WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent.

Permanent neonatal diabetes mellitus (PNDM) caused by homozygous mutations in the glucokinase gene (GCK) is rare and only eight homozygous GCK mutations have been reported so far. Heterozygous GCK mutations cause maturity-onset diabetes of the young (MODY). We report four patients with growth retardation from two separate families (with three siblings in one family and one patient in another family) presenting with persistent hyperglycaemia within the first two days of life. We found one homozygous non-sense mutation (Q98X) in GCK in three siblings from one family and a homozygous missense GCK mutation (G261R) in one patient from another family. Both mutations have been identified previously in GCK-MODY in the heterozygous state. However, this is the first study to report the homozygous forms of these mutations in PNDM. We report four novel cases of PNDM caused by homozygous GCK mutations, including a non-sense mutation in exon 3 (Q98X) and a missense mutation in exon 7 (G261R).

Background:The ages of onset of pubertal characteristics are influenced by genetic, geographic, dietary and socioeconomic factors; however, due to lack of country-specific norms, clinicians in Saudi Arabia use Western estimates as standards of reference for local children.Aims:The aim of the Riyadh Puberty Study was to provide data on pubertal development to determine the average age of onset of pubertal characteristics among Saudi boys.Methods:Cross-sectional study among male school children in Riyadh, Saudi Arabia, in 2006, 542 schoolboys, aged 6 to 16 years old, from diverse socioeconomic levels were selected into the sample using a cluster sample design. Tanner stages were ascertained during physical examination by pediatric endocrine consultants, and also trained pediatric residents and fellows.Results:The mean age (standard deviation) at Tanner Stages 2, 3, 4, and 5 for pubic hair development of Saudi boys was 11.4 (1.6), 13.3 (1.3), 14.4 (1.0) and 15.1 (0.8) years old, respectively. For gonadal development, the mean age (standard deviation) at stages 2, 3, 4, and 5 were 11.4 (1.5), 13.3 (1.2), 14.3 (1.1) and 15.0 (0.9) years old, respectively.Conclusion:The ages of onset of pubertal characteristics, based on gonadal development, among Saudi boys are comparable to those reported in Western populations.

It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.

Wolcott-Rallison syndrome (WRS) is a rare condition characterized by permanent neonatal diabetes (PND), skeletal dysplasia, and recurrent hepatitis. Other features, including central hypothyroidism, have been reported. We compared the phenotype of five patients from two families with WRS caused by the same EIF2AK3 mutation who have been followed up since diagnosis. Direct sequencing of the EIF2AK3 gene identified a homozygous frameshift mutation (c.1259delA) in all patients that has been reported only in these families. All patients presented with PND and four experienced recurrent hepatitis. A 3.5-year-old girl has isolated PND, whereas her younger sister has typical WRS features. Two children developed skeletal abnormalities and two had transient central hypothyroidism. Other reported features of WRS were not detected. The EIF2AK3 c.1259delA mutation results in a variable phenotype, ranging from isolated PND to typical WRS. Thyroid dysfunction in WRS is a transient phenomenon reflecting euthyroid sickness.