Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data.

INTRODUCTION: Heterozygous variants in the ACAN gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). METHODS: The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous ACAN variant. Thirty-six subjects (23 boys, 13 girls) with ACAN deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. RESULTS: We identified 25 different heterozygous ACAN variants in 36 subjects. Median (interquartile range) height SDS at start of GH was -2.6 SDS (-3.2 to -2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating ACAN variant had a shorter height SDS compared to subjects with a non-truncating variant (-2.8 SDS and -2.1 SDS, respectively, p = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9-1.4). In pubertal children, height SDS remained relatively stable. CONCLUSION: The phenotype of subjects with pathogenic heterozygous ACAN variants is highly variable, and genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with ACAN deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment.

Osteoporosis in children and adolescents: how to treat and monitor?

Osteoporosis is a condition of increased bone fragility associated with fractures. Apart from primary genetic osteoporotic conditions, secondary osteoporosis in children is being increasingly recognized. As a result, there is growing interest in its prevention and treatment. Important goals of care are to prevent fractures, increase bone mass and trabecular and cortical thickness, reshape vertebral fractures, prevent (or correct) skeletal deformities, and improve mobility, independence, and quality of life. Secondary pediatric osteoporosis is often of multifactorial origin since affected children frequently have more than one acquired factor that is detrimental to bone health. Typical conditions causing osteoporosis are leukemias, progressive muscle or neurological disorders, as well as chronic inflammatory conditions and their treatment. Management of children with osteoporosis involves a multidisciplinary team involving pediatric experts from different subspecialties. With regard to prevention and early intervention, it is important to provide optimal management of any underlying systemic conditions including avoidance, or dose-reduction, of osteotoxic medications. Basic supporting life-style measures, such as appropriate nutrition, including adequate calcium intake and vitamin D, and physical activity are recommended, where possible. When pediatric treatment criteria for osteoporosis are met, antiresorptive drugs constitute the first pharmacological line treatment. CONCLUSION: This clinical review focuses on the prevention, treatment, and follow-up of children with, or at risk of developing, osteoporosis and the transition from pediatric to adult care. WHAT IS KNOWN: • Osteoporosis and associated fractures can cause significant morbidity and reduce the quality of life. • The developing skeleton has huge potential for recovery and reshaping, thus early detection of fractures, assessment of recovery potential, and treatment of children with osteoporosis can prevent future fractures, deformities, and scoliosis, improve function and mobility, and reduce pain. WHAT IS NEW: • Osteoporosis in children and adolescents requires a multidisciplinary approach with a thorough assessment of recovery potential, and indication for therapy should be personalized. • Although bisphosphonates still represent the drug most commonly used to increase bone mass, improve mobility, and reduce pain and recurrence of fractures, new agents are being developed and could be beneficial in children with specific conditions.

[An infant with a complicated infection of the umbilicus]. / Een zuigeling met een gecompliceerde navelontsteking.

BACKGROUND: An umbilical infection (omphalitis) is frequent in de neonatal period. The infection usually presents as a relatively mild cellulitis. However, in rare cases omphalitis has a complicated course. CASE DESCRIPTION: A 20-day-old infant was referred to our Emergency Department with a fever and red umbilicus. Our diagnosis was "omphalitis" and after taking cultures we started with flucloxacillin and gentamicin intravenously. Upon clinical deterioration, we added ceftazidime and performed an ultrasound of the abdomen. A urachal remnant was found. The umbilical swab was positive for Staphylococcus aureus, which we treated with flucloxacillin monotherapy until the infiltrate disappeared on ultrasound. CONCLUSION: A patient with an omphalitis should be referred to the pediatrician. Clinical admission, obtaining cultures and starting antibiotic treatment is necessary. A large number of health care providers are involved in the care during the neonatal period. Therefore, broad knowledge about prevention and early identification of this disease is important.

Osteoporosis in children and adolescents: when to suspect and how to diagnose it.

Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis. CONCLUSIONS: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children. WHAT IS KNOWN: • Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life. • The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary. WHAT IS NEW: • Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis. • We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis.

Current Insights into the Role of the Growth Hormone-Insulin-Like Growth Factor System in Short Children Born Small for Gestational Age.

BACKGROUND: The reason for the insufficient catch-up growth seen in 10% of children born small for gestational age (SGA) is poorly understood. Disturbances in the growth hormone (GH) - insulin-like growth factor (IGF) axis might underlie this failure to show sufficient catch-up growth. CONCLUSION: This review summarizes insights gained in the molecular and (epi) genetic mechanisms of the GH-IGF axis in short children born SGA. The most notable anomalies of the IGF system are the lowered IGF-I levels in both cord blood and the placenta, and the increased expression of IGF-binding proteins (IGFBP)-1 and IGFBP-2, which inhibit IGF-I, in the placenta of SGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero. IGF-I levels remain reduced in SGA children with short stature, as well as IGFBP-3 and acid-labile subunit levels. Proteolysis of IGFBP-3 appears to be increased.

Possible hints and pitfalls in diagnosing Peutz-Jeghers syndrome.

Background Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal polyposis, mucocutaneous pigmentation and cancer predisposition. Patients with PJS can develop large calcifying Sertoli cell tumors (LCSTs). Case presentation A patient presented at 3 years of age with delayed development, hypermobility and later also with tall stature and advanced bone age. Extensive endocrine evaluation, mutation analysis of genes associated with connective tissue disorders and a single nucleotide polymorphism (SNP) array showed no abnormalities. At 8 years of age, gynecomastia developed as well as pigmentations on the lips, both of which are associated with PJS. Mutation analysis showed a heterozygous deletion of the whole STK11 gene confirming PJS. Testicular ultrasound confirmed the presence of LCSTs. Interestingly, the previously performed SNP array did not report deletion of the STK11 gene. Conclusions We advise excluding LCSTs in children with tall stature and advanced bone age where more common causes have been eliminated. Although STK11 deletions are documented in control databases, reporting the deletion of this gene even in the absence of a phenotype is advised for patient management.

Bone Mineral Density After Cessation of GH Treatment in Young Adults Born SGA: A 5-Year Longitudinal Study.

Context: Short children born small for gestational age (SGA) have below-average bone mineral density (BMD). Growth hormone (GH) treatment improves height and BMD in short SGA children. Longitudinal data on BMD in adults born SGA, after GH cessation (GH-stop), are lacking. Objective: To determine BMD in young adults born SGA during 5 years after GH-stop. Methods: In 173 GH-treated adults born SGA (SGA-GH), BMD of total body (BMDTB) and bone mineral apparent density of lumbar spine (BMADLS) were measured longitudinally at adult height (AH) and 6 months, 2 years, and 5 years thereafter. At 5 years after GH-stop (age 21 years), data were compared with 45 untreated short SGA adults (SGA-S), 59 SGA adults with spontaneous catch-up (SGA-CU), and 81 adults born appropriate for gestational age (AGA). Results: At GH-stop (mean age 16.4 years), estimated mean (standard error) BMDTB standard deviation score (SDS) was -0.40 (0.1) in males and -0.51 (0.1) in females, followed by a trend toward a decrease of BMDTB in males to -0.59 (0.1) at 5 years after GH-stop (P = 0.06), whereas it remained stable in females [-0.57 (0.1); P = 0.33]. At GH-stop, BMADLS SDS was -0.01 (0.1) in males and -0.29 (0.1) in females, followed by a decrease in males and females to -0.38 and -0.55, respectively, at 5 years after GH-stop (P < 0.001). At 5 years after GH-stop, BMDTB and BMADLS in SGA-GH were similar compared with SGA-S, SGA-CU, and AGA. Conclusion: After GH-stop, there is a gradual decline of BMADLS, but at the age of 21 years, BMDTB and BMADLS are similar as in untreated short SGA adults.

Metabolic Health and Long-Term Safety of Growth Hormone Treatment in Silver-Russell Syndrome.

Context: Children with Silver-Russell syndrome (SRS) are born small for gestational age (SGA) and remain short. Growth hormone (GH) treatment improves height in short SGA children, including those with SRS. Data on metabolic health and long-term safety of GH treatment in SRS are lacking. Objective: To investigate metabolic health in SRS patients during and until 2 years after discontinuation of GH treatment. Design: Metabolic health was assessed longitudinally at GH-start, GH-stop, 6 months, and 2 years thereafter. Patients: Twenty-nine SRS patients vs 171 non-SRS subjects born SGA. Main Outcome Measures: Lean body mass (LBM), fat mass percentage (FM%), insulin sensitivity (Si), ß-cell function, blood pressure, and serum lipids. Results: At GH-start [mean age (standard deviation) 5.4 (2.1) years in SRS and 6.7 (2.0) years in non-SRS (P = 0.003)], blood pressure, serum lipids, glucose, and insulin levels were similar and within normal ranges in SRS and non-SRS. LBM standard deviation score (SDS) and FM% SDS were lower than average in both groups. During treatment, LBM SDS remained stable whereas FM% SDS increased in both groups. During the 2 years after GH-stop, LBM decreased and FM% increased, whereas Si and ß-cell function improved. At 2 years after GH-stop (mean age 18 years), all parameters were similar and within normal ranges in SRS and non-SRS. None of the SRS patients developed metabolic syndrome, diabetes mellitus type 2, or adverse events. Conclusion: GH-treated SRS patients have a similar metabolic health and safety profile as non-SRS subjects born SGA, both during and until 2 years after GH-stop.

Bloom syndrome in short children born small for gestational age: a challenging diagnosis.

BACKGROUND: GH treatment has become a frequently applied growth-promoting therapy in short children born small for gestational age (SGA). In some disorders GH treatment is contraindicated, eg, chromosomal breakage syndromes. Bloom syndrome is a rare chromosomal breakage syndrome characterized by severe pre- and postnatal growth deficiency, a photosensitive facial erythema, immunodeficiency, mental retardation or learning disabilities, endocrinopathies, and a predisposition to develop a wide variety of cancers. OBJECTIVE: We report 2 patients with Bloom syndrome illustrating the variety in clinical manifestations. They were initially diagnosed with short stature after SGA birth and Silver Russell syndrome and treated with GH. CASES: Both patients presented with pre- and postnatal growth failure but no clear other characteristic features associated with Bloom syndrome. Photosensitive skin lesions developed only at a pubertal age and were minimal. Also, both children showed normal immunoglobulin levels, normal development, and no signs of endocrinopathies at start of GH. Dysmorphic features resembling Silver Russell syndrome were observed in both patients. Remarkably, during GH treatment IGF-1 levels increased to values greater than 3.5 SD score, with normal IGF binding protein-3 levels. CONCLUSION: Short children born SGA comprise a heterogeneous group. Bloom syndrome should be tested for in children with consanguineous parents, dysmorphic features (particularly resembling Silver Russell syndrome), skin abnormalities, and/or IGF-1 levels greater than 2.5 SD score during standard GH treatment with normal IGF binding protein-3 levels.

Methylphenidate and the response to growth hormone treatment in short children born small for gestational age.

BACKGROUND: Growth hormone (GH) treatment has become a frequently applied growth promoting therapy in short children born small for gestational age (SGA). Children born SGA have a higher risk of developing attention deficit hyperactivity disorder (ADHD). Treatment of ADHD with methylphenidate (MP) has greatly increased in recent years, therefore more children are being treated with GH and MP simultaneously. Some studies have found an association between MP treatment and growth deceleration, but data are contradictory. OBJECTIVE: To explore the effects of MP treatment on growth in GH-treated short SGA children METHODS: Anthropometric measurements were performed in 78 GH-treated short SGA children (mean age 10.6 yr), 39 of whom were also treated with MP (SGA-GH/MP). The SGA-GH/MP group was compared to 39 SGA-GH treated subjects. They were matched for sex, age and height at start of GH, height SDS at start of MP treatment and target height SDS. Serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels were yearly determined. Growth, serum IGF-I and IGFBP-3 levels during the first three years of treatment were analyzed using repeated measures regression analysis. RESULTS: The SGA-GH/MP group had a lower height gain during the first 3 years than the SGA-GH subjects, only significant between 6 and 12 months of MP treatment. After 3 years of MP treatment, the height gain was 0.2 SDS (± 0.1 SD) lower in the SGA-GH/MP group (P = 0.17). Adult height was not significantly different between the SGA-GH/MP and SGA-GH group (-1.9 SDS and -1.9 SDS respectively, P = 0.46). Moreover, during the first 3 years of MP treatment IGF-I and IGFBP-3 measurements were similar in both groups. CONCLUSION: MP has some negative effect on growth during the first years in short SGA children treated with GH, but adult height is not affected.