A Patient with Sickle Cell Disease and Beta-Mannosidosis: A Case Report

Case Report

Austin J Clin Case Rep. 2020; 7(1): 1164.

A Patient with Sickle Cell Disease and Beta-Mannosidosis: A Case Report

Almadani H, Namnqani R* and Kurdi H

Department of Pediatrics, King Fahad Armed Forces Hospital, Jeddah, Kingdom of Saudi Arabia

*Corresponding author: Namnqani R, Department of Pediatrics, King Fahad Armed Forces Hospital, Jeddah, Kingdom of Saudi Arabia

Received: April 26, 2020; Accepted: June 23, 2020; Published: June 30, 2020

Abstract

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 6th position of the B-globin chain. B-mannosidosis is a rare glycoprotein lysosomal storage disease inherited as an autosomal recessive pattern caused by a deficient activity of beta manosidase enzyme. We report here Eight years old male patient diagnosed with Sickle Cell Disease and Beta-mannosidosis, to our knowledge this is the first case to report a patient with SCD and B-mannosidosis.

Keywords: Sickle Cell Disease; Beta mannosidosis; Hypersplenism; Acute Chest Syndrome; 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 vasoocclusive crisis [4]. Splenic 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 Presentation

An 8 years old boy, a product of a full term, Spontaneous Vaginal Delivery (SVD), the second child to consanguineous parents. The patient presented at age of 4 months with pallor and shortness of breath with a complete blood count hemoglobin level of 7.8mg/ 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 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 Exome Sequence (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).

Table 1: Enzymatic assay of Mannosidase enzyme activity in our proband.




  
    Source 
    Enzyme 
    Activity 
    Reference Range 
  
  
    Serum
    Beta-mannosidase
    0.004 umol/ml/min
    1.49 – 8.33 umol/ml/min
  
  
    Serum
    Alpha-mannosidase
    0.14 umol/ml/min
    0.1 – 0.2 umol/ml/min



Table 1: Enzymatic assay of Mannosidase enzyme activity in our proband.

Figure 1: X-ray skull showing calvarial thickening and bullet shaped vertebrae.

    
    
    Figure 1: X-ray skull showing calvarial thickening and bullet shaped
vertebrae.

Figure 2: X-ray of right upper limb showing expansion of medullary spaces with short tubular bones of the hand.

    
    
    Figure 2: X-ray of right upper limb showing expansion of medullary spaces
with short tubular bones of the hand.

Figure 3: X-ray lateral spine showing L2 vertebral beaking with gibbus malformation.

    
    
    Figure 3: X-ray lateral spine showing L2 vertebral beaking with gibbus
malformation.

Figure 4: CT Abdomen showing anterior inferior beaking of L2 vertebrae with gibbus malformation.

    
    
    Figure 4: CT Abdomen showing anterior inferior beaking of L2 vertebrae with
gibbus malformation.

Figure 5: Family pedigree.

    
    
    Figure 5: Family pedigree.

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 (Figure 5).

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).

Table 2A: Beta-mannosidosis phenotype and laboratory findings in reported cases.




  
    Case
    1
    2
    3
    4
    5
    6
    7
    8
    9
    10
    11
  
  
    Sex
    Male
    Male
    Male
    Male
    Male
    Female
    Male
    Female
    Female
    Male
    Male
  
  
    Ethnicity
    European
    Hindu
    Hindu
    Turkish
    Turkish
    Czech
    Czech
    Jamaican
    Turkish
    European
    African
  
  
    Consanguinity
    Negative
    
    
    Positive
    positive
    
    
    Negative
    positive
    Negative
    Negative
  
  
    Diagnosis age (Yr)
    1.5
    44
    19
    8
    6
    20
    30
    1
    6
    3
    14
  
  
    Presenting symptom
    Dysmorphology
    Mental retardation
    
    Feeding difficulty
    
    Developmental delay
    
    Seizures
    Absent speech
    Speech impairment
    Speech impairment
  
  
    Mental retardation
    Positive
    Positive
    Yes
    Yes
    Yes
    Positive
    Positive
    
    Positive
    Positive
    Negative
  
  
    Behavioral problems
    Hyperactive
    aggressive
    
    Troublesome
    
    Aggressive
    
    
    Hyperactive aggressive
    Hyperactive
    Disinterest
  
  
    Hearing impairment
    Mild
    Present
    Present
    Present
    Present
    Present
    Present
    Negative
    Present
    Negative
    Negative
  
  
    Neurological
    Speech retard
    
    
    Speech retard
    
    Developmental delay
    
    Developmental delay
    Motor delay
    Speech impairment
    Peripheral neuropathy
  
  
    dermatologic
    
    Angiokeratoma
    
    
    
    Erysipelas
    
    
    
    
    
  
  
    Facial dysmorphism
    Present
    negative
    Negative
    Negative
    Negative
    Present
    Present
    Present
    Present
    Present
    Negative
  
  
    Skeletal deformation
    Present
    Negative
    Negative
    Negative
    Negative
    Present
    Present
    Negative
    Present
    Negative
    Negative
  
  
    Respiratory infections
    
    
    
    Positive
    positive
    Positive
    Positive
    
    Positive
    Positive
    Negative
  
  
    mannosidase
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
  
  
    Urine disaccharides
    Positive
    Positive
    Positive
    Positive
    positive
    Positive
    Positive
    Positive
    Positive
    Positive
    Faint
  
  
    Reference
    Wenger et al. 1986 [7]
    Cooper et al. 1986-1988 [21,22]
    Cooper et al. 1986-1988 [21,22]
    Dorland et al. 1988 [8]
    Dorland et al. 1988 [8]
    Kleijer et al. 1990 [6]
    Kleijer et al. 1990 [6]
    Cooper et al. 1991 [9]
    Wijburg et al. 1992 [10]
    Poenaru et al. 1992 [11]
    Levade et al. 1994 [3]



Table 2A: Beta-mannosidosis phenotype and laboratory findings in reported cases.

Table 2B: Beta-mannosidosis phenotype and laboratory findings in reported cases (To our knowledge).




  
    
    Sibling sister
    our case
  
  
    Case
    12
    13
    14
    15
    16
    17
    18
    19
    20
    21
    22
    23
  
  
    Sex
    Female
    Female
    Female
    Female
    Male
    Male
    Female
    Female
    Male
    Female
    female
    Male
  
  
    Ethnicity
    white
    
    Arabic
    Arabic
    Japanese
    French
    Spanish
    Arabic
    Algerian
    Asian
    Arabic
    Arabic
  
  
    Consanguinity
    Negative
    Positive
    Positive
    positive
    Positive
    negative
    
    Positive
    Positive
    Positive
    positive
    Positive
  
  
    Diagnosis age
    22 years
    7 months
    2 years
    3.5 years
    51 years
    18 years
    24 years
    36 years
    12 years
    5 months
    7 years
    5 years
  
  
    Presenting symptom
    clumsiness
    Feeding difficulty
    Seizures
    Seizures
    Angiokeratoma
    Developmental delay
    Angiokeratoma
    Angiokeratoma
    Clumsiness
    Seizures
    Dysmorphism
    Dysmorphism
  
  
    Mental retardation
    Negative
    
    Positive
    positive
    Positive
    Positive
    Negative
    Positive
    Positive
    Positive
    Positive
    Positive
  
  
    Behavioral problems
    Scantly communicative
    
    
    
    
    ADHD
    Negative
    Aggressive
    
    
    ADHD
    ADHD
  
  
    Hearing impairment
    Negative
    
    Negative
    negative
    Present
    Present
    Mild
    Present
    Present
    Present
    Present
    Present
  
  
    Neurological
    Negative
    Developmental delay
    Developmental delay, speech    delay
    encephalopathy
    Peripheral neuropathy
    Developmental delay, speech    delay
    Negative
    
    Cerebellar ataxia
    Developmental delay
    Developmental delay
    Developmental delay
  
  
    dermatologic
    Angiokeratoma
    
    Negative
    Negative
    Angiokeratoma
    Negative
    Angiokeratoma
    Angiokeratoma
    Negative
    
    Angiokeratoma
    Negative
  
  
    Facial dysmorphism
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Positive
    Positive
    Positive
  
  
    Skeletal deformation
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Negative
    Positive
    Positive
    Positive
  
  
    Respiratory infections
    Negative
    positive
    Negative
    Negative
    
    Positive
    
    Negative
    
    Positive
    Positive
    Positive
  
  
    mannosidase
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
    Deficient
  
  
    Urine disaccharide
    Positive
    Positive
    
    
    
    Positive
    Positive
    
    
    
    Positive
    Positive
  
  
    Reference
    Rodriguez et al. 1996 [12]
    Gourrier et al. 1997 [13]
    Cherian et al. 2003 [14]
    Cherian et al. 2003 [14]
    Suzuki et al. 2004 [15]
    Sedel et al. 2006 [16]
    Gort et al. 2006 [17]
    Molho et al. 2007 [18]
    Levade et al. 2009 [19]
    Broomfield et al. 2012 [20]
    Almadani et al 2019
    Almadani et al. 2019



Table 2B: Beta-mannosidosis phenotype and laboratory findings in reported cases (To our knowledge).

This patient who is a known case of hypersplenism with multiple splenic sequestration with one intensive care admission with critical hemoglobin level 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 are 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 and Beta mannosidosis.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. Consent is available upon request.

References

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Citation: Almadani H, Namnqani R and Kurdi H. A Patient with Sickle Cell Disease and Beta-Mannosidosis: A Case Report. Austin J Clin Case Rep. 2020; 7(1): 1164.

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Source	Enzyme	Activity	Reference Range
Serum	Beta-mannosidase	0.004 umol/ml/min	1.49 – 8.33 umol/ml/min
Serum	Alpha-mannosidase	0.14 umol/ml/min	0.1 – 0.2 umol/ml/min