Acquired Hypothyroidism in Children.

Acquired hypothyroidism is generally also referred to as juvenile hypothyroidism. Hypothyroidism is due to the deficient secretion of thyroid hormones causing metabolic and neurological sequelae at the cellular level. It can present as overt hypothyroidism wherein the thyroid hormones (T4 and T3) secretion fall and thyrotropin (TSH) rises. Acquired hypothyroidism frequently presents between 9 and 11 y of age and is rarely seen before 4 y of age. Approximately 80% of the children and adolescents are asymptomatic at the time of diagnosis. Children with moderate to severe hypothyroidism often present for evaluation of poor growth, constipation, lethargy and/or dry skin. A detailed history and examination will provide us with enough clues for diagnosing hypothyroidism. Primary hypothyroidism can be diagnosed with raised TSH with subnormal levels of T3 and T4. Titres of thyroid antibodies - Anti-thyroperoxidase (TPO) and anti-thyroglobulin (ATG) antibodies, will be high in autoimmune hypothyroidism. Subclinical hypothyroidism is diagnosed with mildly elevated or high normal levels of TSH with free T4 being in the normal range. Insufficient secretion of thyrotropin from the pituitary causes central hypothyroidism. Acquired hypothyroidism is treated by replacement with levothyroxine. Regular monitoring of thyroid profile is necessary for adjusting doses of levothyroxine. Close monitoring and individualization of levothyroxine therapy is essential for normal growth and development of the child.

A homozygous hypomorphic BNIP1 variant causes an increase in autophagosomes and reduced autophagic flux and results in a spondylo-epiphyseal dysplasia.

BNIP1 (BCL2 interacting protein 1) is a soluble N-ethylmaleimide-sensitive factor-attachment protein receptor involved in ER membrane fusion. We identified the homozygous BNIP1 intronic variant c.84+3A>T in the apparently unrelated patients 1 and 2 with disproportionate short stature. Radiographs showed abnormalities affecting both the axial and appendicular skeleton and spondylo-epiphyseal dysplasia. We detected ~80% aberrantly spliced BNIP1 pre-mRNAs, reduced BNIP1 mRNA level to ~80%, and BNIP1 protein level reduction by ~50% in patient 1 compared to control fibroblasts. The BNIP1 ortholog in Drosophila, Sec20, regulates autophagy and lysosomal degradation. We assessed lysosome positioning and identified a decrease in lysosomes in the perinuclear region and an increase in the cell periphery in patient 1 cells. Immunofluorescence microscopy and immunoblotting demonstrated an increase in LC3B-positive structures and LC3B-II levels, respectively, in patient 1 fibroblasts under steady-state condition. Treatment of serum-starved fibroblasts with or without bafilomycin A1 identified significantly decreased autophagic flux in patient 1 cells. Our data suggest a block at the terminal stage of autolysosome formation and/or clearance in patient fibroblasts. BNIP1 together with RAB33B and VPS16, disease genes for Smith-McCort dysplasia 2 and a multisystem disorder with short stature, respectively, highlight the importance of autophagy in skeletal development.