TY - JOUR
T1 - A novel mutation of the insulin receptor gene in a preterm infant with Donohue syndrome and heart failure
AU - Nobile, Stefano
AU - Semple, Robert K.
AU - Carnielli, Virgilio P.
PY - 2012
Y1 - 2012
N2 - Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the αβ fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure. © 2012 by Walter de Gruyter Berlin Boston.
AB - Donohue syndrome (DS) is a rare autosomal recessive condition caused by mutations in the gene encoding the insulin receptor. It is characterised by severe metabolic and endocrine derangement, prenatal and postnatal linear growth impairment, soft tissue overgrowth, and poor development of adipose tissue and muscle. Causes of death, which is often within the first year of life, include intercurrent infection and, in some cases, heart failure. Management is currently based on case reports and very small case series only, and no formal guidelines or recommendations exist. We describe a preterm infant who had typical features of DS but who later developed hypertrophic cardiomyopathy with heart failure leading to death at 10 weeks old. Molecular genetic analysis revealed compound heterozygosity for the previously reported p.Arg890X nonsense mutation and the novel p.Tyr818Cys missense mutation in the INSR gene. Tyrosine 818 falls in an exquisitely conserved residue of the αβ fibronectin domain of the insulin receptor, whose structure and function are much less well understood than other parts of the receptor. We discuss management options for DS, including the therapeutic dilemma around whether recombinant human insulin-like growth factor 1, one of the few available treatments for the syndrome, may exacerbate hypertrophic cardiomyopathy and cardiac failure. © 2012 by Walter de Gruyter Berlin Boston.
KW - Donohue syndrome
KW - heart failure
KW - insulin receptor gene
KW - preterm
KW - Donohue syndrome
KW - heart failure
KW - insulin receptor gene
KW - preterm
UR - http://hdl.handle.net/10807/223351
U2 - 10.1515/jpem-2011-0448
DO - 10.1515/jpem-2011-0448
M3 - Article
SN - 0334-018X
VL - 25
SP - 363
EP - 366
JO - JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM
JF - JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM
ER -