Molecular genetic analysis and growth hormone response in patients with syndromic short stature.

BACKGROUND: Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response. METHODS: Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature. RESULTS: Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [- 5.05 standard deviation (SD)] to 100.4 cm (- 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (- 2.69 SD) to 145.0 cm (- 2.36 SD), and her increased height SDS was 0.33. CONCLUSIONS: Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.

Characteristics of the spinopelvic parameters of patients with sacroiliac joint pain.

To evaluate the characteristics of the spinopelvic parameters on radiography in patients with sacroiliac joint pain (SIJP). Two hundred fifty patients were included and divided into the SIJP group (those diagnosed with SIJP based on physical findings and response to analgesic periarticular injections; n = 53) and the non-SIJP group (those with low back pain [LBP] because of other reasons; n = 197). We compared their demographic characteristics and spinopelvic parameters using radiography. All differences found in the patients' demographic characteristics and spinopelvic parameters were analyzed. More female participants experienced SIJP than male participants (P = 0.0179). Univariate analyses revealed significant differences in pelvic incidence (PI) (P = 0.0122), sacral slope (SS) (P = 0.0034), and lumbar lordosis (LL) (P = 0.0078) between the groups. The detection powers for PI, SS, and LL were 0.71, 0.84, and 0.66, respectively. Logistic regression analyses, after adjustment for age and sex, revealed significant differences in PI (P = 0.0308) and SS (P = 0.0153) between the groups, with odds ratios of 1.03 and 1.05, respectively. More female participants experienced SIJP than male participants. Higher PI and SS values were related to SIJP among LBP patients.

The acromegalic spine: fractures, deformities and spinopelvic balance.

INTRODUCTION: Axial skeleton arthropathy and osteoporotic vertebral fractures are common findings in acromegalic patients and can result in severe spinal deformity. OBJECTIVE: To investigate the presence of spinal fractures and deformities, sagittal imbalances, and spinopelvic compensatory mechanisms in acromegalics. PATIENTS AND METHODS: 58 patients with acromegaly from a referral neuroendocrinology center were prospectively evaluated by panoramic spine radiographs to detect the presence of fractures and scoliosis, to measure thoracic kyphosis, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT) and sagittal vertical axis (SVA). Sagittal imbalance criteria were considered: thoracic kyphosis > 50°, PI-LL > 10°, PT > 20° and SVA > 5 cm. Their medical records were analyzed for clinical and laboratorial data. RESULTS: The prevalence of fractures was 13.8%, predominantly in the thoracic spine, with mild and anterior wedge compressions. Scoliosis was present in 34.5% of the cases, all with degenerative lumbar curve apex. Thoracic kyphosis > 50º occurred in 36.8% of patients, PI-LL > 10° in 48.3%, PT > 20° in 41.4% and SVA > 5 cm in 12.1%. CONCLUSION: Increased number of vertebral fractures and high prevalence of spinal deformities related to sagittal imbalance were detected, indicating the importance of monitoring bone comorbidities in acromegaly, with radiological evaluation of the spine as part of the follow up.

Radiologic parameters of ankylosing spondylitis patients treated with anti-TNF-α versus nonsteroidal anti-inflammatory drugs and sulfasalazine.

PURPOSE: Limited data are available on the relationship between treatment agents and sagittal balance in ankylosing spondylitis (AS). We investigated radiological features related to treatment agents and compared sagittal balance between patients treated with anti-tumor necrosis factor-α (anti-TNF-α) and those treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and sulfasalazine (SSZ). METHODS: We prospectively enrolled 133 consecutive AS patients. Patients were eligible for the trial if they were under medical treatment with the same treatment agents for at least 1 year. All patients were treated initially with NSAIDs and SSZ. Sixty-nine patients achieved an excellent pain control outcome with these agents (group A). Sixty-four patients who reported of intractable low back pain were switched to anti-TNF-α treatment (group B). Twelve radiographic parameters were measured. Clinical outcome was assessed with the Bath AS Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). All parameters were measured at enrolment, upon changing treatment agents, and every 6 months during follow-up. RESULTS: The mean ESR, CRP, BASDAI, and thoracic kyphosis at baseline were significantly higher in group B. After treatment, group B had significantly higher lumbar lordosis (LL) and significantly better clinical outcomes. Correlation analysis revealed significant relationships between radiologic parameters and BASDAI. On multiple regression analysis, LL was a significant predictor of BASDAI. CONCLUSIONS: This study demonstrated a clear association between treatment agents and radiologic parameters in AS. Anti-TNF-α treatment improved LL with improvement in clinical outcomes. Lumbar lordosis was a significant predictor of clinical outcome in AS patients treated with anti-TNF-α. These slides can be retrieved under Electronic Supplementary Material.

Evaluation of Efficacy of Long-term Growth Hormone Therapy in Patients with Hypochondroplasia

Hypochondroplasia is a cause of disproportionate short stature and characterized by minor clinical manifestations. The aim of this study was to evaluate the efficacy of long-term growth hormone (GH) therapy in hypochondroplastic cases with inadequate response to GH stimulation tests. In this study, six patients who had a height standard deviation score of -3.43 before the treatment and a mean age of 7.42 years and who had received GH treatment at a dose of 0.2 mg/kg/week for a mean period of 4.45 years were evaluated. A good response was found in the first year of treatment, but this increase was not found to be sufficient for the patients to achieve an adequate final height.

Tamoxifen and ICI 182,780 activate hypothalamic G protein-coupled estrogen receptor 1 to rapidly facilitate lordosis in female rats.

In the female rat, sexual receptivity (lordosis) can be facilitated by sequential activation of estrogen receptor (ER) α and G protein-coupled estrogen receptor 1 (GPER) by estradiol. In the estradiol benzoate (EB) primed ovariectomized (OVX) rat, EB initially binds to ERα in the plasma membrane that complexes with and transactivates metabotropic glutamate receptor 1a to activate ß-endorphin neurons in the arcuate nucleus of the hypothalamus (ARH) that project to the medial preoptic nucleus (MPN). This activates MPN µ-opioid receptors (MOP), inhibiting lordosis. Infusion of non-esterified 17ß-estradiol into the ARH rapidly reduces MPN MOP activation and facilitates lordosis via GPER. Tamoxifen (TAM) and ICI 182,780 (ICI) are selective estrogen receptor modulators that activate GPER. Therefore, we tested the hypothesis that TAM and ICI rapidly facilitate lordosis via activation of GPER in the ARH. Our first experiment demonstrated that injection of TAM intraperitoneal, or ICI into the lateral ventricle, deactivated MPN MOP and facilitated lordosis in EB-primed rats. We then tested whether TAM and ICI were acting rapidly through a GPER dependent pathway in the ARH. In EB-primed rats, ARH infusion of either TAM or ICI facilitated lordosis and reduced MPN MOP activation within 30min compared to controls. These effects were blocked by pretreatment with the GPER antagonist, G15. Our findings demonstrate that TAM and ICI deactivate MPN MOP and facilitate lordosis in a GPER dependent manner. Thus, TAM and ICI may activate GPER in the CNS to produce estrogenic actions in neural circuits that modulate physiology and behavior.

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

OBJECTIVE: Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. DESIGN: This was a longitudinal cohort study. PATIENTS: Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. MEASUREMENTS: Serum NT-proCNP levels and height were measured. RESULTS: NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72). CONCLUSION: Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.

Height outcome of short children with hypochondroplasia after recombinant human growth hormone treatment: a meta-analysis.

Hypochondroplasia (HCH) is a genetic skeletal dysplasia, characterized by rhizomelic short height (Ht) with facial dysmorphology and lumbar hyperlordosis. Albeit there are concerns that HCH children may not achieve optimal long-term outcome in response to recombinant human growth hormone (rhGH), anecdotal experiences suggested at least short-term Ht improvement. After thorough search of published studies, meta-analysis of rhGH use in HCH children was performed. In 113 HCH children, rhGH administration (median 0.25 mg/kg/week) progressively improved Ht pattern with 12 months catch-up growth (p < 0.0001). Then, Ht improvement resulted constant until 36 months (p < 0.0001), but stature remained subnormal. While bone age chronologically progressed, no serious adverse events were reported. In conclusion, our meta-analysis indicates that rhGH treatment progressively improved Ht outcome of HCH subjects.

Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort.

BACKGROUND/AIMS: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. METHODS: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤-2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). RESULTS: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse events were reported. CONCLUSIONS: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy.

The use of botulinum toxin in the treatment of the consequences of bruxism on cervical spine musculature.

Hypertonia and hyperactivity of masticatory muscles are involved in pain and contractions of the cervical spine musculature, but their pathophysiology remains nonetheless unknown and its treatment far to be codified. In this study, 8 patients, showing disabling posterior neck muscle contractures linked with bruxism were prospectively treated and followed for an average 15 months period, after having received Injections of botulinum toxin A essentially in masticatory muscles. Injections were made every 3 months, varying from 10 to 100 U Botox* by muscles, without administrating more than 300 U Botox* in the same patient. The angle of cervical lordosis were calculated on lateral sitting radiographs in neutral position, good results being considered to be achieved in the case of a 2 point diminution of VAS score as well as at least a 5° positive gain in the curve. 7 patients out of 8 showed a real improvement in their symptoms after an average of 3 injections, showing a decrease of 4.5 points on the VAS score and an average increment of 15° in cervical lordosis. Although the follow-up period of patients was relatively short and the sample quite small, the general impression, confirmed by the patients' experience, seems to suggest a potential place for the use of botulinum toxin amongst the array of treatments which can be offered in certain selected cases which associate bruxism and posterior cervical contractions.

In vivo and in vitro evaluation of the estrogenic properties of the 17ß-(butylamino)-1,3,5(10)-estratrien-3-ol (buame) related to 17ß-estradiol.

BACKGROUND: Buame [17ß-(butylamino)-1,3,5(10)-estratrien-3-ol] possesses anticoagulant and antiplatelet activities that are potentially antithrombotic. Since its estrogenicity is unknown, it was evaluated by established methods. METHODS: Buame (10, 100, 500, and 1,000 µg/kg), 17ß-estradiol (E(2)) (100 µg/kg), or propylene glycol (10 ml/kg) were subcutaneously (sc) administered for three days to immature Wistar female rats (21 days old). The relative uterotrophic effect to E(2) was 78 (E(2) = 100) with a relative uterotrophic potency of 1.48 (E(2) = 100). Adult ovariectomized Wistar rats received an sc injection at 8:00 h (reversed cycle) of: 7.5 µg of E(2) (≈ 30 µg/kg), buame (≈ 750, 1,500, 3,000 µg/kg), or corn oil (≈ 1.2 ml/kg). After 24 h, progesterone (4-5 mg/kg) was administered. Sexual receptivity was assessed 5 to 7 h later, and the lordosis quotient (LQ; number lordosis/number mounts x 100) was evaluated. RESULTS: Buame induced lordosis (LQmax 85 ± 9; ED50 952 ± 19 µg/kg) and E(2) LQmax 56 ± 8; ED50 10 ± 2 µg/kg; the relative LQ-potency was 0.51 (E(2) = 100). Buame competed with [(3)H]E(2) for the estrogen receptor (Buame RBA= 0.15 and Ki = 5.9 x 10(-7) M; E(2) RBA= 100;Ki = 6.6 x 10(-9) M). Buame increased MCF-7 cells proliferation, from 10(-11) to 10(-)9 M, its proliferative effect was 1.73-1.79 (E(2) = 3.0-3.9); its relative proliferative effect to E(2) was 33-40% (E(2) = 100%) and relative potency 10.4-10.7 (E(2) = 100). Tamoxifen and fulvestrant (ICI 182,780) inhibited buame's proliferation indicating mediation through estrogen receptors in this response. CONCLUSION: Buame is therefore an estrogen partial agonist with a weak estrogenic activity.

[A rare differential diagnosis of waddling gait--osteomalacia caused by vitamin D deficiency]. / Seltene Differentialdiagnose des Watschelgangs-Osteomalazie durch Vitamin-D-Mangel.

The so-called "waddling gait" caused by paresis or mechanical insufficiency of the hip muscles is an ambiguous clinical guiding symptom. This pelvifemorally accentuated muscular weakness coinciding with pain in the range of the locomotor system should make one consider the diagnosis of osteomalacia due to deficiency of vitamin D, especially in Asian patients. In the present case, the course of investigation is described in detail, as well as the effective therapy. The diagnosis of this clinical picture ought to be familiar to any neurologist, since its more frequent appearance must be expected as an increasing number of Asians seek asylum in the years ahead. Social integration of the affected persons may be made easier by treatment on the lines described here.

Uptake of (6,7-3H)estradiol-17beta in ovariectomized rats, guinea pigs, and hamsters: correlation with species differences in behavioral responsiveness to estradiol.

PIP: The amount of estradiol benzoate with progesterone required to induce lordosis in ovariectomized hamsters was determined to compare the responsiveness of hamsters to estradiol benzoate with that of rats and guinea pigs. In addition, the uptake and metabolism of tritiated estradiol in ovariectomized rats, guinea pigs, and hamsters was examined in an attempt to correlate species differences in behavioral sensitivity to estradiol with possible differences in neural affinity for the steroid. A dose of nearly 90 mg/kg was required to induce lordosis in 100% of the hamsters compared with the 2-5 mcg/kg which is effective in rats and guinea pigs. In all 3 species, highest uptake of estradiol was in the uterus and anterior pituitary gland. In the rat and guinea pig brains, the hypothalamus took up more estradiol than either the cortex or midbrain. In the hamster, there were no consistent differences in brain uptake. The affinity of the uterus, anterior pituitary, and hypothalamus of rats and guinea pigs for estradiol was greater than that of hamsters. In all 3 species, estrone was the principal metabolite of estradiol found in the tissues. The authors suggest that the higher the endogenous levels of a steroid, the less sensitive the animal is to that steroid.^ieng