Plasma insulin-like growth factors (IGFs), IGF-Binding proteins (IGFBPs), acid-labile subunit (ALS) and IGFBP-3 proteolysis in individuals with clinical characteristics of Sotos syndrome

OBJECTIVE: Sotos syndrome is an overgrowth syndrome of poorly understood aetiology. We investigated whether this syndrome is related to alterations in plasma insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), acid-labile subunit (ALS) and serum IGFBP-3 proteolysis. DESIGN: Based on clinical criteria, 32 patients with clinical characteristics of Sotos syndrome (median age 8.4 years, range 1.8-48.4) were categorised into three groups: typical (n = 10, group 1), dubious (n = 12, group 2) and atypical (n = 10, group 3). Blood samples were obtained from 29 patients. MEASUREMENTS: Plasma IGF-I, IGF-II, E-II (pro-IGF-II and E-domain fragments), IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6 and ALS were measured by specific radioimmunoassays (RIAs). Except for E-II immunoreactivity, the concentrations were compared with those of age references, and expressed as standard deviation scores (SDS). IGFBP-3 proteolysis was assessed by incubation of serum with [125I]-IGFBP-3, followed by gel electrophoresis and was then compared with that in normal serum and third trimester pregnancy serum. RESULTS: Patients in group 1 showed significantly reduced plasma levels of IGF-II (median -0.9 SDS; p = 0.01), IGFBP-4 (-0.5 SDS; p = 0.02) and IGFBP-3 (-1.0 SDS; p = 0.01). Mean IGFBP-3 proteolysis was higher than in normal standard serum (61% vs 37%; p < 0.01) but lower than in third trimester pregnancy serum (94%; p < 0.01). Plasma IGF-I showed a tendency towards low values (median -0.9 SDS; p = 0.09), IGFBP-6 and ALS a tendency towards elevated levels (median values +0.8 SDS; p = 0.07 and +2.3 SDS; p = 0.09), and IGFBP-2 was normal. The mean value of E-II immunoreactivity was 8.7 nmol/l, similar to that in pooled normal plasma (8.6 nmol/l). Plasma and serum parameters in groups 2 and 3 were similar to reference values with the exception of plasma IGFBP-3 (in groups 2 and 3 median < or = -1.1 SDS; p < or = 0.02) and ALS (in group 3 median +1.3 SDS; p < 0.01). CONCLUSIONS: Patients with typical Sotos syndrome show low plasma IGF-II, IGFBP-3, IGFBP-4, and increased proteolysis of IGFBP-3 in serum. The extent to which these findings are associated with the pathophysiology of Sotos syndrome remains uncertain.     

Auxological data in patients clinically suspected of Sotos syndrome with NSD1 gene alterations

Aim: Nuclear receptor-binding SET domain-containing protein 1 (NSD1) gene mutations and deletions (NSD1^+/−) are the major cause of Sotos syndrome. The aim was to investigate which auxology parameters relate to NSD1^+/− in patients clinically suspected of Sotos syndrome. Methods: In 32 patients clinically suspected of Sotos syndrome, we compared auxology parameters between NSD1^+/− patients and patients without NSD1 gene alterations (NSD1^+/+). The statistical performance of these parameters to predict NSD1^+/− was assessed. Results: Arm span-for-height standard deviation score (SDS) and hand length SDS were significantly higher in NSD1^+/− patients.
Conclusion: Arm span for height and hand length are discriminating parameters between NSD1^+/− and NSD1^+/+.     

Growth in Sotos syndrome.

Although there are several reports on infant and childhood growth in patients with Sotos syndrome, there is little information on the final height achieved and puberty. Growth data on 40 patients (20 female and 20 male) aged 2-31 years were collected. These showed that patients with Sotos syndrome are excessively tall at birth, during infancy, and during childhood. Disproportionately long limbs constitute much of the increase in stature. However, the combination of advanced bone age and early onset of menarche led to a mean (SD) final height of 172.9 (5.7) cm in women. This is within the normal range for the population. Most of the men also attained a final height (mean, 184.3 cm; SD, 6.0) within the normal range, although exceptions were more likely in men than in women. Therefore, these results show that most patients with Sotos syndrome do not require intervention to limit their adult height.     

Growth in Sotos syndrome

Although there are several reports on infant and childhood growth in patients with Sotos syndrome, there is little information on the final height achieved and puberty. Growth data on 40 patients (20 female and 20 male) aged 2-31 years were collected. These showed that patients with Sotos syndrome are excessively tall at birth, during infancy, and during childhood. Disproportionately long limbs constitute much of the increase in stature. However, the combination of advanced bone age and early onset of menarche led to a mean (SD) final height of 172.9 (5.7) cm in women. This is within the normal range for the population. Most of the men also attained a final height (mean, 184.3 cm; SD, 6.0) within the normal range, although exceptions were more likely in men than in women. Therefore, these results show that most patients with Sotos syndrome do not require intervention to limit their adult height.     

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from –3.5 at baseline to –2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.     

Thyroid dysfunction and high thyroid stimulating hormone levels in children with Down's syndrome

In order to delineate the spectrum of thyroid abnormalities in children with Down's syndrome (DS), first visit height data (SDS) and serum TSH, T4 and antiperoxidase antibodies concentrations were retrospectively evaluated in 137 children (71 girls) with DS (0.04-16 years). RESULTS: Congenital hypothyroidism was detected in 2.9% of patients. Thyroid disease occurred in 9%: four hyperthyroidism and eight hypothyroidism. Overt thyroid disease was always related to thyroid autoimmunity. The remaining 121 patients had normal T4 levels but increased mean TSH compared with controls (4.7 +/- 2.8 vs 2.3 +/- 1.3 mU/l). According to TSH levels, they were divided into two groups: G1 (n = 68) with normal TSH (<5 mU/l), and G2 (n = 53) with high TSH (> 5 mU/l). T4 levels were significantly lower in G2 (p < 0.01 vs G1 and controls). Height SDS was not different. CONCLUSIONS: Thyroid disorders are frequent in children with DS. Subtle thyroid abnormalities found in patients with DS with no evidence of clinical dysfunction need further investigation to demonstrate whether there is a need for therapeutic intervention.     

Assessment of protein-energy malnutrition in children with chronic arthritis

Protein-energy malnutrition (PEM) has been estimated to occur in 10 to 50% of children with juvenile chronic arthritis (JCA). Thirty-eight children with JCA were evaluated and their nutritional status determined, and they were compared with 23 healthy sex and age-matched children as controls. A standardized, 9-parameter comprehensive nutritional assessment profile was used. The simple anthropometric measurements, height and weight for age, were abnormal in 30% and 27% of the patients, respectively. A detailed evaluation revealed that 71% had abnormal somatic protein stores, and that they also had significantly low levels of visceral protein stores, when compared to their healthy peers. The results were consistent with the fact that inflammation put the JCA patients at significant risk for developing complicated malnutrition and it might result in PEM without any obvious signs of malnutrition. A nutritional screening test would be very useful in detecting early PEM in children with chronic arthritis.     

A case of cerebral gigantism and hepatocarcinoma.

A 14-year-old boy, who had the physical and neurological characteristics of cerebral gigantism (Sotos syndrome), developed hepatocarcinoma. This tumor is rare in children and has never, to our knowledge, been recorded in a patient with cerebral gigantism. An autopsy was performed, the first we are aware of in a patient with cerebral gigantism without increased size in ventricles.     

Short stature in Noonan syndrome: response to growth hormone therapy.

BACKGROUND: Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. AIMS: To assess the short and long term response to GH therapy in patients with Noonan syndrome. METHODS: Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this post-marketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. RESULTS: Data on 66 patients (54 males) were available for study. At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from -2.9 pretreatment to -2.6 after one year and -2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range -1.1 to 6.5 cm). CONCLUSIONS: GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of effect; initial indications are that final height is not improved substantially in most patients.     

Sotos syndrome: a novel nonsense mutation in NSD1 gene, presenting with neonatal cutis laxa

Sotos syndrome is an overgrowth condition characterized by facial gestalt, macrocephaly, excessive height, and different degrees of developmental delay. We report the case of a 20-month-old boy with a confirmatory molecular study, showing a novel nonsense mutation in NSD1 gene, presenting cutis laxa as the main phenotypic trait in the neonatal period. This association has been previously described in 3 patients with a clinical diagnosis of Sotos syndrome, without confirmatory molecular analysis. Our patient was tested for congenital disorders of glycosilation as part of the cutis laxa differential diagnosis. During the postnatal follow-up period the head circumference and height became greater than 97(th) percentile (having been close to the 50(th) in the newborn period). These facts and the progressive development of characteristic phenotypic features of Sotos syndrome during the first months of life gave us the clue for the clinical diagnosis and the molecular investigation.     

Outcomes for children with gallbladder abnormalities and sickle cell disease

OBJECTIVE: To determine whether elective cholecystectomy is justifiable in children with sickle cell disease (SCD), gallbladder abnormalities, and minimal clinical symptoms. STUDY DESIGN: A retrospective review comparing clinical presentations and abdominal ultrasound results with outcomes in 146 children with SCD. RESULTS: Ultrasound examination showed sludge or stones in 83 of 146 children (57%). This was found during a diagnostic ultrasound in 59 patients (71%) and during a screening ultrasound in 24 asymptomatic patients (29%). Fifty-four (65%) children with a positive ultrasound underwent cholecystectomy; 13 of these were initially asymptomatic patients who had subsequent development of clinical symptoms. Of the patients with cholecystectomy, 93% had histopathologic evidence of cholecystitis. Perioperative complications were rare, and there were no episodes of postoperative acute chest syndrome. Children who underwent elective surgery had an average 12-days-shorter overall hospital stay than those who underwent emergent surgery (4 vs 16 days, P <.001). CONCLUSIONS: Elective laparoscopic cholecystectomy may be safely performed in children with SCD. Surgery should be strongly considered at the time of gallstone diagnosis before symptoms or complications develop. Histopathologic chronic cholecystitis does not correlate with clinical symptoms.     

Sotos综合征的临床表型及遗传学分析

3例男性患儿,年龄7~13个月,均以运动发育迟缓、智力落后就诊,均有前额突出、眼距宽或者下颌尖长等特殊面容,身长和头围方面仅病例1的头围超过2 SD,其中2例患儿的骨龄超前、1例患儿脑电图异常,3例患儿头部CT均显示脑室扩大。全基因组芯片分析发现1例患儿染色体5q35.2区域缺失一个1.75 Mb大小的拷贝,其中包括NSD1基因;荧光定量PCR方法对拷贝数异常区域进行验证：NSD1基因拷贝数减半。高通量测序分析发现另2例患儿的NSD1基因分别存在c.1157T > G杂合突变和c.1177G > T杂合突变,其中c.1157T > G杂合突变未见报道,但生物信息学分析提示该位点突变具有致病性。因此,3例患儿均确诊为Sotos综合征。Sotos综合征是常染色体显性遗传的先天性生长过度症,70%~90%的患者存在NSD1基因突变,约10%存在染色体5q35区域（包括NSD1基因）缺失。     

The natural history of Noonan syndrome: a long-term follow-up study.

OBJECTIVE: To define better the adult phenotype and natural history of Noonan syndrome. DESIGN: A prospective observational study of a large cohort. RESULTS: Data are presented for 112 individuals with Noonan syndrome (mean age 25.3 (range 12-71) years), who were followed up for a mean of 12.02 years. Mutations in PTPN11 were identified in 35% of probands. Ten subjects died during the study interval; three of these deaths were secondary to heart failure associated with hypertrophic cardiomyopathy. Pulmonary stenosis affected 73 (65%) subjects; 42 (58%) required no intervention, nine underwent balloon pulmonary valvuloplasty (three requiring further intervention) and 22 surgical valvuloplasty (three requiring further intervention). Hypertrophic cardiomyopathy affected 21 (19%) patients, which had remitted in two cases, but one subject required cardiac transplant. No subjects died suddenly or had symptoms suggestive of arrhythmia. The mean final adult height was 167.4 cm in males and 152.7 cm in females. Feeding problems in infancy were identified as a predictor of future outcome. The mean age of speaking in two-word phrases was 26 months for those with no feeding difficulties, compared with 39 months for those with severe problems requiring nasogastric feeding. Attendance at a school for children with special needs for the same groups was 12.5% and 58%, respectively. A statement of special educational need had been issued in 44% overall; however, academic achievement was broadly similar to that of the general population. Implications: Although the morbidity for some patients with Noonan syndrome is low, early predictors of poorer outcome have been identified, which will help ascertain those most in need of intervention.     

Medication‐induced diabetes during induction treatment for ALL,an early marker for future metabolic risk?

Medication‐induced diabetes (MID) is seen in children treated for acute lymphoblastic leukemia (ALL) mostly during induction, due to the use of l ‐asparaginase and glucocorticoids. Our objective was to assess whether MID during induction, is a risk factor for future impaired glucose tolerance (IGT), diabetes, or metabolic syndrome. Ninety survivors of pediatric ALL, ages 10 yr and older were recruited, 30 with history of MID and 60 controls. Waist/height ratio >0.5 was considered as an increased risk for central adiposity and insulin resistance. Lipid profile and an oral glucose tolerance test (OGTT) were performed. Study patients were older than controls (17.2 vs. 14.9, p < 0.05). The groups had similar sex distribution, body mass index (BMI) z‐score, and Tanner staging. A waist/height ratio of >0.5 was seen in 60 and 31.7% of the study and control groups, respectively (p = 0.01). Increased frequency of IGT in the study group compared with the control group was seen (13.3 and 1%, respectively) (p = 0.07). We observed a trend toward higher proportion of patients with multiple features of metabolic syndrome in the study compared with control group (16.7 vs. 5%, p = 0.09). In conclusion, MID during induction may be an early marker for metabolic disturbances later in life. The higher rates of increased waist/height ratio, and subjects with multiple metabolic syndrome features, may predict a metabolic risk in children with history of MID. Rates of IGT were four fold higher in the study group although not statistically significant. MID may be a ‘red flag’ indicating the need for ongoing metabolic screening and lifestyle modifications to prevent future metabolic disease.     

肠道病毒71型和柯萨奇病毒A组16型感染的手足口病患儿的相关特征对比研究

目的：比较由肠道病毒71型（EV71）和柯萨奇病毒A组16型（CA16）感染的手足口病（HFMD）患儿流行病学情况及临床特征的差异。方法：采集108名临床诊断HFMD患儿疱疹液和咽拭子标本,使用RT-PCR进行肠道病毒检测,对EV71和CA16感染患儿的临床资料进行回顾性分析并比较。结果：108名患儿的肠道病毒总阳性率为97.2%（105/108）,其中EV71、CA16、其他肠道病毒及EV71和CA16混合感染分别占51.9%（56/108）,36.1%（39/108）,1.9%（2/108）,7.4%（8/108）。EV71感染患儿和CA16感染患儿两组间年龄、性别差异无统计学意义。单因素分析显示,CA16感染患儿口腔疱疹、膝部皮疹、流涕的发生比率高于EV71感染患儿。进一步多因素分析显示,出现膝部皮疹的患儿CA16感染可能性大。结论：发现口腔无疱疹、膝部无皮疹、无流涕等症状的HFMD患儿时,应考虑EV71感染的可能。     

Prevalence and clinical picture of celiac disease in italian down syndrome patients: a multicenter study

BACKGROUND: A multicenter research study of Down syndrome patients was carried out to estimate the prevalence of celiac disease in patients with Down syndrome and to show clinical characteristics and laboratory data of Down syndrome patients. METHODS: The authors studied 1,202 Down syndrome patients. Fifty-five celiac disease patients (group 1) were compared with 55 immunoglobulin A antigliadin-positive antiendomysium antibodies-negative patients (group 2) and with 57 immunoglobulin A antigliadin-negative antiendomysium antibodies-negative patients (group 3). RESULTS: Celiac disease was diagnosed in 55 of 1,202 Down syndrome patients (4.6%). In group 1, weight and height percentiles were shifted to the left, whereas these parameters were normally distributed in groups 2 and 3. In celiac patients, diarrhea, vomiting, failure to thrive, anorexia, constipation, and abdominal distension were higher than in the other two groups. Low levels of hemoglobinemia, serum iron, and calcium were observed more frequently in group 1. The diagnosis of celiac disease was made after a mean period of 3.8 years from the initiation of symptoms. Sixty-nine percent of patients showed a classic presentation, 11% had atypical symptoms, and 20% had silent celiac disease. Autoimmune disorders were more frequent (30.9%) in group 1 than in the other two groups examined (15%; P < 0.05). CONCLUSIONS: This study reconfirms a high prevalence of celiac disease in Down syndrome. However, the diagnostic delay, the detection of atypical symptoms or silent form in one third of the cases, and the increased incidence of autoimmune disorders suggest the need for the screening of celiac disease in all Down syndrome patients.     

Improved final height with long-term growth hormone treatment in Noonan syndrome

Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height. Methods: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria. GH treatment started at an age ranging from 3.1 to 13.8 y and was continued for at least 2 y. Improvement or “gain” in final height (FH) was defined as either the difference between adult height SD scores (SDS) and pre-treatment height SDS (the childhood component of the Swedish reference) or height SDS compared to the Noonan reference. Results: Ten children received a GH dose of 33 μg/kg/d (mean age at start 7.7±2.1 y, mean age at stop 17.6±1.7 y) and 15 received a dose of 66 μg/kg/d (mean age at start 8.6±3.3 y, mean age at stop 18.4±2.1 y). Eighteen out of 25 patients reached FH. A substantial improvement in FH of 1.7 SDS, equivalent to 10.4 cm compared to pre-treatment height, was observed. No significant difference was seen between the two GH doses. Females gained a mean height of 9.8 cm and males 1-13 cm (FH 174.5±7.8 cm vs mean adult height of 162.5±5.4 cm for males with NS) at final height. Moreover, 60% reached a mid-parental height of±1 SD.

Conclusion: GH treatment improves final height in patients with Noonan syndrome, with a mean gain of 1.7 SDS. The prepubertal height gain is maintained to final height and the children achieve a height close to their mid-parental height.     

小儿局灶节段性肾小球硬化38例临床表现与病理特点

目的　了解小儿局灶节段性肾小球硬化 (FSGS)的临床与病理特点。方法　 38例临床诊断为原发性肾病综合征 (NS)或蛋白尿 ,病理确诊为原发性FSGS的患儿 ,进行回顾性分析、总结。结果　FSGS年龄 ( 8.9± 3.7)岁 ,男∶女比为 1 92 ,临床诊断为孤立蛋白尿 3例 ,蛋白尿伴血尿 1例 ,NS34例 (单纯型 16例 ,肾炎型 18例 )。临床伴血尿 2 4例 ( 6 3% ) ,高血压 11例 ( 2 9% ) ,肌酐清除率降低7例 ( 18% )。病理分型为门型 17例 ,周围型 14例 ,Tip型 7例。 38例FSGS中 ,2 1例伴有系膜细胞增生。临床疗效 :34例NS中 ,激素初治敏感 12例 ,观察期末对激素治疗敏感者 6例。 4例非NS中 ,3例激素治疗无效 ,1例不详。应用CTX共 18例次 ,4 4 %缓解或部分缓解 ;应用甲泼尼龙加环磷酰胺冲击或口服环孢霉素A治疗 12例 ,83%缓解或部分缓解。结论　小儿FSGS学龄儿童多见 ,临床多表现为NS ,血尿常见 ,高血压及肾功能不全相对少见 ,病理可表现为多种病变 ,甲泼尼龙加环磷酰胺冲击或口服环孢霉素A治疗方案相对好     

Final height in children with steroid-sensitive nephrotic syndrome

BACKGROUND: Growth retardation following steroid treatment in children is a major problem. Reduction of steroid dose has been tried using immunosuppressive agents such as cyclosporine A or mizoribine in children with frequently relapsing nephrotic syndrome. Few reports concerning final height in steroid-sensitive nephrotic syndrome (SSNS) are available. METHOD: Patients who developed SSNS before 15 years of age and reached their final height were retrospectively studied by standard deviation score (SDS) of height and target height calculated by their parental height. RESULTS: A total of 34 patients were evaluated for their final height. The mean age at onset of SSNS was 8.0 years and the mean age at last follow up was 21.6 years. In total, 22 patients had frequent relapses and were treated with cyclophosphamide, mizoribine or cyclosporin A. All patients had normal renal function at the last evaluation. The mean final height was 168 cm in males and 155 cm in females. The mean height SDS was 0.37 at the time of onset and was -0.43 when they reached their final height (P = 0.0001). The final height was a mean of 2.5 cm below target height and was significantly lower than their siblings (P = 0.007). Final height of two boys who continued to have frequent relapses during puberty and were not treated with cyclosporin A was 146 and 150 cm. CONCLUSION: Final height in children with SSNS was slightly affected by steroid treatment and two patients had severe growth retardation.     

Comorbidities associated with constipation in children referred for colon manometry may mask functional diagnoses

BACKGROUND: In children with prolonged constipation of unclear pathogenesis or unresponsive to treatment, colon manometry can discriminate between functional fecal retention (FFR) and colon neuromuscular diseases. AIM: To identify the clinical features precipitating referral for colon manometry in children with functional constipation. METHOD: Retrospective medical record review of 173 constipated children (116 male, mean age 6.9 years, range 1-17 years) referred for colon manometry. RESULTS: Manometry was normal in 121 (70%). In those with normal manometry, FFR was identified in 96, irritable bowel syndrome (IBS) in 10, and functional constipation in 15. Of the 96 children FFR, 72 (76%) had comorbid conditions that might have interfered with the clinician's ability to diagnose FFR. Of 52 children with colon neuromuscular disease, only 12 (23%) had comorbid conditions (P < 0.001 compared with FFR). Of children more than 4 years, those with FFR were more likely to have fecal incontinence (44 of 62; 71%) than those with other functional disorders (2 of 19; 10%; P < 0.001) or neuromuscular disease (6 of 23; 26%; P < 0.001). CONCLUSIONS: Two thirds of children referred for colon manometry had normal studies and met criteria for a functional diagnosis. Three quarters of those with functional constipation had a comorbid condition that might alter the history sufficiently to obscure the diagnosis.