Purpura fulminans: recognition, diagnosis and management.

Purpura fulminans (PF) is a haematological emergency in which there is skin necrosis and disseminated intravascular coagulation. This may progress rapidly to multi-organ failure caused by thrombotic occlusion of small and medium-sized blood vessels. PF may complicate severe sepsis or may occur as an autoimmune response to otherwise benign childhood infections. PF may also be the presenting symptom of severe heritable deficiency of the natural anticoagulants protein C or protein S. Early recognition and treatment of PF is essential to reduce mortality and to prevent major long-term health sequelae. However, management strategies require accurate identification of the underlying cause. This review focuses on the clinical features, differential diagnosis and laboratory features of the range of PF disorders and includes expert consensus opinion about immediate and on-going management.

Excluding medical and haematological conditions as a cause of bruising in suspected non-accidental injury.

A mistaken diagnosis of child abuse can occur in a number of medical conditions, many of which can be readily diagnosed by experienced paediatricians. Bleeding disorders offer a greater challenge, especially when court proceedings may demand their exclusion. Some of these disorders are rare but more prevalent in areas which have a high incidence of consanguinity. We advocate two stages of laboratory investigations but the limitations of some of these tests and their inability to exclude a bleeding disorder with absolute certainty should be recognised. However, if personal and family histories are absent and both first-stage and second-stage investigations are normal, it is highly unlikely that a bleeding disorder will be missed.

Congenital adrenal hypoplasia presenting as a chronic respiratory condition.

We describe two children with oxygen dependence, which resolved when congenital adrenal hypoplasia was diagnosed and treatment initiated. Chronic respiratory distress can be a symptom of adrenal hypoplasia and this should be taken into consideration when investigating a child with unexplained chronic respiratory difficulties. Respiratory symptoms resolve very quickly when the underlying condition is recognised and treated.

Molecular genetic analysis of severe protein C deficiency.

Severe protein C deficiency is a rare, early onset, venous thrombotic condition that is inherited as an autosomal recessive trait. The protein C (PROC) genes of nine unrelated individuals with severe protein C deficiency were sequenced yielding a total of 13 different lesions. Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter. Evidence for the pathogenicity of the mutations detected was obtained by molecular modelling, in vitro splicing assay and reporter gene assay. Neither the plasma protein C activity level nor the nature of the PROC gene lesions detected were found to be a good prognostic indicator of the age of onset or clinical severity of thrombotic symptoms. Other factors may thus complicate the relationship between genotype and clinical phenotype. Indeed, in two patients, the inheritance of either one or two Factor V Leiden alleles in addition to two PROC gene lesions could have served to precipitate the thrombotic events. No association was however apparent between clinical severity and the possession of a particular promoter polymorphism genotype. Despite the absence of a clear genotype-phenotype relationship, the molecular genetic analysis of the severe recessive form of protein C deficiency potentiates both the counselling of affected families and the provision of antenatal exclusion diagnosis.

Urticaria and hidden salicylates.

A 23-month-old girl had a chronic urticaria resistant to antihistamine therapy. She was found to be using large quantities of a topical salicylate preparation which was being regularly applied to her pacifier. Once this habit was stopped, her urticaria cleared and has not recurred.

Incidence of hereditary bleeding disorders in Bradford, UK: variation with ethnic group.

We have studied the number of patients registered with congenital bleeding disorders at the Haemophilia Centre, Bradford, UK, according to ethnic group. The large Pakistani population in Bradford presents a different spectrum of disorders compared with the indigenous Caucasian population with a significantly higher number of cases of factor VII deficiency and platelet disorders. Other haemophilia centres in the developed world serving large immigrant communities may also manage increased numbers of these rarer disorders with similar implications for resource allocation.

Treatment of homozygous protein C deficiency with subcutaneous protein C concentrate.

Subcutaneous protein C concentrate (Immuno, Vienna) was used to treat a child with homozygous protein C deficiency who was formerly treated with intravenous protein C concentrate. After 3000 units subcutaneous protein C concentrate (250 iu/kg), protective protein C levels were maintained for 48 h after infusion, with peak levels at 12 h. Subcutaneous protein C concentrate is given every third day and is well tolerated by the patient. No thrombotic events have occurred. We conclude that subcutaneous administration of protein C concentrate is a valuable therapeutic option in the long-term management of homozygous protein C deficiency and avoids the potential hazards of long-term central venous lines.

Homozygous protein C deficiency--management with protein C concentrate.

UNLABELLED: Two unrelated female infants with homozygous protein C (Pr C) deficiency are reported. Both are of U.K. Pakistani origin and in each case the parents are consanguinous. A previous sibling had died in each family. Both sets of parents were shown to be carriers. The concentration of Pr C in both infants was low at birth. Both developed necrotic skin lesions (purpura fulminans) and responded well to Pr C concentrate. Both are developing normally although one has visual impairment due to retinal artery thrombosis which occurred before treatment was commenced. Both infants are treated with intravenous Pr C concentrate administered daily by the parents at home. Studies of the half-life of exogenous Pr C in one of the patients has shown an increase from 2.7 to 10.8 h during the course of treatment thus enabling it to be administered once daily while still maintaining effective plasma concentrations. In the other patient half-life has fluctuated but Pr C is also given once daily. This is the first report of this condition being treated in this way in the United Kingdom. CONCLUSION: Infusion of Pr C is a safe and efficient way of treating infants with homozygous Pr C deficiency in the medium term.

Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency.

Protein C replacement therapy with a monoclonal antibody purified, virus inactivated protein C concentrate was carried out in nine infants (three male, six female) with severe congenital protein C deficiency and life-threatening purpura fulminans and/or thrombosis associated with disseminated intravascular coagulation (DIC). Eight infants were homozygous for protein C deficiency; one was a compound heterozygote. The treatment period varied from 22 days to three years. The half-life of protein C was found to be as short as two to three hours during activation of the coagulation system, increasing to approximately ten hours after stabilization. During the acute phase, protein C levels of 0.10 to 0.25 IU/mL were associated with elevated markers of coagulation activation indicating DIC, while protein C levels greater than 0.25 were associated with normalization of coagulation markers. No product-related side effects were reported. Episodes of bleeding or purpura recurred in all patients who were switched to oral anticoagulant therapy, necessitating reinstatement of protein C replacement therapy, either as needed to control symptoms, or on a long-term prophylactic schedule, alone or in addition to oral anticoagulation. Home treatment with protein C concentrate allowed a near-normal life-style for patients who otherwise would be hospitalized for long periods of time.

Campomelic dysplasia: evidence of autosomal dominant inheritance.

We present a mother and daughter with clinical and radiological findings consistent with the diagnosis of campomelic dysplasia. Milder tibial bowing and significant shortening of the phalangeal bones of both hands and feet may distinguish this from the classical autosomal recessive form of the disease.

Computed tomography findings in partial seizures.

The computed tomography findings in 82 children with partial seizures of unknown aetiology were reviewed. All had seizures with predominantly focal motor phenomena and none had abnormality on neurological examination. Findings on computed tomography were normal in 64 children (78%) and abnormal in 18 children (22%). Fourteen children had changes representing static pathology (mainly cerebral atrophy) which did not influence patient management but four had potentially correctable lesions (two tumours and two arteriovenous malformations). There were no correlations between seizure control, seizure duration, intellectual handicap, postictal weakness, electroencephalographic findings, and abnormality on the computed tomogram. In particular, none of these features were useful in predicting the presence of a tumour or arteriovenous malformation. It is concluded that a computed tomogram is indicated in every child with partial seizures.

Asymmetry of gait in normal children demonstrated by polarized light goniometry.

Polarized light goniometry recordings were obtained from 46 neurologically normal children aged 4--15 years. Asymmetry in terms of thigh and knee angle differences between right and left legs was common in children aged less than 10 years but uncommon in children aged more than 10 years. This asymmetry was predominantly in the direction of more flexion on the right side. The tendency for goniometric asymmetry to mirror asymmetry on clinical examination was slight and did not reach statistical significance. It is suggested that angular asymmetry during gait which occurs in some children under 10 years of age may be related to unequal rates of maturation of the two hemispheres. Other minor neurological asymmetries, neuro-anatomical asymmetries nd postural asymmetries which may be found in normal children are discussed.

Food intolerance and food allergy in children: a review of 68 cases.

The clinical and laboratory features of 68 children with food intolerance or food allergy are reviewed. Young children were affected the most with 79% first experiencing symptoms before age 1 year. Forty-eight (70%) children presented with gastrointestinal symptoms (vomiting, diarrhoea, colic, abdominal pain, failure to thrive), 16 (24%) children with skin manifestations (eczema, urticaria, angioneurotic oedema, other rashes), and 4 (6%) children with wheeze. Twenty-one children had failed to thrive before diagnosis. A single food (most commonly cows' milk) was concerned in 28 (41%) cases. Forty (59%) children had multiple food intolerance or allergy; eggs, cows' milk, and wheat were the most common. Diagnosis was based on observing the effect of food withdrawal and of subsequent rechallenge. In many children food withdrawal will mean the use of an elimination diet which requires careful supervision by a dietician. Laboratory investigations were often unhelpful in suggesting or confirming the diagnosis.

Engelmann's disease and the effect of corticosteroids. A case report.

A 13-year-old girl presented with a two-year history of pain in the right thigh and right forearm. Engelmann's disease was diagnosed on the basis of radiological appearances and histological examination of the bone. Her symptoms subsided after biopsy of the bone, but two weeks later she developed severe pain in the left tibia and was unable to walk. Radiological features of Engelmann's disease were found in the left tibia and other long bones although these bones had been radiologically normal one month previously. Treatment with prednisolone gave rapid relief of pain and allowed the patient to become mobile again. Four months later the radiological appearances showed significant improvement. The use of corticosteroids in this disorder is discussed.

Prostaglandin synthetase inhibitor in an infant with congenital chloride diarrhoea.

Hyper-reninaemia, hypokaluria, and hypokalaemia in an infant with congenital chloride diarrhoea improved during treatment with a prostaglandin synthetase inhibitor, ketoprofen. There was evidence of increased activity of therenin-aldosterone system when ketoprofen was stopped. It is suggested that prostaglandins may be involved in stimulating the renin-aldosterone system in congenital chloride diarrhoea.

Haemorrhage responsive to vitamin K in a 6-week-old infant.

A 6-week-old breast-fed infant presented with vomiting, jaundice, and irritability. Haemorrhage occurred after lumbar puncture, and a coagulation abnormality which responded to vitamin K was found. It would seem prudent to estimate the prothrombin time before invasive procedures in breast-fed infants of this age, or to give vitamin K to such infants when doubt exists about previous vitamin K administration.