Volume 34, Issue 5

Objectives Lysosomal storage diseases (LSD) constitute an important group of metabolic diseases, consisting of approximately 60 disorders. In some types of lysosomal diseases, enzyme replacement therapy (ERT) is administered intravenously in weekly or biweekly doses. Unfortunately, scheduled ERT during COVID-19 was disrupted. We considered the possibility of adverse outcomes caused by the disruption in the treatment of patients with lysosomal storage disorders. Methods During the COVID-19 pandemic, we conducted a questionnaire that was delivered via Internet to assess how this vulnerable patient group was affected by the pandemic in terms of their access to treatment and their disease-related symptoms. Results The questionnaire was filled out by 75 patients. There were 35 patients whose treatment dose was missed because of COVID-19. The most common reason for skipping treatment was not wanting to go to the hospital for fear of contracting COVID-19. These 35 patients missed a median of four doses of ERT (range: 1–16 dosages). Twenty-one patients (60%) claimed that they were affected physically by not taking ERT (20 mucopolysaccaridoses, 1 Fabry disease), whereas 14 (40%) did not. Conclusions Interruption of ERT during the COVID-19 pandemic may have significant consequences. It may be beneficial to switch to home treatment or reserve dedicated facilities. With proper planning and management, the treatment disruptions of this particular group can be avoided.

Objectives We performed a cross-sectional study on anthropometric and laboratory characteristics of inhabitants of Rampasasa (Flores, Indonesia). Adults were categorised according to ancestry into three groups: pygmoid (P/P, offspring of pygmoid parents, n=8), mixed pygmoid (P/N, offspring of pygmoid and non-pygmoid parents, n=12) and non-pygmoid (N/N, n=10). Children (n=28) were P/N. Methods Measurements included height, weight, sitting height, arm span, head circumference, haematological analysis and serum albumin, calcium, vitamin D, insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3). Pubertal stage and bone age was assessed in children. Anthropometric data were expressed as standard deviation score (SDS) for age. IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio were expressed as SDS for age, bone age and pubertal stage. Results Mean height SDS showed a gradient from P/P (−4.0) via P/N (−3.2) to N/N (−2.3) (−3.4, −3.1 and −2.2 adjusted for age-associated shrinking). Sitting height and head circumference showed similar gradients. Serum IGF-I SDS was similar among groups (approximately −1 SDS). IGFBP-3 SDS tended toward a gradient from P/P (−1.9) via P/N (−1.5) to N/N (−1.1), but IGF-I/IGFBP-3 ratio was normal in all groups. In P/P and P/N, mean head circumference SDS was >2 SD greater than mean height SDS. Children showed a progressive growth failure and bone age delay, delayed female pubertal onset and an initial low serum IGF-I, normal IGFBP-3 and low IGF-I/IGFBP-3 ratio. Conclusions P/P showed proportionate short stature with relative macrocephaly and relatively low IGFBP-3; P/N presented an intermediate pattern. P/N children were progressively short, showed delayed skeletal maturation, delayed puberty in girls and low IGF-I and IGF-I/IGFBP-3.

Objectives Childhood growth influences their social and psychological behavior, and abnormal growth may reflect underlying pathological etiologies. It is important to diagnose children with short stature as early as possible to be able to manage treatable causes. We aim to study etiologies and characteristics of short stature in children in Jordan. Methods This is a cross-sectional retrospective review of the medical records of children diagnosed with short stature at a referral university hospital. Clinical characteristics, auxological, laboratory, and radiological investigations were collected and analyzed. Results Among a total of 551 children diagnosed with short stature, the number of boys was significantly higher than girls, 304 (55.2%) and 247 (44.8%), respectively with a p-value of 0.015. Average age at presentation for all patients was 10.24 ± 3.23, with no significant difference between boys and girls. Pathological etiology was higher than normal variants 55.7 and 44.3%, respectively with p=0.007. Constitutional delay of growth and puberty (CDGP) was the most frequent cause in the normal variant group, 59.8%. Among the pathological group, the most common etiology was growth hormone deficiency (32.2%) with mean age of presentation of 9.40 years and was not significantly different from the age in other etiological groups, 9.44 years and p=0.931. Conclusions Growth monitoring of children should start at an early age for boys and girls. Referral to the pediatric endocrine clinic should be considered when growth problems are suspected for accurate diagnosis and etiology profiling.

Objectives Pubertal assessment is crucial as puberty is the transition from childhood to adulthood. Pubertal assessment, growth, and secular trend in puberty need to be explored further in India. The objectives were to assess Sexual Maturity Rating (SMR) among children and establish normative data of puberty from western India. We also compared age of attainment of various stages of puberty with BMI and secular trend in menarche. Methods A cross-sectional observational study was undertaken at a tertiary care pediatric center. The study population were healthy girls and boys between 6 and 18 years. Demographic data was noted. Anthropometry and SMR assessment (Tanner staging) were performed. The age of menarche was noted among the girls and their mothers. Data were analyzed using SPSS 21. Results In girls, median age of thelarche, pubarche, and menarche was 9.37 (8.5–10.2), 10.18 (9.87–10.49), and 12.55 years (12.41–12.75) respectively. There was an early appearance of thelarche but menarche was delayed in overweight-obese girls (statistically not significant). Age of menarche showed a shift to left in girls as compared to their mothers (p=0.036). In boys, median age of testicular stage 2 and pubarche was 10.7 (9.9–11.8) and 11.6 years (11.1–12.1) respectively. In overweight-obese boys the pubertal milestones were achieved earlier (statistically not significant). Conclusions Normative data on pubertal assessment from western India is presented. Age of menarche shows a shift to left in girls as compared to their mothers. Pubertal milestones were observed at a younger age in overweight obese children which was not significant.

Objectives Boys with Duchenne Muscular Dystrophy (DMD) are at increased risk for compromised bone health, manifesting as low-impact trauma long bone fractures and vertebral compression fractures. Methods In a prospective observational study, we studied bone health parameters in North Indian boys with DMD. We consecutively enrolled ambulatory boys with DMD on glucocorticoid therapy. Bone health was evaluated with X-ray spine, Dual-energy X-ray absorptiometry (DXA), serum calcium, vitamin D3 (25[OH]D), 1,25-dihyroxyvitamin D3 (1,25[OH] 2 D 3 ), serum osteocalcin, osteopontin, and N terminal telopeptide of type 1 collagen (Ntx) levels. Results A total of 76 boys with DMD were enrolled. The median age was 8.5 (interquartile range [IQR] 7.04–10.77) years. Among these, seven (9.2%) boys had long bone fractures, and four (5.3%) had vertebral compression fractures. Fifty-four (71%) boys underwent DXA scan, and among these 31 (57%) had low bone mineral density (BMD, ≤−2 z-score) at the lumbar spine. The mean BMD z-score at the lumbar spine was −2.3 (95% confidence interval [CI] = −1.8, −2.8), and at the femoral neck was −2.5 (95% CI = −2, −2.9). 25(OH)D levels were deficient in 68 (89.5%, n=76) boys, and 1,25(OH) 2 D 3 levels were deficient in all. Mean serum osteocalcin levels were 0.68 ± 0.38 ng/mL (n=54), serum osteopontin levels were 8.6 ± 4.6 pg/mL (n=54) and serum Ntx levels were 891 ± 476 nmol/L (n=54). Boys with low BMD received glucocorticoids for longer duration, in comparison to those with normal BMD (median, IQR [16.9 (6–34) months vs. 7.8 (4.8–13.4) months]; p=0.04). Conclusions Bone health is compromised in North Indian boys with DMD. BMD at the lumbar spine is reduced in more than half of boys with DMD and nearly all had vitamin D deficiency on regular vitamin D supplements. Longer duration of glucocorticoid therapy is a risk factor for low BMD in our cohort.

Objectives This study aimed to investigate automatic and voluntary motor control performances, which have an important function in maintaining balance, in children and adolescents with mucopolysaccharidosis (MPS). Methods The records of 70 patients were retrospectively analyzed. The results of Computerized Dynamic Posturography (CDP) performed according to the age and development of the individuals were examined. The results of 10 children and adolescents with MPS (mean age: 9.43 ranging from 6 to 14; four males and six females) who completed the sensory analysis, Weight-Bearing Squat Test, and Adaptation Test were retrieved from the database of the CDP. Nine healthy children and adolescents with typical development (mean age: 9.63 ranging from 6 to 14; four males and five females) were included as the control group. Results In the sensory analysis test, there was a statistically significant difference between the two groups in the visual ratio parameter. In the adaptation test, there was a statistically significant difference between the two groups in the toes up and toes down trials. There was no statistically significant difference between the groups in the Weight-Bearing Squat test at 0° knee extension and various knee flexions. Conclusions Children and adolescents with MPS should be directed to the appropriate exercise and therapy programs to develop postural and balance control, which have a significant effect on their quality of life and the ability to independently perform daily activities of living. In addition to routine hearing assessments for patients with MPS, other objective tests used in the differential diagnosis of balance and vestibular system should also be implemented.

Objectives To determine the prevalence and MRI findings of incidentally detected pituitary nonenhancing lesion on brain MRI in children, and to compare the detection rates of pituitary nonenhancing lesion according to magnetic field strength and acquisition technique. Methods Pediatric patients (≤18 years old) who underwent brain MRI with contrast-enhancement between January 2018 and September 2019 were retrospectively included (n=365). The presence, size, and signal intensity of pituitary nonenhancing lesions were assessed by two radiologists. The prevalence of pituitary nonenhancing lesions was compared between different magnetic field strengths and MRI acquisition techniques. Results Pituitary nonenhancing lesions were identified in 76 patients (20.8%). The anteroposterior diameter of pituitary nonenhancing lesion was the smallest diameter in most patients (93.4%; mean diameter ± SD of 2.4 ± 1.5 mm; range: 0.9–9.0 mm). Sixty-seven percent of the pituitary nonenhancing lesions were hypointense on T1-weighted imaging, 44.1% were hyperintense on T2-weighted imaging, and 12.9% showed low signal intensity on susceptibility-weighted imaging. There was no diffusion restriction in any of the nonenhancing lesions. There was no significant difference in the prevalence of pituitary nonenhancing lesions according to magnetic field strength, age, gender, slice thickness, or 2D vs. 3D contrast-enhanced T1-weighted imaging sequence. Conclusions Pituitary nonenhancing lesions were identified on contrast-enhanced brain MRI in 20.8% of pediatric patients, with no significant difference in the prevalence according to magnetic field strength, slice thickness, and 2D or 3D contrast-enhanced T1-weighted imaging.

Objectives In obese adults the shape of the glucose response curve during an oral glucose tolerance test (OGTT) predicts future type 2 diabetes. Patients with an incessant increase or monophasic curves have increased risk compared to those with biphasic curves. Since type 2 diabetes is associated with increased cardiometabolic risk, we studied whether differences in OGTT response curve are associated with differences in cardiometabolic risk factors in healthy adolescents across a wide body mass index (BMI) range. Methods Sixty-nine (33F/36M), white adolescents (age: 15.2 ± 1.7 years; BMI: 21.5 ± 4.7 kg/m 2 ; mean ± SD) were studied. Risk factors measured included percent body fat, blood pressure, lipids, augmentation index, reactive hyperemia, endothelin 1, plasminogen activator 1, inflammatory markers (interleukin 6, c-reactive protein), insulin secretion, insulin sensitivity (Matusda index), and disposition index (DI). Results Thirty-two subjects had biphasic responses; 35 subjects had monophasic responses and two females had incessant increases. Sex did not affect the frequency of responses. Glucose area under the curve during OGTT was greater in those with a mono vs. biphasic curves (p=0.01). Disposition index was markedly lower in subjects with a monophasic curve than in those with a biphasic curve (3.6 [2.3–5.0] vs. 5.8 [3.8–7.6], median [25th, 75th%] p=0.003). Triglyceride to high-density lipoprotein cholesterol (HDL) ratio was higher in subjects with a monophasic curve (p=0.046). Conclusions The decreased disposition index indicates that in healthy adolescents a monophasic response to OGTT is due to decreased insulin secretion relative to the degree of insulin resistance present. This was not associated with differences in most other cardiometabolic risk markers. Trial registration Clinical Trials.gov, NCT02821104.

Objectives Recent evidence linked early menarche to a higher risk of insulin-resistance (IR) and nonalcoholic fatty liver disease (NAFLD) in adulthood. We aimed to evaluate the impact of early menarche on glucose derangements and NAFLD in a sample of Italian adolescents with obesity. Methods Anthropometric and biochemical evaluations were conducted in all the enrolled 318 obese patients (mean age 12.31 ± 2.95 years). NAFLD was defined by the presence of ultrasound detected liver steatosis and/or alanine transaminase (ALT) levels >40 IU/L. Results Patients with early menarche showed both higher homeostasis model assessment of insulin-resistance (HOMA-IR) (p=0.008) and ALT (p=0.02) values, an increased prevalence of NAFLD (p=0.001), and lower Matsuda and Insulinogenic Index (IGI) values than the other obese patients. The association between early menarche and both ALT and Matsuda Index remained significant in General Linear Models (GLMs) in which respectively body mass index standard deviation score (BMI-SDS) and Matsuda Index, and BMI-SDS were included as covariates. Patients with early menarche also showed a higher risk of both HOMA-IR>3 (OR 1.69, CI 1.05–2.70, p=0.02) and NAFLD (OR 1.10, CI 1.01–1.21, p=0.03). Conclusions Girls with obesity presenting early menarche showed higher HOMA-IR levels, lower Matsuda Index and IGI values, and higher risk of NAFLD compared to girls without early menarche.

Objectives Childhood obesity is a public health concern worldwide, with rates continuing to rise, despite preventive measures. Lifestyle modification remains the mainstay in the treatment of patients with excessive weight, but unfortunately, this is not always successful. Options for medical management of obesity in the paediatric population are limited. Methods Seven adolescents (all girls, mean age 14.9 years) with a body mass index (BMI) above 98th percentile and serious complications secondary to obesity were offered an intense weight management programme. The participants were reviewed by a multidisciplinary team every two weeks for advice and support, and treated with daily subcutaneous injections of liraglutide (dose range 1.2–3.0 mg). Scores for anxiety and depression were evaluated using the Revised Child Anxiety and Depression Scale. Results The results showed a significant weight loss over the three months with an average reduction of 5.4 kg (4.2%; 95% CI 1.93–8.78; p=0.0087). The mean drop in BMI was 2.1 kg/m 2 , which is statistically significant (95% CI 0.973–3.199; p=0.0037). Resolution of complications (raised intracranial pressure and steatohepatitis) was noted following weight loss. Anxiety and depressive symptoms improved over the three-month intervention course, especially features of separation anxiety disorder. Liraglutide was well tolerated by all patients. Conclusions Liraglutide medication, alongside a dedicated multidisciplinary team guided lifestyle therapy, is effective and safe in the treatment for excessive weight in adolescents, leading to the reversal of the complications related to obesity and improvement in the psychological symptoms.

Objectives Despite the widespread diffusion of continuous glucose monitoring (CGM) systems, which includes both real-time CGM (rtCGM) and intermittently scanned CGM (isCGM), an effective application of CGM technology in clinical practice is still limited. The study aimed to investigate the relationship between isCGM-derived glycemic metrics and glycated hemoglobin (HbA1c), identifying overall CGM targets and exploring the inter-subject variability. Methods A group of 27 children and adolescents with type 1 diabetes under multiple daily injection insulin-therapy was enrolled. All participants used the isCGM Abbott’s FreeStyle Libre system on average for eight months, and clinical data were collected from the Advanced Intelligent Distant-Glucose Monitoring platform. Starting from each HbA1c exam date, windows of past 30, 60, and 90 days were considered to compute several CGM metrics. The relationships between HbA1c and each metric were explored through linear mixed models, adopting an HbA1c target of 7%. Results Time in Range and Time in Target Range show a negative relationship with HbA1c (R 2 >0.88) whereas Time Above Range and Time Severely Above Range show a positive relationship (R 2 >0.75). Focusing on Time in Range in 30-day windows, random effect represented by the patient’s specific intercept reveals a high variability compared to the overall population intercept. Conclusions This study confirms the relationship between several CGM metrics and HbA1c; it also highlights the importance of an individualized interpretation of the CGM data.

Objectives Chronic metabolic disturbances related to cancer treatment are well reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, few studies have investigated the incidence of these complications during the phase of chemotherapy. We evaluated the incidence of acute metabolic complications occurring during therapy in our cohort of patients diagnosed with ALL. Methods A prospective study involving 50 ALL pediatric patients diagnosed and treated between 2012 and 2016 in our oncology unit. We collected weight, blood pressure, fasting plasma glucose and hemoglobin A1C (HBA1c) levels during the two years of therapy. Results Obesity and overweight occurred in 43 and 25%, respectively among patients and have been reached at 12 months of chemotherapy. About 26% of the patients developed high blood pressure and 14% experienced hyperglycemias without meeting diabetes criteria. There was a significant decrease of HBA1c levels between the beginning and the end of therapy (p<0.0001). Conclusions Increase of body mass index in our ALL pediatric patients occurred during the first months of therapy and plateaued after a year of treatment. We should target this population for early obesity prevention. HbA1c levels measured during therapy did not reveal diabetes criteria. Hence, fasting blood glucose levels are sufficient to monitor ALL pediatric patients’ glycemia.

Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A . The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A . Less frequently, mutations were identified in PDX1 , HNF4A , HNF1B , and KCNJ11 . For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

Objectives Hereditary Hypophosphatemic Rickets (HHR) is a heterogeneous group of disorders characterized by hypophosphatemia. Although the X-linked dominant HHR is the most common form, the genetic etiology of HHR is variable. Recently, developed next-generation sequencing techniques may provide opportunities for making HHR diagnosis in a timely and efficient way. Methods We investigated clinical and genetic features for 18 consecutive probands and their 17 affected family members with HHR. All patient’s clinical and biochemical data were collected. We first analyzed a single gene with Next-generation sequencing if the patients have a strong clue for an individual gene. For the remaining cases, a Hypophosphatemic Rickets gene panel, including all known HHR genes by Next-generation sequencing, was employed. Results We were able to diagnosis all of the consecutive 35 patients in our tertiary care center. We detected nine novel and 10 previously described variants in PHEX (9; 50%), SLC34A3 (3; 17%), ENPP1 (3; 17%), SLC34A1 (1; 5%), CLCN5 (1; 5%), and DMP1 (1; 5%). Conclusions To delineate the etiology of HHR cases in a cost and time-efficient manner, we propose single gene analysis by next-generation sequencing if findings of patients indicate a strong clue for an individual gene. If that analysis is negative or for all other cases, a Next-generation Sequence gene panel, which includes all known HHR genes, should be employed.

Objectives Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. Methods From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. Results Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). Conclusions These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

Objectives Ochoa syndrome (UFS1; Urofacial syndrome-1) is a very rare autosomal recessive disorder caused by mutations in the HPSE2 gene that results bladder voiding dysfunction and somatic motor neuropathy affecting the VIIth cranial nerve. Niemann-Pick disease is a rare autosomal recessive lysosomal storage disorder with systemic involvement resulting from sphingomyelinase deficiency and generally occurs via mutation in the sphingomyelin phosphodiesterase-1 gene ( SMPD1 ). Case presentation Here, we report a 6-year-old girl with symptoms such as urinary incontinence, recurrent urinary tract infections, peculiar facial expression, mainly when smiling, hypertelorism, constipation, incomplete closure of eyelids during sleep and splenomegaly. Homozygote mutations in two different genes responsible for two distinct syndromes were detected in the patient. Homozygous NM_000543.5:c.502G>A (p.Gly168Arg) mutation was found in the SMPD1 gene causing Niemann-Pick disease. In addition, some of the clinical features were due to a novel homozygous mutation identified in the HPSE2 gene, NM_021828.5:c.755delA (p.Lys252SerfsTer23). Conclusions Here, we discuss about the importance of considering dual diagnosis in societies where consanguineous marriages are common. Accurate diagnosis of the patient is very important for the management of the diseases and prevention of complications.

Objectives We report an uncommon case of severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8 with 2p duplication. After ruling out all the possible etiologies of hypercalcemia, we speculated a potential contribution of 2p duplication involving 225 genes. Case presentation An 11-month old female infant with global developmental delay, failure to thrive (FTT), hypotonia, amblyopia, constipation, and recent onset emesis was admitted to the hospital after an incidental diagnosis of severe hypercalcemia. Labs revealed normal serum phosphate, serum 25 (OH) vitamin D levels, and low serum parathyroid hormone (PTH) level. Elevated urinary calcium to creatinine ratio ruled out the possibility of hypocalciuric hypercalcemia. Endocrinological evaluations, including thyroid function test, Adrenocorticotropic hormone (ACTH), Cortisol, Insulin like growth factor 1 (IGF-1) were all normal. Transient elevation of parathyroid hormone related peptide (PTHrP) level was noted, but skeletal survey, chest X-ray and lab values including low 1,25 (OH) 2 cholecalciferol, lactate dehydrogenase (LDH), uric acid (UA), erythrocyte sedimentation rate (ESR) excluded granulomatous diseases and malignancies. Further evaluation with chromosomal microarray (CMA) and whole exome gene sequencing (WES) showed an unbalanced chromosomal translocation with 2p duplication involving 225 genes. The infant showed an improvement with medical management. Conclusions 2p duplication syndrome is a rare syndrome characterized by developmental delay, feeding problems, FTT, hypotonia, constipation, and unusual facial features as noted in our case. However, hypercalcemia has been only reported once earlier in 2p duplication syndrome, which was the presenting feature of our case. We attributed this genetic syndrome as an underlying etiology for hypercalcemia after ruling out all the common potential causes of hypercalcemia.

Objectives Serious hyperinsulinemic hypoglycemia (HH) is generally the main initial symptom of hyperinsulinism. Epilepsy, without any overt feature of hypoglycemia, might be a very rare initial presentation of late-onset isolated hyperinsulinism. Case presentation We describe a case of late-onset HH in a 15-year-old boy with a history of idiopathic generalized epilepsy, now named genetic generalized epilepsy (IGE/GGE), beginning with a tonic–clonic seizure at the age of 11 years. Subsequently, absences with rare eyelid myoclonia were recorded on electroencephalogram (EEG), followed by episodes of impaired consciousness with facial myoclonia. Neurological status was normal except attention-deficit hyperactivity disorder (ADHD). At the age of 15 years, an episode of slight alteration of consciousness with neurovegetative signs could be recorded, which did not correspond to an absence status. Hypoglycemia due to hyperinsulinism was documented (clinically, biologically, and genetically). Diazoxide treatment resolved the glycopenic symptoms, the non-hypoglycemic seizures and normalized brain electrical activity allowing complete withdrawal of antiepileptic medication. Conclusions Epilepsy can be a very rare initial feature of HH starting in childhood. The occurrence of atypical features in the context of GGE as “absence statuses” with unusual vegetative symptoms and facial myoclonia might be suggestive for HH. Careful assessment and specific treatment are necessary to prevent hyperinsulinism related brain damage. Our case showed that diazoxide might also resolve seizures and normalize EEG.

Objectives Exogenous exposure to transdermal testosterone is often overlooked as a cause of precocious sexual development in children. Case presentation A 16-month-old male presented for a second opinion consultation before commencing treatment with bicalutamide and anastrozole for a presumptive diagnosis of familial gonadotropin-independent male-limited sexual precocity. Enlargement of the penis was first observed at four months of age. The initial evaluation showed isolated elevation of his plasma testosterone level; however, by 16 months, his testosterone level was prepubertal and no pathogenic variants in the LHC GR gene were identified. The history revealed that his grandfather, who had cared for him regularly in the first year of life, had used testosterone gel for treatment of hypogonadism. Conclusions Despite the 2009 “black box” warning issued by the United States Food and Drug Administration (FDA) regarding potential consequences of transdermal testosterone exposure to women and children, this continues to be an important cause of sexual precocity in children. Children are often subjected to unnecessary and costly evaluation before this exposure is recognized, underscoring the importance of obtaining a thorough medical, family, and social history tailored to the differential diagnosis.