Not just a Coffin-Siris Syndrome - The diagnosis of pre-symptomatic diseases

Abstract

Introduction Coffin-Siris syndrome is a rare genetic disease, characterized by global developmental delay, typical facial dysmorphisms, hirsutism and bilateral aplasia or hypoplasia of the 5th distal phalange, although other malformations may be found. Several genes (ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1 or SOX11) have been associated with this syndrome, and most of the cases occur as de novo events. The use of array-CGH in clinical practice has several implications. Diagnosis can be found for the manifestations in question, but variants of unknown significance or secondary/incidental findings (mainly for pre-symptomatic diseases) can also be detected. The implications of knowing this kind of information have been the subject of much discussion among the scientific and ethical community. The authors report the case of a 3-year-old male, second child of healthy non-consanguineous parents, with no relevant family history and no prenatal or perinatal complications reported. At the age of 4 months, the child was referred to a Neurodevelopment clinic due to axial hypotonia, with frequent choking episodes and eating difficulties. On physical examination, the hypotonia was confirmed, with no cephalic control, a plagiocephaly and few anti-gravity limb movements. He had a systolic murmur, that came to correspond to a slight supravalvular pulmonary stenosis on the echocardiogram. On the following appointments, facial dysmorphisms and hypoplasia of the nail of the 5th finger were noticed. Meanwhile, with physical therapy support, he started to sit with no support by the age of 9 months, to walk autonomously at the age of 20 months, and said his first words at 24 months old. At 9 months blood tests revealed hypercholesterinaemia (254 mg/L) and hypothyroidism (TSH: 5,97 mg/L, free T4: 0,75 mg/L.), starting treatment with levothyroxine. As first line testing, an array-CGH was performed, revealing a deletion in the 19p13.2 region. This deletion includes several genes such as: SMARCA4-associated with the Coffin-Siris syndrome and risk of developing rhabdoid tumours, LDRL-associated with familial hypercholesterolemia, DMN2 - related with autosomal dominant Charcot-Marie-Tooth and with a centronuclear myopathy, and PRKCSH - related with polycystic hepatic disease in adults. After Genetics clinic, the diagnosis of de novo Coffin-Siris syndrome was made, and this patient was also put on follow-up for the risk of the diseases potentially caused by the incidental findings in the genetic study. Conclusion: Coffin-Siris syndrome is a rare disorder, characterised by dysmorphia (that worsens over time) and intellectual disability, which might point to the diagnosis. This case portrays a rare situation in which a total genetic deletion of the SMARCA4 gene took place, but there were also deletions of other genes that have clinical significance. Genetic testing allows to confirm the diagnosis and family counselling. However, when carrying out the genetic study, as in this case, genes were found for pre-symptomatic diseases that are essential for periodic screening, but there may still be no treatments to date.