Prevalence of thyroid autoantibodies in children, adolescents and young adults with type 1 diabetes in Kuwait.

OBJECTIVE: To investigate the prevalence of thyroid autoimmunity among children and adolescents with type 1 diabetes in Kuwait. SUBJECTS AND METHODS: In a mixed cross-sectional and longitudinal study, anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) were measured in 232 subjects (118 males and 114 females) with type 1 diabetes. RESULTS: The mean age of the total study population was 10.9 ± 3.6 years (range 1-21), and the median diabetes duration was 3.9 years (range 0-16). At the initial screening, 57 out of 232 (24.6%) patients had positive antibodies, and of the remaining 175 patients, who were antibody negative,131 (74.3%) were followed up for 4-9 years. 23 out of these 131 (17.7%) patients became antibody positive, with a cumulative prevalence of elevated antibodies of 34.5%. Anti-TPO was present in 34 (14.7%), anti-TG in 23 (9.9%) and both antibodies in 23 (9.9%) patients. Thyroid antibodies presented early within the first 5 years of the onset of diabetes (63.2 vs. 36.8%, p < 0.05). The prevalence of elevated thyroid antibodies increased after the onset of puberty in both females and males (p < 0.0001). A total of 58.7% of the patients with positive antibodies were females compared to 41% males (p < 0.0001). The basal thyroid-stimulating hormone was higher in subjects with positive antibodies (5.1 ± 10.7 mIU/l) compared to those who were antibody negative (1.79 ± 0.87 mIU/l, p < 0.001). Furthermore, 30 out of 232 (12.9%) patients developed thyroid dysfunction. CONCLUSION: In this study, a high prevalence of thyroid autoimmune antibodies was found in patients either at the onset of type 1 diabetes or within the 4-9 years of follow-up.

Mutation in the TBCE gene is associated with hypoparathyroidism-retardation-dysmorphism syndrome featuring pituitary hormone deficiencies and hypoplasia of the anterior pituitary and the corpus callosum.

CONTEXT: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome, an autosomal recessive disorder characterized by distinct clinical, biochemical, and genetic abnormalities, is characterized by severe short stature, the etiology of which is unclear. Homozygous mutation of the tubulin cofactor E (TBCE) gene leading to loss of four amino acids (c.155-166del12; p.del 52-55) in the TBCE protein has been associated with the syndrome. AIM: The aim of the study was to describe the clinical, biochemical, and neuroradiological features of children with genetically proven HRD syndrome. METHODS: Six children from four independent Middle Eastern pedigrees with clinical features of HRD syndrome were confirmed to have the previously reported homozygous mutation in TBCE (c.155-166del12) and were investigated with magnetic resonance imaging (MRI) of the brain and standard pituitary function testing. RESULTS: Cranial MRI in all children showed severe hypoplasia of the anterior pituitary and corpus callosum, with decreased white matter bulk. Four of five children tested had subnormal GH and cortisol responses to glucagon, and plasma IGF-I concentration was low in all six children. Cortisol response to synacthen was suboptimal in one of three patients tested. Male children (n = 3) had clinical features suggestive of hypogonadotropic hypogonadism. CONCLUSION: GH insufficiency, hypocortisolemia, and abnormal cranial MRI appear to be associated with HRD syndrome and may contribute in part to the short stature. Our data support the need for longer term monitoring for evolving pituitary hormone deficiencies and raise the possibility that TBCE may play a role in development of the anterior pituitary, corpus callosum, and white matter in addition to the parathyroid glands.

Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD).

OBJECTIVE: Homozygous mutations in the gene encoding the pituitary transcription factor PROP1 are associated with combined pituitary hormone deficiency (CPHD) in both mice and humans with a highly variable phenotype with respect to the severity and time of initiation of pituitary hormone deficiency. We have ascertained three pedigrees with PROP1 mutations from a large cohort of patients with variable degrees of CPHD who were screened for mutations in PROP1. RESULTS: Affected individuals from all three pedigrees were found to harbour novel PROP1 mutations. We have identified two siblings in one family who were homozygous for an intronic mutation (c.343-11C > G) that disrupts correct splicing resulting in the loss of exon 3 from the PROP1 transcript. Two siblings from a second, unrelated family are compound heterozygotes for two point mutations in the coding region, a missense mutation (p.R125W) that leads to impaired transcriptional activation, and a deletion of a single nucleotide (c.310delC) resulting in a frameshift and nonfunctional mutant protein. Additionally, we identified a homozygous deletion of the PROP1 locus in two patients born to consanguineous parents. CONCLUSION: Mutations in PROP1 are a frequent cause of familial CPHD. We have described four novel mutations in PROP1 in 3 pedigrees, all resulting in PROP1 deficiency by different mechanisms. The phenotypic variation observed in association with PROP1 mutations both within and between families, together with the evolving nature of hormone deficiencies and sometimes changing pituitary morphology indicates a need for continual monitoring of these patients.

Varicella-associated purpura fulminans: chicken pox is not always benign.

OBJECTIVE: To report a 6-year-old boy with post-chicken pox purpura fulminans (PF). CLINICAL PRESENTATION AND INTERVENTION: A 6-year-old boy presented with purpura of the legs that rapidly progressed to other parts of the limbs and the buttocks. The patient had had chicken pox 10 days prior to presentation. He was afebrile and the chicken pox lesions were dry. He received anti-coagulants, a large volume of fresh frozen plasma, immunoglobulin and steroids. The skin lesions regressed but both hands and parts of the lower limbs remained necrotic; the patient was transferred to an orthopaedic hospital for amputation and skin grafting. CONCLUSION: This case report shows that PF can occur as a post-infection syndrome after primary varicella. Early and aggressive treatment of post-chicken pox PF might reduce the mortality and morbidity associated with this condition.

Further evidence for the rising incidence of childhood Type 1 diabetes in Kuwait.

AIMS: To provide age-gender standardized incidence rate, temporal trend and seasonal variation of Type 1 diabetes in Kuwaiti children aged < or = 14 years. METHODS: Data were prospectively collected over a period of 6 years (1992-1997) according to the DiaMond Project protocol using the capture-recapture method of ascertainment. RESULTS: Data ascertainment varied between 90% and 96%. The incidence rate of Type 1 diabetes was 20.1 per 100,000 children 0-14 years (95% confidence interval (CI) 18.0-22.1); age-standardized incidence rate 20.9 (95% CI 18.8-23.0). The incidence rate among boys, 21.1 per 100,000 (95% CI 18.1-24.1) was slightly higher than that among girls, 19.0 per 100,000 (95% CI 16.1-21.8). The age-standardized incidence rate was 21.9 (95% CI 18.9-24.8) in boys, and 19.9 (95 CI 17.1-22.8) in girls. Incidence rates increased with age in both sexes (boys chi(2) for linear trend = 13.5, P < 0.001; and for girls chi(2) = 27.8, P < 0.0001). There was a significant trend towards increase in overall incidence during the 6-year period (chi(2) = 6.210, P = 0.013), and in age group 5-9 (chi(2) = 10.8, P = 0.001). Seasonality was demonstrated overall, in boys and girls (P < 0.001). CONCLUSION: The incidence of Type 1 diabetes in Kuwait is high compared with the neighbouring Arab countries, and it appears to be increasing as in many European populations.

High frequency of HLA-DQB1 non-Asp(57) alleles in Kuwaiti children with insulin-dependent diabetes mellitus.

The prevalence of polymorphic amino acids at position 57 of the HLA DQB1 in Kuwaiti children with insulin-dependent diabetes mellitus (IDDM) and nondiabetic controls has been determined using a polymerase chain reaction-sequence-specific primers (PCR-SSP) method. Using this approach, 34/55 (62%) IDDM children were found to be homozygous Ala/Ala and 19/55 (35%) were heterozygous with various combinations. Amongst the IDDM children with heterozygous genotype at codon 57 of HLA DQB1, 6/55 (11%) had Asp/Ala, 8/55 (15%) had Ala/Val, 4/55 (7%) had Ala/Ser and 1/55 had Asp/Val allelic combinations. When considered collectively, the nonaspartate (NA) alleles were represented in 87% of the IDDM cases and only 13% cases had Asp(57) allele in different heterozygous combinations, while none of the IDDM subjects had a homozygous Asp genotype. In nondiabetic controls, homozygous non-Asp (NA) alleles were represented in 44% subjects, 37% of the controls were heterozygous (NA/A) and 19% had a homozygous (A/A) genotype. These differences between the IDDM group and the control group were found to be statistically significant. Our data report one of the highest frequency of NA/NA residues at this locus compared with that from different world populations (Sardinians, Norwegians, US Caucasians, US Blacks and Chinese).

Incidence and severity of ketoacidosis in childhood-onset diabetes in Kuwait. Kuwait Diabetes Study Group.

In 1992, the diabetes registry was started in Kuwait, as part of DiaMond, a WHO multinational collaborative project on the incidence of childhood-onset diabetes. Children (243) aged below 15 years, were identified between 1 January 1992 and 31 December 1995. Children (203) were Kuwaiti and 40 were non-Kuwaiti children but resident of Kuwait. For the years 1992, 1993, the annual incidence of childhood onset diabetes for Kuwaiti children was 15.4 per 100,000 (95% confidence interval 12.9-19), and the degree of ascertainment was 92%. Polyuria, polydypsia, weight loss and nocturia were the most frequently reported symptoms; four children were in coma and one in shock at presentation. Nearly half of the children (49%) presented ketoacidosis (venous pH < 7.3 and/or plasma bicarbonate level < 18 mmol/l). and in 53 children (23.5%) it was severe (venous pH < 7.1 and/or plasma bicarbonate level < 10 mmol/l). In 62 children (25.5%) it was mild to moderate (venous pH 7.1-7.3 and/or plasma bicarbonate level 10.1-18 mmol/l). The incidence of severe ketoacidosis was similar in all age groups and sexes. All children recovered completely without major complications and no deaths were recorded. We conclude that diabetic ketoacidosis is a common presentation at the onset of diabetes in childhood in Kuwait and attests to the lack of awareness of general practitioners and parents to the symptoms and signs of diabetes in childhood.

High incidence of childhood-onset IDDM in Kuwait. Kuwait Study Group of Diabetes in Childhood.

OBJECTIVE: To determine the incidence of insulin-dependent diabetes mellitus (IDDM) in children aged 0-14 years in Kuwait, as part of the World Health Organization Multinational Collaborative Study (DIAMOND), and to determine if the incidence rates have increased. RESEARCH DESIGN AND METHODS: All cases of IDDM diagnosed before the child's 15th birthday between 1 January 1992 and 31 December 1993 were recorded. Prospective notification of all children with newly diagnosed diabetes who were admitted to hospitals and periodic review of hospital medical records provided the primary source; notification by physicians working in diabetic clinics, in which registry of all new cases is mandatory, provided the secondary source of ascertainment. RESULTS: The degree of ascertainment was 92.2%. The annual incidence of IDDM for children aged 0-14 years over the 2-year period was 15.4/100,000 (95% confidence interval, 12.4-19), with a male:female ratio of 1.2:1. The age-specific annual incidence rates for the age-groups 0-4, 5-9, and 10-14 years were 12.8, 15.1, and 18.3/100,000, respectively, with a male:female ratio of 1.45:1 in the 0- to 4-year-old age-group and an equal sex ratio in the 5- to 9- and 10- to 14-year-old age-groups. No significant difference was detected between incidence rates of IDDM in boys and girls in the three age-groups. There was no significant linear trend toward an increase in IDDM incidence rates as age advanced. Compared with a previous study by Taha et al. (Taha T, Moussa M, Rashed A, Fenech F: Diabetes mellitus in Kuwait: incidence in the first 29 years of life. Diabetologia 25:306-308, 1983), there was a nearly fourfold increase of IDDM in the age-group 0-14 years, mainly in those children < 5 years old, suggesting a rapid increase in a short period of time. CONCLUSIONS: Kuwait has the highest incidence of IDDM in children in the region, and an apparently increasing incidence has been demonstrated over the last decade.

Towards improving care for children with diabetes in Kuwait.

Presents the results of a medical audit of the records of 199 children diagnosed as diabetic and admitted to Al-Amiri Hospital, Kuwait. Uses the measurement of glycosylated haemoglobin (HbA1) to indicate the levels of control achieved. Finds that the degree of glycaemic control compares favourably with studies done in other hospitals, but unfavourably with specialized diabetic clinics. Proposes that glycaemic control could be improved by provision of the services of specialized support staff such as dietitian, educator, psychologist and health visitor.