Keyword: Acute Chest Syndrome; Beta mannosidosis; Hypersplenism; Sickle Cell Disease; Splenic Sequestration

Introduction

Sickle Cell Disease (SCD) is one of the global health problems, with estimates of approximately 300,000 new cases per year diagnosed with SCD worldwide. It is defined as a homozygous status of the sickle hemoglobin (HbS) gene which results in substitution of the amino acid valine to glutamic acid at the 6^th position of the B-globin chain [1,2]. B-mannosidosis is a rare glycoprotein lysosomal storage disease inherited as an autosomal recessive manner caused by a deficient activity of beta manosidase enzyme [3].Acute Chest Syndrome (ACS)  is the leading cause  of death in SCD patient and the 2^nd most common complication  of Sickle Cell Disease, after vaso-occlusive crisis[4]. Ssplenic sequestration and hypersplenism is a known complication as well of SCD [5]. we report a case of SCD with B-mannosidosis who  is having a recurrent ACS and hypersplenism with acute splenic sequestration.

Case report

An 8 years old boy, a product of a full term, Spontaneous Vaginal Delivery (SVD), the second childtoaconsanguineousparent. The patient presented at age of 4 months with pallor and shortness of breath with a complete blood count hemoglobin level of 7.8 mg/ dl with a sickle cell screen positive, and diagnosed as a sickle cell disease based on hemoglobin electrophoresis (HbS: 34.7% and HbF: 63.7%with no detectable HbA) which was repeated at age of one year and confirmed the diagnosis of SCD with alpha-Thalassemia trait, X-ray chest showed cardiomegaly and Echo was done and results were as dilated left ventricle and atrium with moderate mitral regurgitation and the left ventricle function of FS 17.2% and labelled as having cardiomyopathy. At age of 3 years the patient had global developmental delay, growth parameters were below 3^rd centile for height and weight, he had hepatosplenomegaly, speech retardation with hearing loss and recurrent otitis media requiring later bilateral myringotomy, T tube insertion and a hearing aid. He had coarse facial features (gargoyle-like features) as frontal bossing, flat nasal bridge, large tongue with thick lips and gapped teeth, gibbus malformation with skeletal deformities (Figure 1-4) (Table 1, 2).

At 4 years of age he was diagnosed as Bronchial Asthma, Allergic Rhinitis, myopic astigmatism and Attention Deficit Hyperactive Disease (ADHD) with a lower IQ of 70 at age of 7 years.He underwent splenectomy at age of 5 years.The patient was investigated for a lysosomal storage disorder, urine Glycosamino glycan (GAG) was negative for the patient, normal blood Tandem mass spectrometry, and chromosomal analysis of 46, XY.

Whole ExomeSequence (WES) detected a homozygous variant of exon 6 of the MANBA gene mutation C.704T>G (p.lle235Arg) and both parents are with a heterozygous status. Enzymatic assay of manosidase activity in serum (Table 1).

He has a sister who had the same presentation of coarse facial features, hepatosplenomegaly, and gibbus malformation with sickle cell Trait and Beta-mannosidosis confirmed by genetic whole exome sequencing (homozygous status of MANBA gene mutation) C.704T>G) and enzyme assay (Figure5).

Discussion

Beta-mannosidosis is a pan-ethnic disorder with an autosomal recessive inheritance [6]. Two siblings from Saudi Arabia, described in our report, was associated with gargoyle like facial dysmorphism, hearing impairment, mental retardation, and recurrent respiratory tract infections.To our knowledge the number of patients reported in the literature is small, (Table 2) so, it is difficult to conclude specific symptoms and signs to characterize B-mannosidosis.Various degrees of developmental delay, hearing loss, and mental retardation are common findings. The older sibling has angiokeratoma as an isolated observation as reported previously[21,22]. The observed skeletal changes in our proband are beaked vertebral bodies, thick calvarium, bullet shaped vertebrae, and gibbus malformation (Figure.2).

This patient who is a known case of hypersplenism with multiple splenic sequestration with one intensive care admission with critical hemoglobin level 3.4 mg/dl. Post elective splenectomy the patient had significant decreased rate of admission and blood transfusions. It was noticed that in our proband who has beta- mannosidosis the most frequent complication of sickle cell disease is hypersplenism with sequestration and acute chest syndrome with fewer painful crisis’s although it is the most common feature of sickle cell disease[23]. The patient had frequent admissions as an acute chest syndrome in which after starting azithromycin as an anti-inflammatory agent[24,25] by our pulmonologist, the rate of acute chest syndrome related admission decreased.

The association of Beta mannosidosis and SCD to our knowledge has not been reported before, this combination of both diseases need further reported cases to establish the impact.

Conclusion

This is the first case to report a patient with SCD and B-mannosidosis. We recommend splenectomy for  cases  of Sickle Cell Disease with B-mannosidosis and  hypersplenism,  we recommend using azithromycin as an anti-inflammatory prophylactic agent to reduce Acute Chest Syndrome in patient with Sickle Cell Disease andBeta mannosidosis.