Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION:  Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study. WHAT IS NEW: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.

Mortality and cancer incidence among patients treated with recombinant growth hormone during childhood in Israel.

CONTEXT: The inconclusive evidence regarding long-term safety of recombinant human growth hormone (rhGH) therapy underlines the need for long-term large-scale cohorts. OBJECTIVE: To assess long-term mortality and cancer incidence among patients treated with rhGH during childhood in Israel. DESIGN: A population-based cohort study. SETTING: Data were retrieved from a national register established in 1988. Mortality data from the national population register were available through 31 December 2014. Data on cancer incidence from the national cancer registry were available through 31 December 2012. PARTICIPANTS: All patients ≤19 years approved for rhGH treatment during 1988-2009 were included. Patients were assigned to three risk categories, according to the underlying condition leading to growth disorder. MAIN OUTCOME MEASURES: All-cause mortality and cancer incidence rates were calculated, based on person-years at risk. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated, using the Israeli general population as a reference. RESULTS: Included were 1687 patients assigned to the low-risk category and 440 patients assigned to the intermediate-risk category. In the low-risk category, all-cause mortality and cancer incidence were not significantly different than expected (SMR 0·81, 95% CI 0·22-2·08 and SIR 0·76, 95% CI 0·09-2·73). In the intermediate-risk category, all-cause mortality and cancer incidence were significantly higher than expected (SMR 4·05, 95% CI 1·62-8·34 and SIR 4·52, 95% CI 1·22-11·57). CONCLUSIONS: No increased risk of mortality or cancer incidence was found in low-risk patients treated with rhGH during childhood. Patients with prior risk factors were at higher risk of both mortality and cancer.

Training reduces catabolic and inflammatory response to a single practice in female volleyball players.

We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Thirteen female, national team level, Israeli volleyball players (age 16.0 ± 1.4 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60 minutes of volleyball practice, before and after 7 weeks of training during the initial phase of the season. Training involved tactic and technical drills (20% of time), power and speed drills (25% of time), interval sessions (25% of time), endurance-type training (15% of time), and resistance training (15% of time). To achieve greater training responses, the study was performed during the early phase (first 7 weeks) of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, the catabolic hormone cortisol, the proinflammatory marker interleukin-6 (IL-6), and the anti-inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of vertical jump, anaerobic properties (peak and mean power by the Wingate Anaerobic Test), and predicted VO2max (by the 20-m shuttle run). Volleyball practice, both before and after the training intervention, was associated with a significant increase of serum lactate, GH, and IL-6. Training resulted in a significantly reduced cortisol response ([INCREMENT]cortisol: 4.2 ± 13.7 vs. -4.4 ± 12.3 ng · ml, before and after training, respectively; p < 0.02), and IL-6 response ([INCREMENT]IL-6: 1.3 ± 1.0 vs. 0.3 ± 0.4 pg · ml, before and after training, respectively; p < 0.01) to the same relative intensity volleyball practice. The results suggest that along with the improvement of power and anaerobic and aerobic characteristics, training reduces the catabolic and inflammatory response to exercise.

An open-label extension of a phase 2 dose-finding study of once-weekly somatrogon vs. once-daily Genotropin in children with short stature due to growth hormone deficiency: results following 5 years of treatment.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone (GH) employed as a once-weekly treatment for children with GH deficiency (GHD). A 12-month, phase 2 study of once-weekly somatrogon vs. once-daily GH (Genotropin®) was initiated, after which participants could enroll into an open-label extension (OLE) evaluating the safety and efficacy of long-term somatrogon treatment. METHODS: There were five study periods, Periods I and II were 6 months each while Periods III, IV, and V were 12 months each. In the main study (Periods I and II), 53 prepubertal children with GHD were randomized to once-weekly somatrogon (0.25, 0.48, or 0.66 mg/kg/week) or once-daily Genotropin (0.034 mg/kg/day); 48 continued into the OLE, consisting of Period III (original somatrogon dose; Genotropin recipients randomized to one of three somatrogon doses), Period IV (somatrogon 0.66 mg/kg/week), and Period V (prefilled somatrogon pen [0.66 mg/kg/week]). RESULTS: At the end of Period III, the mean ± SD annual height velocity (HV) for 0.25, 0.48, and 0.66 mg/kg/week somatrogon groups was 7.73 ± 1.89, 7.54 ± 1.28, and 8.81 ± 1.12 cm/year, respectively; HV was sustained during Periods IV/V. Height SD scores (SDS) showed progressive improvement throughout the OLE, regardless of initial cohort assignment, approaching the normal range (-0.69 ± SD 0.87) at the end of Period V Year 1. Mild or moderate treatment-emergent adverse events were reported in 81.3% of participants, most unrelated to study drug. CONCLUSIONS: Up to 5 years of once-weekly somatrogon was well tolerated and resulted in sustained improvement in height SDS and delta height SDS in prepubertal short children with GHD.

Training increases anabolic response and reduces inflammatory response to a single practice in elite male adolescent volleyball players.

We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Fourteen male, elite, national team-level, Israeli volleyball players (age, 16.3±1.1 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60-min volleyball practice, before and after 7 weeks of training during the initial phases of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, and testosterone; the catabolic hormone cortisol; the pro-inflammatory markers interleukin (IL) 6, and the anti-inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of both anaerobic and aerobic properties. Before the training intervention, the typical volleyball practice was associated with a significant increase of GH and testosterone and also with a significant increase of IL-6. Training resulted in a significantly greater GH response (ΔGH, 2.5±2.4 vs. 4.7±3.0 ng/mL, before and after training, respectively; p<0.02) and reduced IL-6 response (ΔIL-6, 2.0±1.6 vs. 0.6±0.7 pg/mL, before and after training, respectively; p<0.01) to the same relative intensity volleyball practice. The results suggest that, along with the improvement of anaerobic and aerobic characteristics, training leads to a greater anabolic and reduced inflammatory response to exercise.

Screening criteria for diagnosis of infantile feeding disorders as a cause of poor feeding or food refusal.

OBJECTIVES: Infantile feeding disorders (IFDs) are a common cause of food refusal, failure to thrive, and vomiting, but they may be difficult to diagnose. We have previously identified certain patterns of pathological feeding and behaviors as high-risk characteristics for IFDs and subsequently developed the diagnostic Wolfson criteria. Here, we evaluate these high-risk behaviors and prospectively compare the Wolfson criteria with 2 existing classifications of IFD, the Chatoor and that in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). PATIENTS AND METHODS: Infants and young children referred for food refusal were invited to participate by completing a feeding pattern questionnaire. Following physicians' interview and examination, patients were scored by all 3 criteria and enrolled in a structured treatment program for IFD. Infants whose food refusal was associated with an organic cause served as a comparison group. The ability of the criteria to detect IFD and to predict response to therapy was compared with an intention-to-treat analysis. RESULTS: Eighty-five infants with new-onset IFD and 55 controls were included. The Wolfson criteria, Chatoor, and DSM-IV accurately diagnosed 100%, 77%, and 56% of the patients with IFD, respectively. Anticipatory gagging occurred in 47% of the children with IFD compared to 2% controls (P < 0.001). The response to therapy was similar among the 3 criteria (73-76%), suggesting that the Wolfson criteria did not incorrectly diagnose organic disease as IFD. The 20 infants who were diagnosed as having IFD by Wolfson but not by Chatoor responded equally well (80%) to an IFD treatment program. CONCLUSIONS: Diagnostic criteria of IFD that are based on food refusal, pathological feeding, and anticipatory gagging have a higher detection rate than the present criteria and are simpler to implement.

The effect of HMB supplementation on body composition, fitness, hormonal and inflammatory mediators in elite adolescent volleyball players: a prospective randomized, double-blind, placebo-controlled study.

The use of ergogenic nutritional supplements is becoming inseparable from competitive sports. ß-Hydroxy-ß-Methylbutyric acid (HMB) has recently been suggested to promote fat-free mass (FFM) and strength gains during resistance training in adults. In this prospective randomized, double-blind, placebo-controlled study, we studied the effect of HMB (3 g/day) supplementation on body composition, muscle strength, anaerobic and aerobic capacity, anabolic/catabolic hormones and inflammatory mediators in elite, national team level adolescent volleyball players (13.5-18 years, 14 males, 14 females, Tanner stage 4-5) during the first 7 weeks of the training season. HMB led to a significant greater increase in FFM by skinfold thickness (56.4 ± 10.2 to 56.3 ± 8.6 vs. 59.3 ± 11.3 to 61.6 ± 11.3 kg in the control and HMB group, respectively, p < 0.001). HMB led to a significant greater increase in both dominant and non-dominant knee flexion isokinetic force/FFM, measured at fast (180°/sec) and slow (60°/sec) angle speeds, but had no significant effect on knee extension and elbow flexion and extension. HMB led to a significant greater increase in peak and mean anaerobic power determined by the Wingate anaerobic test (peak power: 15.5 ± 1.6 to 16.2 ± 1.2 vs. 15.4 ± 1.6 to 17.2 ± 1.2 watts/FFM, mean power: 10.6 ± 0.9 to 10.8 ± 1.1 vs. 10.7 ± 0.8 to 11.8 ± 1.0 watts/FFM in control and HMB group, respectively, p < 0.01), with no effect on fatigue index. HMB had no significant effect on aerobic fitness or on anabolic (growth hormone, IGF-I, testosterone), catabolic (cortisol) and inflammatory mediators (IL-6 and IL-1 receptor antagonist). HMB supplementation was associated with greater increases in muscle mass, muscle strength and anaerobic properties with no effect on aerobic capacity suggesting some advantage for its use in elite adolescent volleyball players during the initial phases of the training season. These effects were not accompanied by hormonal and inflammatory mediator changes.

Neonatal hyperthyrotropinemia: population characteristics, diagnosis, management and outcome after cessation of therapy.

INTRODUCTION: Neonatal hyperthyrotropinaemia (HT), defined by elevated TSH and normal T(4), is either transient or persistent. The eventual outcome of neonatal HT is unpredictable and the management of HT patients is controversial. We assessed perinatal parameters and diagnostic measures that may distinguish between transient and persistent HT, compared with congenital hypothyroidism (CH). We also aimed to recommend optimal treatment in these forms of thyroid impairment. DESIGN AND PATIENTS: A multi-centre, retrospective study was conducted in six paediatric endocrinology units. Forty-three HT patients and 83 CH patients were included in the study. Measurements We evaluated differences in birth weight (BW), gestational age (GA), modes of diagnosis, screening and confirmatory T(4) and TSH levels, thyroid imaging results and optimal thyroxine doses between HT and CH and between the two forms of HT. RESULTS: Newborns with HT had lower BW and GA than those with CH. Transient (n = 18) and persistent HT (n = 25) patients were indistinguishable by most parameters, but those with persistent HT had a higher prevalence of abnormal thyroid imaging (69%vs 8%; P = 0.005). During treatment, 79% and 55% of transient and persistent HT patients respectively experienced elevated levels of free T(4.) Although most HT patients were reevaluated after 2.5 years, six transient HT patients stopped therapy and showed full recovery within the first year of life. CONCLUSIONS: We recommend obtaining thyroid imaging to distinguish between the two forms of HT. Adherence to recommended doses of thyroxine and probably early cessation of therapy in transient HT can prevent iatrogenic hyperthyroidism in these patients.

Soy-derived isoflavones treatment in children with hypercholesterolemia: a pilot study.

AIMS: To evaluate for the first time in children the effect of soy-derived isoflavones on lipid profile and insulin resistance. METHODS: Twelve hypercholesterolemic children (8 females) aged 5.3 to 11.2 years have completed a prospective, controlled pilot study. After a low-fat diet for 12 weeks, children who maintained high cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels were randomly assigned to three intervention periods of either placebo or low and high dose isoflavone (16 or 48 mg) consumption, each period lasting 8 weeks. RESULTS: The diet significantly reduced LDL-C and apolipoprotein B (Apo B) levels. However, isoflavones had no effect on cholesterol, LDL-C, high-density lipoprotein-cholesterol (HDL-C), triglycerides, lipoprotein (a), Apo B, or insulin resistance, at either low or high doses. Isoflavones had no effect on sex hormones, gonadotropins, sex-hormone binding globulin and thyroid hormones. CONCLUSIONS: The results of this pilot study do not suggest a beneficial role of an isoflavone-enriched diet in children with hypercholesterolemia.

Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices.

There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). Derived from the amino acid leucine and its keto acid alpha-ketoisocaproate (KIC), HMB has been well documented as an oral ergogenic supplement commonly used by athletes. Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription. These are described here, and hormonal interactions are discussed, along with HMB dosage and safety issues.

Hormonal and metabolic effects of nutrition in athletes.

Competitive sport and strenuous physical activity make demands on our body above the usual physiological range. Measurable muscle damage and accumulation of metabolic products cause pain and other effects that can be demonstrated. From the medical point of view we have to provide athletes with adequate nutrients and energy for the maintenance of homeostasis and to cover their higher energetic and nutritional needs as compared to sedentary people. Some athletes may need supplements to replace essential nutrients missing from their regular (especially if unbalanced) diet, or to restore special needs, such as fluids and salts, while exercising in extreme climatic conditions. Overload of additives is frequent in both professional and amateur athletes. Very often, the proposed mechanism for the rationale of using these additives, 'supplements' or 'ergogenic compounds', is related to their possible effect on the endocrine-metabolic system, in many cases without solid evidence-based research. Yet it needs to be remembered that there is still disagreement on what are the required physiological needs of athletes for amino acids and other supplements. Different surveys on the use of supplements report that 40-60% of athletes take food additives, and the numbers are rapidly increasing. A more alarming fact is that about 50% of the recommendations to use these supplements come from non-professional people. Since some additives may change the endocrine and metabolic homeostasis in an unexpected way--as an extreme example of close to 50 deaths reported from the use of L-tryptophan supplements--it is important to study carefully the effects of additives given to athletes, and to increase awareness of the lack of knowledge in this field.

The effect of a volleyball practice on anabolic hormones and inflammatory markers in elite male and female adolescent players.

The effect of a single exercise as well as exercise training on the growth hormone (GH)-insulin-like growth factor (IGF-I) axis and inflammatory cytokines was studied mainly in adults participating in individualized endurance-type sports. The gender-specific effect of exercise on these systems in adolescents is unknown. Therefore, the purpose of this study was to evaluate the effect of a typical volleyball practice on anabolic (GH, IGF-I, and testosterone) and catabolic hormones (cortisol) and inflammatory mediators (interleukin-6 [IL-6]) in elite, national team level, male (n = 14) and female (n = 13) adolescent volleyball players (13-18 years, Tanner stage 4-5). Exercise consisted of a typical 1-hour volleyball practice. Blood samples were collected before and immediately after the practice. Exercise led to significant increases in GH (0.2 +/- 0.1 to 2.7 +/- 0.7 and 1.7 +/- 0.5 to 6.4 +/- 1.4 ng x mL, in men and women, respectively, p < 0.05 for both), testosterone (6.1 +/- 0.9 to 7.3 +/- 1.0 and 2.4 +/- 0.6 to 3.3 +/- 0.7 ng x mL, in men and women, respectively, p < 0.05 for both), and IL-6 (1.1 +/- 0.6 to 3.1 +/- 1.5 and 1.2 +/- 0.5 to 2.5 +/- 1.1 pg x mL, in men and women, respectively, p < 0.002 for both). Exercise had no significant effect on IGF-I, insulin-like growth factor binding protein-3, and cortisol levels. There were no gender differences in the hormonal response to training. Changes in GH and testosterone after the volleyball practice suggest exercise-related anabolic adaptations. The increase in IL-6 may indicate its important role in muscle tissue repair. These changes may serve as an objective quantitative tool to monitor training intensity in unique occasions in team sports.

The insulin-like growth factor-I (IGF-I) generation test as an indicator of growth hormone status.

OBJECTIVE: The aim of the study was to evaluate the IGF-I generation test (IGF-I gen) as a possible indirect test of Growth Hormone (GH) secretory status. METHODS: Sixty-five GH deficient (GHD 1 and 2) and 86 control children were studied. Children in the GHD-1 subgroup (n=33) had low GH values (<10 microg/L) after clonidine and levo-dopa while those in the GHD-2 subgroup (n=32) had normal GH values after pharmacologic provocation but low 24-hour GH secretory rates compared to 187 Normal Statured (NS) children. Of the 86 controls, who underwent IGF-I gen,50 were NS and 36 Short-Statured (SS). Serum IGF-I was measured prior to and daily during hGH administration (hGH 0.033 mg/kg/dayx4 days). RESULTS: The prepubertal and pubertal GHD-1 and GHD-2 children had low baseline IGF-I values but their peak IGF-I values during the IGF-I gen reached those of the controls. The percent increase of IGF-I during the test was greater in the GHD groups than in the controls; in the prepubertal groups: 516+/-58% in the GHD-1, 433+/-50% in the GHD-2, 106+/-12% in the NS, and 102+/-18% in the SS (p=0.001); in the pubertal groups: 191+/-28% in the GHD-1, 141+/-20% in the GHD-2, 48+/-8% in the NS, and 61+/-17% in the SS (p=0.003). CONCLUSIONS: The IGF-I response during the IGF-I gen seems to reflect the GH status in children.

Breast development in the first 2 years of life: an association with soy-based infant formulas.

OBJECTIVE: To evaluate the estrogenic effect of soy-based formulas in female infants. These formulas contain significant amounts of phytoestrogens, compounds with structural similarity to estradiol. PATIENTS AND METHODS: A cross-sectional study consisting of 694 female infants ages 3 to 24 months that consecutively attended 10 general pediatric clinics, none of them having been referred for breast development. The presence of breast buds served as a marker for the endocrine effect of soy-derived phytoestrogens. RESULTS: Of the participants, 92 had consumed soy formulas for more than 3 months. Breast tissue was more prevalent in the second year of life in infants fed soy-based formula vs those that were breast-fed and those fed dairy-based formula (22.0% vs 10.3%; P = 0.02) with an odds ratio of 2.45 (95% confidence interval 1.11-5.39). No differences in breast bud prevalence were observed during the first year of life. Unlike infants on dairy-based formulas and breast-feeding, infants fed a soy-based formula did not demonstrate a decline in the prevalence of breast during the second year of life. CONCLUSIONS: We suggest that phytoestrogens impose a preserving effect on breast tissue that is evolved in early infancy, leading eventually to a slower waning of infantile breast tissue.

Adaptive and maladaptive cortisol responses to pediatric obesity.

The recent unprecedented increase of childhood obesity has led to an alarming rise in type 2 diabetes mellitus (T2D) among these children. The process underlying the progression from simple obesity to T2D is not well understood. Cortisol is a candidate factor in the pathogenesis of T2D, as it can exacerbate insulin resistance and provoke other disturbances of the metabolic syndrome. The 24-h integrated concentration (IC) of cortisol is suppressed in non-diabetic obese children compared to lean children. This difference in IC-cortisol is not due to changes in cortisol binding globulin or plasma cortisol to cortisone ratio between groups. In obese individuals, IC-cortisol suppression disappears with age after adolescence, which corresponds with increasing occurrence of T2D and other metabolic disorders of obesity. We consider the IC-cortisol levels of lean insulin sensitive children to be metabolically inappropriate for obese insulin resistant children. Thus, we hypothesize that suppression of IC-cortisol is an important adaptive response to obesity (cortisol adaptive suppression) in childhood that prevents pediatric T2D while failure to suppress IC-cortisol (cortisol suppression failure) exacerbates insulin resistance and contributes to the development of T2D. In further support of this hypothesis is early pilot data suggesting that cortisol suppression failure occurs in obese children with impaired fasting glucose levels. The mechanism(s) underlying cortisol adaptive suppression, how and why these mechanism(s) fail are unknown. Elucidation of these mechanisms may lead to interventions to prevent the development of T2D and its complications in obese individuals.

Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene.

CONTEXT: G to A transition at position 6,664 (G6664A) in human GH-1 results in the substitution of arginine by histidine at position 183 (R183H) of the GH molecule and causes familial isolated GH deficiency type II (IGHD II). OBJECTIVES: The objective of the study was to assess the phenotype-genotype correlation of subjects affected with IGHD II caused by a G6664A mutation in 34 affected members of two large families. DESIGN AND PATIENTS: Sixty-six subjects from two core families were included. The G6664A mutation among family members was determined by restriction fragment length polymorphism. RESULTS: Twenty-four of the 52 members from family 1 and 10 of 14 from family 2 carried the same G6664A mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter [-2.6 vs. -0.1 sd score (SDS), P < 0.0001] and had significantly lower IGF-I serum levels (-1.9 vs. -0.5 SDS, P < 0.0001), compared with normal-genotype family members. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 (mean -2.8 SDS), with five members being of normal height (>-2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although one of these subsequently demonstrated GH insufficiency (6.5 and 3.7 ng/ml). The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age (chronological age - bone age), age at diagnosis, peak GH response, and IGF-I levels. CONCLUSIONS: These detailed phenotypic analyses show the variable expressivity of patients bearing a G6664A mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination. Our findings raise a new dilemma in the guidelines for the diagnosis of GH deficiency and the indications for GH therapy.