embryos expressing a dominant negative (DN) form of thraa recapitulate the key features of RTHα, and that zebrafish and human receptors are functionally interchangeable. This study expressed several human thyroid hormone receptor alpha (hTRα) variants in zebrafish embryos and analyzed the resulting phenotypes. All hTRα-injected embryos showed variable defects, including cerebral and cardiac edema likely caused by an aberrant looping during heart development, anemia, and an incomplete formation of the vascular network. Moreover, the hTRα-injected embryos presented severe defects of motorneurons and craniofacial development, thus affecting their autonomous feeding and swimming behaviors. Surprisingly, expression of all hTRα mutants had no detectable effect on thyrotropin beta and thyrotropin-releasing hormone transcripts, indicating that their DN action is limited on the thyroid hormone reception beta 2 targets at the hypothalamic/pituitary level in vivo. As previously described in vitro, treatment with high triiodothyronine doses can efficiently revert the observed defects only in embryos injected with missense hTRα variants. Injection of human THRA variants in zebrafish embryos causes tissue-specific defects recapitulating most of the RTHα clinical and biochemical manifestations. The described manipulation of zebrafish embryos represents a novel in vivo model to screen the functional consequences of THRA variants and the rescue potential of new therapeutic compounds.

Pituitary Hyperplasia in a Boy with Van Wyk–Grumbach Syndrome due to Long-standing Hypothyroidism

AbstractVan Wyk–Grumbach syndrome (VWGS) is characterized by juvenile hypothyroidism, delayed bone age, and pseudo-precocious puberty. Primary hypothyroidism in the juvenile population generally leads to retardation of linear growth and delayed puberty. However, in rare conditions, children with long-standing hypothyroidism present with signs of VWGS. It can occur in both sexes. In girls, the usual presenting features are early-onset menarche and enlarged bilateral multicystic ovaries, whereas in boys it is rarely associated with testicular enlargement. We present an unusual case of an 8-year-old boy who was referred to us with a pituitary tumor (macroadenoma) and later on diagnosed as having long-standing untreated congenital hypothyroidism with testicular enlargement and pituitary hyperplasia. Eight months after thyroxine replacement therapy, repeat magnetic resonance imaging shows complete resolution of pituitary hyperplasia.

Hypertensive encephalopathy in untreated congenital hypothryroidism: a case report

Hypothyroidism is a well-known cause of poor linear growth in children. In long standing untreated congenital hypothyroidism, short stature, mental retardation and myxedema are common. Sexual precocity associated with bone age advancement can occur, but hypertensive encephalopathy is rare. This case highlights an uncommon finding of hypertensive encephalopathy in a 10 year old Filipino girl who was diagnosed to have hypothyroidism at 18 months old with presenting symptoms of short stature and constipation. She was treated with levothyroxine but with poor compliance. Because of a 2-week history of vomiting, headache, blurring of vision, and increased sleeping time, she was admitted. She was noted to have short stature (height for age Z score -3.62) and obesity (BMI = 26.3, Z score +2.55, WHO) with myxedematous appearance, stubby fingers and toes, and SMR IV. While in the hospital she had seizures, and developed hypertensive encephalopathy. She was noted to have elevated TSH levels (12.5 mIU/L) with normal FT4 and FT3 consistent with subclinical hypothyroidism. Cranial CT scan revealed hypodense foci on the occipital area with cerebral edema. She was given levothyroxine, mannitol and antihypertensive drugs. Her blood pressure was controlled and edema subsided. Prolonged untreated hypothyroidism with elevation of thyroid stimulating hormone leads to mental retardation, short stature, sexual precocity, and hypertension. TSH and gonadotropin hormones have some regions of identical structures in common and may cross react to the same receptors. Prolonged increase in TSH and early rise in gonadotropin have led to ovarian follicles to secrete estrogen, and consequently, breast developent, menarche and skeletal maturation. The hypertension related to hypothyroidism is a result of increased peripheral resistance, changes in renal hemodynamics and hormones. Early recgonition of symptoms and treatment as well as adherenece to levothyroxine therapy is essential in preventing complications of hypothyroidism. Written informed consent was obtained from the parent of the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

English

BACKGROUND: Spondyloepiphyseal dysplasia as a sign of untreated congenital hypothyroidism is rare nowadays due to implementation of neonatal screening and increased awareness of pediatricians to detect hypothyroidism earlier. But neonatal screening is not routinely done in the developing countries. Congenital hypothyroidism is still unrecognized in some parts of developing world. OBJECTIVE: To describe the clinical, radiographic features and to stress the importance of screening of hypothyroidism during infancy and childhood and its current management. METHODS: Detailed history, physical examination and investigations. CONCLUSION: This report underscores the importance of detailed family history and physical examination in the diagnosis of spondyloepiphyseal dysplasia due to untreated congenital hypothyroidism, which was not screened for hypothyroidism during neonatal life. Being a treatable cause, hypothyroidism should always be considered as differential diagnosis of spondyloepiphyseal dysplasia, especially if the patient belongs to the developing world.

004 – Complications of Untreated Congenital Hypothyroidism

004 – Complications of Untreated Congenital Hypothyroidism

Pituitary Hyperplasia and Van Wyk Grumbach Syndrome: A Consequence of Chronic Untreated Congenital Hypothyroidism

An eight-year, 4-month old Indian girl with low IQ and delayed milestones, presented with headache (4 years), breast development (4 months), and menstrual bleeding for 22 days. Examination revealed short stature [height: 91.5 cm; SD score: -5.59], coarse dry skin, umbilical hernia (arrow), delayed reflexes, Tanner’s stage-3 breasts, absent pubic and axillary hair

症例 心エコー図上,左室壁の肥厚を伴った先天性甲状腺機能低下症の1例

症例 心エコー図上,左室壁の肥厚を伴った先天性甲状腺機能低下症の1例

Monocarboxylate Transporter 10 Functions as a Thyroid Hormone Transporter in Chondrocytes

Thyroid hormone is essential for normal proliferation and differentiation of chondrocytes. Thus, untreated congenital hypothyroidism is marked by severe short stature. The monocarboxylate transporter 8 (MCT8) is a highly specific transporter for thyroid hormone. The hallmarks of Allan-Herndon-Dudley syndrome, caused by MCT8 mutations, are severe psychomotor retardation and elevated T(3) levels. However, growth is mostly normal. We therefore hypothesized that growth plate chondrocytes use transporters other than MCT8 for thyroid hormone uptake. Extensive analysis of thyroid hormone transporter mRNA expression in mouse chondrogenic ATDC5 cells revealed that monocarboxylate transporter 10 (Mct10) was most abundantly expressed among the transporters known to be highly specific for thyroid hormone, namely Mct8, Mct10, and organic anion transporter 1c1. Expression levels of Mct10 mRNA diminished with chondrocyte differentiation in these cells. Accordingly, Mct10 mRNA was expressed most abundantly in the growth plate resting zone chondrocytes in vivo. Small interfering RNA-mediated knockdown of Mct10 mRNA in ATDC5 cells decreased [(125)I]T(3) uptake up to 44% compared with negative control (P < 0.05). Moreover, silencing Mct10 mRNA expression abolished the known effects of T(3), i.e. suppression of proliferation and enhancement of differentiation, in ATDC5 cells. These results suggest that Mct10 functions as a thyroid hormone transporter in chondrocytes and can explain at least in part why Allan-Herndon-Dudley syndrome patients do not exhibit significant growth impairment.