Hypoplastic Thyroid Research Articles

Lingual thyroid in a young asymptomatic female patient with hypothyroidism: Case report

Introduction. Lingual thyroid is a rare condition where thyroid tissue is abnormally located at the base of the tongue due to embryological development issues. The precise prevalence is uncertain, as many asymptomatic individuals do not undergo clinical examination. Case report. We present a case of a 28-year-old woman with a history of hypothyroidism. The patient exhibited no symptoms indicative of lingual thyroid. A neck ultrasound identified hypoplastic thyroid tissue centrally in the neck and a solitary nodule in the submandibular region. Further evaluation with an oropharyngeal examination revealed a solid mass at the base of the tongue. A technetium-99m pertechnetate thyroid scintigraphy, performed with single photon emission computed tomography on a hybrid gamma camera, demonstrated functional thyroid tissue at the tongue?s base, measuring 16 mm in diameter, with no functional glandular tissue in the central neck region. Conclusion. Asymptomatic lingual thyroid can be diagnosed through oropharyngeal examination, neck ultrasound and technetium-99m pertechnetate thyroid scintigraphy using a hybrid gamma camera, which provides both functional and anatomical data. Management should be individualized based on the patient?s symptoms and thyroid hormone levels.

Genetic testing can change diagnosis and treatment in children with congenital hypothyroidism.

Guidelines on congenital hypothyroidism (CH) recommend that genetic testing should aim to improve diagnosis, treatment or prognosis, but it is unclear which patients would benefit most from the genetic investigation. We aimed to investigate the genetic etiology of transient CH (TCH) and permanent CH (PCH) in a well-characterized cohort, and thereby evaluate the impact of genetic testing on the management and prognosis of children with CH. A total of 48 CH patients with normal, goitrous (n 5) or hypoplastic thyroid (n 5) were studied by high-throughput sequencing using a custom-designed 23-gene panel. Patients initially categorized as TCH (n 15), PCH (n 26) and persistent hyperthyrotropinemia (PHT, n 7) were re-evaluated after genetic testing. Re-evaluation based on genetic testing changed the initial diagnoses from PCH to PHT (n 2) or TCH (n 3) and from PHT to TCH (n 5), which resulted in a final distribution of TCH (n 23), PCH (n 21) and PHT (n 4). Genetic analysis also allowed us to discontinue treatment in five patients with monoallelic TSHR or DUOX2, or no pathogenic variants. The main reasons for changes in diagnosis and treatment were the detection of monoallelic TSHR variants and the misdiagnosis of thyroid hypoplasia on neonatal ultrasound in low birthweight infants. A total of 41 (35 different, 15 novel) variants were detected in 65% (n 31) of the cohort. These variants, which most frequently affected TG, TSHR and DUOX2, explained the genetic etiology in 46% (n 22) of the patients. The molecular diagnosis rate was significantly higher in patients with PCH (57%, n 12) than TCH (26%, n 6). Genetic testing can change diagnosis and treatment decisions in a small proportion of children with CH, but the resulting benefit may outweigh the burden of lifelong follow-up and treatment.

Serological Characteristics, Etiological Analysis, and Treatment Prognosis of Children with Congenital Hypothyroidism.

Objective The aim of the study is to analyze the serological features, etiology, and prognosis of congenital hypothyroidism (CH) treated with L-thyroxine sodium (L-T4). Methods A total of 126 CH children in our hospital from June 2015 to January 2020 were selected as the research objects, and L-T4 treatment was given immediately after diagnosis. After diagnosis and 24 months of treatment, laboratory serum thyroid function-related indicators were examined, and thyroid changes were determined by ultrasound. We compared serum thyroxine levels in children with different thyroid changes, compared serum thyroid hormone levels, serum ghrelin levels, and body mass index (BMI) changes in children with CH before treatment and after 24 months of treatment, and analyzed the prognosis of treatment in children. In terms of thyroid changes in 126 CH children, 32 cases (25.40%) had a normal thyroid gland, 16 cases (12.70%) had a hypoplastic thyroid gland, 40 cases (31.75%) had an ectopic thyroid gland, 28 cases (22.22%) had an absent thyroid gland, and 10 cases (7.93%) had an enlarged thyroid gland, with an ectopic thyroid gland being the most common. In terms of serological expression of CH children, the TSH level in children with thyroid dysplasia was significantly higher than that in children with basic normal and T3 and T4 levels were significantly lower than those in children with basic normal (P < 0.05). At the same time, the TSH level in children with thyroid absence, ectopic, and enlargement was increased, while thyroxine (T4) and tri-iodothyronine (T3) levels were decreased compared with those in children with thyroid dysplasia. The difference was statistically significant (P < 0.05). Univariate analysis showed that there were statistically significant differences in birth weight, week of gestation at delivery, maternal age at childbirth, household registration, and a family history of thyroid disease compared between the two groups (P < 0.05); multivariate logistic regression analysis showed that birth weight <2,500 g, maternal age >35 years, rural residence, and a family history of thyroid disease were risk factors for neonatal CH (P < 0.05). Serum thyroid-stimulating hormone (TSH) levels, serum ghrelin levels, and the body mass index of children with CH decreased significantly, and T4 levels increased significantly after 24 months of treatment (P < 0.05). Conclusion Screening for common causes of CH is conducive to timely detection of children with CH, and L-T4 treatment can effectively improve thyroid function in children.

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Congenital hypothyroidism with biallelic thyroglobulin (Tg protein, encoded by the TG gene) mutation is an endoplasmic reticulum (ER) storage disease. Many patients (and animal models) grow an enlarged thyroid (goiter), yet some do not. In adulthood, hypothyroid TGcog/cog mice (bearing a Tg-L2263P mutation) exhibit a large goiter, whereas adult WIC rats bearing the TGrdw/rdw mutation (Tg-G2298R) exhibit a hypoplastic thyroid. Homozygous TG mutation has been linked to thyroid cell death, and cytotoxicity of the Tg-G2298R protein was previously thought to explain the lack of goiter in WIC-TGrdw/rdw rats. However, recent studies revealed that TGcog/cog mice also exhibit widespread ER stress–mediated thyrocyte death, yet under continuous feedback stimulation, thyroid cells proliferate in excess of their demise. Here, to examine the relative proteotoxicity of the Tg-G2298R protein, we have used CRISPR–CRISPR-associated protein 9 technology to generate homozygous TGrdw/rdw knock-in mice in a strain background identical to that of TGcog/cog mice. TGrdw/rdw mice exhibit similar phenotypes of defective Tg protein folding, thyroid histological abnormalities, hypothyroidism, and growth retardation. TGrdw/rdw mice do not show evidence of greater ER stress response or stress-mediated cell death than TGcog/cog mice, and both mouse models exhibit sustained thyrocyte proliferation, with comparable goiter growth. In contrast, in WIC-TGrdw/rdw rats, as a function of aging, the thyrocyte proliferation rate declines precipitously. We conclude that the mutant Tg-G2298R protein is not intrinsically more proteotoxic than Tg-L2263P; rather, aging-dependent difference in maintenance of cell proliferation is the limiting factor, which accounts for the absence of goiter in adult WIC-TGrdw/rdw rats.

Infants Diagnosed with Athyreosis on Scintigraphy May Have a Gland Present on Ultrasound and Have Transient Congenital Hypothyroidism

Scintigraphy using technetium-99m (^99mTc) is the gold standard for imaging the thyroid gland in infants with congenital hypothyroidism (CHT) and is the most reliable method of diagnosing an ectopic thyroid gland. One of the limitations of scintigraphy is the possibility that no uptake is detected despite the presence of thyroid tissue, leading to the spurious diagnosis of athyreosis. Thyroid ultrasound is a useful adjunct to detect thyroid tissue in the absence of ^99mTc uptake. Aims: We aimed to describe the incidence of sonographically detectable in situ thyroid glands in infants scintigraphically diagnosed with athyreosis using ^99mTc and to describe the clinical characteristics and natural history in these infants. Methods: The newborn screening records of all infants diagnosed with CHT between 2007 and 2016 were reviewed. Those diagnosed with CHT and athyreosis confirmed on scintigraphy were invited to attend a thyroid ultrasound. Results: Of the 488 infants diagnosed with CHT during the study period, 18/73 (24.6%) infants with absent uptake on scintigraphy had thyroid tissue visualised on ultrasound (3 hypoplastic thyroid glands and 15 eutopic glands). The median serum thyroid-stimulating hormone (TSH) concentration at diagnosis was significantly lower than that in infants with confirmed athyreosis (no gland on ultrasound and no uptake on scintigraphy) (74 vs. 270 mU/L), and median free T4 concentration at diagnosis was higher (11.9 vs. 3.9 pmol/L). Six of 10 (60%) infants with no uptake on scintigraphy but a eutopic gland on ultrasound had transient CHT. Conclusion: Absent uptake on scintigraphy in infants with CHT does not rule out a eutopic gland, especially in infants with less elevated TSH concentrations. Clinically, adding thyroid ultrasound to the diagnostic evaluation of infants who have athyreosis on scintigraphy may avoid committing some infants with presumed athyreosis to lifelong levothyroxine treatment.

Case Report: Primary Hypothyroidism Caused by Autoimmune Thyroiditis in Infancy Requires Early Intervention

Abstract Background: Primary hypothyroidism due to autoimmune thyroiditis is extremely rare in infants, especially under the age of 3 years. For infants, hypothyroidism is most commonly congenital, originating from thyroid dysgenesis with an absent, ectopic, or hypoplastic thyroid gland (1 in 4,000 live births). If left untreated, it can lead to permanent neurodevelopmental deficits. In this report, we describe a male infant who was diagnosed with Hashimoto thyroiditis at 18 months of life, providing a learning example to aid in recognition of this rare disease and enable timely intervention. Clinical Case:Patient was a 2,765 gram, appropriate for gestational age, male born at term with hypospadias of the penis (surgical correction at 11 months). Patient passed meconium in the first 24 hours of life. During the first few months of life, patient developed constipation. Patient had amblyopia necessitating eye patching and began to wear eye glasses at 18 months of life. Patient’s linear and weight growth were within normal limits. Patient had normal motor development, however had language development delay. No known family history of thyroid disease. Screening labs performed at 17-months of age showed abnormal thyroid function: elevated TSH at 14.86 µIU/mL (ref: 0.45 - 4.50 µIU/mL) and normal free T4 level at 1.24 ng/dL (ref: 0.85-1.75 ng/dL). Repeat testing at 18 months of age continued to show elevated TSH at 6.18 µIU/mL (ref: 0.64 - 4.00 µIU/mL), normal free T4 at 1.07 ng/dL (ref: 0.88 - 2.03 ng/dL), and elevated thyroid peroxidase (TPO) antibodies at 163 IU/ml (ref: &amp;lt;35 IU/ml). At 21 months of age, patient was initiated on L-thyroxine therapy for elevation of TSH (9.570 µIU/mL; ref: 0.64 - 4.00 µIU/mL) and free T4 was normal (1.03ng/dL; ref: 0.88 - 2.03 ng/dL). Notably, the newborn screen for hypothyroidism was within normal limits, suggesting chronic autoimmune thyroiditis instead of congenital thyroid dysgenesis. Conclusions: This case report provides insights into autoimmune thyroiditis in infancy, which, although especially rare under age 3 years, should be considered in infants who present with autoimmunity or abnormal thyroid testing. In the neonatal period, infants’ immune systems are learning to discriminate requirements for self-tolerance versus protection against pathogens and may be more prone to infections. Although autoimmunity in this stage of development is uncommon, there can be breakthroughs in tolerance, as seen in this case. In addition to this patient, two other infants were seen with elevated TPO antibodies, diagnosed at 17 and 31 months old, with similar clinical trends. There remains a need for additional studies providing further insights into autoimmunity in infancy. Importantly, this case illustrates that, when infants have abnormal thyroid levels (with or without other autoimmune conditions), consideration should be made for anti-thyroid antibody testing.

MON-466 Dual Ectopic Thyroid with Normally Located Thyroid Gland in a Patient Presenting with Subclinical Hypothyroidism: A Case Report

Background: Ectopic thyroid involves the presence of thyroid tissue in sites other than its normal anatomic location. Dual ectopic thyroid with normally located thyroid gland is extremely rare with only a few cases reported in the literature. Clinical Case: A 24-year-old female presented to the clinic with subclinical hypothyroidism (TSH of 10.54 uIU/ml [ref, 0.27–4.2] and free T4 of 12.96 pmol/L [ref, 12–22]). She noted a gradually enlarging submental mass during the preceding year, which had been present since her adolescent years.Examination was notable for a 2-cm firm, non-tender mass at the submental region that slightly moved with deglutition. The thyroid was not palpable in its normal location. The relaxation phase of the deep tendon reflex was prolonged. Repeat laboratory testing showed persistently elevated TSH of 13.3 uIU/ml and normal free T4 of 13.39 pmol/L. TPO antibody was normal. Thyroid ultrasonography showed a hypoplastic thyroid measuring 2.7 x 0.7 x 0.4 cm on the right and 3.0 x 0.7 x 0.4 cm on the left. A well-circumscribed complex nodule measuring 2.7 x 3.2 x 2.1 cm was noted on the submental region corresponding to the patient’s submental mass. Computed tomography of the neck with contrast showed two hyperdense foci - measuring 3.0 x 2.4 cm at the submental region and 1.4 x 1.2 cm at the base of the tongue. No enhancing thyroid tissue was seen anterior to the thyroid cartilage. 99mTechnetium-pertechnetate scan showed absent focal tracer uptake in the anterior neck and thorax. There were foci of increased tracer activity in the submental and lingual regions. Ultrasound-guided biopsy of the submental area showed cytomorphologic features of a colloid nodule with cystic degeneration (Bethesda Category II). The patient was started on levothyroxine and remained biochemically euthyroid afterwards. The submental neck mass reduced in size. Conclusion: Dual ectopic thyroid with normally located (eutopic) thyroid gland could present with subclinical hypothyroidism. There is no single diagnostic modality that would best identify dual ectopic thyroid; thus, thyroid scan, ultrasonography, CT scan and biopsy are recommended to be used complementarily. For patients with dual ectopic thyroid and hypothyroidism, levothyroxine replacement is recommended to reduce the size of ectopic thyroid and render the patient euthyroid.

Final height of Korean patients with early treated congenital hypothyroidism.

Purpose Congenital hypothyroidism (CH) is the most common endocrine disorder in children. Thyroid hormone deprivation results not only in mental retardation but also growth retardation. This study investigates the final height (FH) in Korean patients with CH detected by newborn screening and examines factors that may affect the FH.Methods The medical records of Korean CH patients (n=45) were reviewed. The FH was examined and target height (TH) was calculated based on mid-parental height. The FH z score (FHZ) and TH z score (THZ) were computed using the 2007 Korean National Growth Chart. The FHZ and THZ were compared with a Student t test. The impact of the etiology of CH (athyreosis, dyshormonogenesis, ectopic thyoid, hypoplastic thyroid), initial serum thyroid stimulating hormone (TSH) level, initial free thyroxine (T4) level, and time of therapy initiation based on FH was assessed.Results The mean FHZ was 0.10±1.01 for male patients and -0.11±1.09 for female patients. There were no significant differences between FHZ and THZ for both female (P=0.356) and male patients (P=0.237). No significant relationship was found between FH and the etiology of CH, initial TSH level, initial free T4 level, and the time of therapy initiation.Conclusion Early intervention and satisfactory management do not appear to impede growth in Korean patients with CH. Thus, early detection and proper management of patients with CH detected by newborn screening program are necessary.

The role of scintigraphy and ultrasound in the imaging of neonatal hypothyroidism: 5‐year retrospective review of single‐centre experience

Congenital hypothyroidism (CH), as indicated by an elevation of capillary thyroid-stimulating hormone (TSH) at newborn screening, is a preventable cause of mental retardation with varying aetiology; it can be transient or permanent. Radionuclide assessment is currently the gold standard for imaging CH. This study aimed to (i) review the different scintigraphic patterns and correlate them with TSH levels/patient outcomes, (ii) assess the role of sonography in neonates with apparent agenesis as indicated by scintigraphy and (iii) develop a diagnostic investigative algorithm. The technetium thyroid scans of 83 consecutive patients (49 females, average age 32 days) with CH scanned between 2005 and 2009 were retrospectively reviewed. Two nuclear medicine physicians blinded to the clinical details interpreted the scans in consensus. Scintigram appearances were categorised into five groups. Patients scintigraphically diagnosed with thyroid agenesis were evaluated with ultrasound. TSH values and scintigraphic and sonographic findings were correlated with patients' final diagnosis. Based on scintigraphy, 14, 13 and 19 patients out of 83 were assessed as having normal thyroid sites with normal, increased and decreased uptake, respectively. Twenty-two of 83 patients had no uptake, and 15 of 83 patients had ectopic uptake. Higher median TSH levels were seen in no-uptake and ectopic uptake subgroups. Eighteen of 22 patients with no uptake were evaluated with ultrasound. Three of the 18 patients had a normal thyroid gland, and three of 18 patients had a hypoplastic thyroid. Scintigram findings in patients with congenital hypothyroidism fall into five major categories, which have therapeutic implications (lifelong thyroxine in agenesis versus trial of stopping thyroxine in other subgroups). Sonographic demonstration of thyroid tissue in patients scintigraphically diagnosed with thyroid agenesis has major management implications.

Identification of PENDRIN (SLC26A4) Mutations in Patients With Congenital Hypothyroidism and “Apparent” Thyroid Dysgenesis

Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.

Programa de Triagem Neonatal para hipotireoidismo congênito de Santa Catarina, Brasil: avaliação etiológica no primeiro atendimento

To evaluate the etiology of primary congenital hypothyroidism (PCH) identified in the Newborn Screening Program from the state of Santa Catarina, Brazil, from July 2007 to June 2009 in the first visit. A prospective study was performed in 45 patients with PCH. For the etiological diagnosis, history, physical examination, and additional tests (TSH, free thyroxine, thyroglobulin, bone age assessment, thyroid ultrasound) were carried out in the first visit. The etiology was established in the first visit in 53.3% of cases. Thyroid dysgenesis represented 51.11% of the cases, from which 20% showed hypoplastic thyroid, 13.3% showed athyreosis, and 17.7% showed ectopic glands; 2.2% were diagnosed with dyshormonogenesis. Umbilical hernia was the most prevalent sign (48.89%) and 20% had no clinical manifestations. Patients with dysgenesis showed significant differences (p < 0.05) in terms of cesarean section delivery, delayed bone age, and very high serum TSH. The diagnostic approach used at first visit for PCH patients may determine the etiology in 53.3% of cases. Half of patients had thyroid dysgenesis.

Normal Pozisyonuyla Lingual Tiroid: İki Olgunun Sunumu

Lingual thyroid is a congenital anomaly caused by failure of migration of the thyroid gland in early embryogenesis. It may be asymptomatic or present with local symptoms. We present two cases with lingual thyroid, first one being in a 28-year-old female and the other in a 25-year-old male who had 20x15 mm and 33x30 mm masses respectively detected by magnetic resonance imaging. The diagnoses of lingual thyroid were confirmed by 99mTc pertechnetate scintigraphy. Thyroid function tests revealed hypothyroidism in both cases. Since most of the patients present with hypothyroidism, the diagnosis of lingual thyroid should be suspected especially in a case with local complaints. In routine examination of hypothyroid patients, palpation of the thyroid gland and ultrasonography must be included. A detailed examination of the neck and the base of the tongue must be performed in terms of lingual thyroid in patients with hypothyroidism and hypoplastic thyroid gland.

Difficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma

Consumptive hypothyroidism is a rare condition related to massive infantile hemangiomas producing an excess of the thyroid-hormone-inactivating enzyme type 3 iodothyronine deiodinase. We report the first case of consumptive hypothyroidism secondary to a large parotid hemangioma, highlighting the difficulties in selecting an adequate therapeutic strategy. The affected child was initially referred to our center for congenital hypothyroidism with a hypoplastic thyroid gland. L-Thyroxine (L-T4) replacement therapy was started at seven days of life. In the following weeks, the hemangioma rapidly increased in volume and the child developed severe hypothyroidism refractory to high doses of L-T4 therapy. The concentration of reverse triiodothyronine was elevated, suggesting that the underlying cause was an excessive conversion of thyroid hormones by high type 3 iodothyronine deiodinase levels in the tumor. Corticosteroid treatment showed only partial benefit. Introduction of propranolol instead led to normalization of thyroid hormones along with a dramatic involution of the hemangioma.

Pitfalls in the diagnosis of thyroid dysgenesis by thyroid ultrasonography and scintigraphy

We aimed to investigate the reliability of thyroid ultrasonography (US) and scintigraphy in determining the type of thyroid dysgenesis (TD). The study included 82 children (8.0±5.6 years) with a diagnosis of TD by thyroid scintigraphy with (99m)Tc and/or US. The patients were re-evaluated 6.0±5.1 years after the diagnosis. Thyroid US was performed in all cases, regardless of the previous US imaging. Scintigraphy images performed at the time of diagnoses (n=60) were re-evaluated during the study. Those who had no scintigraphy at the time of diagnosis (n=22) or had discordant findings with US (n=6) underwent a new scintigraphy. Scintigraphies revealed no uptake in 37, ectopia in 35, and hypoplasia in 10 cases. The sensitivity vs specificity for US to detect athyreosis, ectopia, and hypoplasia at the time of initial diagnoses was 90.5 vs 47.8, 10 vs 100, and 100 vs 80.4% respectively. The sensitivity vs specificity for scintigraphy at the time of initial diagnoses was 96.2 vs 100, 92 vs 97.1, and 100 vs 96%, respectively, for each diagnosis. Re-scintigraphy at the time of the study led to a change in the initial diagnosis of 3/6 cases. Repeated US showed disappearance of previously reported hypoplastic thyroid tissues in eight patients. US alone could not differentiate ectopia and athyreosis, whereas scintigraphy alone is also prone to mistakes in newborns and young ages. Dual thyroid imaging is important for precise structural definition of TD.

Dual Ectopic Thyroid with Normally Located Thyroid: A Case Report

Dual ectopic thyroid is a rare presentation of thyroid ectopia. Only a few cases have been reported in the world literature. Dual ectopic thyroid in the presence of a normally located thyroid is even rarer. We report a case of dual ectopic thyroid in the lingual and submandibular areas in a seventeen-year-old female with hypoplastic thyroid gland in its normal location. The patient presented with a midline swelling at the base of tongue with dysphagia. Thyroid function test revealed primary hypothyroidism. Ultrasonography of the neck showed hypoplastic thyroid in its normal location. A thyroid scan with Technetium-99 m pertechnate showed two intensely hyperfunctioning foci of ectopic thyroid tissue at a higher level in the midline consistent with dual ectopic thyroid, one at the base of tongue and the other in submental region. No uptake was seen in the normal bed.

Characterization of a novel loss‐of‐function mutation of PAX8 associated with congenital hypothyroidism

Congenital hypothyroidism (CH) is a common endocrine disease that occurs in about 1:3000 newborns. In 80-85% of the cases, CH is presumably secondary to thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to an ectopic (30-45%), absent (agenesis, 35-40%) or hypoplastic (5%) thyroid gland. The pathogenesis of TD is still largely unknown. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, mutations in the PAX8 transcription factor have been identified in patients with TD. Our aim was to identify and functionally characterize novel PAX8 mutations with autosomal dominant transmission responsible for TD. The PAX8 gene was sequenced in a mother and child both suffering from congenital hypothyroidism (CH) because of thyroid hypoplasia. Subsequently, expression vectors encoding the mutated PAX8 were generated, and the effects of the mutation on both the DNA-binding capability and the transcriptional activity were evaluated. PAX8 gene sequencing revealed a heterozygous mutation that consists of the substitution of a histidine residue with a glutamine at position 55 of the PAX8 protein (H55Q). When tested in cotransfection experiments with a thyroglobulin promoter reporter construct, the mutant protein turned out to be still able to bind DNA in Electrophoretic Mobility Shift Assay assays but transcriptionally inactive. Our findings confirm the important role of PAX8 in normal thyroid development and support the evidence that in humans haploinsufficiency of PAX8 is associated with TD.

Congenital Thyroid Hypoplasia and Seizures in 2 Littermate Kittens

Congenital Thyroid Hypoplasia and Seizures in 2 Littermate Kittens

Severe skeletal dysplasia caused by undiagnosed hypothyroidism

Due to increased awareness of early clinical signs and introduction of neonatal screening for congenital hypothyroidism, long-term untreated hypothyroidism has become rare. Nevertheless, neonatal screening for congenital hypothyroidism is not performed in all countries, and not every affected patient might be picked up by neonatal screening alone. Here we describe a case of congenital hypothyroidism due to an ectopic thyroid that was not diagnosed for 13 years and resulted in severe skeletal changes beside mental disablement. The patient showed coarse facial features (hypertelorism, broad flat nasal bridge, broad face) and a severe truncal shortening due to kyphoscoliosis of the spine. X-rays detected highly retarded bone age, a widely opened anterior fontanelle, immature, flat bodies of the vertebra with ventral beaked deformities mainly in the lumbar region and no ossification centres in the head of the femurs. In this patient we found no evidence for a mutation of the PAX8 gene known to cause an ectopic and/or hypoplastic thyroid.

Thyroid Morphology and Subclinical Hypothyroidism in Children and Adolescents with Williams Syndrome

To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.

Screening for Pax8 Mutations in Patients with Congenital Hypothyroidism in South-West Germany

Aims: To study the frequency of mutations in the Pax8 gene in a cohort of patients with congenital hypothyroidism (CH) in South West Germany. Methods: A cohort of 95 patients with CH (60 females, 35 males), identified in our newborn screening program, was analyzed for mutations in Pax8 by single-stranded conformational polymorphism (SSCP) and DNA sequencing. Results: SSCP analysis and direct sequencing of exon 3 of a female patient with a hypoplastic thyroid gland revealed two heterozygous mutations in Pax8 resulting in a transition of T to C (codon 34) and G to A (codon 35), replacing isoleucine by threonine and valine by isoleucine. Using allele-specific PCR we could demonstrate that both mutations are located on the same allele. Furthermore, a polymorphism was documented in 24 patients with thyroid hypoplasia in intron 6 at nucleotide +51 (CC, GG, CG). Comparison of the polymorphisms between hypothyroid patients and controls revealed no significant differences suggesting that this polymorphism does not play a role in the pathogenesis of hypothyroidism. No further mutations or polymorphisms were found in the cohort. Conclusions: These findings confirm the contribution of mutations in the Pax8 gene to the etiology of thyroid dysgenesis with a variable penetrance, but also demonstrate the rare overall incidence in CH.