medwireNews: Central congenital hypothyroidism (CCH) is frequently missed in Israeli infants despite a newborn screening programme for thyroid dysfunction, shows research published in the Journal of Clinical Endocrinology & Metabolism.
German Alina (Ha’Emek Medical Center, Afula, Israel) and co-authors explain that CCH is a rare disorder characterised by low levels of total thyroxine (TT4) and low, normal or elevated levels of thyroid-stimulating hormone (TSH). It occurred at a prevalence of one in every 42,842 births in Israel over the study period from 1987 to 2021.
While Israel’s neonatal screening programme measures levels of both TT4 and TSH at 48–72 hours after birth, the researchers explain that “the common thyroxine-binding globulin (TBG) deficiency also causes low TT4 in combination with normal TSH, resulting in a substantial number of false–positive referrals” for TT4 deficiency. Therefore, low levels of TT4 without TSH elevation are not reported to endocrinologists, leading to missed diagnoses of CCH, they write.
The team reports the outcomes of 94 patients (57% boys) who were diagnosed with CCH at one of nine paediatric endocrine units in Israel at a median age of 50 days; 30% of children were diagnosed early, within 2 weeks of birth, and the remainder were diagnosed at an older age. The condition was detected via newborn screening in only three infants.
Overall, 84% of the patients had multiple pituitary hormone deficiency (MPHD), while 16% had isolated CCH. The MPHD patients were less likely to be boys than the isolated CCH patients (53 vs 80%) and more likely to have consanguineous parents (24.4 vs 12.3%), although less likely to have other cases within their family (6.4 vs 53.3%). The median age at diagnosis was comparable (56 vs 46 days), as was the rate of early diagnosis (30 vs 27%).
Infants with an early diagnosis of MPHD or isolated CCH were given a referral most commonly after the development of hypoglycaemia (92.0 vs 0.0%) or prolonged jaundice (33.0 vs 50.0%), and then family history (12.5 vs 75.0%) or newborn screening results (1.0 vs 25.0%).
For those given a late diagnosis of MPHD or isolated CCH, the most common reasons for referral were poor growth (42 vs 9%), prolonged jaundice (18 vs 18%) and developmental delay (7 vs 9%). In addition, 9% of children with isolated CCH were each referred following coarse voice and macroglossia, while 3% of those with MPHD were referred for delayed puberty.
The majority of patients with MPHD had deficiencies in growth hormone (96%) and adrenocorticotropic hormone (73%), with diabetes insipidus present in 5%. In addition, 92% of the 74 patients with MPHD who had magnetic resonance imaging results available had abnormal findings, such as pituitary stalk interruption syndrome (63%) or pituitary hypoplasia (25%).
The researchers also report that genetic mutations were identified in 13 patients with MPHD, including alterations to POU1F1, HESX1 and GLI3, and one case of maternal inherited translocation of 46XXt. In addition, genetic alterations to the X-linked IGSF1 gene were identified in six patients with isolated CCH who were assessed, and a seventh patient was diagnosed with a CHD7 mutation.
Endocrine results were available for 44 of the infants who were born after 2008 and their average screening TSH level was 4.5 mIU/L and their average TT4 level was 7.0 μg/dL. The values for the MPHD patients were 4.2 mIU/L and 6.8 μg/dL, respectively, with comparable values for the isolated CCH patients of 7.1 mIU/L and 5.3 μg/dL.
Alina et al note that 13.6% of the CCH patients, all of whom had MPHD, had a TT4 level above the newborn screening cutoff threshold of the 10th centile. They suggest that “careful refinement” of newborn screening might improve detection of primary CH and CCH, perhaps by following the three-step approach used in the Netherlands – which has a higher prevalence of CCH. There, T4 is measured, then TSH for infants in the lowest 20% of T4 measurements and TBG measurement for those with TT4 levels in the bottom 5%. This permits calculation of the T4 to TBG ratio and an estimation of free T4, they explain.
Finally, the team found neurodevelopmental sequelae in 37% of the CCH patients, namely delayed speech (27%), motor clumsiness (19%), learning difficulties (18%) and mental retardation (12%). These were significantly more common in children with isolated CCH than those with MPHD (60 vs 32%) but there were no other significant differences in neurological function between the two groups.
Nor was there a significant difference detected in the rate of neurodevelopmental sequelae between patients who were diagnosed within 2 weeks of birth and those with a later diagnosis (25 vs 39%) or in the rate of moderate-to-severe CCH (free T4 <10 nmol/L; 78 vs 64%).
However, Alina et al caution against concluding that late diagnosis is not associated with poorer neurodevelopmental outcomes, “as the lack of difference might be attributed to the small size of the early diagnosis group.”
They emphasize that “the overall high prevalence of neurodevelopmental sequelae in our cohort underscores the critical importance of early detection and treatment of CCH to prevent long-term complications”, and therefore recommend further research into the “contributions of delayed diagnosis to the neurologic prognosis of newborns with CCH.”
By Lynda Williams
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