Computer-aided facial analysis as a tool to identify patients with Silver-Russell syndrome and Prader-Willi syndrome.

Genetic syndromes often show facial features that provide clues for the diagnosis. However, memorizing these features is a challenging task for clinicians. In the last years, the app Face2Gene proved to be a helpful support for the diagnosis of genetic diseases by analyzing features detected in one or more facial images of affected individuals. Our aim was to evaluate the performance of the app in patients with Silver-Russell syndrome (SRS) and Prader-Willi syndrome (PWS). We enrolled 23 pediatric patients with clinically or genetically diagnosed SRS and 29 pediatric patients with genetically confirmed PWS. One frontal photo of each patient was acquired. Top 1, top 5, and top 10 sensitivities were analyzed. Correlation with the specific genetic diagnosis was investigated. When available, photos of the same patient at different ages were compared. In the SRS group, Face2Gene showed top 1, top 5, and top 10 sensitivities of 39%, 65%, and 91%, respectively. In 41% of patients with genetically confirmed SRS, SRS was the first syndrome suggested, while in clinically diagnosed patients, SRS was suggested as top 1 in 33% of cases (p = 0.74). Face2Gene performed better in younger patients with SRS: in all patients in whom a photo taken at a younger age than the age of enrollment was available, SRS was suggested as top 1, albeit with variable degree of probability. In the PWS group, the top 1, top 5, and top 10 sensitivities were 76%, 97%, and 100%, respectively. PWS was suggested as top 1 in 83% of patients genetically diagnosed with paternal deletion of chromosome 15q11-13 and in 60% of patients presenting with maternal uniparental disomy of chromosome 15 (p = 0.17). The performance was uniform throughout the investigated age range (1-15 years). CONCLUSION: In addition to a thorough medical history and detailed clinical examination, the Face2Gene app can be a useful tool to support clinicians in identifying children with a potential diagnosis of SRS or PWS. WHAT IS KNOWN: • Several genetic syndromes present typical facial features that may provide clues for the diagnosis. • Memorizing all syndromic facial characteristics is a challenging task for clinicians. WHAT IS NEW: • Face2Gene may represent a useful support for pediatricians for the diagnosis of genetic syndromes. • Face2Gene app can be a useful tool to integrate in the diagnostic path of patients with SRS and PWS.

Glomerular filtration rate, blood pressure and microalbuminuria in adults born SGA: A 5-year longitudinal study after cessation of GH treatment.

BACKGROUND: Growth hormone treatment increases glomerular filtration rate (GFR), as serum IGF-I stimulates the renin-angiotensin system. Infants born with a low birth weight have a smaller number of nephrons, which cause a lower GFR, a higher blood pressure and a higher albumin-to-creatinine ratio in early adulthood. METHOD: A total of 261 young adults born SGA, previously treated with growth hormone (SGA-GH), were longitudinally followed. Glomerular filtration rate, based on serum creatinine levels, was determined at cessation of GH treatment and at 6 months, 2 years and 5 years thereafter. Glomerular filtration rate, blood pressure and urinary albumin-to-creatinine ratio at 5 years after cessation of GH were compared with untreated age-matched controls (56 untreated short subjects born SGA [SGA-S], 118 subjects born SGA with spontaneous catch-up growth [SGA-CU], 135 subjects born appropriate for gestational age [AGA]). RESULTS: Glomerular filtration rate decreased significantly only during the first 6 months after cessation of GH treatment, while remaining well within the normal range (124.6 vs 120.2 mL/min/1.73 m2 , P < .001). SGA-GH adults had a similar GFR, blood pressure and urinary albumin-to-creatinine ratio as the healthy controls born SGA and AGA. CONCLUSION: In conclusion, our 5 years longitudinal follow-up study shows a decrease in GFR during 6 months after GH cessation, but thereafter GFR remained stable and within the normal range. Glomerular filtration rate, blood pressure and urinary albumin-to-creatinine ratio at 21 years of age were similar in GH-treated young adults born SGA and untreated controls born SGA or AGA. We conclude that long-term GH treatment in children born SGA has no unfavourable effects on kidney function in early adulthood. PRÉCIS: We present a longitudinal study on kidney function in the follow-up of growth hormone-treated young adults who were born small for gestational age.

Cerebral white matter hyperintensities in adults born small for gestational age at 12 years after cessation of childhood growth hormone treatment: a prospective cohort study including untreated controls.

Background: Increased cerebrovascular morbidity was reported in adults born small for gestational age (SGA) who were treated with growth hormone (GH) during childhood compared to the general population. Yet, previous studies lacked an appropriate control group which is a major limitation. We prospectively studied cerebral white matter hyperintensities (WMHs) in adults born SGA at 12 years after cessation of childhood GH-treatment (SGA-GH), compared to appropriate controls. Methods: In this prospective cohort study, performed between May 2016 and December 2020, total WMHs, periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) were the primary outcomes of the study, they were qualitatively assessed using 3 Tesla (T) Magnetic Resonance Imaging (MRI) and scored using the Fazekas scale in SGA-GH adults and in 3 untreated control groups: adults born SGA with persistent short stature (SGA-S), adults born SGA with spontaneous catch-up growth to a normal height (SGA-CU) and adults born appropriate for gestational age with a normal height (AGA). Regression analyses were performed in the total cohort to evaluate the associations of GH-treatment and birth characteristics with WMHs. Findings: 297 adults were investigated (91 SGA-GH, 206 controls). Prevalence of total WMHs was 53.8% (95% CI 43.1-64.3) in SGA-GH, 40.5% (95% CI 25.6-56.7) in SGA-S, 73.9% (95% CI 61.9-83.7) in SGA-CU and 41.1% (95% CI 31.1-51.6) in AGA adults. No statistically significant differences in total WMHs, PVWMHs and DWMHs were found between SGA-GH compared to SGA-S and AGA adults. Highest prevalence of all type of WMHs was found in SGA-CU adults compared to all groups. Higher prevalence of total WMHs was associated with lower birth weight standard deviation score (SDS), but not with GH-treatment. Interpretation: Our findings suggest that GH-treatment in children born SGA has no negative impact on the prevalence of all type of WMHs at 12 years after GH cessation compared to appropriate controls. SGA-CU adults had the highest prevalence of all type of WMHs around age 30 years. Funding: Novo Nordisk.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Childhood growth hormone treatment and metabolic and cardiovascular risk in adults born small for gestational age after growth hormone cessation in the Netherlands: a 12-year follow-up study.

BACKGROUND: Childhood growth hormone treatment has been associated with increased cardiovascular mortality and morbidity in adults born small for gestational age (SGA) compared with the general population, but these risks have not been compared with untreated control groups. We aimed to investigate longitundinal metabolic and cardiovascular health in adults born SGA after cessation of growth hormone treatment. METHODS: We longitudinally investigated the metabolic and cardiovascular health profile of 167 adults born SGA and previously treated with growth hormone during the 12 years after growth hormone cessation. Metabolic and cardiovascular parameters were assessed with the frequently sampled intravenous glucose tolerance test, serum lipids and blood pressure were measured, body composition was determined by dual-energy x-ray absorptiometry, and visceral fat was measured by MRI. At approximately age 30 years, we compared the metabolic and cardiovascular health profile of adults born SGA and previously treated with growth hormone (SGA-GH) with 219 untreated adults: 127 born SGA with either persistent short stature (SGA-S) or spontaneous catch-up to typical adult stature (SGA-CU), and 92 born appropriate for gestational age. FINDINGS: During 12 years of follow-up, SGA-GH adults maintained normal ß-cell function (p=0·157 for the difference from growth hormone cessation to 12-year follow-up) and showed an increase in insulin sensitivity (p=0·002), fat mass (p<0·001), total cholesterol (p<0·001), and blood pressure (p<0·001). By around age 30 years, these parameters reached similar levels to those in SGA-S adults (insulin sensitivity p=0·242; fat mass p=0·449; total cholesterol p=0·616; systolic blood pressure p=0·523; diastolic blood pressure p=0·538). By around age 30 years, SGA-GH adults also had similar metabolic and cardiovascular health parameters to adults born appropriate for gestational age, with the exception of lower lean body mass (estimated marginal mean 44·67 kg [95% CI 43·54-45·80] in SGA-GH adults vs 47·65 kg [46·39-48·92] in adults born appropriate for gestational age) and higher concentrations of adverse serum lipids, such as cholesterol (4·75 mmol/L [4·55-4·95] vs 4·33 mmol/L [4·13-4·5]), which were present in all groups born SGA. Abdominal adiposity (visceral adipose tissue p=0·107; subcutaneous adipose tissue: p=0·244), liver fat fraction (p=0·104), and blood pressure (systolic blood pressure 0·927; diastolic blood pressure: 0·737) were similar between SGA-GH adults and all control groups. INTERPRETATION: At approximately age 30 years, SGA-GH adults had a similar metabolic and cardiovascular health profile to untreated adults born SGA or appropriate for gestational age, indicating long-term metabolic and cardiovascular safety of growth hormone treatment for children born SGA with short stature. FUNDING: Novo Nordisk.

Longitudinal Study on Metabolic Health in Adults SGA During 5 Years After GH With or Without 2 Years of GnRHa Treatment.

BACKGROUND: In children born small for gestational age (SGA) with persistent short stature, 2 years of gonadotropin-releasing hormone analogue (GnRHa), in addition to long-term growth hormone (GH) treatment, can improve adult height. We assessed safety on metabolic and bone health of GnRHa/GH treatment during 5 years after cessation of GH. METHODS: A total of 363 young adults born SGA, previously treated with combined GnRHa/GH or GH-only, were followed for 5 years after attainment of adult height at GH cessation and 2 and 5 years thereafter. Data at 5 years after GH cessation, at age 21 years, were also compared with 145 age-matched adults born appropriate for gestational age (AGA). Frequently sampled intravenous glucose tolerance (FSIGT) tests were used to assess insulin sensitivity, acute insulin response, and ß-cell function. Body composition and bone mineral density (BMD) was determined by dual-energy x-ray absorptiometry (DXA) scans. FINDINGS: In the GnRHa/GH and GH-only groups, fat mass increased during the 5 years after GH cessation, but the changes in FSIGT results, body composition, blood pressure, serum lipid levels, and BMD were similar in both groups. At age 21 years, the GnRHa/GH group had similar fat mass, FSIGT results, blood pressure, serum lipid levels and BMD-total body as the GH-only group and the AGA control group, a higher BMD-lumbar spine and lower lean body mass than the AGA control group. INTERPRETATION: This study during 5 years after GH cessation shows that addition of 2 years of GnRHa treatment to long-term GH treatment of children short in stature born SGA has no unfavorable effects on metabolic and bone health in early adulthood. CLINICAL TRIAL REGISTRATION: ISRCTN96883876, ISRCTN65230311 and ISRCTN18062389.

Longitudinal body composition assessment in healthy term-born infants until 2 years of age using ADP and DXA with vacuum cushion.

OBJECTIVES: Accelerated gain in fat mass (FM) in early life increases the risk for adult diseases. Longitudinal data on infant body composition are crucial for clinical and research use, but very difficult to obtain due to limited measurement tools and unsuccessful measurements between age 6-24 months. We compared FM% by dual-energy X-ray absorptiometry (DXA), with cushion to reduce movement artifacts, with FM% by air-displacement plethysmography (ADP) and evaluated the reliability of this cushion during DXA by comparing FM% with and without cushion. Subsequently, we constructed sex-specific longitudinal body composition charts from 1-24 months. METHODS: In 692 healthy, term-born infants (Sophia Pluto Cohort), FM% was measured by ADP from 1-6 months and DXA with cushion from 6-24 months. At 6 months, FM% was measured in triplicate by ADP and DXA with and without cushion(n = 278), later on in smaller numbers. RESULTS: At 6 months, mean FM% by DXA with cushion was 24.1 and by ADP 25.0, mean difference of 0.9% (Bland-Altman p = 0.321, no proportional bias). Mean FM% by DXA without cushion was 12.5% higher compared to ADP (Bland-Altman p < 0.001). DXA without cushion showed higher mean FM% compared to DXA with cushion (+11.6%, p < 0.001) at 6 months. Longitudinally, FM% increased between 1-6 months and decreased from 6-24 months(both p < 0.001). CONCLUSIONS: In infants, DXA scan with cushion limits movement artifacts and shows reliable FM%, comparable to ADP. This allowed us to construct longitudinal body composition charts until 24 months. Our study shows that FM% increases from 1-6 months and gradually declines until 24 months.

Evidence for Accelerated Biological Aging in Young Adults with Prader-Willi Syndrome.

OBJECTIVE: Adults with Prader-Willi syndrome (PWS) are at increased risk of developing age-associated diseases early in life and, like in premature aging syndromes, aging might be accelerated. We investigated leukocyte telomere length (LTL), a marker of biological age, in young adults with PWS and compared LTL to healthy young adults of similar age. As all young adults with PWS were treated with growth hormone (GH), we also compared LTL in PWS subjects to GH-treated young adults born short for gestational age (SGA). DESIGN: Cross-sectional study in age-matched young adults; 47 with PWS, 135 healthy, and 75 born SGA. MEASUREMENTS: LTL measured by quantitative polymerase chain reaction, expressed as telomere/single copy gene ratio. RESULTS: Median (interquartile range) LTL was 2.6 (2.4-2.8) at a median (interquartile range) age of 19.2 (17.7-21.3) years in PWS, 3.1 (2.9-3.5) in healthy young adults and 3.1 (2.8-3.4) in the SGA group. Median LTL in PWS was significantly lower compared to both control groups (P < .01). In PWS, a lower LTL tended to be associated with a lower total IQ (r = 0.35, P = .08). There was no association between LTL and duration of GH treatment, cumulative GH dose, or several risk factors for type 2 diabetes mellitus or cardiovascular disease. CONCLUSIONS: Young adults with PWS have significantly shorter median LTL compared to age-matched healthy young adults and GH-treated young adults born SGA. The shorter telomeres might play a role in the premature aging in PWS, independent of GH. Longitudinal research is needed to determine the influence of LTL on aging in PWS.

Aromatase Inhibitor as Treatment for Severely Advanced Bone Age in Congenital Adrenal Hyperplasia: A Case Report.

INTRODUCTION: Treatment with aromatase inhibitors (AI) is a potential novel treatment in patients with congenital adrenal hyperplasia (CAH) and advanced bone age (BA), to increase near adult height (NAH). Not much is known about the efficacy of AI treatment in CAH and how AI treatment will influence the management of corticosteroid treatment. CASE PRESENTATION: At the age of 6 years and 3 months, a boy with salt-losing CAH presented with a BA 7 years in advance. Treatment with an AI (exemestane) was initiated to decelerate bone maturation. We continued the standard dosage of corticosteroid treatment. Precocious puberty was treated with 4 years of gonadotropin-releasing hormone agonist, while AI treatment was continued until attainment of NAH. His NAH 177.7 cm (-0.8 SDS) was considerably higher than his predicted adult height of 151.3 cm (-4.6 SDS) at the start of AI treatment. The higher serum androgen levels during AI treatment did not result in short adult stature. DISCUSSION/CONCLUSION: This report shows that AI treatment can adequately decelerate bone maturation, causing predicted adult height to increase significantly in patients of CAH with accelerated bone maturation. We suggest continuing the same corticosteroid dosage during AI treatment and accepting higher serum androgen levels.

Long-term follow-up after bilateral percutaneous epiphysiodesis around the knee to reduce excessive predicted final height.

CONTEXT: Percutaneous epiphysiodesis (PE) around the knee to reduce predicted excessive final height. Studies until now included small numbers of patients and short follow-up periods. OBJECTIVE AND DESIGN: This Dutch multicentre, long-term, retrospective, follow-up study aimed to assess adult height (AH), complications, knee function and patient satisfaction after PE. The primary hypothesis was that PE around the knee in constitutionally tall boys and girls is an effective treatment for reducing final height with low complication rates and a high level of patient satisfaction. PARTICIPANTS: 77 treated adolescents and 60 comparisons. INTERVENTION: Percutaneous epiphysiodesis. OUTCOME: AH, complications, knee function, satisfaction. RESULTS: In the PE-treated group, final height was 7.0 cm (±6.3 cm) lower than predicted in boys and 5.9 cm (±3.7 cm) lower than predicted in girls. Short-term complications in file search were seen in 5.1% (three infections, one temporary nerve injury), one requiring reoperation. Long-term complications in file search were seen in 2.6% (axis deformity 1.3%, prominent head of fibula 1.3%). No significant difference in knee function was found between treated cases and comparisons. Satisfaction was high in both the comparison and PE groups; most patients in the PE group recommended PE as the treatment for close relatives with tall stature. CONCLUSION: PE is safe and effective in children with predicted excessive AH. There was no difference in patient satisfaction between the PE and comparison group. Careful and detailed counselling is needed before embarking on treatment.