Providing insight into the incubation period of Mycobacterium ulcerans disease: two case reports.

BACKGROUND: Buruli ulcer caused by Mycobacterium ulcerans is endemic in parts of West Africa and is most prevalent among the 5-15 years age group; Buruli ulcer is uncommon among neonates. The mode of transmission and incubation period of Buruli ulcer are unknown. We report two cases of confirmed Buruli ulcer in human immunodeficiency virus-unexposed, vaginally delivered term neonates in Ghana. CASE PRESENTATION: Patient 1: Two weeks after hospital delivery, a baby born to natives of the Ashanti ethnic group of Ghana was noticed by her mother to have a papule with associated edema on the right anterior chest wall and neck that later ulcerated. There was no restriction of neck movements. The diagnosis of Buruli ulcer was confirmed on the basis of a swab sample that had a positive polymerase chain reaction result for the IS2404 repeat sequence of M. ulcerans. Patient 2: This patient, from the Ashanti ethnic group in Ghana, had the mother noticing a swelling in the baby's left gluteal region 4 days after birth. The lesion progressively increased in size to involve almost the entire left gluteal region. Around the same time, the mother noticed a second, smaller lesion on the forehead and left side of neck. The diagnosis of Buruli ulcer was confirmed by polymerase chain reaction when the child was aged 4 weeks. Both patients 1 and 2 were treated with oral rifampicin and clarithromycin at recommended doses for 8 weeks in addition to appropriate daily wound dressing, leading to complete healing. Our report details two cases of polymerase chain reaction-confirmed Buruli ulcer in children whose lesions appeared at ages 14 and 4 days, respectively. The mode of transmission of M. ulcerans infection is unknown, so the incubation period is difficult to estimate and is probably dependent on the infective dose and the age of exposure. In our study, lesions appeared 4 days after birth in patient 2. Unless the infection was acquired in utero, this would be the shortest incubation period ever recorded. CONCLUSIONS: Buruli ulcer should be included in the differential diagnosis of neonates who present with characteristic lesions. The incubation period of Buruli ulcer in neonates is probably shorter than is reported for adults.

Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate.

In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations.

Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.

Clinico-epidemiological profile and predictors of severe illness in young infants (0-59 days) in Ghana.

BACKGROUND: Young infant mortality has remained high and relatively unchanged compared with deaths of older infants. Strategies to reduce infant mortality, however, are mostly targeted at the older child. OBJECTIVES: To describe the clinical profile of sick young infants presenting to a hospital and to define important signs and symptoms that will enable health workers to detect young infants with severe illness requiring hospital admission. METHODS: Young infants aged 0-59 days presenting to a paediatric out-patient clinic were evaluated by a nurse using a standardised list of signs and symptoms. A paediatrician independently evaluated these children and decided whether they needed hospitalisation. RESULTS: A total of 685 young infants were enrolled, 22% of whom were <7 days of age. The commonest reasons for seeking care were jaundice in the 0-6-day group, skin problems in the 7-27-day group and cough in the 28-59-day group. The primary clinical diagnoses for admissions were sepsis in the 0-6- and 7-27-day groups and pneumonia in the 28-59-day group. Clinical signs and symptoms predicting severe illness requiring admission were general (history of fever, difficult feeding, not feeding well and temperature >37.5 degrees C) and respiratory (respiratory rate > or =60/min, severe chest in-drawing). CONCLUSION: General and respiratory signs are important predictors for severe illness in young infants. Training peripheral health workers to recognise these signs and to refer to hospital for further assessment and management might have a significant impact on young infant mortality.

A prospective survey of patients with cleft lip and palate in Kumasi.

BACKGROUND: There has been a steady increase in the number of patients with cleft lip and palate being treated at our hospital. OBJECTIVE: The aim of the study was to determine the socio-demographic characteristics of patients with cleft lip and palate as seen in a hospital setting. METHODS: New and consecutive patients with cleft lip and palate attending the maxillofacial clinic during the period between February 2003 and January 2004 were prospectively surveyed. Data including age of child, gender, address, type of cleft, associated birth anomalies, family history of cleft, mother's age at birth of child, mother's occupation, and mother's smoking and drinking habits were collected and analyzed using a SPSS package. RESULTS: Seventy-four new cases of cleft lip and palate were seen comprising 33 males and 41 females. Their ages ranged from one day old to 21 years with an overall mean age of 10 months. Cleft lip alone (57%) was the most common presentation. Seventy percent of the mothers were less than 30 years of age. Majority (76%) lived in the Ashanti Region, i.e. within less than 80 kilometres from the clinic. No patient had a family history of facial cleft. Ninety-three percent of the mothers were either unemployed or worked in jobs considered as low earning which included dressmaking, hairdressing, peasant farming, and petty trading. None of the mothers smoked or drank alcohol either before o r duringthe pregnancy. CONCLUSION: Cleft lip and palate was more commonly seen in low income families. The mothers were found to be relatively young. None of the patients and mothers had a family history of cleft. A larger population-based study is warranted to further clarify these findings.