Isolated hypoaldosteronism as first sign of X-linked adrenal hypoplasia congenita caused by a novel mutation in NR0B1/DAX-1 gene: a case report.

BACKGROUND: X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1. Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. CASE PRESENTATION: A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. CONCLUSIONS: AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.

The Approach to a Child with Dysmorphic Features: What the Pediatrician Should Know.

The advancement of genetic knowledge and the discovery of an increasing number of genetic disorders has made the role of the geneticist progressively more complex and fundamental. However, most genetic disorders present during childhood; thus, their early recognition is a challenge for the pediatrician, who will be also involved in the follow-up of these children, often establishing a close relationship with them and their families and becoming a referral figure. In this review, we aim to provide the pediatrician with a general knowledge of the approach to treating a child with a genetic syndrome associated with dysmorphic features. We will discuss the red flags, the most common manifestations, the analytic collection of the family and personal medical history, and the signs that should alert the pediatrician during the physical examination. We will offer an overview of the physical malformations most commonly associated with genetic defects and the way to describe dysmorphic facial features. We will provide hints about some tools that can support the pediatrician in clinical practice and that also represent a useful educational resource, either online or through apps downloaded on a smartphone. Eventually, we will offer an overview of genetic testing, the ethical considerations, the consequences of incidental findings, and the main indications and limitations of the principal technologies.

The impact of BMI on long-term anthropometric and metabolic outcomes in girls with idiopathic central precocious puberty treated with GnRHas.

Background: Gonadotropin-releasing hormone analogs (GnRHas) are effective in increasing the final height of children with idiopathic central precocious puberty (ICPP). However, in previous years, some transient metabolic complications have been described during this treatment, for which there are no long-term outcome data. Our study aimed to evaluate the efficacy of GnRHas and clarify if body mass index (BMI) at diagnosis of ICPP could influence long-term outcomes. Methods: This was an observational, retrospective study that recruited a cohort of girls with ICPP. Data for anthropometric measures, fasting lipid profile, and glucose metabolism were collected at baseline [when GnRHas treatment started (T1)], at the end of the treatment (T2), and near-final height (nFH) or final height (FH) (T3). Predicted adult height (PAH) was calculated at T1 following Bayley and Pinneau's method. Analysis was carried out using BMI standard deviation score (SDS) categories at T1 (group A, normal weight, vs. group B, overweight/obese). Results: Fifty-seven girls with ICPP who were treated with GnRHas were enrolled in the study (group A vs. group B: 33 vs. 24 patients, aged 7.86 ± 0.81 vs. 7.06 ± 1.61 years, respectively; p < 0.05). In the study population, nFH/FH was in line with the target height (TH) (p = 0.54), with a mean absolute height gain of 11.82 ± 5.35 cm compared with PAH. Even if the length of therapy was shorter (group A vs. group B: 1.84 ± 2.15 vs. 2.10 ± 0.81 years, respectively; p < 0.05) and the age at menarche was younger (group A vs. group B: 10.56 ± 1.01 vs. 11.44 ± 0.85 years, respectively; p < 0.05) in group B than in group A, the nFH/FH gain was still comparable between the two groups (p = 0.95). At nFH/FH, BMI SDS was still greater in group B than in group A (p = 0.012), despite the fact that BMI SDS significantly increased in group A only (p < 0.05). Glucose metabolism got worst during GnRHa with a complete restoring after it, independently from pre-treatment BMI. The ratio of low-density to high-density lipoprotein cholesterol transiently deteriorated during treatment with GnRHas in group A only (p = 0.030). Conclusions: Our results confirm the effectiveness of treatment with GnRHas on growth and do not support the concern that being overweight and obese can impair the long-term outcomes of GnRHas therapy. However, the observed transient impairment of metabolic parameters during treatment suggests that clinicians should encourage ICPP girls treated with GnRHas to have a healthy lifestyle, regardless of their pretreatment BMI.

Growth hormone deficiency in a child with benign hereditary chorea caused by a de novo mutation of the TITF1/NKX2-1 gene.

OBJECTIVES: Benign Hereditary Chorea (BHC) (MIM 118700) is a rare childhood-onset movements disorder characterized by non-progressive chorea. It is usually caused by variants in the thyroid transcription factor 1 (TITF-1/NKX2-1) gene and it is associated with thyroid dysfunction and pulmonary symptoms in the brain-lung-thyroid syndrome. CASE PRESENTATION: We reported the clinical case of a toddler presenting with neurological symptoms (hypotonia, delayed motor milestones, and axial dystonia) and subclinical hypothyroidism in which we found a 'de novo' variant in the NKX2-1 gene. CONCLUSIONS: The peculiarity of our case is that the mild alteration of thyroid-stimulating hormone (TSH) levels, hypotonia, and delayed motor milestones were associated with growth hormone deficiency.

Copy Number Variation Analysis Increases the Number of Candidate Loci Associated with Pediatric Obesity.

BACKGROUND/AIMS: Obesity is a multifactorial disease caused by the interaction of genetic, environmental, and behavioral factors. Currently, only a small number of obese children undergo genetic analysis, usually when obesity is associated with dysmorphic features. The aim of this study was to identify genomic rearrangement causing obesity. METHODS: We analyzed the DNA of children and adolescents by single-nucleotide polymorphism-array (platform CytoScan HD, Affymetrix). Patients included in this study were obese with dysmorphic features and/or intellectual disabilities and/or neuropsychomotor signs. RESULTS: Ninety-four children and adolescents with obesity (9.25 ± 4.04 years old, 60 males) were enrolled in the study. Dysmorphic features were found in 64 out of 94 subjects (68.1%), intellectual disability was found in 23 subjects (24.5%), and other neuropsychomotor signs in 31 (32.9%). Copy number variations (CNVs) were identified in 43 out of 94 patients (45.7%): among these 14 subjects showed at least 1 deletion, 22 duplication, whereas 7 patients showed both deletion and duplication. In 20 subjects (13 males), CNVs were linked or possibly related with obesity; in 23 subjects, this correlation cannot be inferred. CONCLUSION: A genetic origin of obesity was detected in about half of our obese children and adolescents with associated dysmorphic features and/or intellectual disability and/or neuropsychomotor signs. In these children, array-CGH analysis can be useful to identify causative genetic mutations, with consequent advantage in therapeutic management and follow-up of these patients.

Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Central Precocious Puberty and Response to GnRHa Therapy in Children with Cerebral Palsy and Moderate to Severe Motor Impairment: Data from a Longitudinal, Case-Control, Multicentre, Italian Study.

BACKGROUND: Children affected by neurodevelopmental disability could experience early pubertal changes at least 20 times more than the general population. Limited data about central precocious puberty (CPP) among children affected by cerebral palsy (CP) are available. METHODS: This is a longitudinal, observational, retrospective, case-control study involving 22 children affected by CPP and CP (group A), 22 paired with CP but without CPP (group B), and 22 children with CPP without CP. Auxological, biochemical, and instrumental data were collected at diagnosis of CPP and at 2 follow-up visits. RESULTS: No differences were detected between groups A (at baseline) and B. At diagnosis of CPP, height SDS adjusted for target height (H-TH SDS) was significantly reduced in A than in C (-0.63 ± 1.94 versus 1.56 ± 1.38), while basal LH and oestradiol levels were significantly elevated in A than in C. During follow-up, despite an effective treatment, growth impairment deteriorated in A than in C (Δ H-SDS from diagnosis of CPP to last follow-up: -0.49 ± 0.91 versus 0.21 ± 0.33, p = 0.023). CONCLUSIONS: Diagnosis of CPP could be partially mislead in CP due to growth failure that got worse during follow-up despite therapy. CPP in CP seems to progress rapidly along time supporting the hypothesis of a more intense activation of hypothalamic-pituitary-gonadal-axis in these patients.

Ten-year longitudinal study of thyroid function in children with Down's syndrome.

BACKGROUND/AIMS: The natural history of thyroid function in children with Down's syndrome is relatively unknown. We hypothesized that in these patients the occurrence of thyroid dysfunction rises during development. METHODS: Thyroid function was assessed yearly in 145 children with Down's syndrome, all followed from birth up to 10 years of age. Heteroskedastic binary and ordinary logistic regression for repeated measures was used to evaluate the relationship of thyroid function with continuous time. RESULTS: Congenital hypothyroidism was detected in 7% of cases. The probability of acquired thyroid dysfunction increased from 30% at birth to 49% at 10 years (p < 0.001). The subclinical hypothyroidism was nearly stable during the follow-up. The probability of hypothyroidism increased from 7 to 24% at 10 years (p < 0.001). Positive anti-thyroglobulin antibodies were associated with higher odds of more severe hypothyroidism (odds ratio 3.6). Positive anti-thyroid peroxidase antibodies were a better predictor of more severe hypothyroidism (odds ratio 6.1). Diffuse hypoechogenicity on thyroid ultrasound was found in 34 out of 145 children. CONCLUSION: The probability of thyroid dysfunction increasing during development is higher than previously reported. Such children should be carefully monitored annually to early identify thyroid dysfunction.