Clinical characteristics, outcome, and predictors of neurological sequelae of persistent congenital hyperinsulinism: A single tertiary center experience.

AIM: Congenital hyperinsulinism (CHI) is a heterogeneous disease with variable genetic etiology, histopathology, and clinical phenotype. This study aims to describe the clinical characteristics of persistent CHI and evaluate long-term neurological outcome and its risk factors in a cohort of Egyptian children. METHODS: Clinical, genetic, and biochemical data of 42 patients with CHI were collected. Patients were invited for neurological assessment, electroencephalogram, and magnetic resonance imaging of the brain. RESULTS: ABCC8 mutation was found in (61%) of cases who underwent genetic testing (17/28). Five cases with homozygous biparental ABCC8 mutation responded to combined diazoxide and octreotide without needing surgery. Seven out of twenty-one patients who had pancreatectomy (33%) developed diabetes after a median period of 4.8 (range:1-10) years following surgery. Fifty-five percent of our patients had neurodevelopmental impairment at follow-up. Logistic regression analysis has shown that delayed referral to tertiary centre for more than 8 days, delayed diagnosis of CHI for more than 14 days and hospital admission for more than 30 days, are significant predictors of unfavorable neurological sequelae in CHI; (OR = 12.7 [2.56], p = 0.001), (OR = 12.7 [2.9-56], p = 0.001), and (OR = 3.8 [0.14.5], p = 0.043), respectively. CONCLUSIONS: ABCC8 mutation was the commonest genetic mutation underlying CHI in this study group. CHI cases with biparental homozygous ABCC8 mutation may show response to combined octreotide and diazoxide therapy. More than half of our patients had neurodevelopmental impairment at follow-up. Delayed referral to expert centre, delayed diagnosis and longer hospital stay are significant predictors of neurological disability in CHI cases.

The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism.

AIM: To examine the hypoglycaemic effect on neurodevelopmental outcome in patients with transient and persistent congenital hyperinsulinism (CHI) born in the 21st century. METHOD: A cohort of 117 patients (66 males, 51 females) with CHI aged 5 to 16 years (mean age 8y 11mo, SD 2y 7mo) were selected from a Finnish nationwide registry to examine all the patients with similar methods. Neurodevelopment was first evaluated retrospectively. The 83 patients with no risk factors for neurological impairment other than hypoglycaemia were recruited and 44 participated (24 males, 20 females; mean age 9y 7mo, SD 3y 1mo) in neuropsychological assessment with the Wechsler Intelligence Scale for Children, Fourth Edition and the Finnish version of the Developmental Neuropsychological Assessment, Second Edition domains of attention, language, memory, sensorimotor, and visual functioning. RESULTS: In retrospective analysis, transient and persistent CHI groups had similar prevalences of mild (22% and 18% respectively) or severe (5% and 7% respectively) neurodevelopmental difficulties. In clinical assessment, the neurocognitive profile was within the average range in both groups, but children with persistent CHI showed significant but restricted deficits in attention, memory, visual, and sensorimotor functions compared with the general population. The transient CHI group did not differ from the standardization samples. INTERPRETATION: Besides the more apparent broader neurological deficits, children with persistent CHI have an increased risk for milder specific neurocognitive problems, which should be considered in the follow-up. WHAT THIS PAPER ADDS: Children with persistent congenital hyperinsulinism showed deficits in attention, memory, visual, and sensorimotor functions. The deficits were potentially of hypoglycaemic origin. Children with transient hyperinsulinism did not differ from the general population.

EL EFECTO DE LA HIPOGLUCEMIA SOBRE EL RESULTADO NEUROCOGNITIVO EN NIÑOS Y ADOLESCENTES CON HIPERINSULINISMO CONGÉNITO TRANSITORIO O PERSISTENTE: OBJETIVO: Examinar el efecto hipoglucémico sobre el resultado del neurodesarrollo en pacientes nacidos en el siglo XXI con hiperinsulinismo congénito (HIC) transitorio y persistente. MÉTODO: Una cohorte de 117 pacientes (66 varones, 51 mujeres) con HIC de 5 a 16 años de edad (media de 8 años 11 meses, DS 2 años 7 meses) fueron seleccionados de un registro nacional finlandés para examinar a todos los pacientes con métodos similares. El neurodesarrollo se evaluó por primera vez de forma retrospectiva. Los 83 pacientes sin factores de riesgo para el deterioro neurológico distintos de la hipoglucemia fueron reclutados y 44 de ellos participaron (24 varones, 20 mujeres; edad media 9 años 7 meses, DS 3 años 1mes) en la evaluación neuropsicológica con la Escala de Inteligencia de Wechsler y la versión finlandesa de la Evaluación Neuropsicológica del desarrollo, segunda edición, incluyendo los dominios de atención, lenguaje, memoria, sensoriomotor y funcionamiento visual. RESULTADOS: En el análisis retrospectivo, los grupos de HIC transitorios y persistentes tuvieron prevalencias similares de dificultades del neurodesarrollo leves (22% y 18% respectivamente) o graves (5% y 7% respectivamente). En la evaluación clínica, el perfil neurocognitivo estuvo dentro del rango promedio en ambos grupos, pero los niños con HIC persistente mostraron déficits significativos pero restringidos en la atención, memoria, funciones visuales y sensomotrices en comparación con la población general. El grupo de HIC transitorio no difirió de las muestras de estandarización. INTERPRETACIÓN: Además de los déficits neurológicos más aparentes generalizados, los niños con HIC persistente tienen un mayor riesgo de presentar problemas neurocognitivos específicos más leves, que deben ser considerados en el seguimiento.

O EFEITO DA HIPOGLICEMIA NO RESULTADO NEUROCOGNITIVO EM CRIANÇAS E ADOLESCENTES COM HIPERINSULINEMIA CONGÊNITA TRANSITÓRIA OU PERSISTENTE: OBJETIVO: Examinar o efeito hipoglicêmico no resultado neurodesenvolvimental em pacientes com hyperinsulinemia congênita (HIC) transitória ou persistente nascidas no século 21. MÉTODO: Uma coorte de 117 pacientes (66 do sexo masculino, 51 do sexo feminino) com HIC e idades de 5 a 16 anos (média de idade 8a 11m, DP 2a 7m) foram selecionados de um registro nacional finlandês para exame com métodos similares. Primeiramente, o neurodesenvolvimento foi avaliado retrospectivamente. Os 83 pacientes sem risco para deficiência neurológica além da hipoglicemia foram recrutados, e 44 participaram (24 do sexo masculino, 20 do sexo feminino; média de idade 9a 7m, DP 3a 1m) na avaliação neuropsicológica com a escala Wechsler de Inteligência, e a versão finlandesa da Avaliação Neuropsicológica Desenvolvimental, segunda edição, nos domínios de atenção, linguagem, memória, sensório-motor, e funcionamento visual. RESULTADOS: Na análise retrospective, os grupos com HIC transitória e persistente tiveram prevalências similares de dificuldades neurodesenvolvimentais leves (22% e 18% respectivamente) ou severa (5% e 7% respectivamente). Na avaliação clínica, o perfil neurocognitivo estava dentro da média para ambos os grupos, mas crianças com HIC persistente mostraram deficits significantes, mas restritos, nas funções de atenção, de memória, visuais e sensório-motoras comparado com a população em geral. O grupo com HIC transitória não diferiu das amostras padronizadas. INTERPRETAÇÃO: Além dos deficits neurológicos mais amplos e aparentes, crianças com HIC persistente têm risco aumentado de problemas neurocognitivos específicos leves, o que deve ser considerado no acompanhamento.

Health-Related Quality of Life of Children and Adolescents With Congenital Hyperinsulinism - A Scoping Review.

Introduction: Despite improvements in diagnosis and therapeutic advances in treatment, congenital hyperinsulinism (CHI) remains a severe disease with high patient impairment. We aimed to review the literature on Health-related Quality of Life in children and adolescents with congenital hyperinsulinism and summarize the findings. Materials and Methods: For this scoping review, a literature search was conducted in PubMed and Web of Science in May 2021. Inclusion and exclusion criteria for the selection of articles were defined a priori. Results: Two hundred and forty-five (245) articles were identified through the search and screened on the basis of title and abstract. The full texts of forty articles were then assessed. Finally, four articles (published 2012-2020) describing Health-related Quality of Life in children and adolescents with congenital hyperinsulinism were included. The study designs were heterogeneous and included cross-sectional observational studies (n=2), clinical trials (n =1), and case reports (n=1) with different sample sizes. Three studies were conducted in European countries and one in Japan. The results for Health-related Quality of Life revealed inconsistencies. Conclusion: There are only a few studies looking at Health-related Quality of Life in children and adolescents with congenital hyperinsulinism. To gain a comprehensive understanding of the impact of congenital hyperinsulinism on Health-related Quality of Life in children and adolescents, it is necessary to use both generic and condition-specific instruments to measure Health-related Quality of Life of young patients in larger samples, to collect longitudinal data, and to consider qualitative research approaches.

Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social-emotional outcome of CHI patients are missing. Until now, neurodevelopmental long-term outcome in CHI patients has only been measured by questionnaires, self-, parental-, or caregiver-administered instruments. METHODS: This is a prospective study of 60 patients (median age 3.3 years, range 3 months to 57 years): 48 with a diffuse, 9 with a focal, and 3 with an atypical histology. Neurodevelopmental outcome was assessed using standardized psychological tests and questionnaires. RESULTS: 28 of 60 patients showed developmental delay (46.7%). 9 of 57 patients had cognitive deficits (15.8%), 7 of 26 patients had speech problems (26.9%), and 17 of 44 patients had motor problems (38.6%). In 5 of 53 patients, social-emotional problems were reported. Outcome and the underlying genetic defect were not correlated. CONCLUSIONS: Motor problems seem to be prominent in CHI patients. Despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients.

Vineland adaptive behavior scales to identify neurodevelopmental problems in children with Congenital Hyperinsulinism (CHI).

BACKGROUND: Congenital Hyperinsulinism (CHI) is a disease of severe hypoglycaemia caused by excess insulin secretion and associated with adverse neurodevelopment in a third of children. The Vineland Adaptive Behavior Scales Second Edition (VABS-II) is a parent report measure of adaptive functioning that could be used as a developmental screening tool in patients with CHI. We have investigated the performance of VABS-II as a screening tool to identify developmental delay in a relatively large cohort of children with CHI. VABS-II questionnaires testing communication, daily living skills, social skills, motor skills and behaviour domains were completed by parents of 64 children with CHI, presenting both in the early neonatal period (Early-CHI, n = 48) and later in infancy (Late-CHI, n = 16). Individual and adaptive composite (Total) domain scores were converted to standard deviation scores (SDS). VABS-II scores were tested for correlation with objective developmental assessment reported separately by developmental paediatricians, clinical and educational psychologists. VABS-II scores were also investigated for correlation with the timing of hypoglycaemia, gender and phenotype of CHI. RESULTS: Median (range) total VABS-II SDS was low in CHI [-0.48 (-3.60, 4.00)] with scores < -2.0 SDS in 9 (12%) children. VABS-II Total scores correctly identified developmental delay diagnosed by objective assessment in the majority [odds ratio (OR) (95% confidence intervals, CI) 0.52 (0.38, 0.73), p < 0.001] with 95% specificity [area under curve (CI) 0.80 (0.68, 0.90), p < 0.001] for cut-off < -2.0 SDS, although with low sensitivity (26%). VABS-II Total scores were inversely correlated (adjusted R2 = 0.19, p = 0.001) with age at presentation (p = 0.024) and male gender (p = 0.036), males having lower scores than females in those with Late-CHI [-1.40 (-3.60, 0.87) v 0.20 (-1.07, 1.27), p = 0.014]. The presence of a genetic mutation representing severe CHI also predicted lower scores (R2 = 0.19, p = 0.039). CONCLUSIONS: The parent report VABS-II is a reliable and specific tool to identify developmental delay in CHI patients. Male gender, later age at presentation and severity of disease are independent risk factors for lower VABS-II scores.

Use of Long-Acting Somatostatin Analogue (Lanreotide) in an Adolescent with Diazoxide-Responsive Congenital Hyperinsulinism and Its Psychological Impact.

Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic ß cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life.

High Risk of Diabetes and Neurobehavioral Deficits in Individuals With Surgically Treated Hyperinsulinism.

CONTEXT: Children with the most common and severe type of congenital hyperinsulinism (HI) frequently require pancreatectomy to control the hypoglycemia. Pancreatectomy increases the risk for diabetes, whereas recurrent hypoglycemia places children at risk of neurocognitive dysfunction. The prevalence of these complications is not well defined. OBJECTIVE: The objective was to determine the prevalence of diabetes and neurobehavioral deficits in surgically treated HI. DESIGN: This was designed as a cross-sectional study of individuals who underwent pancreatectomy for HI between 1960 and 2008. OUTCOMES: Diabetes outcomes were assessed through patient interview and medical record review. Neurobehavioral outcomes were assessed through the Adaptive Behavior Assessment System, 2nd edition (ABAS-II), and the Child Behavior Checklist (CBCL). RESULTS: A total of 121 subjects were enrolled in the study at a median age of 8.9 years (range, 3.5-50.7 y). Thirty-six percent (44 of 121) of subjects had diabetes. Nine subjects developed diabetes immediately after pancreatectomy. Of the remaining 35 subjects who developed diabetes, the median age at diabetes diagnosis was 7.7 years (range, 8 mo to 43 y). In subjects with diabetes, the median hemoglobin A1c was 7.4% (range, 6.5-12.6%), and 38 (86%) subjects required insulin. Subjects with diabetes had a greater percentage of pancreatectomy than subjects without diabetes (95% [range, 65-98] vs 65% [1-98]). Neurobehavioral abnormalities were reported in 58 (48%) subjects. Nineteen (28%) subjects had abnormal ABAS-II scores, and 10 (16%) subjects had abnormal CBCL scores. CONCLUSIONS: Children, who undergo near-total pancreatectomy are at high risk of developing diabetes. Neurobehavioral deficits are common, and developmental assessment is essential for children with HI.