Juliaan Leroy

Oligohydramnios, renal insufficiency, and ileal perforation in preterm infants after intrauterine exposure to indomethacin

Three preterm infants exposed antenatally to indomethacin developed a characteristic syndrome consisting of edema and hydrops with a bleeding disorder at birth, oliguric renal failure during the first 3 postnatal days, and acute pneumoperitoneum resulting from localized ileal perforation(s) at the end of the first week of life. Despite the value of indomethacin for arresting preterm labor, the physician must take into account the potential hazards of drug toxicity.

Recessive Osteogenesis Imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation

Background: Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen α1-chains. Methods: We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation. Results: Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (177/12 years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a “KDEL” endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of α1(I)Pro986 3-hydroxylation and overmodification of type I (pro)collagen chains in skin fibroblasts of the patients. Conclusion: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.

Vacuum extraction, bone injury and neonatal subgaleal bleeding

In a population of 27 flemish newborns with subgaleal bleeding encountered within a period of 6 years, we studied the obstetrical, clinical and radiological data. In contrast with controversial findings from the available literature, there is little doubt that difficult, often elective vacuum extraction is the main cause of this neonatal emergency. Disturbances in haemostasis, when documented, were attributed to focal intrahaematoma consumption, except for one boy who presented with haemophilia and neonatal subgaleal bleeding. Conventional X-ray examination continues to be of importance for the documentation of suture diastasis, fissures and fractures. CT scan reveals both the amount of extra-osseous bleeding, the degree of bone displacement and injury as well as the type and extent of associated intracranial damage. Subgaleal haemorrhage rarely hides a growing synchrondrosal rupture.

Fungal intracranial aneurysm in a child with familial chronic mucocutaneous candidiasis

Abstract We report on a patient who presented at 5 years of age with a hemiparesis due to a middle cerebral artery infarction. An embolism had originated from a mycotic aneurysm located in the internal carotid artery. For several months prior to admission he had been suffering from therapeutically resistant candidiasis of the mouth and nails. Family history revealed chronic mycotic infections of the skin, hair, nails and mouth in the father and paternal grandmother suggestive of chronic mucocutaneous candidiasis with autosomal dominant mode of inheritance. Clipping of the aneurysm, after 3 months of anti-mycotic treatment, followed by sustained treatment with itraconazole and fluconazole, led to a favourable outcome.nConclusion Chronic mucocutaneous candidiasis can be associated with an intracranial aneurysm and complicated by cerebral infarction.

Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes

Multiple epiphyseal dysplasia (MED) is a mild chondrodysplasia affecting the structural integrity of cartilage and causing early-onset osteoarthrosis in adulthood. The condition is genetically heterogeneous. Mutations in the COMP gene and in two genes (COL9A2; COL9A3), coding respectively for the α2(IX) and α3(IX) chains of type IX collagen, can cause the autosomal dominant forms of MED. Mutations in the DTDST gene have recently been identified in a recessive form of MED. However, for the majority of MED cases, the genetic defect still remains undetermined. We report a three-generation family with an autosomal dominant form of MED, characterised by normal stature, joint pain in childhood and early-onset osteoarthrosis, affecting mainly the hips and knees. Based on discordant inheritance among affected individuals linkage of the phenotype to the COMP, COL9A1, COL9A2, COL9A3 genes was excluded. Our study provides evidence that at least another locus, distinct from COL9A1, is involved in autosomal dominant MED.

Bruck syndrome: neonatal presentation and natural course in three patients

Abstract Three unrelated patients with congenital arthrogryposis and brittle bones, the main neonatal signs of Bruck syndrome, are presented. In infancy and early childhood recurrent fractures of ribs and long bones and persistent Wormian bones in the calvarium are reminiscent of osteogenesis imperfecta (OI) even with white sclerae, normal dental quality and normal hearing as important clinical negatives. The diagnosis was made before two years of age in two, and in adolescence in the third patient. The latters radiologically documented long-term natural course reveals slow progressivity of osteopenia and growth deficiency, worsening tendon contractures and pterygia in addition to increasing spine and pelvis deformation. Mental development remains normal. Bruck syndrome is monogenic and probably due to homozygosity of an as yet unidentified gene. As no alteration in the collagens I and III is detected and molecular screening reveals no mutation in the COL1A1 and COL1A2 genes, the pathogenesis of this severe disorder of connective tissue remains largely unknown.

Simple test to distinguish between surgical and non-surgical pneumoperitoneum in ventilated neonates.

A simple and accurate method is described for rapid differentiation of surgical and nonsurgical pneumoperitoneum by measuring the partial pressure of oxygen in intraperitoneal air with a blood gas analyser. Results in five ventilated neonates in whom this distinction was not possible by clinical or radiographic means are presented.

Episiotomy and neonatal lidocaine intoxication

Sir: Recent studies have shown that primary hepatocellular carcinoma (PHC) in childhood is aetiologically related to hepatitis B virus (HBV) infection [1]. So far, there are no prospective studies, however, of the development of PHC in children with chronic type B hepatitis, and little is known about risk factors and early diagnosis of the turnout in this population. In 1976 in Padua we started a longitudinal study of biopsy-proven chronic type B hepatitis, and since 1985 we have introduced alpha-fetoprotein determination among routine tests to be performed every 6 months during follow up. Overall 103 children, including 5 with histological features of cirrhosis, have been followed up for a mean period of 6.1 _+ 2.9 years (mean + SD). During the observation period none of the patients had signs of liver failure or portal hypertension, but one out of five children with cirrhosis developed high alpha-fetoprotein levels and was found to have PHC, before the appearance of any clinical symptoms. We report here the clinical history of this patient. The first child of apparently healthy, non-consanguineous parents, was born in 1978 after an uncomplicated gestation and full-term delivery. He was found to be HBsAg positive at the age of 15 months when his younger brother died of fulminant hepatitis B. At this time his mother was also found to be HBsAg positive. The boy came to our attention at the age of 24 months: he was a well grown asymptomatic child with moderate hepatomegaly and a threefold increase of alanine aminotransferase (ALT) levels. Liver function tests were normal, hepatitis Be antigen (HBeAg) was negative while antiHBe was positive. Six months later liver biopsy showed features of chronic active hepatitis with associated cirrhosis, while HBV DNA was undetectable in serum. By the age of 36 months ALT had become normal and 15 months later liver biopsy was consistent with inactive cirrhosis. Since then the patient has remained asymptomatic, with normal ALT levels. He was followed at regular intervals up to October 1985 when alpha4etoprotein levels were normal. During subsequent years we received information about the childs health but could not see the patient until February 1989.

CT diagnosis of neonatal subarachnoid hemorrhage

A retrospective study of the CT data of the brain was carried out in 48 newborns with neonatal subarachnoid hemorrhage. In addition to the posterior interhemispheric opacities generally accepted as an index of this type of bleeding, anterior interhemispheric, paravermian, cisternal and supratentorial hyperdensities must also be taken into account. CT may be helpful in assessment of the amount of blood lost in the extraosseous epicranial tissues. This amount correlates with the severity of intracranial bleeding and may thus be an index of the degree of mechanical trauma. Major pitfalls leading to overdiagnosis are discussed.

Klinische genetica, cytogenetica en moleculaire genetica

De finalisering van het Humaan Genoom Project (HGP) is een belangrijke mijlpaal in de geschiedenis van de moderne genetica in het laatste decennium. Dit project heeft geleid tot een enorme hoeveelheid nieuwe informatie over het erfelijk materiaal van de mens of het humane genoom en is beschikbaar voor een breed publiek. Dit is grotendeels te danken aan de ontwikkeling van uitstekende genetische databanken op het internet.