ESPE Abstracts (2015) 84 P-3-1193

NKX2-1 p.Asp266Argfs142X De Novo Mutation in a Girl with Congenital Hypothyroidism (CH): Phenotypic Description

Iva Stoevaa, Anne Thorwarthb, Boris Stoilova & Heiko Krudeb

aUniversity Pediatric Hospital Sofia, Medical University Sofia, Sofia, Bulgaria; bResearch Laboratory, Institute Experimental Pediatric Endocrinology, Charite, Berlin, Germany

Background: Ttf1/ mice had complete absence of follicular and parafollicular cells, agenesis of lung parenchyma, ventral forebrain, and pituitary. Congenital hypothyroidism (CH) patients with chromosomal deletions encompassing the TTF1 locus and point mutations in the TTF1 gene confirmed its implication in the phenotype: CH with a thyroid gland in place, associated with respiratory distress syndrome, neonatal hypotonia followed by choreoathetosis or ataxia.

Objective and hypotheses: Description of the phenotype in a patient from the Bulgarian thyroid screening cohort.

Method: Case report and direct sequencing of NKX2-1.

Results: A term female newborn was detected by the neonatal TSH screening (Table 1). Initial L-T4 dosage: 12 μg/kg per day at day 53. Family history – unremarkable. Despite normal TSH and (f)T4 under substitution she developed progressive hypotonia from early infancy, developmental delay, catch down of linear growth (SDSh −3.6 at 2 years), mild bone age retardation during adrenarche. Until the age of six frequent respiratory infections (asthma, CF, and chronic pneumonias were excluded). After start of walking, movement affection resembles choreoathetosis. At reevaluation permanent CH due to hemiagenesia (right lobe) and a hypoplastic left lobe. Until 13 years she was euthyroid, attended a public school, the neurologic and lung involvement did not progress. Some behavior problems became much more important with age. According to the triad of thyroid, neurological and respiratory involvement the family was sequenced for NKX2-1 after informed consent. A small deletion c.796delGA leading at protein level to Asp266ArgfsX142 in the NK2-specific domain in exon 3 was found only in the patient.

Table 1
Age (days)NTSH (mU/l)TSH (mU/l)T4 (nmol/l)
2.5 years76.313757

Conclusion: Monogenic CH is heterogeneous and belongs to rare diseases. Hypotonia despite sufficient L-T4 treatment is an early sign which can guide to the suspicion of underlying NKX2-1 mutations in primary CH.

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