Bengaluru: At nearly eight years old, she weighed just 8.4kg and stood only 81cm tall — about the size of a much younger child. Since infancy, she had suffered from poor growth, developmental delays, recurrent infections and persistent breathing problems, leaving doctors searching for answers for years.That search has now led doctors at state-run Indira Gandhi Institute of Child Health (IGICH) to identify what is believed to be India’s first reported case of MADD-related genetic disorder. The extremely rare condition is caused by a mutation in MADD gene, which encodes the mitogen-activated protein kinase-activating death domain protein.The discovery, published in journal inical Dysmorphology journal, not only solved the mystery behind the child’s complex illness but also revealed several previously unreported features of the disorder.MADD-related disorders are among the rarest known genetic conditions, affecting multiple organs and body systems. Reported cases worldwide have typically involved developmental delays, poor growth, muscle weakness, endocrine abnormalities, heart problems and autonomic dysfunction.However, the Bengaluru child showed an unusually wide range of complications. In addition to severe developmental and hormonal problems, doctors found leukodystrophy-like changes in the brain, an underdeveloped pancreas, delayed tooth eruption, underdeveloped external genitalia and medullary nephrocalcinosis. Some of these features have not previously been reported in patients with MADD-related disorders.“This is a very interesting and rare case. At eight years old, the child weighed only around 8kg and appeared to be the size of an eight-month-old baby,” said Dr Vykunta Raju Gowda, paediatric neurologist at IGICH and one of the treating doctors.According to the case report authored by Dr Gowda, Dr Varunvenkat Srinivasan and colleagues, the child’s health challenges began almost immediately after birth. Born with a low birth weight, she required neonatal intensive care for low blood sugar, jaundice and infection. Throughout infancy, she was repeatedly hospitalised for breathing difficulties, recurrent infections and failure to gain weight, requiring prolonged oxygen support.Her development remained severely delayed. She gained head control only at age two, began walking independently at five-and-a-half, and could climb stairs with support only by six-and-a-half years.When she was referred to IGICH earlier this year, doctors found another clue: she was passing excessive amounts of urine and had multiple hormonal abnormalities. Tests revealed hypothyroidism, growth hormone deficiency and diabetes insipidus, a condition that causes the body to produce excessive amounts of dilute urine.An MRI scan added another piece to the puzzle, showing a small pituitary gland and abnormal white matter changes resembling leukodystrophy, a group of disorders that affect the brain’s white matter.The unusual combination of severe growth failure, developmental delay, endocrine abnormalities and brain changes prompted doctors to investigate a rare genetic cause. Whole-genome sequencing eventually confirmed a pathogenic mutation in MADD gene. Genetic testing also showed that both parents carried one copy of the mutation but had no symptoms. The child has since been started on thyroid hormone replacement, growth hormone therapy and desmopressin, with doctors closely monitoring her progress.“We have seen significant improvement in her condition with our treatment,” Dr Gowda said.Doctors believe the case expands current medical understanding of MADD-related disorders and underscores the value of genome sequencing in diagnosing children with unexplained illnesses involving multiple organ systems.The authors noted, however, that it remains unclear whether the unusual white matter changes seen on MRI were caused directly by MADD mutation or were partly the result of longstanding hypothyroidism.
