We compared the growth of 183 children with short stature (≤ 2SD) and 73 children of normal height at age six who were visiting the Tanaka Growth Clinic. We classified these short children as suffering from either idiopathic short stature (ISS, n = 119), GH deficiency (GHD, n = 33) or small-for-gestational-age short stature (SGASS, n = 31) on the basis of subsequent test results and other factors. We also conducted a retrospective study of changes in their height, wt and nutritional intake over time. The mean changes in height SD score from birth to 6 yr were –0.24 SD in normal height children with a normal birth length and +2.27 SD in normal height children with a low birth length. In short children, these changes were –1.93 SD for children with ISS, –2.41 SD for those with GHD and +0.58 for those with SGASS. The mean changes from birth to 6 mo were –0.84 SD, −1.03 SD and +0.38 SD in children with ISS, GHD and SGASS, respectively. The mean change in height SD score from birth to age 1 yr was –1.07 SD, –1.44 SD and +0.35 SD, respectively. The decrease in height SD score from birth to 6 mo accounted for 43.5% of the decrease in height SD score from birth to 6 yr in children with ISS and it accounted for 42.6% of the decrease in children with GHD. Only 19% of short children bottle-fed well, and 53% fed poorly, as opposed to 56% and 16% of normal height children who fed well and poorly, respectively. Post weaning, only 22% of short children ate well, and 56% fed poorly, as opposed to 53% and 17% of normal height children who fed well and poorly, respectively. These findings demonstrated that growth failure started from early infancy in ISS and GHD children. It was suggested that poor nutritional intake in infancy and early childhood was a partial cause of short stature at age 6.
In 45,X/46,XY DSDs, the proportion of the two cell lineages is uneven in different organs and tissues, and 45,X and 46,XY cells can be found throughout the body. The gonadal development of 45,X/46,XY patients depends on the population of 46,XY cells in the gonads and the clinical features are variable. We had a 45,X/46,XY DSD patient whose 46,XY population in peripheral blood was extremely low, less than 0.2%, and was not detected by FISH analysis. However, the patient showed bilateral testicular development and more than 50% of the cells in the gonads had the 46,XY karyotype. This case suggests that a drastically imbalanced distribution could occur in 45,X/46,XY DSD cases.
The safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children born small for gestational age (SGA) were evaluated based on interim data analysis from a clinical study, including the findings concerning the influence on the onset of puberty and subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at baseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm and 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6 in boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and 9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of puberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children. Treatment-related adverse events were generally mild to moderate in severity; however, adenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject had jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable changes in HbA1c levels were observed, and the levels remained within the reference range. We have confirmed the safety and effectiveness of long-term GH treatment through this ongoing clinical study.
Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient’s mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.