Congenital leptin and leptin receptor deficiencies in nine new families: identification of six novel variants and review of literature.

Early childhood obesity is a real public health problem worldwide. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Measurement of serum leptin levels is helpful in the diagnosis of congenital leptin and leptin receptor deficiencies which are considered important rare causes of early childhood obesity. The main aim of this study was to investigate the frequency of LEP, LEPR, and MC4R gene variants among a cohort of Egyptian patients with severe early onset obesity. The current cross-sectional study included 30 children who developed obesity during the first year of life with BMI > 2SD (for age and sex). The studied patients were subjected to full medical history taking, anthropometric measurements, serum leptin and insulin assays, and genetic testing of LEP, LEPR and MC4R. Disease causing variants in LEP and LEPR were identified in 10/30 patients with a detection rate of 30%. Eight different homozygous variants (two pathogenic, three likely pathogenic, and three variants of uncertain significant) were identified in the two genes, including six previously unreported LEPR variants. Of them, a new frameshift variant in LEPR gene (c.1045delT, p.S349Lfs*22) was recurrent in two unrelated families and seems to have a founder effect in our population. In conclusion, we reported ten new patients with leptin and leptin receptor deficiencies and identified six novel LEPR variants expanding the mutational spectrum of this rare disorder. Furthermore, the diagnosis of these patients helped us in genetic counseling and patients' managements specially with the availability of drugs for LEP and LEPR deficiencies.

Long interspersed nuclear element-1 (LINE1)-mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis-van Creveld syndrome with borderline intelligence.

Previous work has shown Ellis-van Creveld (EvC) patients with mutations either in both alleles of EVC or in both alleles of EVC2. We now report affected individuals with the two genes inactivated on each allele. In a consanguineous pedigree diagnosed with EvC and borderline intelligence, we detected a 520-kb homozygous deletion comprising EVC, EVC2, C4orf6, and STK32B, caused by recombination between long interspersed nuclear element-1 (LINE-1 or L1) elements. Patients homozygous for the deletion are deficient in EVC and EVC2 and have no increase in the severity of the EvC typical features. Similarly deletion carriers demonstrate absence of digenic inheritance in EvC. Further, the phenotype of these patients suggests that the EVC-STK32B deletion also leads to mild mental retardation and reveals that loss of the novel genes C4orf6 and STK32B causes at most mild mental deficit. In an EvC compound heterozygote of different ethnic origin we identified the same LINE-to-LINE rearrangement due to a different recombination event. These findings highlight the importance of L1 repetitive sequences in human genome architecture and disease.

Assessment of pubertal development in Egyptian girls.

Puberty is a significant event of human growth and maturation associated with marked physiological and psychological changes. The aim of this study was to assess normal pubertal development in Egyptian girls to define normal, precocious and delayed puberty. The present study included a cross-sectional sample of 1,550 normal Egyptian girls of high and middle socioeconomic class living in Cairo. Their ages ranged from 6.5 to 18.5 years. Pubertal assessment was made according to Tanner staging. The mean menarcheal age (MMA) was estimated using probit analysis. Weight and height were measured and body mass index (BMI) was calculated. The mean age at breast bud stage (B2) was 10.71+/-1.6, pubic hair stage (PH2) was 10.46+/-1.36, while axillary hair stage (A2) was 11.65+/-1.62 and MMA was 12.44 years. The mean age at attainment of puberty was compared with those of other Egyptian studies and other populations. Girls of the present study started pubertal development and achieved menarche earlier than those of previous Egyptian studies confirming a secular trend. Differences between the present study and other worldwide studies can be attributed to various genetic, racial, geographical, nutritional, and secular trend factors.