Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation

TY - JOUR

T1 - Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation

AU - Girisha, Katta M

AU - Lewis, Leslie E

AU - Phadke, Shubha R

AU - Kutsche, Kerstin

N1 - © 2010 Wiley-Liss, Inc.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Costello syndrome is a rare developmental disorder characterized by coarse face, postnatal growth retardation, skin and musculoskeletal anomalies, cardiovascular abnormalities, mental retardation, and tumor predisposition. Dermatological manifestations usually include redundant, soft and thickened skin. Loose skin is especially present over the neck, hands, and feet. Heterozygous missense mutations in HRAS are causative for Costello syndrome, with the c.34G > A (p.G12S) mutation as the most commonly found alteration. In the majority of affected individuals pathogenic sequence changes appeared de novo, however, two individuals with somatic mosaicism for the HRAS mutation have been reported. Here, we describe a boy with somatic mosaicism for the c.34G > A mutation in HRAS. Allelic quantitation revealed the mutation in approximately 58% of his lymphocytes; however, in DNA derived from buccal cells we could not detect the sequence change. The patient presented with the typical clinical findings of Costello syndrome such as increased birth weight, severe failure to thrive, characteristic facial appearance, and skin abnormalities. The dermatological anomalies were remarkable as he showed severe skin laxity with wrinkling of skin on all parts of the body due to loss of subcutaneous fat that decreased significantly by age 13 months. This case further adds to the phenotypic variability seen in patients with somatic mosaicism for an HRAS mutation and highlights the awareness of mosaic mutations in Costello syndrome when molecular testing is performed.

AB - Costello syndrome is a rare developmental disorder characterized by coarse face, postnatal growth retardation, skin and musculoskeletal anomalies, cardiovascular abnormalities, mental retardation, and tumor predisposition. Dermatological manifestations usually include redundant, soft and thickened skin. Loose skin is especially present over the neck, hands, and feet. Heterozygous missense mutations in HRAS are causative for Costello syndrome, with the c.34G > A (p.G12S) mutation as the most commonly found alteration. In the majority of affected individuals pathogenic sequence changes appeared de novo, however, two individuals with somatic mosaicism for the HRAS mutation have been reported. Here, we describe a boy with somatic mosaicism for the c.34G > A mutation in HRAS. Allelic quantitation revealed the mutation in approximately 58% of his lymphocytes; however, in DNA derived from buccal cells we could not detect the sequence change. The patient presented with the typical clinical findings of Costello syndrome such as increased birth weight, severe failure to thrive, characteristic facial appearance, and skin abnormalities. The dermatological anomalies were remarkable as he showed severe skin laxity with wrinkling of skin on all parts of the body due to loss of subcutaneous fat that decreased significantly by age 13 months. This case further adds to the phenotypic variability seen in patients with somatic mosaicism for an HRAS mutation and highlights the awareness of mosaic mutations in Costello syndrome when molecular testing is performed.

KW - Amino Acid Sequence

KW - Amino Acid Substitution

KW - Base Sequence

KW - Costello Syndrome

KW - Cutis Laxa

KW - DNA Mutational Analysis

KW - Female

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Molecular Sequence Data

KW - Mosaicism

KW - Mutation

KW - Pregnancy

KW - Proto-Oncogene Proteins p21(ras)

U2 - 10.1002/ajmg.a.33687

DO - 10.1002/ajmg.a.33687

M3 - SCORING: Journal article

C2 - 20979192

VL - 152A

SP - 2861

EP - 2864

JO - AM J MED GENET A

JF - AM J MED GENET A

SN - 1552-4825

IS - 11

ER -