Lysosomal acid lipase deficiency in pediatric patients: a scoping review

Abstract Objective: Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review. Sources: Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020. Summary of the findings: The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases. Conclusions: Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.

Lysosomal acid lipase deficiency in Brazilian children: a case series / Deficiência de lipase ácida lisossomal em crianças brasileiras: casuística

Abstract Objective: To describe the demographic, clinical, laboratory and molecular characteristics of patients with lysosomal acid lipase deficiency. Methods: A retrospective review of the medical records of children with the disease. Results: Seven children with lysosomal acid lipase deficiency (5 male; 2 female); 6 were mixed race, and 1 was black. The mean ages at the first onset of symptoms and at diagnosis were 5.0 years (4 months to 9 years) and 6.9 years (3-10 years), respectively. Symptom manifestations at onset were: 3 patients had abdominal pain, one had bone/joint pain due to rickets, and 1 had chronic diarrhea and respiratory insufficiency due to interstitial pneumonitis. One was asymptomatic, and clinical suspicion arose due to hepatomegaly. Six patients had hepatomegaly, and none had splenomegaly. Two patients were siblings. Enzymatic assay and molecular analysis confirmed the diagnoses. Genetic analysis revealed a rare pathogenic variant (p.L89P) in three patients, described only once in medical literature and never described in Brazil. None of those patients were related to each other. Lysosomal acid lipase deficiency was previously described as an autosomal recessive disease, but three patients were heterozygous and undoubtedly had the disease (low enzyme activity, suggestive lab findings and clinical symptoms). Conclusion: This case series supports that lysosomal acid lipase deficiency can present with highly heterogeneous signs and symptoms among patients, but it should be considered in children presenting with gastrointestinal symptoms associated with dyslipidemia. We describe a rare variant in three non-related patients that may suggest a Brazilian genotype for lysosomal acid lipase deficiency.

Resumo: Objetivo: Descrever as características demográficas, clínicas, laboratoriais e moleculares de pacientes com deficiência de lipase ácida lisossomal. Métodos: Análise retrospectiva dos prontuários médicos de crianças com a deficiência de lipase ácida lisossomal. Resultados: Sete crianças com deficiência de lipase ácida lisossomal (5 M:2F); seis eram pardas e uma negra. As faixas etárias no início dos sintomas e no diagnóstico foram 5 anos (4 meses a 9 anos) e 6,9 anos (3 a 10 anos), respectivamente. As manifestações dos sintomas no início foram as que seguem: três pacientes apresentaram dor abdominal, um apresentou dor nos ossos/articulações devido a raquitismo e um apresentou diarreia crônica e insuficiência respiratória devido à pneumonite intersticial. Os outros não apresentaram sintomas e a suspeita clínica surgiu devido à hepatomegalia. Seis pacientes apresentaram hepatomegalia e um apresentou esplenomegalia. Dois pacientes eram irmãos. O ensaio enzimético e a análise molecular confirmaram os diagnósticos. A análise genética revelou uma variante patogênica rara (p.L89P) em três pacientes, descrita uma única vez na literatura médica e nunca descrita no Brasil. Nenhum desses pacientes tinha parentesco com os outros. A deficiência de lipase ácida lisossomal foi anteriormente descrita como uma doença recessiva autossômica, porém três pacientes eram heterozigotos e, sem dúvida, apresentaram a doença (atividade enzimática baixa, achados laboratoriais sugestivos e sintomas clínicos). Conclusão: Esta casuística afirma que a deficiência de lipase ácida lisossomal pode se manifestar com sinais e sintomas altamente heterogêneos entre os pacientes, porém deve ser considerada em crianças que apresentam sintomas gastrointestinais associados à dislipidemia. Descrevemos uma variante rara em três pacientes não relacionados que pode sugerir um genótipo brasileiro para deficiência de lipase ácida lisossomal.

Deficiencia de lipasa ácida lisosomal, una patología infrecuente / Lysosomal acid lipase deficiency, a rare pathology

Resumen El déficit de lipasa ácida lisosomal es una enfermedad genética poco prevalente, con alta morbimortalidad en niños y adultos. Se caracteriza por alteración del metabolismo lipídico que genera depósitos de ésteres de colesterol y triglicéridos en el organismo. La presentación clínica depende de la actividad enzimática. Se debe sospechar en pacientes con alteraciones lipídicas o alteraciones hepáticas después de descartar otros diagnósticos. Actualmente existe la opción de utilizar enzima recombinante, la cual puede mejorar los parámetros lipídicos y hepáticos, así como detener la progresión de la enfermedad. Es imperioso realizar el diagnóstico oportuno para iniciar de forma temprana el tratamiento específico, con el fin de prevenir la morbimortalidad. Se llevó a cabo revisión de la literatura en torno del déficit de lipasa ácida lisosomal, para orientar acerca de su fisiopatología, manifestaciones clínicas, diagnóstico y tratamiento.

Abstract Lysosomal acid lipase deficiency is a genetic disease with a low prevalence and high morbidity and mortality in children and adults. It is characterized by an alteration of lipid metabolism, which generates cholesterol and triglyceride esters deposits in the body. Its clinical presentation depends on enzymatic activity. This condition should be suspected in patients with lipid or liver alterations after ruling out other diagnoses. Currently, there is the option of using a recombinant enzyme, which can improve lipid and liver parameters, as well as disease progression. Establishing a timely diagnosis in order to initiate specific treatment early is imperative for the prevention of morbidity and mortality. The purpose of this work is to perform a review of the literature about lysosomal acid lipase deficiency and to guide about its pathophysiology, clinical manifestations, diagnosis and treatment.

Importância da biópsia hepática no diagnóstico da deficiência de lipase ácida lisossomal: relato de caso / Importance of liver biopsy in the diagnosis of lysosomal acid lipase deficiency: a case report

RESUMO Objetivo: Descrever a doença de depósito de ésteres de colesterol (DDEC) e a importância da biópsia hepática na realização do diagnóstico. Descrição do caso: Paciente feminina, dois anos e dez meses de idade, com queixa de aumento do volume abdominal secundário à hepatomegalia há quatro meses. Ultrassonografia abdominal demonstrou hepatomegalia e esteatose hepática. Exames laboratoriais mostraram aumento de enzimas hepáticas e dislipidemia. A biópsia hepática foi compatível com DDEC. Comentários: Embora a medida da atividade enzimática seja o padrão-ouro para o diagnóstico de DDEC, a biópsia hepática é muito útil na investigação de casos suspeitos, particularmente quando há outros diagnósticos diferenciais a serem considerados.

ABSTRACT Objective: To describe a case of cholesteryl ester storage disease (CESD) and discuss the importance of liver biopsy for diagnosis. Case description: A female patient, aged two years and ten months, presented with an increased abdominal volume following hepatomegaly for four months. Abdominal ultrasound demonstrated hepatomegaly and hepatic steatosis. Laboratory tests showed elevated liver serum enzymes and dyslipidemia. Liver biopsy was consistent with CESD. Comments: Although measuring enzyme activity is the gold standard for CESD diagnosis, liver biopsy is very helpful when investigating suspected cases of CESD, particularly upon other differential diagnoses to be considered.

Guía colombiana para el diagnóstico de la deficiencia de lipasa ácida / Colombian Guidelines for Diagnosis of Lipase Acid Deficiency

Resumen Introducción: la deficiencia de lipasa ácida lisosomal (LAL-D) es una entidad de herencia autosómica recesiva que lleva a la acumulación de esteres de colesterol y triglicéridos en el hígado, bazo y otros órganos. La edad de inicio y la tasa de progresión son muy variables, lo que posiblemente sea explicado por las mutaciones presentes en el gen LIPA. Las manifestaciones clínicas son las mismas que para otras patologías hepáticas, cardiovasculares y metabólicas, lo que hace difícil reconocerla en la práctica clínica. Objetivo: proveer una guía que permita a los clínicos reconocer los principales grupos de riesgo en los cuales se debe sospechar de LAL-D y mejorar su diagnóstico. Metodología: este documento se diseñó como un consenso de expertos en el cual participaron médicos especialistas en gastroenterología, hepatología, endocrinología, genética, patología y pediatría. Se realizó una revisión de la literatura acerca de las manifestaciones clínicas y de las herramientas para el diagnóstico de LAL-D y se siguió la metodología de técnica de grupo nominal. Resultados: se generaron algoritmos diagnósticos por consenso para cada uno de los grupos de riesgo, que facilitaran la sospecha y el diagnóstico de LAL-D. Conclusiones: esta guía propone algoritmos para el diagnóstico de LAL-D con base en el consenso clínico, que buscan optimizar la ruta diagnóstica en los pacientes con dicha patología.

Abstract Introduction: Lysosomal acid lipase deficiency (LAL-D) is an inherited autosomal recessive entity that leads to the accumulation of cholesterol and triglyceride esters in the liver, spleen and other organs. The age of onset and rate of progression vary greatly, possibly explained by mutations of the LIPA gene. Clinical manifestations are the same as those of other hepatic, cardiovascular and metabolic pathologies which makes it difficult to recognize in clinical practice. Objective: The objectives of these guidelines is to help clinicians recognize the major groups at risk for LAL-D and to improve its diagnosis. Methodology: This document was designed as a consensus of experts in gastroenterology, hepatology, endocrinology, genetics, pathology and pediatrics. A review of the literature regarding clinical manifestations and tools for diagnosis of LAL-D was conducted and the nominal group technique was followed. Results: Diagnostic algorithms which facilitate suspicion and diagnosis of LAL-D were generated by consensus for each of the risk groups. Conclusions: This guide proposes algorithms for the diagnosis of LAL-D based on clinical consensus. The algorithms seek to optimize diagnosis for patients with this pathology.

Wolman disease with novel mutation of LIPA gene in a Chinese infant / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore the clinical characteristics of Wolman disease and diagnostic methods using enzymatic and molecular analysis.</p><p><b>METHOD</b>Lysosomal acid lipase activity was measured using 4-methylumbelliferyl oleate in the leukocytes of an infant suspected of Wolman disease and LIPA gene mutational analysis was performed by PCR and direct sequencing in the proband and his parents. After the diagnosis was confirmed, the clinical, biochemical, radiological and histopathological findings in this case of Wolman disease were retrospectively reviewed.</p><p><b>RESULT</b>The sixteen-day-old boy was failing to thrive with progressive vomiting, abdominal distention and hepatosplenomegaly. Abdominal X-ray revealed adrenal calcifications which were confirmed on abdominal CT scan. Xanthomatosis were observed on enlarged liver, spleen and lymph nodes during abdominal surgery. Liver and lymph node biopsy showed foamy histiocytes. The lysosomal acid lipase activity in leukocytes was 3.5 nmol/(mg·h) [control 35.5 - 105.8 nmol/(mg·h)]. Serum chitotriosidase activity was 315.8 nmol/(ml·h) [control 0 - 53 nmol/(ml·h)]. The patient was homozygote for a novel insert mutation allele c.318 ins T, p. Phe106fsX4 in exon 4 on LIPA gene. His both parents were carriers of the mutation.</p><p><b>CONCLUSION</b>The clinical features of Wolman disease include early onset of vomiting, abdominal distention, growth failure, hepatosplenomegaly and bilateral adrenal calcification after birth. A plain abdominal X-ray film should be taken to check for the typical pattern of adrenal calcification in suspected cases of Wolman disease. The enzymatic and molecular analyses of lysosomal acid lipase can confirm the diagnosis of Wolman disease.</p>

Wolman disease: diagnosis by leucocyte acid lipase estimation.

Wolman disease is a rare fatal autosomal recessive disorder caused by absence of acid lipase enzyme leading to accumulation of cholesterol ester. Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life. Progressive mental deterioration may occur after few weeks of onset of symptoms. Adrenal calcification seen on X-ray abdomen, USG or CT scan is the hallmark of Wolman disease. For the first time in Indian literature, the authors report a case of Wolman disease that was confirmed by acid lipase enzyme estimation.

Wolman disease in an Egyptian patient

Lysosomal acid lipase deficiency leads to accumulation of cholesteryl esters and triglycerides in different body tissues. This disorder is manifested in two clinical forms; cholesteryl ester storage disease which is a benign adult form and Wolman disease [WD], a fatal autosomal recessive form. We present an Egyptian infant with WD whose diagnosis was based on clinical, laboratory and imaging features. This is the first reported patient with WD from Egypt

[Wolman disease: a case report]

The Wolman disease is a rare autosomal recessive disorder associated with reduced activity of lysosomal acid lipase [LAL] witch leads to the tissue accumulation of cholestryl esters and triglycerides. The authors report a case of 3 month-old infant who was admitted for abdominal distension with hepato-splenomegaly, diarrhea, vomiting, anemia and inanition. The diagnosis was made on the radiological evidence of bilateral adrenal calcifications. The patient died during the first 3 months of life. It is recommended that plain abdominal X-Ray must be obtained to check for the typical pattern of adrenal calcification in any young infant with evidence of a storage disease without dysmorphic features

Wolman's disease--a case report.

Wolman's disease is a rare autosomal recessive lysosomal storage disorder. We report a case, which we identified with foamy histiocytes in bone marrow and adrenal calcification in radiological imaging. The diagnosis can be made on minimal investigation when clinically suspected. But cytogenetic study is required to substantiate the diagnosis further.

Imaging Findings of Neonatal Adrenal Disorders

In newborn infants, normal adrenal glands are characterized by a relatively thin echogenic center surroundedby a thick, hypoechoic cortical rim as seen on ultrasound (US). Various disorders involving the neonatal adrenalgland include adrenal hemorrhage, hyperplasia, cyst, Wolman's disease, and congenital neuroblastoma. Adrenalhemorrhage is the most common cause of an adrenal mass in the neonate, though differentiation between adrenalhemorrhage and neuroblastoma is in many cases difficult. We describe characteristic US, CT and MR imaging findingsin neonates with various adrenal disorders.

Imaging Findings of Neonatal Adrenal Disorders

In newborn infants, normal adrenal glands are characterized by a relatively thin echogenic center surroundedby a thick, hypoechoic cortical rim as seen on ultrasound (US). Various disorders involving the neonatal adrenalgland include adrenal hemorrhage, hyperplasia, cyst, Wolman's disease, and congenital neuroblastoma. Adrenalhemorrhage is the most common cause of an adrenal mass in the neonate, though differentiation between adrenalhemorrhage and neuroblastoma is in many cases difficult. We describe characteristic US, CT and MR imaging findingsin neonates with various adrenal disorders.

Woman's disease: the King Faisal specialist Hospital and research centre experience.

Wolman's disease is a rare autosomal recessive lysosomal storage disease. A recent review indicates that approximately 50 patients have been reported in the world. Reports of patients from the Arabian peninsula are rare due to lack of awareness among pediatricians. We retrospectively reviewed the clinical, radiological, biochemical and histopathological findings of four Saudi patients diagnosed with Wolman's disease at King Faisal Specialist Hospital and Research Centre. The diagnosis was confirmed by deficient acid lipase activity in the leukocytes and fibroblasts, which was measured using 4-methylumbelliferyl palmitate. All patients were failing to thrive with progressive hepatosplenomegaly. Abdominal x-ray revealed calcifications which were confirmed on abdominal CT scan. Peripheral blood film showed vacuolated lymphocytes and the bone marrow aspiration showed foamy histiocytes. Liver biopsy in one patient showed marked steatosis and elliptical empty clefs predominantly in the Kupffer cells, indicating cholesterol storage in the reticulo-endothelial cells. The acid lipase activity was less than 6% in all patients. In all suspected cases of Wolman's disease, a plain abdominal x-ray should be obtained to check for the typical pattern of adrenal calcification characteristic of the disease, especially in any young infant with failure to thrive and progressive hepatosplenomegaly

Enfermedad de Wolman en una niña mexicana / Wolman disease in a mexican female infant

La deficiencia de lipasa ácida lisosomal o enfermedad de Wolman es una enfermedad autosómica recesiva que se presenta en diversos grupos étnicos. Los niños con esta enfermedad presentan síndrome de mal absorción intestinal, hepatoesplenomegalia, desnutrición y deterioro neurológico; la mayoría de los pacientes mueren durante el primer año de vida. Un hallazgo casi constante en estos enfermos es la presencia de calcificaciones en las glándulas suprarrenales además de acúmulos de lípidos en diversos tejidos. Se describe el caso de una niña originaria del estado de México con enfermedad de Wolman; clínicamente presentaba datos sugestivos de un tumor abdominal después de un cuadro de diarrea por lo que se le hizo una laparotomía exploradora en la que se encontraron adherencias intensas y "perlas amarillas" en el epiplón. La evolución postoperatoria se complicó con septicemia por germen gramnegativo e insuficiencia hepática secundaria a necrosis hepática. El diagnóstico se estableció con la autopsia en la que se encontraron acúmulos de lípidos en los tejidos y las características calcificaciones de las glándulas suprarrenales