Disease

Brief Summary

Also called Congenital Hypothyroidism. It is a permanent thyroid hormone deficiency, present at birth, which is due to inborn errors in the synthesis of the thyroid hormone. The associated tissues are thyroid, brain and pituitary, causing large goiters in most patients.

Source

Image:

Infant with thyroid dyshormogenesis

Frequency

It affects about 1 in 2,000 to 4,000 newborns; affects females twice as that of males.

Inheritance

Thyroid dysmorphogenesis is inherited in an autosomal recessive manner.

History of Disease

A case of congenital goiter with defective thyroglobulin synthesis has been studied by Ierie together with the other researchers, and documented the first individual with TG gene mutations.

The index patient and 2 of her 5 siblings show signs of congenital goiter, hypothyroidism and a marked impairment of TG synthesis. The analysis of a restriction fragment length polymorphism (RFLP) in the Thyroglobulin gene exhibit that the affected individuals were homozygous for the allele and TG mRNA obtained from the goitrous tissue was a bit reduced in size compared to normal individuals. In addition, sequencing of the cDNA showed that exon 4 was missing from the major TG transcript in the goiter, and analysis of genomic DNA exhibits a C-to-G transversion in the acceptor splice site of intron 3.

Brief Summary

History of Disease

THYROID DYSHORMONOGENESIS

Pathogenesis

Achondroplasia is caused by a mutation in the FGF3 gene in chromosome 4 at 4p 16.3. This mutation causes a decreased production of fibroblast growth factor receptor 3 which is crucial in the conversion of cartilage into bone which is vital in the proper development of a person. This mutation is inherited in an autosomal dominant manner. More than 80 percent of people with achondroplasia have parents with normal characteristics and are born with achondroplasia due to a recent (de novo) gene modification (mutation).

Pathogenesis

Thyroid Dyshormonogenesis is caused by homozygous or compound heterozygous mutation in the thyroglobulin (TG) gene. It is inherited in an autosomal recessive manner.

Image:

Location of TG gene on chromosome 8

Symptoms

Endocrine Features:
hypothyroidism

Neoplasia:
thyroid cancer

Laboratory Abnormalities:
thyroid hormone coupling defect
excessive iodide trapping
high ft3/ft4 ratio

Head And Neck:
goiter

Neurologic Central Nervous System:
mental retardation (if untreated in infancy)

Social Concerns

Congenital hypothyroidism is one of the most common congenital diseases, with an incidence of 1 per 4000 live births. One of the severe complications of untreated congenital hypothyroidism is mental retardation. Congenital hypothyroidism at birth may already have had substantial damage to the central nervous system even with substantial treatment within the first few days of the infant.

The fetal thyroid status can be correctly assessed by fetal blood sampling via cordocentesis, however the risk of fetal death with this procedure is reported to be about 1%, even with the hands of the professionals. Fetal therapy is also problematic because of limited thyroxine crosses the placenta.

Treatment

Neonatal screening programs have been used because of the critical neurologic consequences of untreated congenital hypothyroidism. Which measurement of TSH or T4 levels in heel-prick blood specimens are based on. When the diagnosis is confirmed, T4 is instituted at a dose of 10–15 μg/kg per day, and the dose is adjusted by close monitoring of TSH levels. In order to normalize TSH, a high circulating T4 level is needed. Subtle neurodevelopmental abnormalities may arise when treatment is delayed. However, when treated early, it results in normal IQ levels. If transient hypothyroidism is suspected, or the diagnosis is unclear, treatment can be stopped safely after the age of 3 years followed by further evaluation.

Prenatal Diagnosis:

Researchers reported that diagnosis of fetal dyshormonogenetic goiter with hypothyroidism is due to defective thyroglobulin synthesis, by ultrasound and cordocentesis at 28 weeks of gestation. After a single injection of levothyroxine, the fetal goiter decreased in size, and at birth the neonate had normal thyroid function. Afterwards, they deduced that disease can be prenatally diagnosed with intraamniotic injection of thyroxine.

Diagnosis:

Iodination of the serum albumin that diffuses into the hyperplastic thyroid is the result of the increase in metabolic activity of the gland or any block in thyroglobulin synthesis.

Management and Treatment

The treatment choice for this disorder is levothyroxine. The immediate goal of the treatment is to raise the serum T4 above 130 nmol/L as rapidly as possible. The aforementioned dose helps normalize serum TSH in 2 - 4 weeks. Additionally, frequent laboratory monitoring is important in ensuring optimal neurocognitive outcomes. In the first 6 months of life, serum TSH and T4 or free T4 should be measured every 1-2 months. Between 5 months and 3 years of age, it should be measured every three months.