Euthyroid sick syndrome and its association with complications of type 1 diabetes mellitus onset.

OBJECTIVE: To evaluate (i) the prevalence and association of euthyroid sick syndrome (ESS) [decreased FT3 and/or FT4 and normal/decreased TSH] with severity indexes of type 1 diabetes mellitus (T1DM) onset such as diabetic ketoacidosis (DKA) and kidney damage [acute kidney injury (AKI) based on KDIGO criteria, acute tubular necrosis (ATN), renal tubular damage (RTD)], (ii) relationship between clinical/metabolic parameters at T1DM onset and thyroid hormones, and (iii) ESS as a prognostic indicator of delayed recovery from kidney damage. METHODS: A total of 161 children with T1DM onset were included. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin (NGAL) and/or tubular reabsorption of phosphate <85% and/or fractional excretion of Na>2%. ATN was defined by RTD+AKI. RESULTS: Of 161 participants, 60 (37.3%) presented ESS. It was more prevalent in case of more severe T1DM presentation both in terms of metabolic derangement (DKA) and kidney function impairment (AKI, RTD and ATN). Only ATN, however, was associated with ESS at adjusted analysis. FT3 inversely correlated with serum triglycerides and creatinine, and urinary calcium/creatinine ratio and NGAL. Participants with euthyroidism showed earlier recovery from AKI than those with ESS. ESS spontaneously disappeared. CONCLUSIONS: ESS is associated with T1DM onset severity and spontaneously disappears. ESS delayed the recovery from AKI. IMPACT: This is the first longitudinal study describing in detail the relationship between clinical/metabolic factors at type 1 diabetes mellitus (T1DM) onset and thyroid hormones, with particular attention to the relationship between diabetic ketoacidosis (DKA)-related kidney function impairment and euthyroid sick syndrome (ESS). Participants with more severe T1DM onset presentation both in terms of metabolic derangement and kidney function impairment had an increased prevalence of ESS. Children with ESS had a slower recovery from acute kidney injury compared with those without ESS. ESS spontaneously disappeared in all participants.

Rare PHEX intron variant causes complete and severe phenotype in a family with hypophosphatemic rickets: a case report.

OBJECTIVES: Lower limb deformities in children need careful orthopedic evaluation to distinguish physiological forms from pathological ones. X-linked hypophosphatemia (XLH) is a rare hereditary condition caused by PHEX gene mutations where tibial varum can be the first sign. CASE PRESENTATION: We report a family presenting with severe tibial varum, harbouring a rare PHEX intron mutation, c.1586+6T>C. This is the first clinical description available in literature for this variant. Despite the previous prediction of a mild phenotype in functional study, our patients showed important bone deformities, rickets and impaired growth since infancy followed by severe bone pain, hearing loss and reduced life quality in adulthood. Burosumab therapy improved biochemical and radiological findings in children and ameliorated quality of life in adults. CONCLUSIONS: This case demonstrated c.1586+6T>C causes a severe XLH phenotype, responsive to Burosumab. Familial genetic screening, enlarged to intronic region analysis, when XLH is suspected, allows precocious diagnosis to start timely the appropriate treatment.

Central precocious puberty during COVID-19 pandemic and sleep disturbance: an exploratory study.

BACKGROUND: Increased incidence of central precocious puberty (CPP) after coronavirus infectious disease-19 lockdown has been reported. Our study aims in investigating changes in CPP rates and in sleep patterns in CPP and healthy controls. METHODS: CPP were retrospectively evaluated from April 2020 to April 2021. Parents of girls diagnosed with CPP during lockdown and of matched healthy controls filled out a questionnaire about sleep disturbances (SDSC questionnaire) and sleep schedules. RESULTS: Thirty-five CPP and 37 controls completed the survey. Incidence of new CPP cases significantly increased in 2020-2021 compared to 2017-2020 (5:100 vs 2:100, p = 0.02). Sleep disturbance rates did not differ between CPP and healthy controls before lockdown. During lockdown, CPP reported higher rates of sleep disturbs for total score (p = 0.005), excessive somnolence (p = 0.049), sleep breathing disorders (p = 0.049), and sleep-wake transition disorders (p = 0.005). Moreover, CPP group more frequently shifted toward later bedtime (p = 0.03) during lockdown compared to controls. Hours of sleep and smartphone exposure around bedtime did not differ between groups. CONCLUSIONS: Our study confirms the observation of increased incidence of CPP after lockdown measures. Additionally, CPP showed higher rates of sleep disturbances and later bedtime compared to controls. The causality link between sleep disturbances and CPP should be further investigated to gain knowledge in this association.

Growth Hormone Receptor (GHR) 6Ω Pseudoexon Activation: a Novel Cause of Severe Growth Hormone Insensitivity.

CONTEXT: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies. OBJECTIVE: This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals. METHODS: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. RESULTS: We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation. CONCLUSION: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

CONTEXT: Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies. OBJECTIVE: Identification of the genetic cause of growth failure in 3 'classical' GHI subjects. DESIGN: A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function. RESULTS: We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation. CONCLUSION: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.

Genetic Evaluation of Patients With Delayed Puberty and Congenital Hypogonadotropic Hypogonadism: Is it Worthy of Consideration?

Delayed puberty is a common reason of pediatric endocrinological consultation. It is often a self-limited (or constitutional) condition with a strong familial basis. The type of inheritance is variable but most commonly autosomal dominant. Despite this strong genetic determinant, mutations in genes implicated in the regulation of hypothalamic-pituitary-gonadal axis have rarely been identified in cases of self-limited delayed puberty and often in relatives of patients with congenital hypogonadotropic hypogonadism (i.e., FGFR1 and GNRHR genes). However, recently, next-generation sequencing analysis has led to the discovery of new genes (i.e., IGSF10, HS6ST1, FTO, and EAP1) that are implicated in determining isolated self-limited delayed puberty in some families. Despite the heterogeneity of genetic defects resulting in delayed puberty, genetic testing may become a useful diagnostic tool for the correct classification and management of patients with delayed puberty. This article will discuss the benefits and the limitations of genetic testing execution in cases of delayed puberty.

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study.

BACKGROUND: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. METHODS: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2-8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17ß-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. RESULTS: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). CONCLUSIONS: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study.

PURPOSE: Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty. METHODS: We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2-8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2-8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9-14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients. RESULTS: No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:-0.35; p:0.02), Luteinizing Hormone (r:-0.35; p:0.03), FSH (r:-0.37; p:0.02), and (17)estradiol (r: -0.36; p:0.02). CONCLUSIONS: We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome, GH deficiency, Arnold Chiari malformation and pituitary hypoplasia.

BACKGROUND: Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder (prevalence 1:125,000) characterised by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa and short stature. The known genetic causes are point mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) (5%). CASE PRESENTATION: We describe, for the first time in literature, a RTS Caucasian girl, 14-year-old, with growth hormone (GH) deficiency, pituitary hypoplasia, Arnold Chiari malformation type 1, double syringomyelic cavity and a novel CREBBP mutation (c.3546insCC). CONCLUSION: We hypothesize that CREBBP mutation we have identified in this patient could be responsible also for RTS atypical features as GH deficiency and pituitary hypoplasia.