Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation

TY - JOUR

T1 - Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation

AU - Storr, Helen L

AU - Metherell, Louise A

AU - Dias, Renuka

AU - Savage, Martin O

AU - Rasmussen, Åse Krogh

AU - Clark, Adrian J L

AU - Main, Katharina M

N1 - Copyright 2010 S. Karger AG, Basel.

PY - 2010/2

Y1 - 2010/2

N2 - Background/Aims: Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-α (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals. Methods: A 10.5-year-old male was diagnosed with PPNAD; the patient's mother also had iPPNAD. A 13-year-old sibling and 7 other relatives (mean age 58.2, range 29.1-80.2 years) were referred for PRKAR1A mutation analysis. Results: DNA analysis of the index case and parent revealed a novel germline heterozygous PRKAR1A mutation at the +1 position of the acceptor site of intron 3 [c.349 G>T]. The same heterozygous splice site mutation was present in the sibling with no PPNAD or CNC manifestations and 2 other individuals aged 54.9 and 57.1 years who had subclinical Cushing's syndrome but no features of CNC. Conclusion: We conclude that c.349 G>T, a novel splice site germline PRKAR1A defect, has low penetrance resulting in incomplete clinical expression in this kindred.

AB - Background/Aims: Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-α (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals. Methods: A 10.5-year-old male was diagnosed with PPNAD; the patient's mother also had iPPNAD. A 13-year-old sibling and 7 other relatives (mean age 58.2, range 29.1-80.2 years) were referred for PRKAR1A mutation analysis. Results: DNA analysis of the index case and parent revealed a novel germline heterozygous PRKAR1A mutation at the +1 position of the acceptor site of intron 3 [c.349 G>T]. The same heterozygous splice site mutation was present in the sibling with no PPNAD or CNC manifestations and 2 other individuals aged 54.9 and 57.1 years who had subclinical Cushing's syndrome but no features of CNC. Conclusion: We conclude that c.349 G>T, a novel splice site germline PRKAR1A defect, has low penetrance resulting in incomplete clinical expression in this kindred.

U2 - 10.1159/000277629

DO - 10.1159/000277629

M3 - Journal article

SN - 1663-2818

VL - 73

SP - 115

EP - 119

JO - Hormone Research in Paediatrics

JF - Hormone Research in Paediatrics

IS - 2

ER -