W. Oostdijk

Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement

Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

Beneficial Effects of Growth Hormone Treatment on Cognition in Children with Prader-Willi Syndrome: A Randomized Controlled Trial and Longitudinal Study

BACKGROUND Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited. METHODS Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores. RESULTS During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores. CONCLUSIONS Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment.

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues

BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long‐term effect of GH therapy in children with Idiopathic short stature.

Longitudinal analysis of growth and puberty in 21-hydroxylase deficiency patients.

Aims: To evaluate growth from diagnosis until final height (FH) in 21-hydroxylase deficiency patients. Methods: A retrospective longitudinal study was performed. Only patients treated with hydrocortisone and fludrocortisone (in case of salt wasting) were evaluated. This resulted in a sample of 34 (21 male, 13 female) salt wasting patients (SW) and 26 (13 male, 13 female) non-salt wasting patients (NSW). Auxological data were compared to recent Dutch reference values. Results: In the first three months of life, the mean length SDS decreased to −1.50, probably because of the high average glucocorticoid dose (40 mg/m2/day). FH corrected for target height (FHcorrTH) was −1.25 and −1.27 SDS in females and males, respectively. Patients treated with salt supplements during the first year, had a better FHcorrTH (−0.83 SDS). In NSW patients, FHcorrTH was −0.96 and −1.51 SDS in females and males, respectively. In SW and NSW, age at onset of puberty was within normal limits, but bone age was advanced. Mean pubertal height gain was reduced in males. Body mass index was only increased in NSW females. Conclusion: In SW, loss of final height potential might be a result of glucocorticoid excess in the first three months and sodium depletion during infancy. In NSW, loss of FH potential was caused by the delay in diagnosis. In SW and NSW, the advanced bone age at onset of puberty (undertreatment in prebertal years) resulted in loss of height gain during puberty. The effect of intensive sodium chloride support in early infancy should be examined prospectively. Neonatal screening is required if the height prognosis in NSW patients is to be improved.

Developing evidence-based guidelines for referral for short stature

Objective: To establish evidence-based guidelines for growth monitoring on a population basis. Study design: Several auxological referral criteria were formulated and applied to longitudinal growth data from four different patient groups, as well as three samples from the general population. Results: Almost 30% of pathology can be detected by height standard deviation score (HSDS) below −3 or at least two observations of HSDS below −2.5 at a low false-positive rate (<1%) in 0–3-year-old infants. For 3–10-year olds, a rule concerning distance to target height of >2 SD in combination with HSDS <−2.0 has the best predictive value. In combination with a rule on severe short stature (<−2.5 SDS) and a minor contribution from a rule on “height deflection”, 85.7% of children with Turner syndrome and 76.5% of children who are short because of various disorders are detected at a false-positive rate of 1.5–2%. Conclusions: The proposed guidelines for growth monitoring show high sensitivity at an acceptably low false-positive rate in 3–10-year-old children. Distance to target height is the most important criterion. Below the age of 3 years, the sensitivity is considerably lower. The resulting algorithm appears to be suitable for industrialised countries, but requires further testing in other populations.

Final Height after Gonadotrophin Releasing Hormone Agonist Treatment for Central Precocious Puberty: The Dutch Experience

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p < 0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment started < 6 years of age, height gain was significantly higher than when started > 8 years of age. Bone age (BA) and chronological age (CA) at start of treatment, as well as BA advance at cessation of treatment, were the most important variables influencing height gain in multiple regression analysis. BA advance at start of treatment was most important in simple correlation. In girls, GnRHa treatment seems to restore FH into the target range. A younger age and advanced bone age at start of treatment are associated with more height gain from GnRHa treatment.

Eight Years of Growth Hormone Treatment in Children With Prader-Willi Syndrome : Maintaining the Positive Effects

BACKGROUND The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition. OBJECTIVES The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment. SETTING This was a multicenter prospective cohort study. METHODS We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≈ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat. RESULTS After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = .06, P = .14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation. CONCLUSION This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.

Effects of two years of methionyl growth hormone therapy in two dosage regimens in prepubertal children with short stature, subnormal growth rate, and normal growth hormone response to secretagogues

Thirty short, slowly growing children with normal plasma growth hormone response to standard provocation tests were randomly assigned to a group (n = 20) undergoing therapy with methionyl growth hormone, 2 IU/m2 subcutaneously once daily, (group 1) or a control group (n = 10, group 2). The mean (+/- SD) height velocity increment in group 1 was 3.0 +/- 1.9 cm/yr in the first year, compared with -0.2 +/- 0.7 cm/yr in group 2. Of the 18 children who completed the first year of treatment, 12 had a height velocity increment of more than 2 cm/yr and 11 of them continued treatment for a second year (group 1A). The remaining six children also reached height velocities greater than the mean for bone age, but because of a low height velocity increment they were termed nonresponders and their growth hormone dosage was increased to 4 IU/m2/day (group 1B). Of the 10 children in the control group, seven received authentic biosynthetic growth hormone in the second year of the study (group 2); the remaining three received no therapy (group 3). The mean height velocities (measured in centimeters per year) before and during the first and second years of therapy were 3.6, 7.6, and 6.1 in group 1A; 5.7, 6.9, and 7.3 in group 1B; 4.2, 4.0, and 6.7 in group 2; and 5.0, 4.9, and 5.2 in group 3. The effect of doubling the dosage was a further increase of 1.9 cm/yr. Bone age advance paralleled growth acceleration, resulting in an unchanged height standard deviation score for bone age and ambiguous results on final height prediction. Growth hormone therapy in such short children appears to be safe and efficacious in increasing growth velocity for 2 years, but its efficacy in terms of increasing final height is uncertain.

The IGSF1 Deficiency Syndrome: Characteristics of Male and Female Patients

CONTEXT Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. OBJECTIVE Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. METHODS All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. RESULTS Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. CONCLUSION In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Prediction of height achievement at five years of age in children born very preterm or with very low birth weight: continuation of catch-up growth after two years of age

To predict height at five years in a cohort of 565 very preterm and/or very low‐birth‐weight children, hypothesized growth determinants were subjected to discriminant analysis. Many neonatal parameters were not significantly associated with short stature at five years of age. A correct classification of stature (smaller/larger than the 10th percentile at five years of age) could be obtained in 85% of children, using the following variables: height at two years of age; total (or mid) parental height; parental level of education; length at one year of age; hypertension during pregnancy; sex; weight at two years of age; length percentile at one year of age. However, when compared to actual longitudinal data, the false‐positive rate was 37%. The survey also demonstrated the continuing catch‐up growth in very preterm and very low‐birth‐weight infants after two years of age.