Case report
An 11 years old female was born out of non-consanguineous marriage with normal birth weight (3.2 kg) and length (51 cm). She was growing well till 1 year of age when she developed recurrent loose stools and had poor weight gain. At 15 months of age, in view of poor weight gain and bilateral infiltrates on chest X ray (CXR), anti-tubercular treatment was given for 6 months but she had no response. At 5 years of age, she was diagnosed to have celiac disease with anti-tTG IgA levels- 300 U/ml (normal value <15 U/ml) and hypothyroidism (TSH-52.3 mIU/L) (normal value 0.5-5.5 mIU/L). She was started on gluten free diet and L-thyroxine and had shown symptomatic improvement with some weight gain. At 8 years of age, she developed insidious onset fast breathing which gradually progressed from MRC grade 1 to 4 over 3 years along with dry, non-productive cough. She had minimal response to bronchodilators and inhaled steroids. She underwent CT Chest which was reported as having fibrotic changes. There were no similar family history or any sibling death. There was history of exposure to pigeons. In view of no response in respiratory symptoms and further evaluation, she was referred to our centre.
At presentation to our centre, she had tachypnea and respiratory distress with normal oxygen saturation, grade 3 clubbing and growth failure [weight 19.3 kg (-2.83 Z score), height 122 cm (-2.88 Z score), body mass index (BMI) 12.96 (-1.88 Z score)]. She was evaluated for various causes of childhood interstitial lung disease (ILD) mainly autoimmune diseases, hypersensitivity pneumonitis and NKX2.1 mutation.
Complete hemogram and metabolic panel were within normal limits. CXR revealed bilateral reticulonodular shadows in all lung fields. CT chest showed organizing pneumonia in right upper lobe. Other lobes showed septal thickening and fibrotic changes (Fig 1). Spirometry was suggestive of severe restrictive disease. Autoimmune antibody panel were negative. Bronchoalveolar lavage (BAL) CD4:CD8 ratio (0.79) was reduced. Serum precipitins for avian antigen were negative. Lung biopsy couldn’t be done due to refusal by parents. Echocardiography showed features suggestive of mild pulmonary hypertension. Whole exome sequencing revealed a novel mutation in STAT5B gene which was a homozygous missense variation in exon 16 (chr17:40359647A>C; c.2006T>G) that results in the amino acid substitution of Glycine for Valine at codon 669 (p.Val669Gly). The in-silico predictions of the variant were probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The phenotype is still largely unknown for this mutation. Her parents and siblings couldn’t be tested due to cost issues.
Due to the reported associations of STAT5B mutation with immunodeficiency and GHI, we evaluated the patient for the same. Her primary immunodeficiency evaluation suggested CD8 cell deficiency and raised IgG. (Table 1). On hormonal evaluation, normal baseline and stimulated Growth hormone (GH) levels while reduced IGF-1 levels were suggestive of GHI (Table 1). Her thyroid function tests revealed hypothyroidism with normal Anti-TPO antibody levels (Table 1). Repeat celiac serology (anti-tTG IgA) was negative.
The child was started on oral steroids (Prednisolone at 1 mg/kg/day) and hydroxychloroquine (10 mg/kg/day) for ILD. She was discharged after 10 days of hospital stay. On follow up after 8 months, there was improvement in breathlessness (MRC scale 4 to 2) and cough as well as weight gain. There were no exacerbations in this period. She was continued on low dose steroids (0.5 mg/kg every alternate day) and hydroxychloroquine. She was being followed up with pediatric endocrinologist for hypothyroidism and GHI and continued on L-Thyroxine (50 mcg). However, she couldn’t be started on any GH replacement therapy due to cost issues.