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.