Screening for hypophosphatasia: does biochemistry lead the way?

OBJECTIVES: Patients with childhood hypophosphatasia (HPP) often have unspecific symptoms. It was our aim to identify patients with mild forms of HPP by laboratory data screening for decreased alkaline phosphatase (AP) within a pediatric population. METHODS: We conducted a retrospective hospital-based data screening for AP activity below the following limits: Girls: ≤12 years: <125 U/L; >12 years: <50 U/L Boys: ≤14 years: <125 U/L; >14 years: <70 U/L. Screening positive patients with otherwise unexplained hypophosphatasemia were invited for further diagnostics: Re-test of AP activity, pyridoxal 5'-phosphate (PLP) in hemolyzed whole blood, phosphoethanolamine (PEA) in serum and urine, and inorganic pyrophosphate in urine. Sequencing of the ALPL gene was performed in patients with clinical and/or laboratory abnormalities suspicious for HPP. RESULTS: We assessed a total of 14,913 samples of 6,731 patients and identified 393 screening-positive patients. The majority of patients were excluded due to known underlying diseases causing AP depression. Of the 30 patients who participated in the study, three had a decrease in AP activity in combination with an increase in PLP and PEA. A heterozygous ALPL mutation was detected in each of them: One patient with a short stature was diagnosed with childhood-HPP and started with enzyme replacement therapy. The remaining two are considered as mutation carriers without osseous manifestation of the disease. CONCLUSIONS: A diagnostic algorithm based on decreased AP is able to identify patients with ALPL mutation after exclusion of the differential diagnoses of hypophosphatasemia and with additional evidence of increased AP substrates.

Isolated Hypomethylation of IGF2 Associated with Severe Hypoglycemia Responsive to Growth Hormone Treatment.

Hypomethylation of H19 and IGF2 can cause Silver-Russell syndrome (SRS), a clinically and genetically heterogeneous condition characterized by intrauterine growth restriction, poor postnatal growth, relative macrocephaly, craniofacial abnormalities, body asymmetry, hypoglycemia and feeding difficulties. Isolated hypomethylation of IGF2 has been reported in single cases of SRS as well. Here, we report on a 19-month-old patient who presented with two episodes of hypoglycemic seizures. No intrauterine growth restriction was observed, the patient did not present with SRS-typical facial features, and postnatal growth in the first months of life was along the lower normal percentiles. Exome sequencing did not reveal any likely pathogenic variants explaining the phenotype; however, hypomethylation studies revealed isolated hypomethylation of IGF2, while the methylation of H19 appeared normal. Hypoglycemia responded well to growth hormone therapy, and the boy showed good catch-up growth. Our case demonstrates that SRS and isolated IGF2 hypomethylation should be considered early in the diagnosis of recurrent hypoglycemia in childhood, especially in combination with small gestational age and poor growth.

Frequency of thyroid dysfunction in pediatric patients with congenital heart disease exposed to iodinated contrast media - a long-term observational study.

Background The thyroid gland of patients with congenital heart disease may be exposed to large doses of iodine from various sources. We assessed the thyroid response after iodine exposure during conventional angiography in cardiac catheterization and angiographic computer tomography in childhood. Methods Retrospective mid- to long-term follow-up of 104 individuals (24% neonates, 51% infants, 25% children) with a median age and body weight of 104 days [0-8 years] and 5.3 kg [1.6-20]. Serum levels of thyroid-stimulating hormone, free triiodthyronine and free thyroxine were evaluated at baseline and after excess iodine. We also assessed risk factors that may affect thyroid dysfunction. Results Baseline thyroidal levels were within normal range in all patients. The mean cumulative iodinate contrast load was 6.6 ± 1.6 mL/kg. In fact, 75% had experienced more than one event involving iodine exposure, whose median frequency was three times per patient [1-12]. During the median three years follow-up period [0.5-10], the incidence of thyroid dysfunction was 15.4% (n=16). Those patients developed acquired hypothyroidism (transient n=14, long-lasting n=2 [both died]) with 10 of them requiring temporary replacement therapy for transient thyroid dysfunction, while four patients recovered spontaneously. 88 individuals (84.6%) remained euthyroid. Repeated cardiac interventions, use of drugs that interfere with the thyroid and treatment in the intensive care unit at the index date were strong predictors for acquired thyroid dysfunction. Conclusions The incidence of acquired hypothyroidism after iodine excess was 15.4%. However, most patients developed only transient hypothyroidism. Systemic iodine exposure seems to be clinically and metabolically well tolerated during long-term follow-up.

Start low, go slowly - mental abnormalities in young prolactinoma patients under cabergoline therapy.

Background Prolactin-secreting pituitary adenomas in childhood and adolescence are rare. First-line therapy consists of dopamine agonists (DAs) like cabergoline. Experience in treating prolactinomas in paediatric and adolescent patients is limited. Methods This study was a retrospective analysis of clinical data, laboratory data, radiological findings and medical treatment of paediatric and adolescent patients with prolactinomas between 2009 and 2018. Results Our cohort of nine patients had a median age at diagnosis of 13 years (range 5-17). Main presenting symptoms were weight gain, disorders of the pituitary-gonadal axis and headache. Treatment with cabergoline resulted in a marked reduction in prolactin concentration in all nine patients. Tumour mass reduction was confirmed by magnetic resonance imaging (MRI) scan in seven patients. Noteworthy is that cabergoline therapy triggered frequent adverse effects in a total of eight patients - seven of whom suffered from mental disorders, five of whom had neurological symptoms and five of whom had gastrointestinal problems. The adverse effects occurred at a median dose of only 0.5 mg/week (range 0.25-2.0). Most symptoms were alleviated after the cabergoline dose was lowered. Therapy discontinuation was not necessary in any patient. Conclusions Cabergoline effectively lowers prolactin levels and may reduce tumour mass in paediatric and adolescent patients with prolactinomas. Potential adverse effects may include mental disorders and behavioural problems even at low cabergoline doses. Low starting doses and careful individual dose adjustments are required to enable therapy adherence.

Transfer of Topical Testosterone to Subcutaneous Microdialysate, Blood and Saliva in Healthy Young Men.

OBJECTIVE: We evaluated percutaneous penetration of topical testosterone and subsequent transfer to subcutaneous tissue, blood and saliva. METHODS: This microdialysis trial involved eight healthy male volunteers. Five participants received a single dose of 50 mg testosterone gel on the abdominal skin and three untreated participants served as controls. Two microdialysis probes were inserted percutaneously into the abdominal subcutaneous adipose tissue. On the skin above one probe, testosterone gel was applied (ipsilateral side). A second control probe was inserted on the contralateral side. For the determination of total and free testosterone, samples of subcutaneous microdialysate, serum, and saliva were collected over six hours, frozen, and analysed using ELISA procedures. RESULTS: Testosterone values in the ipsilateral microdialysate of treated subjects increased significantly within 6 h after gel application compared to controls. Salivary testosterone levels showed a rapid increase within 20 min after transdermal application followed by a plateau phase with tenfold increased testosterone levels. Microdialysate testosterone of the contralateral site started to rise moderately within the normal range 1 h after administration of testosterone gel whereas total and free testosterone serum concentrations increased within 2 h in each case followed by a plateau phase. SUMMARY AND CONCLUSION: Single topical administration of testosterone gel leads to a continuous increase of testosterone in the subcutaneous ipsilateral microdialysate. Rapid salivary testosterone increase happens after gel administration followed by tenfold increased testosterone plateau values. Despite continuous influx, testosterone concentrations in serum, saliva, and contralateral microdialysate show a plateau formation thus avoiding testosterone excess.

Dysphagia after arteria lusoria dextra surgery: Anatomical considerations before redo-surgery.

Aberrant right subclavian artery (arteria lusoria) is the most common congenital root anomaly, remaining asymptomatic in most cases. Nevertheless, some of the 20%-40% of those affected present tracheo-esophageal symptoms. We report on a 6-year-old previously healthy girl presenting with progressive dysphagia over 4 wk. Diagnostics including barium swallow, echocardiography and magnetic resonance angiography (MRA) revealed a retro-esophageal compression by an aberrant right subclavian artery. Despite the successful, uneventful transposition of this arteria lusoria to the right common carotid via right-sided thoracotomy, the girl was suffering from persisting dysphagia. Another barium swallow showed the persistent compression of the esophagus on the level where the arteria lusoria had originated. As MRA showed no evidence of a significant re-obstruction by the transected vascular stump, we suspected a persisting ligamentum arteriosum. After a second surgical intervention via left-sided thoracotomy consisting of transecting the obviously persisting ligamentum and shortening the remaining arterial stump of the aberrant right subclavian artery, the patient recovered fully. In this case report we discuss the potential relevance of a persisting ligamentum arteriosum for patients with left aortic arch suffering from dysphagia lusoria and rational means of diagnosing, as well as the surgical options to prevent re-do surgery.

Thyroidal response following iodine excess for cardiac catheterisation and intervention in early infancy.

BACKGROUND: Cardiac catheterisation requiring the use of contrast medium is increasingly utilised in infants with congenital heart disease. Thyroid function in infants is potentially vulnerable to relatively high doses of iodine. METHODS: Single-centre prospective study of 21 patients (10 neonates, 11 infants) exposed to iodine during cardiac catheterisation. Median age was 30days (1-180), median body weight 3.3kg (1.6-7.0). Serum-levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) were measured at baseline before, and at three different times points after intervention. RESULTS: Baseline thyroidal levels were within normal range in all patients. After applying contrast media of median 6.8ml/kg (range 4.5-14.9), we observed a wide range of TSH values: median 5.01µg/l (range 0.59-37.73; reference 0.72-11.0) three to five days after catheterisation. Five of the 10 neonates demonstrated transient TSH elevation consistent with latent hypothyroidism, and a sixth a transient drop in all hormone levels typical of non-thyroidal illness syndrome. However, circulating thyroid hormones remained within normal range, except for two borderline-low fT4 values within the first week after catheterisation that normalised without any medical intervention. CONCLUSION: Systemic iodine exposure during cardiac catherterisation seems to be clinically well tolerated in early infancy. However, exposure to iodine has demonstrable but apparently reversible effects on thyroid hormones during a potentially important developmental period. The implications of this are unclear, but warrant further investigation in larger cohorts.

Clinical and electromyographic results of proximal and distal realignment procedures in young patients with recurrent patellar dislocations.

BACKGROUND: Until now, no study has been published about the electromyographic changes in the extensor apparatus after the Green procedure for proximal realignment in young patients with recurrent patellar dislocations. This electromyographic study was performed to analyze imbalances between the vastus medialis and vastus lateralis muscles after different patellar realignment procedures. HYPOTHESIS: Surgical proximal realignment leads to electromyographic changes in the extensor apparatus of the knee and to imbalances between the vastus medialis and vastus lateralis muscles. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 28 knees of 25 patients, with a mean age of 15 years, were treated operatively for recurrent patellar dislocations. The mean follow-up was 6.3 years. Depending on the type of surgical intervention, the patients were assigned to 3 different groups: the patients of group 1 underwent only the Green vastus medialis obliquus (VMO) advancement, group 2 was treated with a combination of the Green proximal and the Roux-Goldthwait distal realignment, and group 3 was treated with a combination of the Green proximal realignment and an additional tubercle transfer. All patients underwent clinical, radiological, and electromyographic examinations. The muscle activities of a healthy control group without patellar dislocations were used for comparison. RESULTS: A combination of the Green procedure and tubercle transfer led to significantly better clinical results and a lower number of redislocations (P < .05) compared with patients who underwent only the Green proximal realignment. While ascending or descending stairs, the ratio between the electromyographic activities of the vastus medialis and vastus lateralis muscles in groups 1 and 2 was significantly smaller compared with the control group (P < .02). Only the electromyograms of group 3 revealed a balanced extensor apparatus during loading with comparable activities of the vastus medialis and vastus lateralis muscles and no significant difference to the control group (P = .37). CONCLUSION: Our electromyographic investigations showed the importance of the vastus medialis in the pathogenesis of malalignment of the extensor mechanism. The Green VMO advancement without tibial tubercle transfer is not able to balance the activities of the vastus medialis and vastus lateralis muscles and cannot be recommended for further use.

Marked increase of final height by long-term aromatase inhibition in a boy with idiopathic short stature.

Growth hormone (GH) is the most frequently used treatment in children with idiopathic short stature (ISS). Aromatase inhibitor (AI) therapy is still in an experimental state, and both final height (FH) and long-term efficacy data in ISS have not been published. We present a 14.5-year-old boy with ISS and a height of 142.7 cm [standard deviation score (SDS) -2.79]. Based on the baseline bone age (BA) of 13.5-14 years, his predicted adult height (PAH) by Bayley/Pinneau was 154 cm (SDS -3.77)-158.2 (SDS -3.15). After a 5-year letrozole monotherapy, FH was 169 cm (SDS -1.57) showing a height difference between PAH and FH from 10.8 to 15 cm. No permanent side effects of the medication have been observed. Both a transient occurrence and a spontaneous recovery of decreased bone mineral apparent density were seen, verified by dual-energy X-ray absorptiometry. Spinal magnetic resonance imaging revealed no vertebral abnormalities. All therapy might be an effective and low-cost alternative to the use of GH. Further controlled trials should prove efficacy and safety of long-term AI therapy in boys with ISS.

Difficulties in diagnosis and treatment of 5alpha-reductase type 2 deficiency in a newborn with 46,XY DSD.

BACKGROUND/AIMS: Steroid 5alpha-reductase deficiency (MIM*607306) caused by mutations in the SRD5A2 gene is characterized by a predominantly female phenotype at birth and significant virilization at puberty. The undermasculinization at birth results from low dihydrotestosterone (DHT) levels during fetal development as the type 2 isoenzyme activity is reduced. In puberty, when the type 1 isoenzyme activity increases, significant virilization occurs. Most 46,XY individuals with 5alpha-reductase 2 deficiency develop a male gender identity. CASE REPORT AND RESULTS: We present a case with a predominantly female phenotype and ambiguous external genitalia but a normal 46,XY karyotype. Plasma steroid analysis after beta-hCG stimulation at 8 days of age revealed a steroid profile estimated as normal with a testosterone (T)/DHT ratio of 9.5 initially misleading to the exclusion of 5alpha-reductase deficiency. However, mutation analysis of the SRD5A2 gene revealed a homozygote point mutation (Leu55Gln) confirming the diagnosis of 5alpha-reductase deficiency. A male phenotype was successfully achieved by hormone treatment with T and DHT after diagnosing 5alpha-reductase deficiency and a masculinization operation. As a side effect skeletal age accelerated temporarily. CONCLUSION: In individuals with predominantly female phenotype and suspected 5alpha-reductase deficiency, a T/DHT ratio during the neonatal period >8.5 might point to 5alpha-reductase deficiency. After confirmation of the diagnosis by molecular analysis of the SRD5A2 gene, a satisfactory change to a male phenotype can be achieved by hormone treatment preceding surgery.

Autonomous thyroid adenoma: only an adulthood disease?

We identified somatic activating thyrotropin-receptor gene mutations within autonomous thyroid nodules (ATN) in 2 girls with 1 ATN and in 1 girl with 3 ATN. A fourth patient had a somatic activating gene mutation of the alpha-subunit of the stimulating G-protein in 2 ATN. Activating somatic mutations in ATN can cause non-autoimmune hyperthyroidism in children.