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We present a male patient with neonatal severe primary hyperparathyroidism, whose manifestation was exceptionally serious for the heterozygous inactivating mutation he carried in the CASR gene. The patient presented soon after birth with respiratory distress requiring long-term mechanical ventilation, bone and chest deformities, feeding problems, and hypotonia. He had hypercalcaemia, hypophosphataemia, and hyperparathyroidism. There was no known history of calcium metabolism disorders in the family. As the impact on calcaemia of a rescue therapy with bisphosphonates was only transient, a subtotal and subsequently total parathyroidectomy were performed in the fourth month of life. Afterwards his clinical status improved and the fractures healed, but his neuropsychological development is delayed due to cerebral atrophy. Genetic analysis revealed a heterozygous missense CASR mutation R185Q, and an approximately equal expression of the mutated and wild-type RNA in the parathyroid tissue. The mother of the child was homozygous for the wild-type allele; the father is unknown. In conclusion, this patient demonstrates how serious neonatal hyperparathyroidism can be when caused by a heterozygous mutation. This may be attributable to a combination of dominant-negative action of the mutant allele with an intrauterine foetal hyperparathyroidism developed in the mother's normocalcaemic environment, further aggravated by a putative maternal vitamin D deficiency during pregnancy.

MeSH
bodová mutace genetika MeSH
dospělí MeSH
fenotyp MeSH
heterozygot MeSH
hyperkalcemie genetika komplikace MeSH
hyperparatyreóza genetika chirurgie komplikace MeSH
lidé MeSH
nedostatek vitaminu D diagnóza epidemiologie MeSH
novorozenec MeSH
paratyreoidektomie MeSH
prenatální diagnóza MeSH
receptory "calcium-sensing" genetika MeSH
stupeň závažnosti nemoci MeSH
těhotenství MeSH
Check Tag
dospělí MeSH
lidé MeSH
novorozenec MeSH
těhotenství MeSH
ženské pohlaví MeSH
Publikační typ
kazuistiky MeSH
práce podpořená grantem MeSH

Článek

Thyroidectomy in a patient with multinodular dyshormonogenetic goitre--a case of Pendred syndrome confirmed by mutations in the PDS/SLC26A4 gene

Journal of pediatric endocrinology & metabolism. 2008 ; 21 (12) : 1179-1184.

J Pediatr Endocrinol Metab
ISSN 0334-018X
Medvik
Zdroj

We report a young woman with genetically confirmed Pendred syndrome and discuss the current therapeutic strategies of dyshormonogenetic goitre. A small diffuse thyroid enlargement developed during infancy and although substitution therapy with L-thyroxine was adequate, it progressed and underwent multinodular transformation. Cervical ultrasound at the age of 22 years demonstrated three solid nodules and fine-needle aspiration biopsy showed a finding typical of follicular adenoma. It is known that dyshormonogenetic goitres have a tendency to grow despite appropriate treatment with L-thyroxine. Management of a patient with Pendred syndrome requires careful follow-up and regular imaging of the thyroid. Although the therapeutic approach to dyshormonogenetic goitres is still controversial, in our patient we chose total thyroidectomy as the most advantageous method to prevent the development of malignancies that may arise more frequently from dyshormonogenetic goitres than from goitres of other aetiologies.

MeSH
dospělí MeSH
financování organizované MeSH
lidé MeSH
membránové transportní proteiny genetika MeSH
mutace genetika MeSH
percepční nedoslýchavost genetika MeSH
syndrom MeSH
thyreotropin krev MeSH
thyroxin terapeutické užití MeSH
tyreoidektomie MeSH
uzlová struma farmakoterapie genetika chirurgie MeSH
vnitřní ucho abnormality MeSH
Check Tag
dospělí MeSH
lidé MeSH
ženské pohlaví MeSH
Publikační typ
kazuistiky MeSH

Článek

Pendredův syndrom u pacientů s hypotyreózou: genetická diagnostika, fenotypová variabilita a výskyt fenokopií
[Pendred syndrome among patients with hypothyroidism: genetic diagnosis, phenotypic variability and occurrence of phenocopies]

Časopis lékařů českých. 2008 ; 147 (12) : 616-622.

ISSN 0008-7335
Medvik
Zdroj

Pendredův syndrom (OMIM274600) je jednou z příčin kongenitální hypotyreózy na podkladě dyshormonogeneze. Jedná se o autozomálně recesivní onemocnění definované jako asociace senzorineurální hluchoty a dyshormonogenetické strumy. Onemocnění je způsobeno mutacemi v PDS/SLC26A4 genu kódujícím pendrin – aniontový transportér, který je exprimován hlavně ve štítné žláze a vnitřním uchu. Dyshormonogeneze se u Pendredova syndromu projeví jen u 80 % pacientů jako eutyreoidní nebo hypotyreoidní struma a jen zřídka je klinicky významná již při narození, kdy může být diagnostikována novorozeneckým skríninkem. Cílem studie bylo identifikovat pacienty s klinickou diagnózou Pendredova syndromu mezi dětmi s vrozenou nebo postnatálně vzniklou non-autoimunitní hypotyreózou a následně diagnózu potvrdit nalezením mutací v genu pro pendrin. Metody a výsledky. Vyšetřili jsme 236 dětí s hypotyreózou zjištěnou novorozeneckým skríninkem nebo později v dětství. Klinická diagnóza Pendredova syndromu byla založena na laboratorních a sonografických známkách tyreoidální dyshormonogeneze (vysoké TSH, nízké T4/fT4, struma nebo normální velikost štítné žlázy) ve spojení se senzorineurální poruchou sluchu. U pacientů s klinickou diagnózou Pendredova syndromu bylo přímou sekvenací vyšetřeno všech 21 exonů a přilehlých intronových úseků PDS/SLC26A4 genu. Z 236 dětí splňovalo diagnostická kritéria Pendredova syndromu devět. Molekulárně-genetické vyšetření PDS/SLC26A4 genu prokázalo složeně heterozygotní nosičství mutací u čtyř pacientů, ostatních pět bylo uzavřeno jako fenokopie Pendredova syndromu. Závěry. Naše studie potvrzuje vysokou fenotypovou variabilitu postižení štítné žlázy u pacientů s Pendredovým syndromem a poukazuje na potřebnost genetického vyšetření k potvrzení klinické diagnózy vzhledem k častému výskytu fenokopií. Z endokrinologického hlediska však má molekulárně-genetické vyšetření genu pro pendrin smysl zřejmě jen u pacientů s vrozenou hypotyreózou na podkladě dyshormonogeneze, která je spojena se středně těžkou až těžkou senzorineurální poruchou sluchu.

Pendred syndrome (OMIM274600) is one of the causes of congenital hypothyroidism due to thyroid dyshormonogenesis. It is an autosomal recessive disease classically characterized by dyshormonogenetic goitre and sensorineural deafness. It is caused by mutations in PDS/SLC26A4 gene encoding for pendrin – an anion transporter, mostly expressed in the thyroid gland and the inner ear. The thyroid impairment in Pendred syndrome develops only in 80% of affected individuals in form of a euthyroid or hypothyroid goitre, which is rarely present at birth, when it can be diagnosed by the neonatal screening for congenital hypothyroidism. The study was aimed to identify patients with Pendred syndrome among children with congenital or postnatal non-autoimmune hypothyroidism and subsequently confirm the diagnosis by finding mutations in the PDS/SLC26A4 gene. Methods and Results. We examined two-hundred thirty-six Caucasians with hypothyroidism diagnosed by screening or developing later in childhood. The clinical diagnosis of Pendred syndrome was based on the laboratory and ultrasonographic signs of thyroid dyshormonogenesis (elevated TSH, low T4/fT4, goitre or normal thyroid volume) in association with sensorineural hearing loss. In subjects clinically diagnosed as Pendred syndrome, we sequenced all 21 exons of the PDS/SLC26A4 gene and their flanking intron-exon junctions. Among 236 children, nine fulfilled the diagnostic criteria of Pendred syndrome. In four, the diagnosis was confirmed by identification of mutations in the PDS/SLC26A4 gene, the remaining five patients were concluded phenocopies. Conclusions. Our study confirms the high phenotypic variability of thyroid impairment in Pendred syndrome and underlines the necessity of a molecular-genetic investigation for establishing the diagnosis in regard of the great number of phenocopies. However, from the endocrinologist’s point of view, the genetic testing is only reasonable in patients with congenital hypothyroidism due to dyshormonogenesis in association with sever to profound sensorineural hearing loss.

MeSH
dítě MeSH
dospělí MeSH
fenotyp MeSH
financování organizované MeSH
kojenec MeSH
kongenitální hypotyreóza diagnóza genetika MeSH
lidé MeSH
membránové transportní proteiny genetika MeSH
mladiství MeSH
mladý dospělý MeSH
mutace MeSH
percepční nedoslýchavost genetika MeSH
předškolní dítě MeSH
rodokmen MeSH
sekvenční analýza DNA MeSH
struma genetika MeSH
syndrom MeSH
Check Tag
dítě MeSH
dospělí MeSH
kojenec MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
předškolní dítě MeSH
ženské pohlaví MeSH

Článek

Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: identification of two novel PDS/SLC26A4 mutations

European journal of pediatrics. 2008 ; 167 (7) : 777-783.

Eur J Pediatr
Medvik
Zdroj

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.