Expanding the clinical spectrum of the ‘HDAC8‐phenotype’ – implications for molecular diagnostics,counseling and risk prediction

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin‐related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS‐overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X‐inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.     

Optimal management strategies for placenta accreta

Objective  To determine which interventions for managing placenta accreta were associated with reduced maternal morbidity.
Design  Retrospective cohort study.
Setting  Two tertiary care teaching hospitals in Utah.
Population  All identified cases of placenta accreta from 1996 to 2008.
Methods  Cases of placenta accreta were identified using standard ICD-9 codes for placenta accreta, placenta praevia, and caesarean hysterectomy. Medical records were then abstracted for maternal medical history, hospital course, and maternal and neonatal outcomes. Maternal and neonatal complications were compared according to antenatal suspicion of accreta, indications for delivery, preoperative preparation, attempts at placental removal before hysterectomy, and hypogastric artery ligation.
Main outcome measures  Early morbidity (prolonged maternal intensive care unit admission, large volume of blood transfusion, coagulopathy, ureteral injury, or early re-operation) and late morbidity (intra-abdominal infection, hospital re-admission, or need for delayed re-operation).
Results  Seventy-six cases of placenta accreta were identified. When accreta was suspected, scheduled caesarean hysterectomy without attempting placental removal was associated with a significantly reduced rate of early morbidity compared with cases in which placental removal was attempted (67 versus 36%, P = 0.038). Women with preoperative bilateral ureteric stents had a lower incidence of early morbidity compared with women without stents (18 versus 55%, P = 0.018). Hypogastric artery ligation did not reduce maternal morbidity.
Conclusions  Scheduled caesarean hysterectomy with preoperative ureteric stent placement and avoiding attempted placental removal are associated with reduced maternal morbidity in women with suspected placenta accreta.     

Meningitis and midline facial deformity

A baby with unilateral cleft lip, midline cleft palate and hypertelorism developed meningitis in the first 48 h of life. Examination of the nasopharynx showed a soft tissue mass, which was confirmed as a basal encephalocele by computed tomography. There was also congenital hydrocephalus and the corpus callosum was absent. Surgical treatment included repair of the anterior basal skull defect, repair of the lip and palate, and ventriculo-peritoneal shunt. There is currently evidence of developmental delay and right-sided visual impairment due to Morning Glory syndrome. This case demonstrates that basal encephalocele should be considered in any baby with midline facial deformity who develops meningitis.     

Isolated congenital tuberculosis otitis in a preterm infant

We report an unusual case of localized congenital tuberculosis otitis in a preterm infant. Unlike disseminated congenital cases, the manifestations of localized otitis are associated with a triad of signs: (i) regional lymphadenopathy in the absence of typical systemic features of tuberculosis; (ii) delayed onset of presentation; and (iii) refractory otitis unresponsive to conventional antimicrobial agents. The need for greater diligence in looking for neonatal tuberculosis is emphasized, especially in an ethnic or socioeconomic environment where the disease is prevalent. Congenital tuberculosis, otitis, preterm
PC Ng, Department of Paediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong     

Two cases of congenital toxoplasmosis with a central nervous system damage--delayed diagnosis

OBJECTIVES: The intrauterine toxoplasma gondii infection is linked with a high risk of central nervous system/CNS/damage in the fetus. Why, despite the wide knowledge of this neurodegenerative disease prophylaxis and therapy, do we still meet neonates with the CNS damage? DESIGN, MATERIALS AND METHODS: Authors present two cases of congenital toxoplasmosis with the CNS involvement. RESULTS: One of the cases was identified as the internal hydrocephalus during a prenatal ultrasound examination but no further diagnostics tests were undertaken. The congenital toxoplasmosis and severe CNS damage was diagnosed post delivery. In the other case some clinical symptoms of the CNS infection appeared in the neonatal period. Now this patient is eight months old and presenting mild motor developmental delays. CONCLUSIONS: 1. There are many clinical symptoms of the congenital toxoplasmosis, that can occur in the prenatal/case 1/and postnatal/case 2/period. 2. No serologic tests for toxoplasmosis were performed in mothers during pregnancy, what delays treatment and diagnosis of sick children. 3. Fetus presenting the CNS anomalies identified during ultrasound examinations should be immediately diagnosed.     

Pneumocystis carinii pneumonia studied by gallium-67 scanning

The validity and reliability of gallium-67 (Ga-67) scanning for diagnosis and follow-up of Pneumocystis carinii pneumonia (PCP) were assessed in 34 patients thought to have pulmonary complications of acquired immunodeficiency syndrome (AIDS). Overall sensitivity was 94% and specificity 74%. Among patients with normal or equivocal chest radiographs at the time of admission, sensitivity was 86% and specificity 85%. The authors consider Ga-67 scanning a valid and reliable adjunct in the diagnosis of PCP in AIDS patients with respiratory symptoms when the chest radiograph is normal or equivocal.     

The Accelerating Access Initiative: experience with a multinational workplace programme in Africa

Problem

A multinational company with operations in several African countries was committed to offer antiretroviral treatment to its employees and their dependants.

Approach

The Accelerating Access Initiative (AAI), an initiative of six pharmaceutical companies and five United Nations’ agencies, offered the possibility of obtaining brand antiretroviral drugs (ARVs) at 10% of the commercial price. PharmAccess, a foundation aimed at removing barriers to AIDS treatment in Africa, helped to establish an HIV policy and treatment guidelines, and a workplace programme was rolled out from September 2001.

Local setting

Private sector employers in Africa are keen to take more responsibility in HIV prevention and AIDS care. An important hurdle for African employers remains the price and availability of ARVs.

Relevant changes

The programme encountered various hurdles, among them the need for multiple contracts with multiple companies, complex importation procedures, taxes levied on ARVs, lack of support from pharmaceutical companies in importation and transportation, slow delivery of the drugs, lack of institutional memory in pharmaceutical companies and government policies excluding the company from access to ARVs under the AAI.

Lessons learned

The launch of the AAI enabled this multinational company to offer access to ARVs to its employees and dependants. The private sector should have access to these discounted drugs under the AAI. A network of local AAI offices should be created to assist in logistics of drugs ordering, purchase and clearance. No taxes should be levied on ARVs.