Short CommunicationCoexistence of Gaucher Disease and severe congenital neutropenia
Introduction
Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder, in which a deficiency of the enzyme glucocerebrosidase leads to the accumulation of glucocerebroside in the lysosomes of monocytes and macrophages. The disease has traditionally been classified into three clinical phenotypes: type 1 – adult, non-neuronopathic; type 2 – an infantile or acute neuronopathic form (rapidly progressive neurovisceral storage disease, with death during infancy); and type 3 – a juvenile or chronic neuronopathic form (less rapidly progressive neurovisceral storage disease). Hepatosplenomegaly and pancytopenia are typical for all types [1].
Genotype-phenotype correlations in GD are poor, although various mutations are known to predispose to certain disease type [2]. The presence of the N370S mutation on one or both alleles is thus associated with type 1 disease. The presence of the L444P/L444P or D409H/D409H (c.1342 G>C) mutation is associated with the development of neurological manifestations at some time during the subject's life. Mean age at diagnosis in patients who are homozygous for the L444P mutation is 2.3 years, and type 3 is dominant (75% of cases) [3,4].
Severe congenital neutropenia (SCN) is a heterogeneous group of diseases progressing with arrest of maturation in bone marrow. It is characterized by recurring skin, lung, and deep tissue infections from the first months of life [5]. Clinically, SCN is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. SCN also exhibits genetic heterogeneity. Inheritance may be autosomal dominant, autosomal recessive, X-linked or sporadic [6]. Historically, ELANE is the gene responsible for the first identified SCN. However, ELANE gene defect was not determined in the Kostmann family in which the disease was identified, and the HAX1 gene has been found in studies of Swedish and Turkish patients [7]. ELANE defect is inherited in an autosomal dominant manner, and the autosomal dominant form is more common worldwide However, SCN associated with autosomal recessively inherited HAX1 gene defect is more frequent in Europe, probably due to the presence of migrants of Turkish and Arab origin [5]. The HAX-1 gene encodes HCLS1-associated protein X-1. HCLS1-associated protein X-1 is principally present in the mitochondrial membrane, and also in the nuclear membrane and endoplasmic reticulum. It controls the integrity of mitochondrial membrane protein and protects myeloid cells against apoptosis [8].
GH and SCN are rare diseases that both affect hematopoietic cells. To the best of our knowledge, no case of comorbid GD and SCN has to date been described in the literature. We report a case of Gaucher Type III disease and SCN associated with a mutation in the HAX1 gene.
Section snippets
Case report
The patient was referred to us at 4 months of age because of anemia and neutropenia. He was born prematurely in the 32nd gestational week with a birth weight of 1660 g. His complex previous history was remarkable for admission to the neonatal intensive care unit at another hospital due to premature delivery and recurrent severe infections during hospitalization. The family history revealed that he was born from a first-degree consanguineous marriage between healthy parents, with four siblings
Discussion
SCN has recently been recognized as a genetically heterogeneous disorder with multiple modes of inheritance, including autosomal recessive, autosomal dominant, X-linked and sporadic transmission [9]. Mutations associated with SCN have been identified in HAX1, ELA 2, GFI1, WAS, CSF3R and G6PC3 [10]. While the majority of patients with autosomal dominant or sporadic SCN bear heterozygous mutations in the neutrophil elastase (ELA-2/ELANE) gene [11], biallelic mutations in the gene encoding the
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