M.Z. Haider

Avascular Necrosis of the Hip in Children with Sickle Cell Disease and High Hb F: Magnetic Resonance Imaging Findings and Influence of α-Thalassemia Trait

Avascular necrosis (AVN) of the hip is a common cause of morbidity in sickle cell disease (SCD). Its prevalence increases with age and predisposing factors include coexistent α-thalassemia trait, frequent vaso-occlusive crisis and a high hematocrit (Hct). SCD is relatively mild among Kuwaiti patients because of their elevated Hb F levels, but a subset exists with severe recurrent vaso-occlusive crises. We carried out a prospective magnetic resonance imaging (MRI) study of the hip in a group of patients being followed in the Pediatric Hematology clinics of Al-Mubarak and Al-Amiri Hospitals. The association of AVN with age, frequency of hospitalization, α-thal trait, steady-state Hb, Hct, Hb F, WBC and platelet counts was investigated. MRI was carried out with a 1.5-tesla GE unit with a super-conducting magnet. Thirty patients (19 males, 11 females) (23 SS and 7 SβThal) were studied. Their ages ranged from 6 to 17 years, with a mean of 9.8 ± 3.5 years, and Hb F from 11 to 35% with a mean of 22.8 ± 5.7%. Among the SS patients, 11 (47.8%) had coexistent α-thal trait (–3.7-kb deletion). A total of 8 (26.7%) patients (6 SS and 2 SβThal) had varying degrees of osteonecrosis of the hip. Four (36.4%) of the 11 SS patients with α-thal trait and 2 (16.7%) of those without α-thal trait had osteonecrosis. This difference is, however, not statistically significant (χ2 = 0.3, p = 0.5). While there was also no significant difference in the mean age and hematological parameters (Hb, Hct, Hb F, WBC, platelets), the SS patients with osteonecrosis had a significantly higher number of hospitalizations for vaso-occlusive crisis in the preceding 3 years than those without osteonecrosis.

A C597→A Polymorphism in the Norrie Disease Gene Is Associated with Advanced Retinopathy of Prematurity in Premature Kuwaiti Infants

Retinopathy of prematurity (ROP) is a retinal vascular disease which occurs in infants with a short gestational age and low birth weight and may lead to retinal detachment and blindness. In some premature infants, ROP progresses to advanced stages despite rigorous intervention, but in the majority, it spontaneously regresses before the threshold stage. Genetic factors, e.g. mutations in the Norrie disease (ND) gene, have been implicated in determining the progression of ROP to advanced stages. We have identified a novel C597A polymorphism of the ND gene; we screened this and another mutation in the ND gene, C110G, in 210 premature Kuwaiti infants using PCR-RFLP, DNA sequence analysis and DNA enzyme immunoassay hybridization to investigate their association with advanced-stage ROP. In this cohort of premature Kuwaiti newborns, 115 of 210 babies had no eye problems and served as controls, while 95 were found to have ROP. In 71 of the 95 ROP cases, the disease spontaneously regressed at or before stage 3, while in 24 of 95 ROP cases, the disease progressed to advanced stages 4 or 5. The incidence of the AA genotype of the C597A polymorphism was considerably higher in advanced-stage ROP cases (83.3%) compared to spontaneously regressing ROP cases (0%) and the normal controls (10.4%) (p < 0.0001). For the other genotypes, no significant difference was detected between the controls and ROP cases. In the case of the C110G mutation in the ND gene, no significant differences were detected between the controls and ROP cases, and the majority of subjects had a CC genotype in all three groups.

Angiotensin Converting Enzyme Gene Insertion/Deletion Polymorphism in Idiopathic Nephrotic Syndrome in Kuwaiti Arab Children

OBJECTIVE Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. MATERIALS AND METHODS The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. RESULTS The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. CONCLUSION Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children.Objective: Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. Materials and methods: The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. Results: The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. Conclusion: Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children.

Influence of α‐thalassemia trait on spleen function in sickle cell anemia patients with high HbF

Spleen function was studied in a group of 20 Kuwaiti SS patients (aged 2–12 years), using 99mTc‐labeled tin colloid scintigraphy. They were screened for the α‐thalassemia determinants which are prevalent in the Arabian Peninsula [‐α (3.7 kb) deletion, α2‐globin gene polyadenylation signal (AATAAA → AATAAG) mutation, and 5′ IVS‐I splice junction pentanucleotide (GAGGTGAGG → GAGG) deletion] with a combination of polymerase chain reaction and allele‐specific oligonucleotide (ASO) hybridization techniques. The patients were divided into three groups depending on the result of their colloid uptake. Group I consisted of 7 patients (35.0%) with normally visualized spleens, Group II consisted of 5 (25.0%) with partial visualization, and in Group III there were 8 (40.0%) in whom the spleen was not visualized at all. The significant distinguishing features among those in Groups I and III were mean corpuscular volumes (MCVs) of 74.1 ± 5.1 and 90.1 ± 6.6 fl (P < 0.0001) and mean corpuscular hemoglobins (MCHs) of 22.4 ± 2.7 and 27.5 ± 4.0 pg (P < 0.05), respectively. The overall frequency of α‐thalassemia determinants in the study was 35.0%; however, the frequencies in Groups I, II, and III were 57.1, 30.0, and 18.8%, respectively. α‐Thalassemia trait, therefore, appears to be associated with normal splenic function in these patients.

Are 25(OH)D levels related to the severity of knee osteoarthritis and function

Objective: To investigate the effect of 25-hydroxyvitamin D [25(OH)D] in Kuwaiti patients with primary knee osteoarthritis (OA) and to assess its relation with radiological grading and functional status. Subjects and Methods: In this cross-sectional study, 25(OH)D was measured using radioimmunoassay in 99 patients [90 women and 9 men; mean age 56.5 ± 9.1 years (range: 36–80)] with clinical and radiological findings of primary knee OA. X-ray grading using the Kellgren-Lawrence grading scale and the Osteoarthritis Research Society International (OARSI) Atlas grading scale and functional assessments using Lequesne’s indices were evaluated in relation to the 25(OH)D level. Other variables studied were age at onset of symptoms, body mass index and duration of disease. Results: The age of the patients at the onset and the duration of disease were 51.58 ± 7.14 and 3.88 ± 2.51 years, respectively. Mean scoring for functional assessment was 10.31 ± 4.35 and mean Kellgren-Lawrence radiological grading was 2.43 ± 0.85. Radiological finding according to the OARSI Atlas revealed joint space narrowing of grades 2–3 in 87 (87.9%) patients and the presence of osteophytes in 55 (55.6%) patients. The mean value of 25(OH)D level was 11.4 ± 6.07 ng/ml. Of the 99 patients, 92 (92.9%) were vitamin D deficient. Comparison of 25(OH)D levels to radiological findings and different functional classes showed no significant association. Conclusion: Most of our patients had vitamin D deficiency, but the level of 25(OH)D was not related to the severity of the knee X-ray grading or to the functional assessment in our patients with primary knee OA.

Avascular necrosis of the femoral head in adult Kuwaiti sickle cell disease patients.

While sickle cell disease (SCD) is generally mild in most Kuwaitis, because of their elevated fetal Hb levels, avascular necrosis of the femoral head (AVNFH) appears to be a common complication. It was recently documented in 26.7% of Kuwaiti children with SCD. There have, however, been no previous studies of adult patients. This is a 1-year study of consecutive, steady-state SCD patients seen in the hematology clinic of Mubarak Al-Kabeer Hospital. The patients’ charts were reviewed for frequency of hospitalizations, any documented complications and steady-state complete blood count (CBC). MRI was performed using T1- and T2-weighted FATSAT sequences in coronal and axial planes with 4-mm-thick slices on a 1.5-tesla GE super-conducting magnet. Thirty-five patients were studied, consisting of 25 SS and 10 Sβ⁰Thal patients aged between 17 and 44, with a mean age of 26.7 ± 9.3 years. Seventeen (48.6%) had varying degrees of AVNFH; among the 70 hips examined, 29 (41.1%) were affected. Of the 17 patients affected, 11 (64.7%) were SS, while 6 (35.3%) were Sβ⁰Thal. There were 14 (82.4%) males and 3 (17.6%) females (χ2 = 8.6, p < 0.01). The mean age of those affected, 27.5 ± 10.7 years, was not significantly higher than that of the unaffected (26.3 ± 8.0 years). Eleven (64.7%) of those affected had a history of frequent vaso-occlusive crisis. No significant differences could be demonstrated in the mean CBC and Hb F values of the two groups; coexistent α-thal trait was not a factor in the SS group. Male gender was the only significant predisposing factor identified. While more patients with frequent vaso-occlusive crises were affected, the difference was not significant. AVNFH is, indeed, quite common among Kuwaiti SCD patients and there is a need for early institution of preventive and therapeutic protocols.

Missense Mutations in Norrie Disease Gene Are Not Associated with Advanced Stages of Retinopathy of Prematurity in Kuwaiti Arabs

Retinopathy of prematurity (ROP) is a disease characterized by retinal neovascularization, possibly leading to retinal detachment and finally blindness. In a proportion of ROP cases, the disease progresses to advanced stages despite rigorous intervention. Missense mutations of the Norrie disease (ND) gene have been associated with progression of the disease in ROP cases from the USA. We have investigated the presence of ND gene mutations in 102 premature newborns of Kuwaiti Arab origin to replicate this finding in a different population/racial group. 56 (55%) of these newborns had normal eyes and served as controls. In 35 (34%) cases, the ROP regressed spontaneously during stage 1–3. In 11 (11%) cases, ROP progressed to advanced stages. A PCR-RFLP method was used to detect the mutations in exon 3 of the ND gene and confirmed the DNA sequence by direct sequencing of the PCR product. The [R121W] mutation of the ND gene was not detected in the premature newborns screened from our Kuwaiti population/group. For the second mutation [L108P], a genotype (PP) was present in 98% of the premature newborns screened and only in 1 of 56 normal infants was the (LL) genotype detected. Our population is genetically homogenous in that genotype (PP) was detected at codon 108 in almost all controls and ROP cases. We did not find an association between the presence or absence of missense mutations of the ND gene and the risk of severe ROP.

Angiotensin-Converting Enzyme Gene Insertion/Deletion Polymorphism in Kuwaiti Children with Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a disease characterized by neovascularization which occurs in infants with short gestational age and low birth weight and can lead to retinal detachment and blindness. In a proportion of ROP cases, the disease progresses to advanced stages despite rigorous intervention. The genotypes for angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism were determined in 181 premature Kuwaiti infants using a polymerase chain reaction (PCR) method. The incidence of different I/D genotypes was compared in ROP cases (n = 74) and non-ROP controls (n = 107) and within 2 subgroups of ROP patients: (1) in which ROP regressed spontaneously (stages 1–3, n = 53), and (2) in which ROP progressed to advanced stages (stages 4 and 5, n = 21). When the ROP cases were considered collectively as one group, the incidence of the DD genotype was almost identical to that of non-ROP controls. The incidence of heterozygous ID genotype was higher in non-ROP controls. The incidence of the II genotype was higher in ROP cases compared to non-ROP controls (p < 0.01). In contrast to this, when ROP cases were divided in 2 subgroups the incidence of the DD genotype was significantly higher in advanced stage ROP cases compared to spontaneously regressing ROP cases (p < 0.04). The incidences of ID and II genotypes were not significantly different amongst the 2 subgroups of ROP patients.

Retinopathy of prematurity: Mutations in the Norrie disease gene and the risk of progression to advanced stages

Abstract Background : Retinopathy of prematurity (ROP) is a retinal vascular disease that occurs in infants with short gestational age and low birth weight and may lead to retinal detachment and blindness. Missense mutations in the Norrie disease (ND) gene have been associated with the risk of progression to advanced stages in cases of ROP from the US and also in clinically similar ND and familial exudative vitreoretinopathy.

Hemoglobin F Concentration as a Function of Age in Kuwaiti Sickle Cell Disease Patients

Objective: This study aimed to document the transition of hemoglobin (Hb) F levels from early childhood to adulthood in Kuwaiti sickle cell disease patients, investigating its relationship to sex, Hb genotype and coexistence of α-thalassemia trait. Subjects and Methods: The following parameters were extracted from the patients’ records: age, sex, Hb, mean corpuscular volume, mean corpuscular Hb, red blood cell count, Hb F, Hb S, Hb A2 and α-globin genotype. Hb quantitation was performed with cation exchange HPLC, while α-globin genotype was determined by PCR. Results: Records were available for 149 patients, made up of 94 SS and 55 Sβ⁰thal; 83 males and 66 females, aged 3 months to 60 years (mean 10.5 ± 1.8). The mean Hb F level in the whole population was 21.5 ± 8.1% and was not significantly different between males and females, and SS or Sβ⁰thal. When the age groups were analyzed, the Hb F level was highest (28.9 ± 10.9%) in those below 5 years. Indeed, patients ≤2 years had a mean level of 31.9 ± 13.0%. There was no significant difference in the Hb F levels in SS patients with or without coexistent α-thal trait. Conclusions: Kuwaiti sickle cell disease patients below 5 years of age have close to 30% Hb F and this is probably a major reason why they usually do not present before this age, unlike patients elsewhere who present within the first year of life.