Inge Gies

Management of familial hypercholesterolemia in children and young adults: Consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization

UNLABELLED Since heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations. 1. Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent.2. The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) levelabove 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children. 3. A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist.4. The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL). CONCLUSION The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.

Can pubertal boys with Klinefelter syndrome benefit from spermatogonial stem cell banking

BACKGROUND Although early development of testes appears normal in boys with Klinefelter syndrome (KS), spermatogonial stem cell (SSC) depletion occurs in mid puberty, leading to infertility. Cryopreservation of SSCs prior to stem cell loss is an option that is currently offered to boys who have to undergo gonadotoxic treatments. This study aimed to explore the possibility of preserving SSCs in pubertal KS adolescents by testicular tissue banking. METHODS A retrospective study was conducted in seven non-mosaic 47,XXY adolescents, aged 13-16 years, who were invited for an experimental testicular tissue banking programme during their follow-up at the Paediatric Endocrinology Department of the UZ Brussel between 2009 and 2011. Paraffin-embedded testicular tissue was sectioned and stained with haematoxylin-eosin, and immunostainings were performed for Mage-A4, anti-Mullerian hormone, Inhibin α and steroidogenic acute regulatory protein. The presence of spermatogenesis and/or spermatogonia was evaluated. RESULTS Massive fibrosis and hyalinization was observed in all but one KS patients. Although spermatogonia were seen in five patients, spermatogonia were only present in tubules showing normal architecture in the youngest patient who also had normal follicle-stimulating hormone and inhibin B concentrations. CONCLUSIONS Testicular tissue cryopreservation in KS adolescents should be recommended as soon as possible, probably before hormonal changes of failing Sertoli cell function are detected.

Failure of a combined clinical- and hormonal-based strategy to detect early spermatogenesis and retrieve spermatogonial stem cells in 47,XXY boys by single testicular biopsy

BACKGROUND Although germ cells in boys with Klinefelter syndrome (KS) are reduced in number as early as infancy, a severe germ cell loss occurs during mid-puberty. Therefore, we wanted to detect spermatogenesis at an early stage and investigate the strategy of preserving spermatozoa and/or testicular spermatogonial stem cells in adolescents with KS when signs of deteriorating spermatogenesis are observed. METHODS Tanner staging, testicular size, serum inhibin B and spermaturia were assessed every 4 months before the attempt to procure gametogenic cells in seven non-mosaic 47,XXY adolescents, aged between 10 and 16 years. RESULTS Despite an increasing testis volume in the youngest and a Tanner staging of more than three in the oldest patients, no spermaturia was observed. In two patients serum inhibin B increased gradually, while in all others a rather rapid but variable decline was observed at different ages. No spermatozoa were observed after electroejaculation. No spermatocytes or spermatids were found at microscopic examination of single biopsies, while spermatogonia were identified in four subjects, three of whom had measurable serum inhibin B. Massive fibrosis and hyalinization were observed in all biopsies. CONCLUSION No spermatogenesis was documented in non-mosaic 47,XXY adolescents either by spermaturia, electroejaculation or testicular biopsy. Neither clinical nor hormonal parameters were of value in determining the timing for optimal spermatogonial stem cell retrieval. More data are needed to elucidate the potential role of testicular tissue cryopreservation in adolescents with KS. Therefore, at present, the cryopreservation of testes tissue for clinical reasons should not be recommended.

Trabecular Bone Mineral Density and Bone Geometry of the Distal Radius at Completion of Pubertal Growth in Childhood Type 1 Diabetes

Aim: To identify disease-related risk factors for an altered bone mineral density (BMD) and geometry at young adulthood in patients with diabetes mellitus type 1 (DM1). Methods: Fifty-six DM1 patients (23 females, 33 males) with prepubertal onset of diabetes were studied after completion of skeletal growth. Bone parameters at the distal radius were investigated by peripheral quantitative computed tomography. Disease-related parameters, in particular average HbA1c during the 2 years around peak height velocity, were analyzed. Forty-seven healthy controls (32 females, 15 males) were studied. Results: Trabecular BMD was similar between DM1 patients and controls. The mean (±SD) cross-sectional bone area (CSA) was smaller in DM1 patients compared to controls (282.5 ± 45.4 vs. 326.7 ± 52.2 mm2, p = 0.002 and males 391.0 ± 61.3 vs. 423.4 ± 81.9 mm2, p = 0.1). In female DM1 patients, the CSA z-score correlated negatively with the body mass index z-score (r = -0.52, p = 0.01) and positively with the height z-score (r = 0.49, p = 0.02). Conclusions: DM1 patients are at risk for smaller bone sizes at the distal radius at the end of pubertal growth, especially females with increased adiposity. Diabetes-specific parameters seem to have a low impact on forearm volumetric apparent mineral density.

Spermatogonial stem cell preservation in boys with Klinefelter syndrome: to bank or not to bank, that's the question

Although early development of testis appears normal in boys with Klinefelter syndrome (KS), spermatogonial stem cell (SSC) depletion occurs in midpuberty, leading to infertility. Therefore, freezing of semen samples or testicular tissue sampling could be offered to boys with KS at onset of puberty. However, only in about half of patients with KS, adult or prepubertal, spermatozoa or SSCs can be observed, and to date, no clinical parameters are available to detect patients who might benefit from these techniques. Furthermore, strategies for the further use of the cryopreserved material are still under investigation. Retrieval of spermatogonial cells in prepubertal boys with KS should therefore still be viewed as experimental and patients and their parents must be counseled accordingly.

Testicular biopsy and cryopreservation for fertility preservation of prepubertal boys with Klinefelter syndrome: a pro/con debate

In about one-half of adult Klinefelter syndrome (KS) patients, spermatozoa can be retrieved by means of testicular biopsy (TESE). Given the expected increase in the number of diagnosed KS patients owing to the use of noninvasive prenatal testing, the probable questions of young KS patients and their parents regarding future fertility, and the fact that widespread apoptosis of spermatogonia occurs at onset of puberty, an attempt to increase the retrieval rates at TESE above those found in adult KS men by undertaking preservation techniques peripubertally has been initiated. To date, however, only a limited number of KS adolescents have been examined, demonstrating no increases in the chances of finding sperm. Furthermore, spermatogonial stem cell and testicular tissue freezing techniques, as well as in vitro maturation strategies, require further validation. Given these controversies, banking testicular tissue from prepubertal KS boys should be performed only in a research framework.

Comparative bone status assessment by dual energy X-ray absorptiometry, peripheral quantitative computed tomography and quantitative ultrasound in adolescents and young adults with cystic fibrosis

PURPOSE Quantitative ultrasound bone sonometry (QUS) might be a promising screening method for cystic fibrosis (CF)-related bone disease, given its absence of radiation exposure, portability of the equipment and low cost.The value of axial transmission forearm QUS in detecting osteopenia in CF was therefore studied. METHODS We investigated the application of QUS in the evaluation of bone status in a group of 64 adolescents (>12 years) and young adults (<40 years) with CF in a comparison with a dual X-ray absorptiometry (DXA) of the whole body and peripheral quantitative computed tomography (pQCT) of the radius at 4% and 66% sites. RESULTS Mean (SD) Z-scores of speed of sound (SOS), whole body bone mineral content (BMC), radial trabecular bone mineral density (BMD), and radial cortical BMD were respectively -0.31 (0.78), -0.09 (1.28), 0.10 (1.16) and -0.62 (2.88). The pQCT determined bone geometry values (cortical bone area and cortical thickness) were more depressed than the BMD data. QUS had a sensitivity and specificity of respectively 0% and 96% for diagnosing osteopenia (based on a whole body BMC Z-score<-2). CONCLUSIONS QUS cannot replace DXA, but can screen out patients with normal bone mass. Further and larger studies are needed to examine if QUS may reflect other aspects than bone mass, or if it is possible to improve its sensitivity by supplementing the SOS results with clinical risk factors.

TRANSITION IN ENDOCRINOLOGY: Management of Klinefelter syndrome during transition

Klinefelter syndrome (KS) is the most common sex chromosomal disorder in males. Key findings in older adolescents and young men are small testes with variable hypo-androgenism, but almost universal azoospermia, most frequently in combination with a history of learning difficulties and behavior problems. Males with KS may come to medical attention through different medical presentations, given its association with several congenital malformations, and psychiatric, endocrine, and metabolic disorders. Preventive care is to be provided from diagnosis, preferentially through a multidisciplinary approach, including that from an endocrinologist, clinical psychologist or psychiatrist, neurologist, urologist, geneticist, sexologist, and a fertility team. Accurate information about the condition and assessment of associated medical conditions should be offered at diagnosis and should be followed by psychological counseling. Medical treatment during transition into adulthood is focused on fertility preservation and testosterone replacement therapy in the case of hypo-androgenism, and alleviation of current or future consequences of testicular fibrosis. However, more research is needed to determine the need for pro-active testosterone treatment in adolescence, as well as the conditions for an optimal testosterone replacement and sperm retrieval in adolescents and young men with KS. Furthermore, screening for associated diseases such as metabolic syndrome, autoimmune diseases, thyroid dysfunction, and malignancies is warranted during this period of life. The practical medical management during transition and, more specifically, the role of the endocrinologist are discussed in this article.

Cognitive, emotional and psychosocial functioning of girls treated with pharmacological puberty blockage for idiopathic central precocious puberty

Central precocious puberty (CPP) develops due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in early pubertal changes and rapid bone maturation. CPP is associated with lower adult height and increased risk for development of psychological problems. Standard treatment of CPP is based on postponement of pubertal development by blockade of the HPG axis with gonadotropin releasing hormone analogs (GnRHa) leading to abolition of gonadal sex hormones synthesis. Whereas the hormonal and auxological effects of GnRHa are well-researched, there is a lack of knowledge whether GnRHa treatment influences psychological functioning of treated children, despite the fact that prevention of psychological problems is used as one of the main reasons for treatment initiation. In the present study we seek to address this issue by exploring differences in cognitive function, behavior, emotional reactivity, and psychosocial problems between GnRHa treated CPP girls and age-matched controls. Fifteen girls with idiopathic CPP; median age 10.4 years, treated with slow-release GnRHa (triptorelin acetate—Decapeptyl SR® 11.25) and 15 age-matched controls, were assessed with a comprehensive test battery consisting of paper and pencil tests, computerized tasks, behavioral paradigms, heart rate variability, and questionnaires filled in by the childrens parents. Both groups showed very similar scores with regard to cognitive performance, behavioral and psychosocial problems. Compared to controls, treated girls displayed significantly higher emotional reactivity (p = 0.016; Cohens d = 1.04) on one of the two emotional reactivity task conditions. Unexpectedly, the CPP group showed significantly lower resting heart rates than the controls (p = 0.004; Cohens d = 1.03); lower heart rate was associated with longer treatment duration (r = −0.582, p = 0.037). The results suggest that GnRHa treated CPP girls do not differ in their cognitive or psychosocial functioning from age matched controls. However, they might process emotional stimuli differently. The unexpected finding of lower heart rate that was associated with longer duration of the treatment should be further explored by methods appropriate for assessment of cardiac health.

Insulin sensitivity modulates the growth response during the first year of high-dose growth hormone treatment in short prepubertal children born small for gestational age

Aim: To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). Methods: Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. Results: Mean height SDS increased from –3.3 ± 0.7 to –2.3 ± 0.7 after 1 year, and to –1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p < 0.05) with the change in height SDS in the first year. Conclusion: Higher insulin sensitivity at the start of GH therapy is associated with greater first-year growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies.