Pendred syndrome among patients with congenital hypothyroidism detected by neonatalscreening: identification of two novel <Emphasis Type="Italic">PDS/SLC26A4</Emphasis> mutations

Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by mutations in the PDS/SLC26A4 gene (OMIM 605646) encoding for pendrin. Hypothyroidism in Pendred syndrome can be—although rarely—present from birth and therefore diagnosed by neonatal screening. The aim of our study was to identify patients with Pendred syndrome among a historical cohort of patients with congenital hypothyroidism (CH) identified by neonatal screening, and to find their mutations in the PDS/SLC26A4 gene. We investigated 197 Czech Caucasian children with CH detected by the neonatal screening between the years 1985 and 2005. The clinical diagnosis of Pendred syndrome was based on the laboratory and sonographic signs of thyroid dyshormonogenesis in association with sensorineural hearing loss. In subjects clinically diagnosed with Pendred syndrome, we sequenced all exons and exon-intron boundaries of the PDS/SLC26A4 gene. Hearing loss was present in 10/197 children with screening-detected CH. Of these, three fulfilled the diagnostic criteria of Pendred syndrome. Two patients were compound heterozygotes for PDS/SLC26A4 mutations: patient 1 carried c.2089+1G>A / c.3G>C and patient 2 carried p.Tyr530His / p.Val422Asp. Two of the four identified mutations were novel (c.3G>C in patient 1 and p.Val422Asp in patient 2). The third patient was free of mutations in the PDS/SLC26A4 gene, representing a phenocopy. In conclusion, our results indicate the rarity of Pendred syndrome as a cause of CH. The identification of two novel mutations expands the spectrum of mutations in the PDS/SLC26A4 gene and emphasizes their marked allelic heterogeneity. The study was supported by grants of the Czech Ministry of Education (MSM 0021620814) and Charles University in Prague (GAUK 2008/2007).     

Toxic adenoma in childhood — case report

ABSTRACT. A 12-year-old girl was noted to have a left sided thyroid nodule on routine examination. Although clinically euthyrold she was found to have an elevated T3 value, and the TSH failed to rise following TRH injection. Thyroid scan showed a hyperfunctioning nodule in the left lobe of the thyroid gland. Following surgical removal of the nodule the patient became biochemically euthyroid and a repeat thyroid scan demonstrated the previously suppressed normal right lobe.     

Differential diagnosis between Pendred and pseudo-Pendred syndromes: clinical, radiologic, and molecular studies

The disease gene for Pendred syndrome has been recently characterized and named PDS. It codes for a transmembrane protein called pendrin, which is highly expressed at the apical surface of the thyroid cell and functions as a transporter of chloride and iodide. Pendrin is also expressed at the inner ear level, where it appears to be involved in the maintenance of the endolymph homeostasis in the membranous labyrinth, and in the kidney, where it mediates chloride-formate exchange and bicarbonate secretion. Mutations in the PDS gene and the consequent impaired function of pendrin leads to the classic phenotype of Pendred syndrome, i.e. dyshormonogenic goiter and congenital sensorineural hearing loss. In the present study, we performed a detailed clinical, radiologic, and molecular analysis of six families presenting with clinical diagnosis of Pendred syndrome. In two families a homozygous pattern for PDS mutations was found, whereas the affected members of the other four families were compound heterozygotes. One family did not harbor PDS mutations. Among the four novel mutations described, one is a transversion in exon 2 (84C>A), leading to the substitution S28R. Two other novel mutations lie in exon 4 (398T>A) and in exon 16 (1790T>C), leading to the substitutions S133T and L597S, respectively. The fourth novel mutation (1614+1G>A) is located in the first base pair of intron 14, probably affecting the splicing of the PDS gene. Clinically, all patients had goiter with positive perchlorate test, hypothyroidism, and severe or profound sensorineural hearing loss. In all the individuals harboring PDS mutations, but not in the family without PDS mutations, inner ear malformations, such as enlargement of the vestibular aqueduct and of the endolymphatic duct and sac, were documented. The pseudo-Pendred phenotype exhibited by the family without PDS mutations is likely caused by an autoimmune thyroid disease associated with a sensorineural hearing loss of different origin.     

Recurrent Thyroid Nodule: Spindle Epithelial Tumor with Thymus-like Differentiation (SETTLE)

Thyroid nodules are uncommon in childhood and recurrent thyroid nodules even rarer. Spindle epithelial tumor with thymus-like differentiation (SETTLE), a rare and distinctive lowgrade neoplasm is amongst the differential diagnosis of solitary thyroid nodule in children. We describe a boy who underwent completion thyroidectomy for SETTLE in the thyroid remnant four years after initial lobectomy was performed for the same diagnosis. Patients with SETTLE are to be closely followed as multifocality may manifest and be detected later.     

The association of thyroid dyshormonogenesis and deafness (Pendred syndrome): Experience of the Victorian Neonatal Thyroid Screening Programme

Between 1977 and 1989, the Victorian Neonatal Thyroid Screening Programme detected five subjects with thyroid dyshormonogenesis and sensorineural deafness. These patients have been diagnosed as having Pendred syndrome. In two of the children, thyroid function tests which were initially abnormal at birth returned to normal spontaneously without treatment. However, hypothyroidism subsequently recurred and the children required thyroxine therapy. These two children could have been mistakenly diagnosed as having transient hypothyroidism. The detection of five patients with Pendred syndrome illustrates the importance of audiological assessment in all babies with thyroid dyshormonogenesis in whom there is increased uptake of isotope on thyroid scanning. In our experience, hearing loss in patients with Pendred syndrome may be progressive over time, so that repeated audiological assessments are necessary.     

Identification of SLC26A4 gene mutations in Iranian families with hereditary hearing impairment

Mutations in the SLC26A4 gene at the DFNB4 locus are responsible for Pendred syndrome and non-syndromic hereditary hearing loss (DFNB4). This study included 80 nuclear families with two or more siblings segregating presumed autosomal recessive hearing loss. All deaf persons tested negative for mutations in GJB2 at the DFNB1 locus and were, therefore, screened for autozygosity by descent (ABD) using short tandem repeat polymorphisms (STRPs) that flanked SLC26A4. In 12 families, homozygosity for STRPs suggested possible ABD in this genomic region. Affected individuals in five families had a positive perchlorate discharge test. Sequence analysis of SLC26A4 identified ten mutations in eight families (T420I, 1197delT, G334V, R409H, T721M, R79X, S448L, L597S, 965insA and L445W), of which, four are novel (T420I, G334V, 965insA and R79X). These results imply that Pendred syndrome is the most prevalent form of syndromic hereditary hearing loss in Iran.     

An Egyptian family with H syndrome due to a novel mutation in SLC29A3 illustrating overlapping features with pigmented hypertrichotic dermatosis with insulin‐dependent diabetes and Faisalabad histiocytosis

The SLC29A3 gene, encoding hENT3, a member of the equilibrative nucleoside transporter family, has recently been found mutated in Faisalabad histiocytosis, pigmented hypertrichotic dermatosis with insulin‐dependent diabetes, familial sinus histiocytosis with massive lymphadenopathy (SHML), and H syndromes. We here report clinical and genetic findings of an Egyptian family with H syndrome. We describe two siblings, a 19‐yr old girl and a 15‐yr old boy, of consanguineous parents. From 5 yr of age, the girl developed bilateral flexion deformity of interphalengeal joints and insulin‐dependent diabetes mellitus. At age 7 yr, prominent hyperpigmented patches appeared on the skin at lower limbs, genitalia, and trunk. On clinical examination, she had hepatosplenomegaly, generalized lymphadenopathy, left ventricular hypertrophy, sensorineural hearing loss, hypogonadism, short stature, and characteristic dysmorphic features. Her brother had fixed flexion contractures of the feet, profound sensorineural hearing loss, characteristic dysmorphic features, but no diabetes. DNA sequence analysis revealed a homozygous mutation (c.300+1G>C) in SLC29A3 in both siblings. The phenotype and genotype of the siblings were compatible with that of the H syndrome, although the features were overlapping with those found in pigmented hypertrichotic dermatosis with insulin‐dependent diabetes, familial SHML, and Faisalabad histiocytosis, indicating that these four syndromes may be regarded as one disease with varying phenotypic features. A new, common name for these conditions is warranted.     

Thyroid Nodules in Childhood: a Single Institute Experience

Objective

Thyroid nodules are rare in children. Multiple diagnostic modalities are used to evaluate the thyroid mass. The aim of this study was to determine results of management of thyroid nodules in children with special attention to the role of fine needle aspiration biopsy (FNAB) in diagnosis.

Methods

Thirty-two children who underwent surgery for thyroid nodules in Mofid Children''s Hospital within 10 years (1996 to 2005) were retrospectively studied. From clinical records we obtained data about demographic characteristics, clinical manifestations, ultrasonography (USG) findings, and FNAB results, pathological reports, surgical therapy and complications. Data was analyzed statistically for association with thyroid cancer.

Findings

Twenty-five patients (78.1%) were girls, and 7 (21.9%) boys. Mean age was 10.9 (range 8 to 14) years. 24 (75%) patients had benign and 8 (25%) malignant tumors. 18 (56.25%) nodules were located in the right lobe. Statistical analysis revealed sensitivity, specificity, accuracy, and positive and negative predictive values as follows: 80%, 65%, 63%, 25%, and 86% for USG; 35%, 41%, 40%, 18%, and 66% for RNS; 91%, 94%, 90%, 74%, and 96% for FNAB respectively.

Conclusion

Clinical judgment as determined by serial physical findings with USG continues to be the most important factor in the management of thyroid nodules in children. FNAB is the most accurate method of investigation and its accuracy is improved by USG guidance.     

Surveillance following head,neck, and chest radiotherapy: Thyroid ultrasound monitoring for secondary thyroid malignancy

Children who receive head, neck, or chest radiotherapy for various primary malignancies have increased risk for secondary thyroid malignancy. Thyroid nodules are difficult to identify by physical examination and/or laboratory tests. Thyroid ultrasound can detect non‐palpable nodules without adverse side effects. We performed a retrospective chart review of 36 patients who received radiotherapy and underwent thyroid ultrasound. Forty‐seven percent (n = 17) had ≥1 nodule(s) detected. Seven patients underwent thyroidectomy; four of whom were diagnosed with thyroid malignancy. Our study suggests routine use of thyroid ultrasound in high‐risk patients detects subclinical thyroid nodules and potential thyroid malignancy post‐radiotherapy. Pediatr Blood Cancer 2013; 60: 140–142. © 2012 Wiley Periodicals, Inc.     

Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma

BACKGROUND: Survivors of Hodgkin lymphoma and other patients who receive neck irradiation are at increased risk of thyroid cancer. Ultrasonography provides an inexpensive and non-invasive method of thyroid screening, but the clinical significance of thyroid nodules detected by ultrasound screening is uncertain. PROCEDURE: We reviewed the demographics, clinical characteristics, method of detection, and outcome of patients who developed thyroid nodules after treatment for pediatric Hodgkin lymphoma at our institution. One radiologist reviewed all imaging studies. RESULTS: Sixty-seven children treated for Hodgkin lymphoma from 1962 to 2001 developed thyroid nodules. The study group represented 9,024 person-years of follow-up after the diagnosis of Hodgkin lymphoma and 581 person-years after diagnosis of a thyroid nodule. A median of 10.5 years (range, 0.2-24.8 years) elapsed between the diagnoses of Hodgkin lymphoma and thyroid nodule(s). All but one patient had received neck irradiation for Hodgkin lymphoma, with a median thyroid radiation dose of 35 Gy (range, 12-45 Gy). Thyroid nodules were found to be malignant in seven patients (10%), at a median of 16.2 years (range, 8.4-23.7 years) after diagnosis of Hodgkin lymphoma. Only one malignancy was found through screening ultrasonography. All patients with thyroid cancer remained disease-free at 0.4-16.2 years of follow-up. CONCLUSIONS: Thyroid nodules are common in Hodgkin lymphoma survivors treated with neck irradiation, but the majority of these lesions have an indolent clinical course and do not undergo malignant transformation. Only patients with a palpable mass or clinical symptoms need more extensive evaluation, including Doppler-flow ultrasonography and fine-needle aspiration.     

Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter

Thyroid hormones are known to be essential for growth, development, and metabolism. Recently, the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter, and MCT8 mutations have been associated with Allan-Herndon-Dudley syndrome, an X linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. Here we describe in detail the clinical and biochemical features and the response to thyroid hormone (L-thyroxine (LT4)) administration in a boy with an MCT8 mutation (c.1649delA) that truncates the protein in the twelfth transmembrane domain. It is of note that brain magnetic resonance imaging (MRI) revealed delayed myelination from infancy. Endocrine functions other than thyroid hormone regulation and metabolism were intact, resulting in normal hypothalamic/pituitary function tests. While LT4 administration suppressed thyrotropin (TSH) secretion, no significant changes in thyroid hormone values or clinical symptoms were observed. Conclusion: the characteristic thyroid hormone function tests and brain MRI findings may allow screening of high-risk populations for a better understanding of MCT8 pathophysiology.     

Patients exposed to diagnostic head and neck radiation for the management of shunted hydrocephalus have a significant risk of developing thyroid nodules

Purpose

External radiation to the head and neck can lead to an increased incidence of thyroid nodules. We investigated whether patients requiring repeated head and neck imaging for the management of shunted hydrocephalus had a higher incidence of ultrasound-detected thyroid nodules compared to reports of comparable age.

Methods

Patients treated at our institution for shunted hydrocephalus from 1990 to 2003 were contacted. Enroled patients underwent a thyroid ultrasound. Demographic data and radiation exposure history were obtained retrospectively.

Results

Thyroid nodules were identified sonographically in 15/112 patients (13.6 %). Patients with thyroid nodules were older (mean 24.3 ± 7.6 years) than those without (mean 18.4 ± 8.0 years) (p = 0.005). Those with a detectable thyroid nodule had a longer follow up time compared to those who did not (mean 21.9 ± 5.5 vs. 15.1 ± 7 years, respectively) (p = 0.018).

Conclusion

Patients with shunted hydrocephalus are exposed to substantial head and neck radiation from diagnostic imaging and have a higher incidence of thyroid nodules detected by ultrasonography. These patients should be provided ongoing surveillance for detection of thyroid nodules and the possibility of malignancy.

     

Pleuropulmonary blastoma in an infant

Pleuropulmonary blastomas (PPB) are rare and highly aggressive tumors. Herein, we report an infantile case of type III PPB. A 9-mth-old boy presented to our unit with a history of cough and tachypnea for 2 days. Chest computed tomography revealed a mass in the left upper lobe, emphysema in the left upper lung, and mediastinum and heart shifted towards the right. The mass was removed completely by left upper lobectomy and histology confirmed diagnosis of type III PPB. The immature blastematous tissue was positive for vimentin while benign epithelium was positive for epithelial membrane antigen and cytokeratin. No lymph nodule metastasis was found in the 7 lymph nodules obtained from the hilum of the lung near the tumor. Currently, the patient is under close follow-up and is doing well.     

A novel non-sense mutation in the <Emphasis Type="Italic">SLC2A10</Emphasis> gene of an arterial tortuosity syndrome patient of Kurdish origin

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient’s DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.     

Diagnostic dilemma. The goiter

The incidence of goiters in children is about 4% to 5%. The first step in the evaluation is to decide whether the swelling indeed involves the thyroid. After careful examination, one determines if the thyroid is diffusely or focally enlarged. A solitary nodule merits an extensive workup because of the high rate of malignancy. The evaluation of a diffuse goiter proceeds after deciding if the patient is euthyroid, hypothyroid, or hyperthyroid. In most cases, the child is euthyroid and the diagnosis is either CLT or simple colloid goiter. Laboratory tests for thyroid function and antibodies usually make the diagnosis. The hypothyroid patient most likely has CLT, although drugs or goitrogens, dyshormonogenesis, and thyroid resistance are also possible. The hyperthyroid patient usually has Graves' disease. The incidence of malignancy of solitary thyroid nodules is 15% to 40%; therefore, evaluation must be sensitive enough not to miss cancer. Ultrasonography helps to delineate the anatomy and to reveal if the nodule is cystic. Radionuclide scans are useful, as warm or hot lesions are rarely malignant. Cold nodules require further investigation, and in most institutions, this amounts to open biopsy. Fine-needle aspiration may be used if the clinician and pathologist are experienced. With this aggressive approach to thyroid nodules, malignancies are given early treatment. The prognosis is good in most thyroid carcinomas.     

Lung abscess in a child with Mycoplasma pneumoniae infection

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in children, while lung abscess is a severe complication of bacterial pneumonias caused mainly by pyogenes. Here we report a previously healthy 10-year-old boy admitted to our unit for a right upper lobe pneumonia, with a 15-day history of fever and cough insensitive to oral amoxicillin and intramuscular ceftriaxone. Chest computed tomography scan revealed that the right upper lobe consolidation was an abscess and that a similar formation was present in the right mid region. Serology allowed the diagnosis of M. pneumoniae infection. The clinical picture rapidly improved after initiation of oral clarithromycin, and radiographic resolution, without sequelae, was observed after 1-month treatment. Lung abscess in children is a rare complication of M. pneumoniae infection and only three previous cases have been described in the literature, all associated with a delayed diagnosis and late initiation of macrolide therapy. A long-term treatment with oral macrolide allows a prompt recovery and restitution ad integrum of the lung.     

Hürthle cell carcinoma in an autonomous thyroid nodule in an adolescent

A 16-year-old girl presented with a palpable thyroid nodule which was found to be functioning autonomously by radioiodine (¹²³I) scintigraphy. After needle biopsy proved nondiagnostic, surgical excision showed the nodule to be Hürthle cell carcinoma. Functional thyroid nodules are rarely malignant, thyroid carcinoma is rare in childhood, and Hürthle cell carcinoma is a rare thyroid neoplasm, so the presence of these three rare conditions in one patient makes it a very unusual case.     

Papillary carcinoma of the thyroid gland in a child of thyrotoxicosis patient receiving radioactive iodine therapy: report of a case

Herein we present the case of a 9-year-old girl who had an enlarged right lobe of the thyroid gland and sub-clinical hypothyroidism (thyroid stimulating hormone at 9.24 mIU/L). The patient had a history of unintentional exposure to radiation while her mother was receiving radionuclide therapy for diffuse toxic goiter. Ultrasonography of the young girl showed right lobe enlargement with diffuse coarse heterogenous echogenicity, compatible with a microcalcification pattern identified in both lobes of the thyroid gland. Histopathology of the tissue from a thyroidectomy revealed papillary thyroid carcinoma in the right lobe and chronic lymphocytic thyroiditis in the remaining tissue. Molecular pathology demonstrated an RET/PTC1 rearrangement in both tumor and non-tumorous tissue harboring thyroiditis. Considering the history of exposure and the characteristics of the thyroid pathology together, the PTC in this patient was likely a secondary-to-genetic alteration induced by external radiation. This case emphasizes the importance of stringent restrictions when giving radioactive iodine therapy to a patient with small children.