Sickle cell disease and age at menarche in Jamaican girls: observations from a cohort study

AIMS—(1) To investigate the distribution of age at menarche in a representative sample of 99 patients with homozygous sickle cell (SS) disease, 69 with sickle cell haemoglobin C (SC) disease, and 100 controls with a normal haemoglobin (AA) genotype followed in a cohort study from birth. (2) To explore the determinants of the age at menarche.METHODS—Children ascertained in a newborn screening programme were followed prospectively from birth to age 18-26.5 years with regular assessments of height, weight, pubertal stage, and haematological indices at the Sickle Cell Clinic of the University Hospital of the West Indies.RESULTS—All subjects have now reached menarche and the mean age in normal controls (13.0 years) was significantly earlier than in SC disease (13.5 years) or SS disease (15.4 years). Greater weight and earlier age at menarche was the only association significant across all genotypes although additional contributions occurred from fetal haemoglobin and red cell count in SS disease. Alpha thalassaemia, which ameliorates many of the effects of SS disease, had no discernible effect on menarche.CONCLUSIONS—Mean age at menarche is delayed by 0.5 years in SC disease and by 2.4 years in SS disease. Weight appears to be the principle determinant of age at menarche.     

Delayed adolescent growth in homozygous sickle cell disease

Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95% confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth.     

Delayed adolescent growth in homozygous sickle cell disease.

Analysis of the growth abnormalities in sickle cell disease has been limited by the lack of longitudinal observations in individuals, and by an inability to quantitate the observed patterns. To investigate the timing and pattern of the adolescent growth spurt, longitudinal observations of height from the Jamaican cohort study were fitted to a mathematical model of growth (Preece-Baines model 1). The study included 44 children with homozygous sickle cell (SS) disease, 44 age and sex matched subjects with sickle cell haemoglobin C (SC) disease, and 44 age and sex matched controls with normal (AA) haemoglobin. Compared with AA controls, the onset of the adolescent growth spurt was delayed in SS disease by 1.4 years (95% confidence interval 0.8 to 2.0) with no significant sex difference. The age at peak height velocity was delayed by 1.6 years (0.9 to 2.3) in SS compared with AA subjects but the adolescent growth of SS children was otherwise normal and there was no difference in the attained height by age 17.9 years. The growth spurt was not delayed in SC disease. The age at menarche in girls with SS disease (mean (SD) 15.4 (1.3) years) was significantly later than girls with SC disease (13.7 (1.7) years) and those with AA haemoglobin (13.1 (1.3) years) but these genotype differences were no longer significant after controlling for the delay in the adolescent growth spurt. The normally coordinated but slightly delayed pattern of growth and normal adult heights suggests a good prognosis for adolescent growth delay in SS disease. Most children with SS disease can therefore be reassured on the outcome of retarded adolescent growth.     

Factors affecting prepubertal growth in homozygous sickle cell disease

OBJECTIVE: To investigate the role of haematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease. METHOD: Height, weight, and haematology were serially recorded in a cohort study of 315 children with SS disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. RESULTS: Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at age 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemolglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. CONCLUSION: A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship of haematology and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account.     

Factors affecting prepubertal growth in homozygous sickle cell disease.

OBJECTIVE: To investigate the role of haematological indices, socioeconomic status, and morbidity in prepubertal growth in homozygous sickle cell (SS) disease. METHOD: Height, weight, and haematology were serially recorded in a cohort study of 315 children with SS disease from birth to 9 years at the sickle cell clinic of the University Hospital of the West Indies, Kingston, Jamaica. RESULTS: Height increment between 3 and 9 years correlated positively with total haemoglobin at age 7 years in boys but not girls. Attained height and weight at age 7 years correlated positively with haemoglobin and fetal haemoglobin in boys but not girls. Only the correlation between haemoglobin and weight showed a significant gender difference. Partial correlation analysis suggested that the effect of haemoglobin was accounted for by the effect of fetal haemolglobin and further analysis indicated that height correlated with F reticulocyte count (a measure of fetal haemoglobin production) in both sexes but not with the ratio of F cells to F reticulocytes (a measure of F cell enrichment). Growth was not significantly related to mean red cell volume, proportional reticulocyte count, alpha thalassaemia, socioeconomic status, or morbidity. CONCLUSION: A high concentration of fetal haemoglobin in boys with SS disease is associated with greater linear growth. It is postulated that in boys, low concentrations of fetal haemoglobin increase haemolysis and hence metabolic requirements for erythropoiesis, putting them at greater risk of poor growth. Differences in the relationship of haematology and growth between boys and girls with SS disease dictate that future analyses of growth take gender into account.     

Pneumonia in young children with homozygous sickle cell disease: risk and clinical features

The incidence and clinical features of pneumonia have been examined in children with homozygous sickle cell (SS) disease and in age/sex matched control children with a normal haemoglobin (AA) genotype followed in a cohort study of sickle cell disease from birth.Survival curve analysis indicated a similar incidence of pneumonia in the two genotypes up to the ages of 8 months after which pneumonia became significantly more prevalent in SS disease, the relative risk exceeding a factor of four by 4 years of age. Children with SS disease were also more prone to multiple episodes. Comparison of clinical features in the two genotypes yielded no difference in sex or seasonal involvement, or in the results of bacteriological and radiological investigations. Children with SS disease and pneumonia had an increased frequency and increased duration of hospital admission, and mortality was confined to this group.It is concluded that children with SS disease have an increased prevalence of single and multiple attacks of pneumonia and that these events run a more serous clinical course than in control children.Abbreviations SS sickle cell disease - AA normal haemoglobin genotype     

Factors associated with lowered intelligence in homozygous sickle cell disease.

The intelligence quotient (IQ) of 60 patients with homozygous sickle cell (SS) disease and 60 age and sex matched controls with a normal haemoglobin (AA) genotype aged 15-18 years, followed up in a cohort study from birth, was assessed by the Wechsler intelligence scales for children or for adults. IQ appeared to be normally distributed in both genotypes but mean values in SS disease were 5.6 points (95% confidence interval (CI) 1.0 to 10.2) lower than in AA controls (p = 0.016). The difference occurred in both verbal (5.5 points, p = 0.017) and performance (5.0 points, p = 0.044) subscales of the IQ score and the IQ defect in SS disease was associated with a significantly lower attention factor score (p = 0.005) but not with other factor scores. The genotype difference in IQ was not accounted for by differences in parental occupational level, school absenteeism, or school drop out, or reported activity level. In SS disease, IQ was not related to mean steady state haemoglobin, fetal haemoglobin, or mean cell haemoglobin concentration, or clinical severity as judged by the frequency of painful crises, hospital admission, or sick visits. IQ, at age 15-18 years, correlated with the patients'' height at all ages from 1 to 10 years (partial correlations increasing from 0.14 (p = 0.15) at age 1 to 0.27 (p = 0.004) at age 10). Adjusting for height reduced the mean genotype difference in IQ to 5.5 (95% CI 0.6 to 10.3) points at age 1 and to 2.6 points (95% CI to -2.3, 7.5) at age 10. Prepubertal height therefore accounted for much of the genotype difference in IQ. It is speculated that early factors, possible nutritional, contribute to both impaired growth and mental development in sickle cell disease.     

Prepubertal growth and skeletal maturation in children with sickle cell disease

In a longitudinal study of 298 children with homozygous sickle cell (SS) disease and 157 children with hemoglobin SC disease, between birth and 9 years of age, observations of weight and height were made. These were compared with similar data derived from an age- and sex-matched group of 231 children with a normal hemoglobin (AA) genotype. Growth in children with SC disease was not significantly different from that in normal children, but children with SS disease had statistically significant, and progressive, deficits in both weight and height before 2 years of age. The average deficit approached 1 SD below the normal mean for age by 9 years. Observations of skeletal maturity, based on radiologic assessment of bone age at the wrist, were made on a proportion of these children at 5 and 8 years of age. Children with SS disease were significantly retarded at 8 years but not 5 years, which is consistent with increasing deficit in height. These observations confirm the early impact of SS disease on physical development and provide standards from which clinical expectations of growth may be derived. The relevance of these findings and their relationship to the characteristic delay in pubertal development is discussed together with a review of possible etiologic factors. The benign nature of SC disease is endorsed by the absence of an effect on growth in the prepubertal child.     

Nocturnal enuresis in sickle cell haemoglobinopathies.

The prevalence of nocturnal enuresis (wet at least two nights a week) was investigated in children, aged 8, who were being followed up as part of a prospective cohort study. There were 175 children with homozygous sickle cell disease, 106 with sickle cell haemoglobin C disease, and 150 controls with a normal haemoglobin genotype. In homozygous sickle cell disease, 48 boys (52%) and 31 girls (38%) were enuretic, a significantly higher prevalence than in those with sickle cell haemoglobin C disease--five boys (10%) and 11 girls (20%)--or in normal children--16 boys (22%) and 13 girls (17%). There was no significant difference between children with sickle cell haemoglobin C disease and the normal genotype. Boys with homozygous sickle cell disease were significantly more likely to be enuretic if they came from large families; there was a similar trend for girls with homozygous sickle cell disease, although it did not reach significance. Enuresis was more common in boys with homozygous sickle cell disease who had low concentrations of fetal haemoglobin and in girls with sickle cell haemoglobin C disease who had high mean corpuscular haemoglobin concentrations. Similar associations were not shown for girls with homozygous sickle cell disease or boys with sickle cell haemoglobin C disease.     

Decreased serum tuftsin concentrations in sickle cell disease.

The serum concentrations of the phagocytosis-stimulating peptide, tuftsin, were determined by radioimmunoassay in 21 patients with sickle cell disease and in 12 healthy controls. The mean serum tuftsin concentration was significantly lower in patient with haemoglobin SS disease (154.3 +/- 35.1 ng/ml; 308.6 +/- 70.2 nmol/l, P < 0.01) and in patients with haemoglobin SC and CC disease (180.9 +/- 42.7 ng/ml; 361.8 +/- 85.4 nmol/l, P < 0.05) than in healthy controls (228.7 +/- 46.7 ng/ml; 457.4 +/- 93.4 nmol/1). Tuftsin deficiency is an indicator of splenic hypofunction and may contribute to the increased susceptibility of patients with sickle cell disease to severe infection.     

Enuresis in children with sickle cell disease]

POPULATIONS AND METHODS: In order to analyze epidemiological and clinical characteristics of enuresis in children with sickle cell disease, and identify risk and aetiological factors, 987 subjects (aged 5-20 years) took part in a cross-sectional study. These children were divided into two groups: group 1 consisted of 456 homozygous children with sickle cell disease (haemoglobin SS), while group 2 consisted of 531 normal children. These groups were paired according to age and sex. RESULTS: The prevalence of enuresis was 50.9% in group 1 and 16.4% in group 2, and was significantly higher (P < 0.05) in the girls. The frequency decreased significantly between the ages of 5-20. At age 16, frequency of enuretic children with sickle cell disease remained statistically greater (15.9% vs. 8.0%). The frequency of wet nights was higher (P < 0.05) in group 1. In addition, anaemia crisis and painful crisis were related to prevalence of enuresis. There was a significant (P < 0.01) negative correlation between haemoglobin F percentage and prevalence of enuresis. CONCLUSION: Enuresis is frequent in children with sickle cell disease and its intensity is linked to severity of disease.     

Sickle cell disease in Saudi Arabs in early childhood.

Haemoglobin electrophoresis screening of 2341 infants from the oases of eastern Saudi Arabia, performed in an attempt to detect cases early and then to follow up and give better management to patients with sickle cell disease, showed 20% with S-trait and 43 with sickle cell disease (37 HbSS and 6 S-beta(0) thalassaemia). On follow-up from birth (or from 3 months) for a mean of 3 1/2 years there was more morbidity and mortality than in matched Saudi Arab controls, but these rates were lower than for affected black infants in the US or Jamaica. Serial haemoglobin levels were l g/dl lower than for controls; height and weight increases were the same. Mean fetal haemoglobin level was 32% at 4-5 years. Half of a subsample of 23 cases had evidence of coexistent alpha-thalassaemia which appeared to protect against functional asplenia, judged by the presence of Howell-Jolly bodies; however there was no difference in degree of anaemia or clinical course. Early screening is recommended for infants at risk for sickle cell disease, and comprehensive care should be given even if the infant has the less severe type.     

Plasma lipids and lipoproteins in Nigerian children with sickle cell anemia.

Plasma lipids and lipoproteins were estimated in 67 Nigerian children (mean age 10.19 years) with sickle cell anaemia (HbS) and 67 age- and sex-matched non-anaemic controls with normal haemoglobin (HbA). Plasma cholesterol and HDL-cholesterol levels were significantly lower while the plasma triglyceride level was significantly higher in the subjects with sickle cell anaemia. LDL-cholesterol levels were higher in sickle cell anaemia patients, but were not of statistical significance. These results do not support suggestions that sickle cell anaemia patients are at low risk of developing coronary artery disease.     

Neuropsychologic performance in school-aged children with sickle cell disease: a report from the Cooperative Study of Sickle Cell Disease

OBJECTIVES: To compare the results of serial neuropsychologic testing in children with sickle cell disease with the results of serial magnetic resonance imaging (MRI) examinations, particularly to evaluate neuropsychologic function in the absence of overt stroke. STUDY DESIGN: In the Cooperative Study of Sickle Cell Disease, serial neuropsychologic and MRI tests were performed in 373 patients (255 with hemoglobin SS and 118 with hemoglobin SC), 6 to 18 years of age. MRI of the brain and a neuropsychologic battery that included the Wechsler Intelligence Scale for Children (WISC-R or WISC-III) and the Woodcock-Johnson Math and Reading Achievement Tests were performed concurrently and repeated every 2 to 3 years. A silent infarct was defined as an MRI finding of increased signal intensity on T(2) imaging in a patient without a history of stroke. RESULTS: Twenty-seven patients, all with hemoglobin SS, had overt strokes and 62 had silent infarcts (52 with hemoglobin SS). Patients with hemoglobin SS and silent infarcts had significantly lower scores for math and reading achievement, Full-Scale IQ, Verbal IQ, and Performance IQ, when compared with those with normal MRI findings. In children with hemoglobin SS and normal MRI findings, the scores for Verbal IQ, math achievement, and coding (a subscale of Performance IQ) declined with increasing age. CONCLUSIONS: School-aged children with sickle cell disease had compromised neuropsychologic function in the presence of silent infarcts. In addition, they had declines in performance in certain areas of function over time. Therapeutic interventions that prevent or lessen cognitive impairment are needed before school entry for children with sickle cell disease.     

Height and weight reference curves for homozygous sickle cell disease.

OBJECTIVE: To derive height and weight growth reference curves for children with homozygous sickle cell disease. STUDY DESIGN: Subjects (n = 315) were participants in a population based, longitudinal cohort study of sickle cell disease in Kingston, Jamaica. Regular measurements of height and weight were made from enrollment into the study at birth up to 22 years of age. RESULTS: Sex specific growth reference curves for height for age and weight for age covering the age range 0-18 years are presented. CONCLUSION: These growth reference curves are suitable for identifying coincidental growth problems in children with homozygous sickle cell disease.     

Bacteremia in sickle hemoglobinopathies

We analyzed 178 episodes of bacteremia that occurred during 13,771 patient-years of follow-up of 3451 patients with sickle hemoglobinopathies. Age-specific incidence rates of bacteremia were calculated for patients with sickle cell anemia (SS) and sickle cell-hemoglobin C (SC) disease. The incidence rate was highest among children with SS and SC younger than age 2 years. Children with SC showed an abrupt decrease after age 2 years, whereas children with SS had a gradual decline in rate from 2 to 6 years of age. The predominant pathogen in patients younger than 6 years was Streptococcus pneumoniae (66%); gram-negative organisms were responsible for 50% of bacteremias in patients 6 years and older. Urinary tract infection was present during 73% of Escherichia coli bacteremias, and 77% of Salmonella bacteremias were associated with osteomyelitis. In contrast, no focus of infection was present in 52% of pneumococcal bacteremias. The incidence of pneumococcal bacteremia in children with SS younger than age 3 years was 6.1 events/100 patient-years; the case fatality rate for pneumococcal sepsis in this age group was 24%. No hematologic or demographic variables were associated with occurrence of pneumococcal bacteremia in young children. Retrospective analysis of pneumococcal bacteremia suggests that the prophylactic use of penicillin may decrease the incidence in children younger than 3 years of age.     

Early blood transfusions protect against microalbuminuria in children with sickle cell disease

BACKGROUND: Microalbuminuria (MA) is an early indicator for glomerulopathy in sickle cell disease (SCD). PROCEDURE: We reviewed the medical records of asymptomatic patients ages 4-20 with sickle hemoglobinopathies, who were screened for MA in order to find out its prevalence and risk factors. RESULTS: Nineteen of 120 (15.8%) screened patients had MA detected by spot urine (mean albumin absolute value 6.95 +/- 0.56 mg/dl) and abnormal albumin to creatinine ratios (79.8 +/- 0.62 mg/g creatinine). Twenty four-hour urine collections confirmed 57% of MA cases by spot urine. There was no difference in hyperfiltration between positive and negative patients. From the MA-positive patients, 15 had SS (16.8% of SS group) and 4 had SC (18% of SC group). Nineteen percent of children 10 years of age or older had MA, as compared to 8% of the younger children (P = 0.018), demonstrating that increasing age is a risk factor for MA. There was a positive correlation between MA and acute chest syndrome. Young age at start of chronic transfusions was inversely related to MA and therefore renoprotective (P = 0.03). We did not see a protective effect in the group of patients taking hydroxyurea for a relatively short time, mean age at start of treatment 12 +/- 5 years; however the sample was small. CONCLUSIONS: We conclude that: (1) children with sickle cell hemoglobinopathies 10 years or older should be screened for MA and (2) chronic transfusions starting at an early age may be renoprotective.     

Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination

Rates and severity of pneumococcal infections in children with sickle cell disease were examined before licensure of pneumococcal-conjugated vaccine (PVC). Rates of peak invasive infection rates in 1-year-old children with hemoglobin SS and mortality in those 0 to 10 years of age were 36.5 to 63.4 and 1.4 to 2.8 per 1000 person-years, respectively (>10 and 100 times as frequent as in the general population). Overall, 71% of serotyped isolates (n=80) were PVC serotypes and 71% of nonvaccine serotype strains were penicillin-sensitive. Clinical presentation in children with hemoglobin SS (n=71; more with hypotension) and hemoglobin SC (n=18; more with acute chest syndrome, otitis media) differed. Penicillin nonsusceptibility (38% of isolates) varied between geographic study sites. Penicillin prophylaxis appeared less effective against intermediate and resistant strains. Of all infected children, meningitis developed in 20% and 15% died (hemoglobin SS, n=15 and 11; hemoglobin SC, n=1 each). Factors associated with death included age >4 years (58%), serotype 19F, and not being followed by a hematologist (42% each). The pneumococcal-polysaccharide vaccine was 80.4% effective within 3 years after vaccination (95% CI, 39.7, 93.6). Children with sickle cell disease of all ages may benefit from PVC boosted with polysaccharide vaccination.     

Body shape in young children with homozygous sickle cell disease

Body shape, defined by detailed anthropometric measurement, was compared in 64 children with homozygous sickle cell (SS) disease, and in 123 children with a normal hemoglobin (AA) genotype, aged 4 to 6 years. Children with homozygous sickle cell disease showed an average reduction in weight, height, sitting height, limb length, interacromial and intercristal diameters, and skinfold thickness. They showed increased anteroposterior chest diameters with an increased anteroposterior-lateral chest diameter ratio. This report establishes that the effect of homozygous sickle cell disease on growth patterns in childhood is apparent before the age of 6 years. The relationship to changes in body shape, seen during adolescence and in affected adults, and their possible determinants, are discussed.     

Molecular analysis of Iranian families with sickle cell disease

Sickle hemoglobin is a mutant hemoglobin in which valine has been substituted for the glutamic acid normally at the sixth amino acid of the beta-globin chain. Detection of the single base pair mutation at codon 6 of the beta-globin gene is important for the prenatal diagnosis of sickle cell anemia and sickle cell disease. Application of the polymerase chain reaction technology to detect sickle cell patients and heterozygous carriers in a group of patients suspected for sickle cell disease was carried out. The sample was composed of 52 normal individuals and 52 unrelated outpatients who were attending the Hematology Research Center. All patients were interviewed. Results of their medical histories, physical examination, and the hematological analysis were recorded. The blood samples were collected in EDTA and genomic DNA was extracted from leukocytes. An amplified 110 base pair fragment of the beta-globin gene containing codon 6, was digested with the restriction enzyme MS II, and electerophoresed in 3 per cent agarose. We have established the technical condition for detection of sickle cell disease using a PCR assay. Fifteen patients having haemoglobin (Hb SS) and 37 patients in the heterozygous state (Hb AS) were identified. We confirm that the normal controls have the Hb AA genotype. The standardization of a highly sensitive and specific diagnostic test for sickle cell disease permitted us to identify the normal controls, the homozygotes and heterozygotes. This amplification method is rapid, sensitive and simple, and also has application research that is important for the prenatal diagnosis of sickle cell disease.