Hyperinsulinism-hyperammonemia syndrome in two Peruvian children with refractory epilepsy.

OBJECTIVES: Congenital hyperinsulinism (HI) is a heterogeneous clinical disorder with great variability in its clinical phenotype, and to date, pathogenic variants in 23 genes have been recognized.  Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most frequent cause of this disease that shows an autosomal dominant pattern and is caused by an activating mutation of the GLUD1 gene, which responds favorably to the use of diazoxide. HI/HA syndrome presents with fasting hypoglycemia; postprandial hypoglycemia, especially in those with a high protein content (leucine); and persistent mild hyperammonemia. Neurological abnormalities, in the form of epilepsy or neurodevelopmental delay, are observed in a high percentage of patients; therefore, timely diagnosis is crucial for proper management. CASE PRESENTATION: We report the clinical presentation of two Peruvian children that presented with epilepsy whose genetic analysis revealed a missense mutation in the GLUD1 gene, one within exon 11, at 22% mosaicism; and another within exon 7, as well as their response to diazoxide therapy. To the best of our knowledge, these are the first two cases of HI/HA syndrome reported in Peru. CONCLUSIONS: HI/HA syndrome went unnoticed, because hypoglycemia was missed and were considered partially controlled epilepsies. A failure to recognize hypoglycemic seizures will delay diagnosis and adequate treatment, so a proper investigation could avoid irreversible neurological damage.

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group.

BACKGROUND: Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10-5 ). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non-genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow-up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non-genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible.

Association of Central Precocious Puberty with a Rare Presentation of Schimmelpenning-Feuerstein-Mims Syndrome in a Peruvian Girl.

Schimmelpenning-Feuerstein-Mims syndrome (SFM), an epidermal nevus syndrome characterized by skin lesions, has an estimated incidence of 1 per 10 000 live births. Nevus sebaceous, the most common cutaneous lesion, and verrucous nevus, the less frequent lesion, are coupled with a wide range of extracutaneous manifestations. As part of these manifestations, rarely, central precocious puberty can arise. We report the case of a 1-year-5-month-old girl who presented to the Endocrinology and Metabolism Department with breast enlargement that began at one year of age, growth of pubic and axillary hair three months later, and vaginal bleeding that occurred five months later. During clinical examination, melanocytic nevi, with a diameter ranging from 3 to 5 mm, were noted on the face. Verrucous nevi of variable size with a tendency for coalescence following the lines of Blaschko and melanocytic nevi with a diameter ranging from 3 to 6 mm were observed on the right hemibody and on the left hemibody, respectively. Right asymmetry of the lower extremities was observed. Laboratory findings showed a significant increase in the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) after the gonadotropin-releasing hormone (GnRH) stimulation test; additionally, imaging demonstrated advanced bone age and pubertal changes in the internal genitals. Analyses of the H-RAS, K-RAS, and N-RAS genes in the blood and in the skin were performed, and a missense mutation in exon 2 of the gene, H-RAS c37G > C (p.G13R), was detected in the latter. Treatment with triptorelin, a GnRH analog, was initiated, and it gave good clinical response. Epidermal nevus syndrome has a wide and variable systemic involvement. Thus, it is important to consider the development of precocious puberty for a prompt diagnosis and to strategize a multidisciplinary approach from the beginning.

Progresión clínica de la tiroiditis autoinmune en niños y adolescentes atendidos en el Instituto Nacional de Salud del Niño / Clinical progression of autoimmune thyroiditis in children and adolescents treated at the Instituto Nacional de Salud del Niño

La tiroiditis autoinmune es la causa más frecuente de hipotiroidismo adquirido en la edad pediátrica. El cuadro clínico al diagnóstico depende de la condición bioquímica en la que se encuentre y el seguimiento es fundamental para adoptar las medidas terapéuticas que garanticen un adecuado crecimiento y desarrollo. Objetivo. Describir la progresión clínica de la tiroiditis autoinmune en niños y adolescentes. Diseño. Estudio de serie de casos, longitudinal y retrospectivo. Lugar. Servicio de Endocrinología, Instituto Nacional de Salud del Niño, Lima, Perú (institución docente). Participantes. Niños y adolescentes con tiroiditis autoinmune. Intervenciones. Sesenta y cinco pacientes con tiroiditis autoinmune (58 mujeres y 7 varones), menores de 18 años, atendidos entre los años 2000 y 2012, tuvieron seguimiento por más de un año, con evaluaciones clínicas y bioquímicas periódicas. Se excluyó del estudio a los portadores de síndromes genéticos o diabetes mellitus tipo 1. Principales medidas de resultados. Progresión clínica de la tiroiditis autoinmune. Resultados. El bocio (78,5 por ciento) fue el signo predominante y a la vez factor de riesgo para evolucionar a hipotiroidismo establecido (adquirido) en quienes debutaron con hipotiroidismo subclínico. Al ingreso, el 48 por ciento de prepúberes presentó disfunción tiroidea frente al 26,6 por ciento de los púberes. De la población total, 46 por ciento tuvo hipotiroidismo establecido, 26 por ciento hipotiroidismo subclínico y 23 por ciento estado eutiroideo. El 27 por ciento de eutiroideos y 47 por ciento de hipotiroideos subclínicos evolucionaron a hipotiroidismo establecido. No hubo diferencia estadísticamente significativa de los puntajes Z promedio de talla o IMC al diagnóstico o durante el seguimiento. Conclusiones. Los niños y adolescentes con tiroiditis autoinmune que debutan en estado eutiroideo o hipotiroideo subclínico tienen riesgo alto de evolucionar a hipotiroidismo establecido, siendo...

Autoimmune thyroiditis is the most common cause of hypothyroidism in children. Clinical diagnosis depends on biochemical condition and monitoring is essential to adopt therapeutic measures and ensure proper growth and development. Objective. To describe the clinical progression of autoimmune thyroiditis in children and adolescents. Design. Retrospective, longitudinal series of cases study. Setting. Department of Endocrinology, Instituto Nacional de Salud del Niño, Lima, Peru (a teaching institution). Participants.Children and adolescents suffering of autoimmune thyroiditis. Interventions. Sixty-five patients-58 women and 7 men- under the age of 18 suffering of autoimmune thyroiditis and admitted between 2000-2012 were followed with clinical and biochemical evaluations over one year; carriers of genetic syndromes or with type 1 diabetes mellitus were excluded. Main outcome measures. Clinical progression of autoimmune thyroiditis. Results. Goiter (78.5 per cent) was a predominant sign and risk factor for development of acquired hypothyroidism in those who debuted with subclinical hypothyroidism. At admission 48 per cent of prepubescent infants presented thyroid dysfunction compared with 26.6 per cent of pubescent subjects. Out of the total population 46 per cent suffered of acquired hypothyroidism, 26 per cent subclinical hypothyroidism, and 23 per cent were euthyroid; 27 per cent of euthyroid patients and 47 per cent of subjects with subclinical hypothyroidism evolved into acquired hypothyroidism. There was no statistically significant difference in the mean Z score for height or BMI at diagnosis nor during follow-up. Conclusions. Children and adolescents with autoimmune thyroiditis debuting as euthyroid or with subclinical hypothyroidism had a high risk of developing acquired hypothyroidism. It seems important to monitor thyroid function for timely initiation of hormone replacement therapy...