|Year : 2017 | Volume
| Issue : 2 | Page : 116-120
Congenital protein C deficiency with renal vein thrombosis and central retinal venous occlusion in a term neonate due to novel mutation in the PROC gene
Mahmoud Oklah1, Hussain Parappil2, Hilal Al Rifai2, Abubakr Imam3, Wafaa Abdelghany4, Anant Pai5
1 Department of Neonatology, Hamad Medical Corporation, Doha, Qatar
2 Department of Neonatology, Hamad Medical Corporation; Department of Pediatrics, Weill Cornell Medical College, Doha, Qatar
3 Department of Pediatrics, Weill Cornell Medical College; Department of Pediatric Nephrology, Hamad Medical Corporation, Doha, Qatar
4 Department of Pediatric Hematology, Hamad Medical Corporation, Doha, Qatar
5 Department of Pediatrics, Weill Cornell Medical College; Department of Pediatric Opthalmology, Hamad Medical Corporation, Doha, Qatar
|Date of Web Publication||13-Apr-2017|
Department of Neonatology, Hamad Medical Corporation, Doha
Source of Support: None, Conflict of Interest: None
Severe protein C (PC) deficiency is a rare disorder caused by homozygous or compound heterozygous genetic anomalies. PC deficiency is inherited as autosomal dominant, and most patients are heterozygous for a genetic defect. Homozygous or compound heterozygous for a mutation or other genetic defect affecting PC is typically due to inheritance of an abnormal allele from both parents. In the neonatal period, homozygous PC deficiency is usually associated with the development of severe, and often fatal, purpura fulminans and disseminated intravascular coagulation and if untreated is incompatible with life. Here, we report a case of congenital PC deficiency due to novel homozygous mutation in the protein coding gene (PROC) in a term neonate which presented with severe purpura fulminans, perinatal right renal vein thrombosis (RVT), bilateral adrenal hemorrhage, and early neonatal central retinal venous occlusion with retinal detachment. Perinatal RVT and early neonatal central retinal vein occlusion have not been reported previously in the literature.
Keywords: Adrenal hemorrhage, central retinal vein occlusion, protein C deficiency, renal vein thrombosis
|How to cite this article:|
Oklah M, Parappil H, Al Rifai H, Imam A, Abdelghany W, Pai A. Congenital protein C deficiency with renal vein thrombosis and central retinal venous occlusion in a term neonate due to novel mutation in the PROC gene. J Clin Neonatol 2017;6:116-20
|How to cite this URL:|
Oklah M, Parappil H, Al Rifai H, Imam A, Abdelghany W, Pai A. Congenital protein C deficiency with renal vein thrombosis and central retinal venous occlusion in a term neonate due to novel mutation in the PROC gene. J Clin Neonatol [serial online] 2017 [cited 2019 Aug 18];6:116-20. Available from: http://www.jcnonweb.com/text.asp?2017/6/2/116/204504
| Introduction|| |
Protein C (PC) is part of a complex regulatory system, which has an important influence on the physiological function of hemostasis to ensure patency of the microcirculation. It was discovered in 1976, by Stenflo as the zymogen of an anticoagulant protein, which could be activated by thrombin. The clinical importance of PC became evident when Griffinet al. demonstrated an association with thromboembolic events. Severe PC deficiency is a rare disorder caused by a homozygous or compound heterozygous genetic anomalies. Transmission of inherited PC deficiency is autosomal dominant, and most patients with inherited PC deficiency are heterozygous for a genetic defect. The gene for PC is located on chromosome 2, and over 160 different mutations and other genetic abnormalities have been described., Homozygous or compound heterozygous for a mutation or other genetic defect affecting PC is typically due to inheritance of an abnormal allele from both parents. Severe deficiency can lead to neonatal purpura fulminans at birth.
Among the general population, the incidence of PC deficiency may be as high as 1 in 200–500 people although the defect is not severe enough to cause clinical illness. People with heterozygous PC deficiency can range from being totally healthy to having single or recurrent venous thromboses, such as deep vein thrombosis, pulmonary embolism, pregnancy-associated thrombosis, or mesenteric thrombi. Severe homozygous or compound heterozygous PC deficiency occurs in approximately 1 in 500,000–1 in 750,000 live births.
In the neonatal period, homozygous PC deficiency is usually associated with the development of severe, and often fatal, purpura fulminans and disseminated intravascular coagulation and if untreated is incompatible with life. The age of onset of the first symptoms can range from a few hours to 2 weeks., Homozygous patients may be treated with fresh frozen plasma (FFP) or PC concentrate.
We are reporting a case of congenital PC deficiency due to novel homozygous mutation in the PROC gene presented in a term neonate with severe purpura fulminans, perinatal right renal vein thrombosis (RVT), bilateral adrenal hemorrhage, and central retinal venous occlusion with retinal detachment. Perinatal RVT and early neonatal retinal vein occlusion have not been reported previously in the literature.
| Case Report|| |
A female infant born at-term to a 30-year-old mother gravida 4 para 3 with normal previous babies with birth weight of 2.6 kg and Apgar score of 8 and 9 at 1 and 5 min, respectively. The parents were the first cousins. The previous pregnancies were uneventful with normal babies. During this pregnancy, the mother had gestational diabetes and her antenatal ultrasounds were all normal.
At the age of 40 min, the infant had gross hematuria and had developed bluish discoloration of the scalp at the left parietal area of size of 3 cm × 3.5 cm which increased to 4 cm × 5 cm within 24 h [Figure 1]. The infant developed mild tachypnea with desaturation and was kept under nasal cannula; and later, at the age of 24 h, the infant developed blackish decolorization of dorsum of the left hand, including all the fingers except the thumb. At 36 h, the lesion became slightly edematous and gradually extended beyond the wrist [Figure 2]. The radial pulses were palpable well, and the Doppler study was normal. Her investigations showed the following results: urine dipstick for blood showed 3+, complete blood count revealed thrombocytopenia (64 × 103/μL) in the initial 2 days; and urea and electrolytes, liver function test, coagulation profile, and factor V assay were all within normal range. The C-reactive protein was 19 mg/L; virology screening and blood culture were negative.
|Figure 2: Severe purpura fulminans of the left hand and wrist at 24 h of age|
Click here to view
Renal ultrasound with Doppler was done at 12 h of life which showed that the right kidney was enlarged and edematous. There was no vascularity seen in the right kidney. The right renal artery and vein could not be traced by Doppler scan [Figure 3]. The infant was diagnosed to have the right RVT. The infant was suspected to have severe neonatal purpura fulminans, and the investigations revealed PC level was zero. Protein S, homocysteine, and thyroid results were all normal. The infant was managed with FFP and low-molecular weight heparin (LMWH). PC concentrate was added to the management at 12 days of life (PC concentrate was not available initially).
|Figure 3: Right kidney appears enlarged, shows prominent low echogenicity of renal pyramids with thinned out renal cortex. Marked hypovascularity and low perfusion of the right kidney. The main right renal artery and vein could not be traced by colored Doppler scan|
Click here to view
PC deficiency was suspected, and a full gene sequencing of PROC gene was carried out. A previously unreported homozygous variant in the PROC gene (c.479G>T (p. Cys 160Phe) was detected. This variant is located in a moderately conserved nucleotide and highly conserved amino acid position with large physicochemical differences between the exchanged amino acids (Alamut v 2.7.1). SIFT and Mutation Taster and Polyphen-2 indicate that it is probably damaging, whereas Align-GVGD predicts toleration. To date, this mutation variant is not reported in the literature. The PC levels of the parents were low (mother 47%, father 46% [normal >60%]), and asymptomatic. Both parents were unwilling to do their genetic sequencing.
Repeat renal ultrasound at 5 days of age showed enlarged and edematous right kidney with bilateral adrenal hemorrhage measuring 25 mm × 11 mm (right) and 9 mm × 2 mm (left) [Figure 4] and [Figure 5]. The serum cortisol levels were normal. The left kidney was of normal size. Brain ultrasound showed multiple diffuse subcortical tiny hemorrhagic foci. The Doppler study of middle cerebral artery was normal. The echocardiogram was normal. Ophthalmology evaluation in the 1st week revealed multiple retinal hemorrhages and grossly dilated tortuous central retinal vein suggesting central retinal venous occlusion in the right eye. The left fundus examination showed diffuse chorioretinal degenerative changes.
Repeat renal ultrasound at 1 month showed that adrenal hemorrhages had disappeared on both sides; however, the right kidney showed echogenic renal parenchyma with loss of corticomedullary differentiation whereas the left one was normal. Dimercaptosuccinic acid showed nonperfused (absent) right kidney and a fairly well-functioning left kidney with some prolongation of parenchymal transit time. Magnetic resonance imaging of head at 5 weeks of age revealed multiple small hemorrhagic foci noted at the bilateral frontal, parietal, and left posterior temporal lobes. Follow-up ophthalmology evaluation at 5 weeks of age showed vitreous hemorrhage and fibrovascular bands starting from the optic disc causing tractional retinal detachment in the right eye. The left eye fundus remained status quo at follow-up visits (fundus imaging facility was not available in the unit).
PC concentrate therapy was stopped at 50 days of age as the lesion of the scalp, and the fingers improved. The infant had lost the tips of four fingers due to autoamputation. PC levels were normal by 50 days of age. The infant was discharged at 2 months of age on prophylactic dose of LMWH in a good general condition. The infant was readmitted in the pediatric floor, after 2 weeks due to reappearance of scalp lesion with low PC level. Infant was restarted on PC concentrate supplementation. The scalp lesions healed within 2 weeks of medication [Figure 6] and [Figure 7]. Currently, the infant is on subcutaneous prophylaxis of PC concentrate and LMWH.
|Figure 7: Healed hand lesion with autoamputated tips of the four fingers at 12 weeks of age|
Click here to view
| Discussion|| |
PC is a vitamin K-dependent natural inhibitor of coagulation. It is synthesized in the liver in an inactive form and converted into the active form by limited proteolysis process. Activated PC prevents the formation of blood clots by specifically inactivating factor V and VIII, thereby downregulating the coagulation cascade and preventing propagation of thrombosis.
RVT in the neonatal period due to PC deficiency which improved with treatment has been reported previously by Rogers et al. in 1989; and Szafranska et al. reported left RVT in the 1st day of life, leading to loss of renal function at 3 months due to abnormal factor VIII level. Our infant was diagnosed to have right RVT within the 12 h of age with poor renal perfusion and complete loss of function of the right kidney. This early loss of function of the kidney is likely due to renal thrombosis developed in the late third trimester that caused permanent loss of function of the right kidney which was detected after birth. Al Hawsawi et al. have reported on bilateral adrenal hemorrhage in PC deficiency which improved with treatment in a neonate. Our case had the findings of bilateral adrenal hemorrhage which completely disappeared by 5 weeks with treatment.
Ocular problems are common in patients with PC deficiency. Some commonly occurring complications include nonreactive pupils, microphthalmos, retinal vein occlusion, vitreous hemorrhage, and retinal detachment. The most frequently seen problem is vitreous hemorrhage. Although the exact cause is unknown, the most likely reason is retinal vein occlusion. In our case also, there was right central retinal vein occlusion at 1 week of age, and at 5 weeks, it had progressed to vitreous hemorrhage with retinal detachment. To the best of our knowledge, this is the first case of retinal venous occlusion which was detected at 7 days of life in an infant with congenital PC deficiency.
Congenital PC deficiency can also cause antenatal and postnatal thromboses of the brain leading to neonatal ischemic stroke, brain hemorrhage, and hydrocephalus., Our case revealed multiple small hemorrhagic foci noted at the bilateral frontal, parietal, and left posterior temporal lobes.
Transmission of inherited PC deficiency is usually autosomal dominant and most patients with inherited PC deficiency are heterozygous for a genetic defect. The clinical presentation of the heterozygous form of the disease is usually of venous thromboembolism in adolescent and adult patients. The homozygous type usually presents as purpura fulminans. The onset of symptoms is usually within 2–12 h after birth. However, infants presenting with a delayed onset of purpura fulminans between 6 and 12 months of age have been reported. Autosomal recessive (AR) inheritance with severe purpura fulminans also has been reported by Miller in 2000. In our case, the infant presented with severe purpura fulminans within 1 h of birth with undetected PC levels in the blood. The PROC gene sequencing in the infant showed a novel homozygous variant (c.479G>T (p. Cys 160Phe) which we conclude to be unique in our case and the disease causing. The infant's parents were first cousins with low PC levels. Hence, this mutation presented in a homozygous state in our symptomatic neonate and in a heterozygous state in both asymptomatic parents. However, the biochemical results need to be confirmed by molecular genetic studies of the parents.
Prenatal diagnosis of severe PC deficiency is available for women at risk of having a child with PC deficiency. This requires chorionic villous sampling that is associated with a 1% risk of fetal loss. Despite the identification of almost 200 unique mutations in the PC gene, the underlying defect is not always identified. Fetal blood sampling in the second trimester offers an alternative method in diagnosing this condition. The complications of congenital PC deficiency in the central nervous system may occur in the third trimester. Hence, the antenatal diagnosis may provide an opportunity for early intervention through timely delivery and initiation of replacement therapy. In our case, the antenatal diagnosis will be very beneficial for the future pregnancies since there are chances of having severe congenital PC deficiency in the fetuses.
The management of PC deficiency in the acute phase includes replacement therapy with FFP or PC concentrate, and a maintenance therapy that includes anticoagulation with warfarin or LMWH. Liver transplant has been performed as a successful treatment of homozygous PC deficiency when replacement therapy was not readily available. This can normalize the PC levels, and the thrombotic disorder is eliminated. Disadvantages of liver transplantation are the need for lifelong immunosuppression and the possibility of forming autoantibodies against the foreign PC. Recently, Cisneros and Khatib reported effective prophylaxis with rivaroxaban in severe congenital PC deficiency. Our case was managed with FFP initially, and then, with PC replacement and LMWH in the acute period. Currently, the infant is on long-term supplementation of subcutaneous PC and LMWH.
| Conclusion|| |
Congenital homozygous PC deficiency is a rare but a life-threatening condition which can cause perinatal RVT with the loss of renal function and early neonatal retinal vein occlusion with retinal detachment in the neonatal period. Antenatal or early recognition of the clinical symptoms with prompt diagnosis and judicious PC replacement therapy is essential to decrease both the morbidity and mortality associated with this condition.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors are grateful to Dr. Afaf Shaddad (Consultant in Neonatology), Dr. Mai Al Qubaisi (Consultant in Neonatology) for their involvement in the management of the baby and their support in writing this paper.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Knoebl Pn. Severe Congenital Protein C Deficiency: The Use Of Protein C Concentrates (Human) As Replacement Therapy For Life-Threatening Blood-Clotting Complications. Biologics 2008;2:285-96.
Tcheng WY, Dovat S, Gurel Z, Donkin J, Wong WY. Severe congenital protein C deficiency: Description of a new mutation and prophylactic protein C therapy and in vivo
pharmacokinetics. J Pediatr Hematol Oncol 2008;30:166-71.
Reitsma PH. Protein C deficiency: From gene defects to disease. Thromb Haemost 1997;78:344-50.
Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, et al.
Protein C deficiency: A database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995;73:876-89.
Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008;14:1214-21.
Abu-Amero KK, Owaidah TM, Al-Mahed M. Severe type I protein C deficiency with neonatal purpura fulminans due to a novel homozygous mutation in exon 6 of the protein C gene. J Thromb Haemost 2006;4:1152-3.
Müller FM, Ehrenthal W, Hafner G, Schranz D. Purpura fulminans in severe congenital protein C deficiency: Monitoring of treatment with protein C concentrate. Eur J Pediatr 1996;155:20-5.
Marlar RA, Montgomery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiency. Report of the working party on homozygous protein C deficiency of the subcommittee on protein C and protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 1989;114(4 Pt 1):528-34.
Pescatore SL. Clinical management of protein C deficiency. Expert Opin Pharmacother 2001;2:431-9.
Esmon C. The protein C pathway. Crit Care Med 2000;28 9 Suppl: S44-8.
Rogers PC, Silva MP, Carter JE, Wadsworth LD. Renal vein thrombosis and response to therapy in a newborn due to protein C deficiency. Eur J Pediatr 1989;149:124-5.
Szafranska A, Pajak A, Kilis-Pstrusinska K, Królak-Olejnik B. Renal vein thrombosis in a newborn with abnormal factor VIII level: Clinical case report. Medicine (Baltimore) 2015;94:e1197.
Al Hawsawi ZM, Alhejaili AA, Uddin MM, Abdelkarim ME. Hereditary protein C deficiency in a Saudi neonate with bilateral adrenal gland haemorrhages: A rare case report. J Taibah Univ Med Sci 2016;11:485-8.
Stutterd C, Savoia H, Fink AM, Stark Z. Severe fetal ischaemic brain injury caused by homozygous protein C deficiency. Prenat Diagn 2014;34:192-4.
Kelly A, Pearson GD. Protein C deficiency: A case review. Neonatal Netw 2011;30:153-9.
Tuddenham EG, Takase T, Thomas AE, Awidi AS, Madanat FF, Abu Hajir MM, et al.
Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months. Thromb Res 1989;53:475-84.
Millar DS, Johansen B, Berntorp E, Minford A, Bolton-Maggs P, Wensley R, et al.
Molecular genetic analysis of severe protein C deficiency. Hum Genet 2000;106:646-53.
Millar DS, Allgrove J, Rodeck C, Kakkar VV, Cooper DN. A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal purpura fulminans: Prenatal diagnosis in an at-risk pregnancy. Blood Coagul Fibrinolysis 1994;5:647-9.
Barnes C, Newall F, Higgins S, Carden S, Monagle P. Perinatal management of patients at high risk of homozygous protein C deficiency. Thromb Haemost 2002;88:370-1.
Price VE, Ledingham DL, Krümpel A, Chan AK. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med 2011;16:318-22.
Lee MJ, Kim KM, Kim JS, Kim YJ, Lee YJ, Ghim TT. Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation. Pediatr Transplant 2009;13:251-4.
Casella JF, Bontempo FA, Markel H, Lewis JH, Zitelli BJ, Starzl TE. Successful treatment of homozygous protein deficiency by hepatic transplantation. Lancet 1988;1:435-8.
Cisneros S, Khatib Z. Rivaroxaban prophylaxis in severe congenital protein C deficiency. Blood 2016;128:4945.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]