Clinical and genetic characteristics of Dutch children with central congenital hypothyroidism, early detected by neonatal screening

Abstract

Objective: To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD). Design: nationwide, cross-sectional study. Methods: Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1-1-1995 and 1-1-2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing. Results: During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25,642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53%, 16% and 16% respectively). Conclusion: Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis. (This investigator-initiated study received a support grant from Pfizer; WI219179).

Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction

“…Such cases in preterm infants are rare, likely with an incidence matching term infants:! :25,000 ( 26 ).…”

Low free thyroxine and normal thyroid-stimulating hormone in infants and children: possible causes and diagnostic work-up

“…Central congenital hypothyroidism may occur in isolation (25% of cases) but is more often accompanied by additional pituitary hormone deficiencies (75%). Most children with multiple pituitary hormone deficiency (MPHD) exhibit a pituitary malformation characterized by an absent or thin pituitary stalk, a hypoplastic anterior pituitary lobe, and an ectopic posterior pituitary lobe, known as pituitary stalk interruption syndrome (PSIS) [ 1 ]. Most cases of PSIS occur in isolation although they may be accompanied by additional midline brain abnormalities.…”

“…Variants in genes encoding transcription factors involved in pituitary formation and pituitary cell differentiation are found in less than 5% of patients with MPHD ( HESX1, LEPR, LHX3, LHX4, OTX2, POU1F1, PROP1, SOX3 ). In contrast, a genetic cause is often found in patients with isolated central hypothyroidism [ 1 ]. The five genes associated with isolated congenital central hypothyroidism are thyrotropin-releasing hormone receptor gene ( TRHR ), thyroid-stimulating hormone β-subunit gene ( TSHB ), and the more recently described genes IGSF1, TBL1X , and IRS4 [ 8 , 9 ].…”

“…Furthermore, the medical history must be interrogated for gestational age, birth weight, use of medication, and a family history of central hypothyroidism. As central hypothyroidism is frequently part of multiple pituitary hormone deficiencies, there should be attention for signs and symptoms of hypopituitarism (Table 1 ) [ 1 ].…”

“…goitre, Graves’ ophthalmopathy, or myxedema). In younger children, the likelihood of congenital HPT axis disorders is much higher, while complaints of hypothyroidism can be vague or absent [ 1 ]. Thus, a combined TSH and FT4 measurement should be performed in order not to miss these conditions.…”