OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: TPO

Iodide peroxidase deficiency
Thyroid peroxidase deficiency
Thyroid organification defect II
TIOD

Thyroid deficiency
Mental retardation
Congenital hypothyroidism
Developmental delay

Thyroid Oxidase Deficiency, 2A

Clinical Characteristics

General description (for patients):

A defect in the synthesis of normal thyroid hormones causes severe developmental delay and mental retardation.  Early diagnosis and treatment, during infancy, is necessary to prevent the more severe consequences of this genetic condition.  Early evidence of low thyroid in such infants includes poor eating, constipation, and a large tongue.

Medical description:  

Lack of organification of iodine causes a severe form of congenital hypothyroidism resulting in general developmental delays and irreversible mental retardation.  The Iodide is not retained in the thyroid gland due to the failure of the defective thyroid peroxidase to bind it to tyrosine residues within the thyroglobulin substrate.  The result is a deficiency in thyroid hormones, T3 and T4.  Neurological damage occurs within the first year of life and thus diagnosis and replacement therapy during infancy is important to ensure normal development.  Early signs are poor eating, general failure to thrive, large tongue, and constipation.  This type of congenital hypothyroidism is different from another seen in the Ohio Amish (see congenital hypothyroidism, OMIM #218700) in its clinical presentation and response to replacement therapy.  Administering thiocyanate or perchlorate can be diagnostic upon finding discharge of a large amount of labeled iodide from the thyroid.

Genetics:

Within the Adams County, IN, Amish community, five nuclear families with sixteen affected individuals were identified.  All traced to a single ancestral couple who emigrated from Switzerland.  Two missense mutations, 2485G>A, and 2033G>A, were found in the TPO gene among 15 individuals.  The E799K mutation was homozygous in 11 affected individuals while both mutations were present in three compound heterozygotes with clinical disease thereby confirming autosomal recessive disease.  The TPO gene is located on chromosome 2 (2p25).

Treatment:

Thyroid hormone replacement therapy.

Prognosis:

Excellent if treatment initiated in infancy, poor if treatment is begun later.

Ancillary treatments and support:

None.

Specialists and specialty centers:

Pediatrician, endocrinologist.

References:

Pannain, S., Weiss, R.E., Jackson, C.E., Dian, D., Beck, J.C., Sheffeld, V.C., Cox, N., and Refetoff, S.:  Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping.  J. Clin. Endocr. Metab. 84: 1061-1071, 1999.  PubMed ID: 10084596

Bakker, B., Bikker, H., Vulsma, T., De Randamie, J.S.E., Wiedijk, B.M., and De Vijlder, J.J.M.:  Two decades of screening for congenital hypothyroidism in the Netherlands: TPO gene mutations in total idodide organification defects (an update). J. Clin. Endocr. Metab. 85: 3708-3712, 2000.  PubMed ID: 11061528

Resources:

Medline Plus thyroid disease
The Hormone Foundation
Endocrine Web

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