Serum 25-hydroxyvitamin D threshold and risk of rickets in young children: a systematic review and individual participant data meta-analysis to inform the development of dietary requirements for vitamin D.

PURPOSE: The objective of this systematic review was to determine a minimum serum 25-hydroxyvitamin D (25OHD) threshold based on the risk of having rickets in young children. This work was commissioned by the WHO and FAO within the framework of the update of the vitamin D requirements for children 0-3 years old. METHODS: A systematic search of Embase was conducted to identify studies involving children below  4 years of age with serum 25OHD levels and radiologically confirmed rickets, without any restriction related to the geographical location or language. Study-level and individual participant data (IPD)-level random effects multi-level meta-analyses were conducted. The odds, sensitivity and specificity for rickets at different serum 25OHD thresholds were calculated for all children as well as for children with adequate calcium intakes only. RESULTS: A total of 120 studies with 5412 participants were included. At the study-level, children with rickets had a mean serum 25OHD of 23 nmol/L (95% CI 19-27). At the IPD level, children with rickets had a median and mean serum 25OHD of 23 and 29 nmol/L, respectively. More than half (55%) of the children with rickets had serum 25OHD below 25 nmol/L, 62% below 30 nmol/L, and 79% below 40 nmol/L. Analysis of odds, sensitivities and specificities for nutritional rickets at different serum 25OHD thresholds suggested a minimal risk threshold of around 28 nmol/L for children with adequate calcium intakes and 40 nmol/L for children with low calcium intakes. CONCLUSION: This systematic review and IPD meta-analysis suggests that from a public health perspective and to inform the development of dietary requirements for vitamin D, a minimum serum 25OHD threshold of around 28 nmol/L and above would represent a low risk of nutritional rickets for the majority of children with an adequate calcium intake.

The evolving epidemiology of acute gastroenteritis in hospitalized children in Italy.

Few data are available on the prevalence and features of acute gastroenteritis (AGE) in hospitalized children in Italy, where specific rotavirus vaccines were introduced into the national vaccination plan in 2017. To evaluate vaccination effects on AGE epidemiology, we analysed data from children aged ≤ 18 years admitted for AGE at the University Hospital of Pisa in 2019, comparing them with those recorded in 2012. Demographical, clinical, diagnostic, and treatment data were collected reviewing medical records and were therefore compared. In 2019 and 2012, 86 (median age 2.5 years [IQR 1.4-5.9]) and 85 children (median age 2.3 years [IQR 1.3-5.1]) were respectively admitted with AGE. The most common symptoms were diarrhoea and vomiting; decreased skin turgor was more frequent in 2019 (54% and 34% respectively, p = 0.01). Viral infections were more common than bacterial ones; in 2019, a decrease in rotavirus infections (67% and 22%, p = 0.003) and an increase in adenovirus infections (50% and 10%, p = 0.002) and in the number of patients with negative stool testing (58% and 39%, p = 0.04) were found.Conclusions: Viral infections are the leading cause of AGE in hospitalized children in Italy. The introduction of rotavirus vaccines did not reduce the number of hospitalizations per year. Adenovirus and other non-routinely screened viruses may be undergoing a selection process making them common causative agents for AGE. What is Known: • Rotavirus is the leading cause of acute severe gastroenteritis in children worldwide, especially < 5 years of age. • The introduction of specific vaccines may be changing its epidemiology. • Few data are available on acute gastroenteritis in hospitalized children in Italy. What is New: • Viral infections are the leading cause of acute gastroenteritis in hospitalized children in Italy. • Specific vaccines are reducing rotavirus infections, but adenovirus and other non-routinely screened viruses may be undergoing a selection process making them common causative agents for gastroenteritis.

Pulp chamber features, prevalence of abscesses, disease severity, and PHEX mutation in X-linked hypophosphatemic rickets.

INTRODUCTION: Rickets, growth failure, and recurrent periapical abscesses with fistulae are main signs in patients with X-linked hypophosphatemic rickets (XLH). Prevalence of abscesses, pulp chamber features, biochemical findings, disease severity, and PHEX gene mutation were examined. MATERIALS AND METHODS: Pulp chambers size, shape, and morphology were assessed by orthopantomography in XLH patients (n = 24, age 5.8 ± 1.6 years) and in sex and age-matched healthy controls (n = 23, age 6.2 ± 1.4 years). XLH patients received conventional treatment (3.5 ± 1.9 years). Pulp chamber features were assessed in teeth of primary dentition and in the permanent left mandibular first molar and compared with those of controls. Rickets severity score was assessed at wrist, knee, and ankle. RESULTS: The mean pulp chamber area/tooth area ratio, mean pulp chamber height/pulp chamber width ratio, and prominence of pulp horns into the tooth crown in primary and secondary molars were significantly higher in patients than in controls and in patients suffered abscesses than in patients without abscesses. Sixteen patients (67%) had a history of abscesses; incisors were affected more than canines and molars. Severity of rickets and mean serum parathyroid hormone (PTH) levels were significantly higher, and mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels significantly lower in patients suffered abscesses than in patients without abscesses. PHEX gene mutations were not correlated with dental phenotype and disease severity. CONCLUSION: Enlarged pulp chambers with altered shape and morphology affected the majority of XLH patients predisposing to recurrent periapical abscesses with fistulae. Dental phenotype was associated with severity of rickets, high serum PTH, and low serum 1,25(OH)2D levels.

Complete Androgen Insensitivity Syndrome: From Bench to Bed.

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.

Adult height after spontaneous pubertal growth or GnRH analog treatment in girls with early puberty: a meta-analysis.

Early puberty (EP) has been defined as the onset of puberty in the low-normal range; it may be a cause for concern regarding a possible impairment of adult height (AH). This paper meta-analysed data on AH after spontaneous growth or after gonadotropin-releasing hormone (GnRH) analog treatment in girls with EP. A computerized literature search was conducted from 1980 to June 30, 2016. Only published studies in English were considered. Eight papers were selected (483 cases). In untreated girls (n = 300), predicted adult height (PAH) at start of follow-up (-0.559 SDS (95%CI -1.110 to 0.001); P = 0.050) was close to mid-parental height (MPH) (-0.557 SDS (95%CI -0.736 to -0.419); P < 0.0001) and AH (-0.663 SDS (95%CI -0.803 to -0.524); P < 0.0001). In GnRH analog treated girls (n = 183), PAH before the start of treatment was slightly reduced (-0.939 SDS (95%CI -1.401 to -0.477; P < 0.0001) vs MPH (-0.678 SDS (95%CI -0.942 to -0.414); P < 0.0000), but AH (-0.604 SDS (95%CI -0.877 to -0.338); P < 0.0000) was close to MPH. CONCLUSION: Present meta-analysis indicates that girls with EP spontaneously reach their MPH and that GnRH analog treatment does not widely change growth outcome. Differences among the selected studies for definition of EP, inclusion criteria, treatment duration, age at discontinuation of therapy, definition of AH may affect results. What is Known: • Early puberty represents a main cause of consultation in paediatric endocrinology offices due to concerns of both practitioners and parents. • Treatment with GnRH analogs is sometimes attempted with the aim to improve adult height. What is New: • Untreated and GnRH analog treated girls with early puberty reached similar adult height. • Adult height was consistent with mid-parental height in both untreated and GnRH analog treated girls with early puberty.

Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.

BACKGROUND: The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of two genes (POLR3A and POLR3B) responsible for the syndrome demonstrates that these three main characteristics can be variably combined among "Pol-III (polymerase III)-related leukodystrophies." CASE PRESENTATION: We report on the clinical, neuroradiological and endocrinological follow-up of a male affected by 4H syndrome with confirmed POLR3B mutations (c.1568 T > A/p.V523E variant in exon 15 and the novel c.1988C > T/p.T663I mutation in exon 19). Spastic-ataxic gait with worsening of motor performance, progressive moderate intellectual disability and language difficulties were the main neurological findings observed. The first six years of substantial stability of the clinical and imaging features were followed by additional six years that showed a progressive worsening of motor, language and learning disabilities in relation to a progression of the cerebellar involvement. Hypogonadotropic hypogonadism and growth hormone deficiency followed by central hypocortisolism became part of the patient's phenotype. Thyroid function resulted unaffected during follow up. CONCLUSIONS: A novel mutation in POLR3B in a patient with an analogue phenotype than those previously described but with more extensive endocrinological features, including hypogonadotropic hypogonadism, growth hormone deficiency and hypocortisolism, was described. These findings permit to better define the clinical spectrum of the disease, to direct specific genetic tests and to tailor clinical management.

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets.

BACKGROUND AND OBJECTIVE: X-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia. Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions. Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few. In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. METHODS: Five Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8-1.2 mg/kg, s. c. QW2). Burosumab was continued for 12-48 months and, once discontinued, patients were followed-up for 6-12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3-6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. RESULTS: At entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DISCUSSION: Our data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Pamidronate treatment stimulates the onset of recovery phase reducing fracture rate and skeletal deformities in patients with idiopathic juvenile osteoporosis: comparison with untreated patients.

Although spontaneous remission occurs in patients with idiopathic juvenile osteoporosis (IJO), permanent bone deformities may occur. The effects of long-term pamidronate treatment on clinical findings, bone mineral status, and fracture rate were evaluated. Nine patients (age 9.8 ± 1.1 years, 7 males) with IJO were randomized to intravenous pamidronate (0.8 ± 0.1 mg/kg per day for 3 days; cycles per year 2.0 ± 0.1; duration 7.3 ± 1.1 years; n = 5) or no treatment (n = 4). Fracture rate, phalangeal quantitative ultrasound, and lumbar bone mineral density (BMD) by dual energy X-ray absorptiometry at entry and during follow-up (range 6.3-9.4 years) were assessed. Bone pain improved in treated patients. Difficulty walking continued for 3-5 years in untreated patients, and vertebral collapses occurred in three of them. During follow-up, phalangeal amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and lumbar BMDarea and BMDvolume progressively increased in treated patients (P < 0.05-P < 0.0001). In untreated patients AD-SoS and BTT decreased during the first 2-4 years of follow-up (P < 0.05-P < 0.01); lumbar BMDarea increased after 6 years (P < 0.001) whereas BTT and lumbar BMDvolume increased after 7 years of follow-up (P < 0.05 and P < 0.001, respectively). At the end of follow-up, AD-SoS, BTT, lumbar BMDarea, and BMDvolume Z-scores were lower in untreated patients than in treated patients (-2.2 ± 0.3 and -0.5 ± 0.2; -1.9 ± 0.2 and -0.6 ± 0.2; -2.3 ± 0.3 and -0.7 ± 0.3; -2.4 ± 0.2 and -0.7 ± 0.3, P < 0.0001, respectively). Fracture rate was higher in untreated patients than in treated patients during the first 3 years of follow-up (P < 0.02). Our study showed that spontaneous recovery of bone mineral status is unsatisfactory in patients with IJO. Pamidronate treatment stimulated the onset of recovery phase reducing fracture rate and permanent disabilities without evidence of side-effects.

Risk of thyroid neoplasms in patients with 22q11.2 deletion and DiGeorge-like syndromes: an insight for follow-up.

Introduction: The chromosome 22q11.2 deletion syndrome comprises phenotypically similar diseases characterized by abnormal development of the third and fourth branchial arches, resulting in variable combinations of congenital heart defects, dysmorphisms, hypocalcemia, palatal dysfunction, developmental or neuropsychiatric disorders, and impairment of the immune system due to thymic dysfunction. Other genetic syndromes, often called DiGeorge-like, share clinical and immunological features with 22q11.2 deletion syndrome. This syndrome has been rarely associated with malignancies, mainly hematological but also hepatic, renal, and cerebral. Rarely, malignancies in the head and neck region have been described, although no aggregate of data on the development of thyroid neoplasms in patients with this clinical phenotype has been conducted so far. Materials and methods: To characterize this possible association, a multicenter survey was made. Thus, we present a case series of five pediatric patients with 22q11.2 deletion syndrome or DiGeorge-like syndrome who were occasionally found with confirmed or highly suspected neoplasms of the thyroid gland during their follow-up. In three cases, malignancies were histologically confirmed, but their outcome was good due to an early recognition of suspicious nodules and precocious surgery. Conclusions: This study underlines for clinicians the higher risk of neoplasms in the head and neck district for patients affected by these syndromes. It also emphasizes the importance of a prolonged clinical and ultrasound follow-up for patients with this clinical and immunological phenotype.

Hypoparathyroidism Associated with Benign Thyroid Nodules in DiGeorge-like Syndrome: A Rare Case Report and Literature Review.

BACKGROUND: DiGeorge-like syndrome (DGLS) is a rare genetic disorder due to the presence of the same classical clinical manifestations of DiGeorge syndrome (DGS) without its typical deletion. In the DGLS phenotype, hypoparathyroidism seldom occurs and is considered rare. In DGS, hypocalcemia affects up to 70% of patients, and a considerable share often has asymptomatic thyroid abnormalities. CASE DESCRIPTION: In this study, we describe an unusual case of a 16-year-old patient with DGLS due to a duplication of 365 kb in the 20p11.22 region, affected by hypoparathyroidism associated with thyroid nodule. The intraoperative parathyroid evaluation ruled out agenesis as a cause of hypoparathyroidism. In addition, we carried out a thorough literature review from 2010 to 2023 of DGLS cases using specific keywords, such as "22q11.2 deletion syndrome", "DiGeorge-like Syndrome", "hypoparathyroidism", "thyroid", and "children", analyzing 119 patients with DGLS. CONCLUSION: Interestingly enough, the present case represents, to our knowledge, the first report of a patient with DGLS associated with hypoparathyroidism and the presence of thyroid nodules where an intraoperative observation reported a non-functional parathyroid gland.

Central precocious puberty: treatment with triptorelin 11.25 mg.

BACKGROUND: Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). AIM: To assess the efficacy of triptorelin 11.25 mg in children with CPP. PATIENTS: 17 patients (16 females) with CPP (7.9 ± 0.9 years) were treated with triptorelin 11.25 mg/90 days. METHODS: Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7 ± 16.5 IU/L at baseline to 0.9 ± 0.5 IU/L at M3 (P < 0.0001); they did not significantly changed at M6 and M12. CONCLUSIONS: Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Clinical, Immunological, and Genetic Findings in a Cohort of Patients with the DiGeorge Phenotype without 22q11.2 Deletion.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype that is highly suggestive of this syndrome but without the 22q11.2 deletion. The cardinal features of 22q11.2DS, such as congenital heart defects, hypoparathyroidism, and facial dysmorphisms, were observed in the majority of the patient cohort. The unusual features are described in detail. The immunologic assessment showed various degrees of immunodeficiency of the T-cell compartment, notably a reduction in the thymic output. Half of the patient cohort exhibited a reduction in total dendritic cells. Array comparative genomic hybridization (CGH) revealed six patients harboring copy number variations (CNVs) never reported in normal subjects. The gene content of these CNVs was carefully analyzed to understand the mechanisms leading to 22q11.2DS phenocopies. According to these results, we suggested that array-CGH should be used as a first-tier tool for patients resembling 22q11.2DS.

Burosumab for X-linked hypophosphatemia in children and adolescents: Opinion based on early experience in seven European countries.

Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthood.

X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management.

X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.

Management of patients with X-linked hypophosphatemic rickets during Covid-19 pandemic lockdown.

OBJECTIVES: To identify a safe pathway for management and treatment of patients with X-linked hypophosphatemic rickets (XLH) during Covid-19 pandemic lockdown. METHODS: Twenty-six patients with XLH (age 3.1-25.7 years) were enrolled in Pediatric Endocrine Unit; nine of them were receiving human monoclonal anti-fibroblast growth factor 23 antibody (burosumab) and 17 (pediatric patients, age 9.5-17.9 years, n=7; young-adult patients, age 20.1-25.7 years, n=10) received conventional treatment with inorganic oral phosphate salts and active vitamin D metabolites. A Covid-19 free pathway was addressed for XLH patients receiving burosumab treatment in hospital. XLH patients receiving conventional treatment were followed by phone calls, e-mails, or telemedicine. RESULTS: All XLH patients receiving burosumab continued the scheduled follow-up and treatment; none of them was infected by Covid-19. Seven XLH patients out of 17 (41%) receiving conventional treatment showed some complication related to the disease itself or its treatment: periapical abscess with gingival fistula was diagnosed in five patients (three children and two young-adults) and treated with antibiotics with complete resolution; one child showed abdominal pain due to the administration of high doses of inorganic oral phosphate salts solved by reducing the dosage, and one child had severe legs pain during deambulation after orthopedic surgery solved with common analgesics. CONCLUSIONS: Covid-19 free pathway was safe and effective to manage XLH patients receiving burosumab. E-health technologies were useful methods to follow XLH patients receiving conventional treatment during Covid-19 pandemic lockdown.

Disorders/Differences of Sex Development Presenting in the Newborn With 46,XY Karyotype.

Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions, resulting in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. The management of a newborn with suspected 46,XY DSD remains challenging. Newborns with 46,XY DSD may present with several phenotypes ranging from babies with atypical genitalia or girls with inguinal herniae to boys with micropenis and cryptorchidism. A mismatch between prenatal karyotype and female phenotype is an increasing reason for presentation. Gender assignment should be avoided prior to expert evaluation and possibly until molecular diagnosis. The classic diagnostic approach is time and cost-consuming. Today, a different approach may be considered. The first line of investigations must exclude rare life-threatening diseases related to salt wasting crises. Then, the new genetic tests should be performed, yielding increased diagnostic performance. Focused imaging or endocrine studies should be performed on the basis of genetic results in order to reduce repeated and invasive investigations for a small baby. The challenge for health professionals will lie in integrating specific genetic information with better defined clinical and endocrine phenotypes and in terms of long-term evolution. Such advances will permit optimization of counseling of parents and sex assignment. In this regard, society has significantly changed its attitude to the acceptance and expansion beyond strict binary male and female sexes, at least in some countries or cultures. These management advances should result in better personalized care and better long-term quality of life of babies born with 46,XY DSD.

Acute dacryocystitis with giant lacrimal abscess: a case report.

BACKGROUND: We report a case of a 4-year-old girl with acute dacryocystitis complicated with giant lacrimal abscess who underwent open dacryocystectomy as resolutive surgery. CASE PRESENTATION: A 4-year-old previously healthy girl presented to the emergency department with a voluminous and erythematous, fluctuant warm mass localized inferiorly to the medial canthus of the right eye. She had a 2-week history of right inferior eyelid oedema and hyperemia, treated firstly with dexamethasone and netilmicin by eye drops, and then with per oral amoxicillin clavulanate. Ultrasound examination showed a well-circumscribed round lesion filled by anechoic fluid with punctate echoes, confirming a diagnosis of acute dacryocystitis complicated by lacrimal abscess. Parents refused a head CT. Systemic antibiotic treatment was started and, on 5th day from admission, open dacryocystectomy was performed with good esthetical result. CONCLUSIONS: Pediatric acute dacryocystitis is a potentially serious condition, which must be treated with intravenous antibiotic therapy followed by surgery tailored to the clinical history. Even if probing and dacryocystorhinostomy are the most used surgery in adults and children, open dacryocystectomy is a safe and successful option, mainly in severe cases where imaging studies are not available.

Body mass index and body composition in adolescents treated with gonadotropin-releasing hormone analogue triptorelin depot for central precocious puberty: data at near final height.

BACKGROUND/AIM: In children with central precocious puberty (CPP), gonadotropin-releasing hormone (GnRH) analogue treatment has been associated with an increase in body mass index (BMI). We evaluated BMI and body composition in adolescents treated with GnRH analogue at their near final height to assess the long-term effects of therapy on these parameters. PATIENTS AND METHODS: We studied 20 patients (14.8 +/- 1.6 years; 17 females) previously treated with triptorelin depot for CPP (3.75 mg/28 days) from 8.1 +/- 0.8 to 11.5 +/- 0.8 years. 23 healthy adolescents with normal onset of puberty (14.7 +/- 2.1 years, 19 females) were the controls. BMI and body composition (dual-energy x-ray absorptiometry) were assessed. RESULTS: Patients reached their near adult height (-0.5 +/- 1.1 standard deviation score (SDS)); the girls were menstruating and the majority (15/17) had regular cycles, the boys showed normal testicular function. BMI was unchanged from the start of GnRH analogue therapy (0.4 +/- 1.0 SDS) to near adult height (0.2 +/- 1.0 SDS, p = NS vs. 0). Total fat mass (TFM) was significantly increased (16,144 +/- 8,065 g; controls 10,712.1 +/- 4,120.4 g, p < 0.02); glucose homeostasis and lipid profile corresponded to reference ranges. CONCLUSIONS: GnRH analogue therapy did not show long-term detrimental effects on BMI, but it may increase TFM, suggesting that body composition should be monitored till adulthood.

Paternity in 5α-Reductase-2 Deficiency: Report of Two Brothers with Spontaneous or Assisted Fertility and Literature Review.

Fertility remains a challenge for men with 5α-reductase-2 deficiency. Such a diagnosis was made in 2 adult brothers who are compound heterozygous for the 5α-reductase type 2 gene (SRD5A2; c.308G>C; c.689A>C). They were born with ambiguous genitalia and the male sex was assigned. Both brothers underwent reconstructive genital surgery during pediatric age and had spontaneous virilization at puberty. The older brother experienced natural conception, while the younger had a son by assisted reproductive technology. Other family members were demonstrated to be compound heterozygous or heterozygous for the same genetic variants. The older brother is the third man with 5α-reductase-2 deficiency and spontaneous paternity. The little series of men with 5α-reductase-2 deficiency and documented spontaneous or assisted paternity is reviewed. In conclusion, the possibility of fatherhood is a main indication for male sex assignment in patients with 5α-reductase-2 deficiency.