Background: Autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in children. The natural outcome of AIT in childhood has been reported previously however follow-up duration is generally short and results variable.Objectives: To characterize clinical and biochemical findings at presentation of AIT, evaluate long-term outcomes and assess which factors at presentation predict evolution over time.Study cohort: 201 children under 18 years of age at presentation (82% female) were enrolled. Subjects were divided into five subgroups according to thyroid stimulating hormone (TSH) level at referral.Results: Mean follow-up was 8.1 years (range 0-29 years). At presentation, 34% of patients had overt hypothyroidism, 32% subclinical hypothyroidism (SCH), 16% compensated hypothyroidism, 14% were euthyroid, and 3.7% had Hashitoxicosis. Children with overt hypothyroidism were younger (10.6 vs. 13.2 years) and had higher thyroid peroxidase antibody titers. At the time of the study, levothyroxine (LT 4 ) therapy was required in 26% of children who were euthyroid at presentation, 56% of SCH patients, 83-84% of those with TSH above 10 mIU/L, and 57% of those with Hashitoxicosis. Over the years, 16% of children presenting with overt hypothyroidism stopped therapy. Free T 4 at presentation was the only predictor of outcome over time.Conclusions: Our findings suggest that only 26% children who were euthyroid at presentation developed hypothyroidism, whereas over 50% of those with SCH went on to require treatment. Of those presenting with overt hypothyroidism, 16% recovered with time. The only predictive parameter for LT 4 therapy at the end of the study was free T 4 levels at presentation. Long-term follow-up is required to determine ongoing therapy needs and screen for additional autoimmune diseases.

<b><i>Background:</i></b> An association between hearing impairment (HI) and congenital hypothyroidism (CH) has been reported previously. However, in general, studies were retrospective and had small sample sizes, and the results were variable and inconclusive. The aim of our study was to assess the prevalence of HI among patients with CH and to examine factors potentially predictive of HI including severity of CH, etiology of CH, and timing of treatment initiation. <b><i>Methods:</i></b> Audiometry was undertaken prospectively in 66 patients aged 3–21 years diagnosed with primary CH and 49 healthy matched controls. All patients with HI underwent examination by an otolaryngologist, and in patients with sensorineural loss, brainstem evoked response audiometry was performed. A next-generation sequencing (NGS) panel for genes involved in deafness was performed in patients with sensorineural HI to exclude additional genetic etiologies. <b><i>Results:</i></b> HI was found in 19 patients (28.7%). Among them, 5 (7.6%) had moderate to severe bilateral sensorineural impairment and 14 (21.2%) had mild conductive HI. Conductive HI was bilateral in 5 of these patients (36%). None of the controls had HI. No specific etiology was found in patients with HI, and no differences were identified in age at diagnosis, age at initiation of levothyroxine (LT₄) therapy, gender, or ethnicity between patients with and without HI. A nonsignificant trend toward lower mean screening TT₄ levels was found in patients with HI (compared to those without HI) (3.42 vs. 5.34 μg/dL, <i>p</i> = 0.095). No pathogenic variants in genes attributed to HI were identified by NGS in the 5 patients with sensorineural deafness, indicating that HI in these patients was likely attributable to CH rather than other genetic etiologies. <b><i>Conclusions:</i></b> Our findings indicate a high prevalence of HI among patients with CH, predominantly of the conductive type. HI was not associated with the etiology of CH or with delayed initiation of LT₄ therapy. Audiometry is recommended for children diagnosed with CH and repeat monitoring may be warranted to identify acquired HI and to prevent long-term sequelae of undiagnosed deafness.

Objective: Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. Methods: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two patients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. Conclusions: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management, and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.

Niemann-Pick disease Type C (NPC) is a rare autosomal recessive neurovisceral lysosomal disorder. Perinatal and early infantile onset NPC are the most severe types of the disease. Early infantile type is characterized by a rapidly progressive neurodegenerative course, which entails significant morbidity and usually results in death within 5 years. Miglustat, an iminosugar that selectively inhibits the glycosylceramide synthase enzyme, is known to stabilize or delay neurological progression in individuals with NPC, but its impact on affected infants is yet to be elucidated. We present two siblings with early infantile NPC due to the previously reported devastating homozygous mutation c.2279_2281delTCT in NPC1 . Their considerably discrepant neurological disease courses were dependent on the timing of initiation of miglustat treatment. The outcomes support the significant role of early treatment with miglustat in the disease course of early infantile NPC and suggest that therapy should be considered even before the occurrence of neurological involvement. Moreover, this report emphasizes the importance of early diagnosis, in light of the availability of a potential disease-modifying medication.

Context and objective:Ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), have key roles in appetite control and growth regulation. To date, only few mutations of GHSR have been identifi ed in children with obesity and short stature. We hypothesized that mutations in ghrelin or GHSR will result in disrupted growth and weight regulation in children. Design: A total of 98 subjects (38 females and 60 males) were enrolled with failure to thrive (FTT) (n = 9), GH defi ciency (GHD) (n = 44), idiopathic short stature (ISS) (n = 22) or obesity (n = 23). The coding exons of both ghrelin and GHSR genes were screened for mutations by sequencing. Results: Seven different sequence changes were identifi ed in GHSR , two of them novel and fi ve described previously. One previously described sequence change (p.L72M) in the ghrelin gene was identifi ed in fi ve patients; however, the same variant was identifi ed at a higher rate in controls. A high rate of sequence changes was shown in ghrelin and its receptor, GHSR , in our population, but none of these changes affected the coding region of the protein. Conclusions:Despite the major role of ghrelin in growth and appetite regulation, our results indicate that mutations in ghrelin and GHSR do not explain short stature and weight regulation disorders in children in our population.

Background: Disorders of sex development (DSD) are classified as a congenital discrepancy between external genitalia, gonadal and chromosomal sex. Despite extensive laboratory and imaging investigations, the etiology of DSD is unknown in more than 50% of patients and the diagnosis is often delayed to the second decade of life. Our objective was to evaluate the etiology of DSD by whole-exome sequencing (WES) in children in whom hormonal and candidate gene approaches had not identified the etiology. Methods: Nine patients diagnosed with DSD (eight 46,XY and one 46,XX) were enrolled. Patients underwent hormonal evaluation, including ACTH, GnRH and hCG tests. Candidate genes were sequenced in accordance with the hormonal results. WES was performed for the probands and their parents. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient with fusion of the labia majora. In six of the nine patients (66%), a pathogenic mutation was identified by WES that explained the phenotype: four known DSD-causing genes—POR, CHD7, HSD17B3 and WT1—and two novel genes—BMP4 and RFXP2. In three patients, variants of unknown significance were found. An 11-y-old boy had a novel de-novo mutation in BMP4. In humans, mutations in this gene, encoding bone morphogenetic protein 4, are associated with autosomal dominant microphthalmia. BMP4 is expressed in the urethral epithelium and has a role in the development of external genitalia and the pituitary. This is the first report of a BMP4 mutation in a child with DSD. A 12-y-old boy had a mutation in RFXP2, encoding insulin-like 3 hormone receptor, which has been previously reported in adult males with cryptorchidism. This is the first case of an RFXP2 mutation in a child with DSD. Conclusions: WES has a crucial role in early diagnosis of the etiology of DSD, making extensive endocrine testing unnecessary, and has important implications for sex of rearing decisions.

Background and Aims: Growth impairment is common in children with inflammatory bowel diseases (IBD). However, the magnitude of short stature at adulthood is not well characterized. We aimed to determine the prevalence and predictors of growth impairment at diagnosis and adulthood in children with IBD. Methods: Height z-scores at diagnosis of IBD and at adulthood among 291 children with Crohn's disease (CD) and 125 with ulcerative colitis (UC) were retrieved retrospectively and compared to matched controls. Growth impairment at diagnosis was defined as height z-score for age less than or equal to-1 and short stature at adulthood as less than or equal to-2. Results: Mean height z-score at adulthood in subjects with CD or UC was significantly different from controls although mean height did differ in males only (CD 172.3 cm ± 6.7, UC 172.7 cm ± 5.3, controls: 174.2 cm ± 7.3, p = 0.003 and p = 0.047, respectively). Diagnosis prior to final stage of puberty and male gender were risk factors for being short statured at adulthood in CD (mean difference [MD] 2.5, p = 0.013 and MD 6.25, p = 0.001, respectively) and UC (MD 4.9, p = 0.011 and MD 3.3, p = 0.034, respectively). Conclusion: Increased proportion of pediatric-onset IBD patients has growth impairment at adulthood. Male gender and diagnosis prior to puberty were found to impose risk for reduced adult height in both diseases.