A novel compound heterozygous form of severe protein C deficiency causing bleeding without purpura fulminans

SummaryWe report genetic abnormalities of protein C gene in a male infant who developed neonatal purpura fulminans. DNA-sequence analysis of all exons in protein C gene in this family revealed two mutations. The first abnormality, derived from the mother, was a deletion of one of four consecutive G at nucleotide number 10758 in exon IX which would result in a frame shift mutation and completely change amino acid sequence from Gly381 in the carboxyl-terminal region of protein C. The second abnormality, derived from the father, was a single nucleotide mutation from G to A in the codon (GAG to AAG) at nucleotide number 2977 in exon III, which would result in a substitution of Lys for γ-carboxyglutamic acid (Gla)26. This change would be responsible for the reduced immunological protein C levels of the patient and the father, estimated by a monoclonal antibody which recognizes the Gla-domain in a Ca2+-dependent manner (3.8% and 57%, respectively). Partially purified abnormal protein C from the father’s plasma showed a normal amidolytic activity and a change in the electrophoretic mobility. We detected the above mutations in his family members using two methods; one was a creation of new restriction enzyme sites using mutagenic primers and the other was single nucleotide primer extension. Both methods are rapid and useful for the diagnosis of prenatal protein C abnormalities.

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A rare case of protein C mutation causing neonatal purpura fulminans

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20213658 ◽

2021 ◽

Author(s):

Abdul Tawab ◽

Madhu George ◽

Jino Joseph ◽

Ann Mary Zacharias

Keyword(s):

Protein C ◽

Autosomal Recessive ◽

Purpura Fulminans ◽

Rare Condition ◽

Autosomal Recessive Inheritance ◽

Fresh Frozen Plasma ◽

Compound Heterozygous ◽

Protein C Deficiency ◽

Fresh Frozen ◽

Proc Gene

Congenital protein C deficiency presenting as purpura fulminans is a rare condition in neonates. It is a disorder with autosomal recessive inheritance and is caused by homozygous or compound heterozygous mutations in PROC gene. The authors report a case of autosomal homozygous PROC gene transversion mutation in a newborn baby born to third degree consanguineous parents who presented as purpura fulminans at birth. She had almost undetectable protein C levels. As protein C concentrate was not readily available, she was managed with low molecular weight heparin along with fresh frozen plasma. Despite our best efforts, baby succumbed to her illness on day 21 of life. Autosomal recessive protein C deficiency should always be sought as an explanation for thrombotic disorders in the newborn with manifestations of disseminated intravascular coagulation.

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Genotypic and phenotypic character of Chinese neonates with congenital protein C deficiency: a case report and literature review

Thrombosis Journal ◽

10.1186/s12959-019-0208-6 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 1

Author(s):

Xiaoying Li ◽

Xiaoyan Li ◽

Xiao Li ◽

Yuanhua Zhuang ◽

Lili Kang ◽

...

Keyword(s):

Literature Review ◽

Protein C ◽

Molecular Genetic ◽

Purpura Fulminans ◽

Protein S ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Molecular Testing ◽

Compound Heterozygous ◽

Protein C Deficiency

Abstract Background Our objective was to study the phenotype of and molecular genetic mechanisms underlying congenital protein C (PC) deficiency in Chinese neonates. We report the case of a neonate who presented 4 h after birth with purpura fulminans of the skin and thrombosis in the kidney. We also carried out a through literature review to study the genotype and phenotype, relevance, diagnosis, management, and prognosis of neonates with congenital PC deficiency in China. Case presentation and literature review Following a septic work-up and check of PC and protein S (PS) levels that showed PC deficiency, we investigated the patient’s and her parents’ genotypes. Our patient was found to have a plasma PC level of 0.8%. Molecular testing revealed a compound heterozygous mutation of the PROC gene: From the father, a c._262 G > T p. ASP88Tyr mutation in exon 4; from the mother, a C. 400 + 5G mutation in intron 5 that had been previously reported as likely pathogenic. Both parents were found to have heterozygous mutations for PC deficiency. In China, 5 other cases of congenital PC deficiency in the neonatal period were reported in the literature. In those cases, purpura fulminans and thrombosis were the main symptoms, and homozygous or compound heterozygous mutations of the PROC gene were identified. Conclusion Congenital PC deficiency should be ruled out for neonates presenting with purpura fulminans and thrombosis.

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Severe Homozygous Protein C Deficiency: Identification of a Splice Site Missense Mutation (184, Q → H) in Exon 7 of the Protein C Gene

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648812 ◽

1994 ◽

Vol 72 (01) ◽

pp. 065-069 ◽

Cited By ~ 2

Author(s):

J M Soria ◽

D Brito ◽

J Barceló ◽

J Fontcuberta ◽

L Botero ◽

...

Keyword(s):

Missense Mutation ◽

Gene Product ◽

Splice Site ◽

Protein C ◽

Purpura Fulminans ◽

Single Strand Conformation Polymorphism ◽

Donor Splice Site ◽

Protein C Deficiency ◽

Donor Splice ◽

Newborn Child

SummarySingle strand conformation polymorphism (SSCP) analysis of exon 7 of the protein C gene has identified a novel splice site missense mutation (184, Q → H), in a newborn child with purpura fulminans and undetectable protein C levels. The mutation, seen in the homozygous state in the child and in the heterozygous state in her mother, was characterized and found to be a G to C nucleotide substitution at the -1 position of the donor splice site of intron 7 of the protein C gene, which changes histidine 184 for glutamine (184, Q → H). According to analysis of the normal and mutated sequences, this mutation should also abolish the function of the donor splice site of intron 7 of the protein C gene. Since such a mutation is compatible with the absence of gene product in plasma and since DNA sequencing of all protein C gene exons in this patient did not reveal any other mutation, we postulate that mutation 184, Q → H results in the absence of protein C gene product in plasma, which could be the cause of the severe phenotype observed in this patient.

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Purpura fulminans skin lesions in a newborn with complete protein C deficiency

The Journal of Pediatrics ◽

10.1016/s0022-3476(98)70043-5 ◽

1998 ◽

Vol 132 (3) ◽

pp. 558 ◽

Cited By ~ 3

Author(s):

Gideon Paret ◽

Asher Barzilai ◽

Zohar Barzilay

Keyword(s):

Protein C ◽

Purpura Fulminans ◽

Skin Lesions ◽

Protein C Deficiency ◽

Complete Protein

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Purpura Fulminans in a Chinese Boy With Congenital Protein C Deficiency

PEDIATRICS ◽

10.1542/peds.77.5.670 ◽

1986 ◽

Vol 77 (5) ◽

pp. 670-676

Author(s):

Patrick Yuen ◽

Alfred Cheung ◽

Hsiang Ju Lin ◽

Faith Ho ◽

Jun Mimuro ◽

...

Keyword(s):

Disseminated Intravascular Coagulation ◽

Protein C ◽

Purpura Fulminans ◽

Fresh Frozen Plasma ◽

Protein C Deficiency ◽

Intravascular Coagulation ◽

The Family ◽

Fresh Frozen ◽

Frozen Plasma ◽

Congenital Protein C Deficiency

Severe and recurrent purpura fulminans developed in a Chinese boy at one day of age. Results of coagulation studies performed on the patient during attacks were compatible with the diagnosis of disseminated intravascular coagulation. Subsequent investigations have revealed that the patient is homozygous and that his parents are heterozygous for protein C deficiency. Cryoprecipitate and fresh frozen plasma induced a remission, and administration of warfarin has been successful in preventing recurrence of attacks for as long as 8 months without infusion of any plasma components. None of the family members who are heterozygous for protein C deficiency have had thrombotic episodes.

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Compound heterozygous protein C variants undetectable by common laboratory testing causing purpura fulminans after the neonatal period

American Journal of Hematology ◽

10.1002/ajh.25976 ◽

2020 ◽

Vol 95 (12) ◽

pp. 1616-1621

Author(s):

Kyle L. MacQuarrie ◽

Olatundun Williams ◽

Kenneth D. Friedman ◽

Rachel S. Bercovitz

Keyword(s):

Laboratory Testing ◽

Protein C ◽

Neonatal Period ◽

Purpura Fulminans ◽

Compound Heterozygous ◽

Common Laboratory

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TWO CASES OF NEONATAL PURPURA FULMINANS HOMOZYGOUS FOR PROTEIN C DEFICIENCY IN A CHINESE FAMILY

10.1055/s-0038-1644308 ◽

1987 ◽

Author(s):

M C SHEN ◽

S H CHEN ◽

K S LIN

Keyword(s):

Vitamin K ◽

Protein C ◽

Newborn Infants ◽

Purpura Fulminans ◽

Coagulation Factors ◽

Chinese Family ◽

Factor V ◽

Autosomal Dominant Disorder ◽

Protein C Deficiency ◽

Venous Thromboembolic

Protein C (PC) deficiency associated with hereditary venous thromboembolic disease was first reported in 1981 and is inherited as an autosomal dominant disorder. The prevalence of heterozygous PC deficiency is estimated to be 1 to 4% in venous thrombotic diseases. The homozygous PC deficiency is even rare, and has been reported in only about 10 families througout the world. It usually presents in newborn infants as purpura fulminans or severe thrombotic disease. We herein report two newborn brothers in a Chinese family, who manifested with purpura fulminans soon after birth and died at age of 21 days and 27 days respectively. Vitamin K was administered to the second baby after birth. Both parents are not consanguineous and there were no family histories of thromboembolism on paternal and maternal sides. Blood sample was not available for specific studies in the first baby. PC antigen level by electroimmunoassay was <6% in the second baby and 49% and 60% respectively in their mother and father. Antithrombin III activity by amidolytic method was 49% in the second baby, and 90% and 97% respectively in their mother and father. Vitamin K-dependent coagulation factors and factor V were within the expected range for a newborn. Factor VIII and fibrinogen level were notably decreased. Autopsy findings of the two newborns demonstrated the similar pictures characterized by fibrin thrombi in blood vessels causing extensive hemorrhagic infarts of skin, lung, liver, kidneys, testis, urinary bladder, esophagus and brain. Our Data indicate that neonatal purpura fulminans can be familial and caused by severe homozygous PC deficiency.

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