Peripheral Thyroid Hormone Resistance (PTHR) was first described by Refetoff in 1967. It is characterized by raised serum hormone values of T4 and T3 and inappropriately elevated values of TSH. PTHR has been shown to be caused by a mutation in the TR beta gene resulting in impaired nuclear binding of thyroid hormones or an impaired post receptor hormone effect. The patients are often characterized phenotypically by impairment of bone, heart or cerebral function.1 The syndrome presents in three forms: Generalized Resistance of Thyroid Hormone, Pituitary Resistance to Thyroid Hormone and Peripheral Tissue Resistance to Thyroid Hormone. The illness appears in both familial and sporadic forms. Mild resistance at the receptor level to thyroid hormone has been reported. L-T4 treatment in high doses has been suggested in GRTH if patients have signs of clinical hypothyroidism such as growth retardation and developmental delay.

A case of PTHR is presented here. The patient showed clinical evidence of hypothyroidism and ‘normal serum hormone values of T4 and T3 and inappropriately elevated values of TSH.’ The baby responded to high dose of L –Thyroxine [7-10 microg/kg].

SHK; Six weeks old - First born -female child, born of a non consanguineous marriage was brought with abdominal distension, constipation and nasal stuffiness.

FTND .Wt at birth-03.500 kg

At 1 month 14 days- Her vital signs were normal.

Weight was 04.750 kg and head circumference and length –within normal limits

Examination of cardiovascular and respiratory system did not show any abnormality.

Abdomen was distended with tympanic note on percussion.

Neonatal reflexes were normal.

Anterior fontanel was normal. Posterior fontanel was open.

The patient was investigated to rule out Congenital Hypothyroidism.

Haemogram was within normal limits. Bone age was delayed.

Thyroid tests done on ‘Fully automated chemiluminescence system’ [07.02.2003]

TSH-14.04 uIU /ml normal 0.3—10

T3- 226.7 ng/ dl normal 86—226

T4- 06.72ug/dl normal 4.5—14.5

Free T3 and T4 were not measured at this stage.

The patient showed clinical evidence of hypothyroidism n spite of normal levels of T3 and T4. Peripheral Thyroid Hormone Resistance (PTHR) was suspected. In view of increased serum TSH the baby was put on exogenous thyroid hormone replacement therapy [about 8-10 microgram/kg/day].

The baby was seen at regular intervals and since the patient showed good clinical response, satisfactory weight gain, normal physical and mental development the same dose was continued. At the age of 13 months - Anthropometry and development was satisfactory

Thyroid tests were repeated in detail at the age 13 months

TSH - 0.30 uIU / ml - normal 0.3-10 [26.01.2004]

Free T3 - 004.8 pg/dl [normal 1.5-4.1];

T3 - 186.4 ng/dl [normal 86-226]

Free T4 - 1.90 pg/dl [normal 0.80-1.90]

T4 - 13.2 ug/dl [normal 4.5-14.5]

Serum Protein Electrophoresis and thyroglobulin levels by CLIA were normal.

The patient responded to thyroid hormone supplementation therapy. Her plasma sugar, serum calcium, phosphorus, alkaline phosphatase levels were normal. These tests were done to rule out any other endocrine abnormalities. TRH test could not be done. The patient was seen again at age of 18 months and physical, mental development was normal; weight gain was satisfactory. Wt-09.750 kg, Height-76.50 cms, Head -45.00 cms,

The same dose was continued [07.50 micrograms/kg/day; 75 micrograms/day].

When seen last at the age of 2 years 2 months she showed near normal mental and physical development.

Resistance to thyroid hormone encompasses a clinically heterogeneous group of conditions characterized by reduced responses of target tissues to a supply of thyroid hormone that under normal circumstances would be excessive.

Peripheral Thyroid Hormone Resistance (PTHR) may be caused by

1. Mutation in the TR beta gene resulting in impaired nuclear binding of thyroid hormones or
2. Impaired post receptor hormone effect. It may mean-

- Involvement of an abnormal nuclear cofactor serving a specific function in the regulation of thyroid hormone action,

- Defects in the regulation of TR genes or

- Mutations in transcriptional cofactors involved in TR signaling.

The patients are often characterized phenotypically by impairment of bone, heart or cerebral function.2,3

Under normal conditions, TRs remain bound to Corepressors and are inactive. T3 replaces Corepressors and T3TR complexes attach to TREs. The reaction is modified by Coactivators.4 The clinical manifestation of patients with RTH is heterogeneous and the varied phenotypes are due to point mutations in TR beta. There are two T3-receptor genes, alpha and beta, located on chromosomes 17 and 3, respectively. In the pituitary, the binding of T3-TR complexes to TREs [Thyroid Receptor Element] serves to inhibit the expression of genes for the synthesis of alpha and beta sub units of TSH. The variable lack of T3 responsiveness in different tissues [resistance] is due to point mutations in the T3 binding domain of the TRbeta.

Clinical states range between two extremes: the generalized form, with global euthyroidism, and the predominantly pituitary form, with thyrotoxicosis. Surprisingly, these various clinical situations are usually determined by the same genetic defect, i.e., an anomaly of one of the two alleles of the gene encoding the thyroid hormone receptor TR beta. A high level of circulating thyroid hormone in the presence of detectable thyroid stimulating hormone (TSH) level is the characteristic biological feature.5 Mild resistance at the receptor level to thyroid hormone has been reported.6 Thyroid hypoplasia and persistent congenital hypothyroidism is reported due to mutations of the human thyrotropin receptor gene.7

Clinical manifestations of resistance to thyroid hormone do not often correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors. Clinical severity of RTH, determined by thyrotroph resistance, can be predicted from the degree of T3 binding impairment and dominant negative potency of mutant TR betas, but the degree of peripheral tissue resistance and related clinical manifestations can not be predicted. The pathogenesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of alpha and beta thyroid hormone receptors and variable dominant negative activity of mutant receptors on different target genes.8,9

There are three forms of this syndrome: Generalized Resistance of Thyroid Hormone, Pituitary Resistance to Thyroid Hormone and Peripheral Tissue Resistance to Thyroid Hormone. The illness appears in both familial and sporadic forms.10

Some mutations in the gene that code for hTRbeta are associated with resistance to effects of T3 T4. Most commonly there is resistance to thyroid hormone in peripheral tissues and pituitary. These patients maintain plasma levels of T3, T4 that are high enough to overcome the resistance. Plasma levels TSH are inappropriately high for high levels of T3, T4 and cannot be suppressed by exogenous thyroid hormone.

Some patients have hypermetabolic rates and thyroid hormone resistance only in the pituitary. They have high levels of T3, T4 and normal, nonsuppressible levels of TSH. A few patients have peripheral resistance with normal pituitary sensitivity. They have hypometabolism despite normal plasma levels of T3, T4 and TSH. They require large doses of thyroid hormone to increase their metabolism.

Though this patient showed normal levels of T3and T4; increased serum TSH suggested the need for supplemental hormone therapy. L-T4 treatment in high doses has been suggested in GRTH if patients have signs of clinical hypothyroidism such as growth retardation and developmental delay.11 High LT4 starting doses rapidly normalize serum TSH concentrations resulting in an improvement of the IQ at 4 years of age.12

The patient showed good clinical response with high doses of L-Thyroxine; indicating that the peripheral resistance to thyroid hormone could be easily overcome and that the resistance was ‘mild’. TSH levels returned to normal indicating that the pituitary was sensitive to thyroid hormone at higher concentrations. Exact defect could not be delineated, since molecular studies could not be done due to want of such facilities.

However there are few possibilities-

1] Mechanisms for the dominant negative effect by mutant TRs likely involve either increased binding to TREs by mutant homodimers that cannot bind T3 (hence cannot dissociate from DNA) and or the formation of inactive mutant TR heterodimers. Mutant TRs have high affinity for T3 and low dissociation pattern and therefore in spite of elevated concentrations of T3; normal receptors remain free of T3 with no physiological effects. Only when the mutant receptors are saturated with T3 supplementation; normal receptors can bind with T3 and are able to exert their effect.

2] Abnormalities of Nuclear Corepressors, Coactivators, and Coregulators with Resistance to Thyroid Hormone without Mutations in Thyroid Hormone Receptor ß also need to be considered [The Corepressors can be displaced and Coactivators and Coregulators are activated at higher concentration of T3].

Since the patient showed good weight gain; normal physical and mental development the same dose is being continued even today. When the baby is three years old, discontinuation of hormone replacement therapy for 2 to 3 weeks and repeating the thyroid tests may be considered. Reports of the tests [TSH and T3, T4] and the clinical features would dictate the treatment then.

RTH has to be considered in all patients with inappropriate TSH secretion.