背景:与甲状腺激素α(RTH-α)抵抗相关的甲状腺功能减退表型与不同的临床表现有关。另一方面,促甲状腺激素(TSH)水平正常。游离三碘甲状腺原氨酸(fT3)和游离甲状腺素(fT4)水平也可以正常;然而,正常或大细胞性贫血通常出现在报告的病例中。诊断具有挑战性,关于筛查方法的数据有限。
目的:本研究旨在评估RTH-α筛查策略的效率。
方法:在2年以上的儿科神经科门诊接受评估的6540名儿童中,接受了全血细胞计数和甲状腺功能检查,432人被发现患有贫血。在这个群体中,我们确定了42名没有潜在的特定神经系统病因的儿童,他们表现出正常或大细胞贫血,正常TSH水平,fT3水平在正常范围的上半部分或高,和fT4水平在正常范围的下半或低。我们排除了一名已经被诊断为RTH-α的患者,而9名患者无法到达。随后,临床评估,生化评估,对32名儿童进行THRA测序分析。将这些发现与我们单位已知的RTH-α患者的发现进行了比较。
结果:患者的中位年龄为5.7(5.1-7.4)岁,其中22人是男性(69%)。在儿科神经科诊所进行评估的主要原因是自闭症谱系障碍(n=12,38%),癫痫(n=11,34%),发育阶段延迟(n=8,25%)。其中5例(16%)出现便秘,前font门的闭合和牙齿萌出延迟了2例(6%)和1例(3%),分别。身长/身高和体重标准差(SD)评分中位数分别为0.3[(-0.8)-(1.1)]和-0.1[(-0.8)-(0.3)],分别。中位数fT3,fT4和TSH水平为4.6(4.2-5.0)pg/mL,0.9(0.8-1.0)ng/dL,和2.2(1.8-3.1)uIU/mL,分别。13例患者(41%)的fT3水平较高,而他们都没有低fT4水平。正常或大细胞性贫血率为47%(正常/大细胞,n=8/7)在重新评估时。5例患者(16%;1例贫血)的血清肌酸激酶(CK)升高。没有受试者在THRA中具有病理变异。已知的RTH-α患者的中位身高SD评分明显较低,较高的延迟牙齿萌出和前font门闭合率,较低的血红蛋白水平,与没有RTH-α的人相比,平均红细胞体积(MCV)和CK水平更高。
结论:该方法发现了一名已知的RTH-α患者,但未发现任何新病例。值得注意的是,在接受筛查的患者中,近一半的正常或大细胞贫血没有持续.考虑到提示RTH-α的临床发现和突出实验室特征的筛查策略可以降低出现神经系统问题的患者对THRA的不必要遗传分析。
The hypothyroid phenotype associated with resistance to thyroid hormone alpha (RTH-α) is associated with a diverse clinical picture. On the other hand, thyroid-stimulating hormone (TSH) levels are normal. Free triiodothyronine (fT3) and free thyroxine (fT4) levels can also be normal; however, normo- or macrocytic anaemia is usually present in reported cases. Diagnosis is challenging and there is limited data regarding screening methods.
The study aimed to assess the efficiency of a screening strategy for RTH-α.
Out of a total of 6540 children evaluated at the outpatient clinics of paediatric neurology over 2 years and who underwent complete blood count and thyroid function tests, 432 were found to have anaemia. Within this group, we identified 42 children without an underlying specific neurological aetiology who exhibited normo- or macrocytic anaemia, normal TSH levels, fT3 levels in the upper half of the normal range or high, and fT4 levels in the lower half of the normal range or low. We excluded one patient who had already been diagnosed with RTH-α and nine patients could not be reached. Subsequently, clinical evaluation, biochemical assessment, and THRA sequencing analysis were conducted on 32 children. The findings were compared with those of the known RTH-α patients in our unit.
The median age of the patients was 5.7 (5.1-7.4) years, and 22 of them were males (69%). The main reasons for assessment in paediatric neurology clinics were autism spectrum disorder (n = 12, 38%), epilepsy (n = 11, 34%), and delay in developmental stages (n = 8, 25%). Constipation was present in five of the cases (16%), while the closure of the anterior fontanelle and tooth eruption were delayed in two cases (6%) and one case (3%), respectively. The median length/height and weight standard deviation (SD) scores were 0.3 [(-0.8)-(1.1)] and -0.1 [(-0.8)-(0.3)], respectively. The median fT3, fT4, and TSH levels were 4.6 (4.2-5.0) pg/mL, 0.9 (0.8-1.0) ng/dL, and 2.2 (1.8-3.1) uIU/mL, respectively. Thirteen of the patients (41%) had high fT3 levels, while none of them had low fT4 levels. The normo- or macrocytic anaemia rate was 47% (normocytic/macrocytic, n = 8/7) at the time of reassessment. Serum creatine kinase (CK) was elevated in five patients (16%; one had anaemia). None of the subjects had a pathological variant in THRA. Known RTH-α patients had significantly lower median height SD score, higher rates of delayed tooth eruption and closure of the anterior fontanelle, lower haemoglobin levels, and higher mean corpuscular volume (MCV) and CK levels as compared to those found without RTH-α.
This approach found one known patient with RTH-α but did not reveal any new cases. Notably, normo- or macrocytic anaemia did not persist in nearly half of the screened patients. A screening strategy that takes clinical findings and prominent laboratory features suggestive of RTH-α into account could lower unnecessary genetic analysis of THRA in patients presenting with neurological problems.