Subclinical hypothyroidism is a relatively common condition characterized by a mild thyroid failure. It can occur at any age from neonatal period to adulthood in both transient or persistent form. Newborns with SH may have a transient impairment of thyroid function due to environmental or mother-derived causes, but they can also have genetic abnormalities of thyroid structure and function. During childhood the main cause of SH is generally represented by autoimmune SH, other known causes being mild developmental thyroid abnormalities, iodine deficiency, obesity, non-thyroidal chronic diseases or inherited syndromes and mutations in the TSH-R gene. Loss of function mutations in genes encoding proteins involved in the TSH pathway, TSH-R anomalies or alterations in the proteins involved in the signaling pathway downstream the receptor, have been widely demonstrated to be responsible of SH [11, 14–18]. In a recent study, Rapa et al. evaluated the clinical characteristics and TSH-R gene variation in a series of children with slight to moderate elevation of TSH with normal thyroid hormone due to non autoimmune SH. Non-synonymous mutations of TSH-R gene or polymorphisms were found in 21.5% of cases . The prevalence of a positive family history of thyroid diseases was two-fold higher in patients with mutations than in those with no mutations. An even higher prevalence of mutation in the TSH-R gene (29%) was detected by Nicoletti et al.. Eleven mutations of TSH-R gene were identified in a cohort of 38 children and adolescents with non-autoimmune SH. In our first patient the main causes of persistent SH were ruled out at first examination. The diagnosis of partial resistance to TSH was suggested by the familiar history of thyroid diseases. Although both sibs were carrying the same mutation, they had completely different clinical phenotype. The first boy had a slight persistent increase of TSH (less than 10 μU/ml), normal thyroid ultrasound and did not show any signs or symptoms of mild hypothyroidism requiring L-T4 treatment. Conversely, the younger brother presented a moderate increase of TSH with serum levels persistently above 10 μU/ml with low normal serum FT4 concentrations, morphological thyroid anomalies with a mild thyroid hypoplasia. He needed to be treated in early infancy and relapsed when treatment was withdrawn. Indeed, even with a mild increase in TSH levels, he presented slight symptoms of hypothyroidism that prompted us to restore L-T4 treatment. Despite treatment, his IQ was slightly low thus raising the question on whether the delay in starting replacement treatment or a low initial dose of L-T4 may have influenced the suboptimal IQ outcome . Pituitary TSH is critical for thyroid development and function and exerts its activity by binding to the extracellular domain of TSH-R, a G protein-coupled seven-transmembrane domain receptor located in the basolateral membrane of thyroid follicular cells. The principal biological effects of TSH on the thyrocite occur by receptor-mediated activation of Gsα and subsequent generation of intracellular cAMP [20, 21]. The human TSH-R gene is located on chromosome 14q31 and encodes a protein of 764 amino acids. The gene is comprised of 10 exons, with the first nine encoding the extracellular domain and the large exon 10 encoding the transmembrane domain and the cytoplasmic tail . Patients with the syndrome of TSH unresponsiveness may have compensated [17, 22–24] or overt hypothyroidism [25–30] depending on the presence of a partial or complete TSH resistance. These conditions include a wide spectrum of biochemical, as well as clinical and morphological alterations depending on the degree of impairment of TSH-R function. The metabolic consequences can range from mild SH to severe CH. TSH is a prerequisite not only for normal thyroid hormone synthesis but also for proliferation. Accordingly, the inherited CH in the hyt/hyt mouse was shown to be caused by homozygosity for a loss of function mutation of the TSH-R (P556L) leading to thyroid hypoplasia and severe CH . The mutation R109Q in the extracellular domain of TSH-xR, found in our two brothers, was first described by Clifton-Bligh et al. in a child compound heterozygote for another missense mutation in the fourth transmembrane segment of receptor. This child presented with markedly increased serum TSH concentrations and low normal thyroid hormone levels identified after a positive result on neonatal screening for CH, normal thyroid morphology and treated with L-T4 since 8 weeks of age . Similarly to our second patient, after the L-T4 withdrawal at the age of 2 years, he showed a significant increase of TSH levels that required a resumption of therapy. Moreover, the R109Q mutation has also been documented in Italian children with non-autoimmune SH [11, 14]. In particular, the two siblings reported by Nicoletti et al. , carrying the same heterozygous R109Q loss of function mutation found in our two patients, had a mild phenotype characterized by a slightly increase in serum TSH, normal thyroid gland at ultrasound and no clinical features of thyroid dysfunction. Similarly to our first patient they do not need treatment, thus highlighting the wide phenotypic variability in children with SH due to the same TSH-R mutation. In the earlier studies in which only probands with large TSH elevations were screened for mutations, the disease was linked to homozygous or compound heterozygous mutations and was described to follow a recessive pattern of inheritance [17, 18, 20–29]. More recently inheritance of TSH-R resistance has been associated with an autosomal dominant pattern without evidence for incomplete penetrance, but with variable expressivity. Several families have been described with dominant transmission of partial TSH resistance due to heterozygous inactivating mutations in TSH-R [30, 31]. The recent finding that TSH-R, like other G protein-coupled receptors, can oligomerize in living cells led to the hypothesis that the formation of complexes between wild-type and mutant receptors may be responsible for partial TSH resistance in patients with heterozygous TSH-R mutations . The clinical heterogeneity in our 2 patients carrying the same mutation, is not surprising as other monogenic diseases have been already shown to have a different phenotype despite the same causing mutation [32–36]. For most of these conditions, molecular basis of this heterogeneity are not well delineated. Disease modifying genes, variation in environmental exposures, as well as system dynamics may come into play in modulating clinical expression of the disease. If the treatment should be indicated or not in patients with only slight elevation of TSH due to TSH-R resistance is controversial. In fact, the elevation of circulating TSH would represent the compensatory mechanism allowing gland development and the maintenance of a normal thyroid hormone secretion in the presence of partial refractoriness to TSH action. Currently, there is no evidence that children with only slight increase in TSH levels (less than 10 μU/ml) and normal FT4 concentrations suffer any clinical or neurological abnormality that would be eventually restored to normal by L-T4 treatment [6, 8]. Therefore the decision to treat with L-T4 SH still represents a clinical dilemma.