Case presentation Dr Waceke N Kombe

HISTORY M.H.N Age: 1 year 3 months C/O Abdominal Distension for 1 week. No yellowness of eyes, not easily fatigued, passing urine normally. No vomiting, No diarrhoea. Feeding has been good. Seen at another hospital, Ultrasound done and reported to show enlarged liver and spleen.

HISTORY Mother reports that she lost a sibling at 23 months of age who started to have Abdominal Distension and was diagnosed to have hepatosplenomegaly. An autopsy was done but the results were inconclusive. One surviving sibling, 2years 8 months, no known medical conditions. This is the first admission. Born at term. BWT 3.0Kg. c/s due to a previous scar. She walks with support.

EXAMINATION O/E low set ears with flat nasal bridge. No simian crease. Short stature. Current weight 10kg Length 75.5cm, H/Cir 45cm at 2 years. Apex beat 5th ICS MCL . Normal heart sounds. Abdomen looked distended uniformly. No scars, no superficial veins. Bowel sounds normal. Hepatosplenomegaly noted. Liver 6-8 cm below costal margin. Spleen 4cm below costal margin. Difficult to assess for ascites. Normal bowel sounds. Kidneys not palpable.

Growth chart

INVESTIGATIONS FBC Hb 9.8, MCV 57.1, MCH 18.9, PLT 134, WBC 6.98 (L 1.9, N 3.93). HIV- NEGATIVE HEB B s Ag , CMV Ig M- NEGATIVE No evidence of Beta Thalassemia or Hemoglobinopathy LFT’S GAMMA GT 47 (N=22) AST 80 (N=48)

INVESTIGATIONS FERRITIN 141 (N=67) U/E/C NORMAL THYROID MARKERS NORMAL ALPHA FETO PROETIN NORMAL URINE REDUCING SUBSTANCES- NEGATIVE

Abdominal ultrasound The liver is grossly enlarged having a span of 13.3cm X 8.4cm X9.4 cm. Normal echotexture, intrahepatic bile ducts not dilated. Gall bladder is normal, no gall stones. Spleen is markedly enlarged measuring 10.8 x 12.5x 9.82 cm. It has a normal echotexture, no obvious portal varices. Adrenal, kidney and pancreas are normal. No bowel lesion seen. There is no ascites.

BONE MARROW ASPIRATE Patchy infiltration by large cells with abundant wrinkled cytoplasm, some multinucleated. Features of a lysosomal storage disease. LIVER BIOPSY Reactive hepatocytes with sinusoidal expansion by enlarged Kupfer cells with abundant wrinkled paper cytoplasm. Features favour Gauchers Disease.  

 ENZYME ASSAYS. Beta Glucosidase activity in serum: not detectable. Deficient activity of beta glucosidase noted in leucocytes.

What could this be?

GAUCHERS DISEASE

Lysosomal lipid storage disease. One of the most common lysosomal storage diseases. Autosomal recessive. Incidence of Type 1(99% of cases) among Ashkenazi Jews 1-1000 live births; 1:50,000 European Jewish population. 3 clinical subtypes: Type 1 – adult, nonneuronopathic form Type 2- infantile or acute neuronopathic form Type 3- juvenile or subacute neuronopathic form

Gaucher disease results from the deficient activity of Glucosylceramide β glucosidase. This results in the accumulation of the substrate glucosylceramide. Accumulation occurs in the reticuloendothelial system. The progressive deposition results in infiltration of the bone marrow, progressive hepatosplenomegaly, and skeletal complications.

Pathophysiology of Gauchers disease

GENETICS Deficiency encoded by a gene located on chromosome 1q21-q31. Four mutations account for approximately 95% of mutant alleles among Ashkenazi Jews. N370S L444P 84insG IVS2+2

CLINICAL MANIFESTATIONS TYPE 1 Age of onset- variable. Early childhood to adolescent. Easy bruising- thrombocytopenia; chronic fatigue- anaemia; hepatomegaly, splenomegaly and bone pain. Pulmonary involvement Growth retardation Bone pain, pathologic fractures, pseudosteomyelitis, lytic lesions, osteosclerosis, bone crises with severe pain Radiologic evidence of skeletal involvement- Erlenmeyer flask deformity of the distal femur

Erlenmeyer flask deformity. Modelling abnormality. So named because of its similarity to the glass flask invented by a German scientist.

TYPE 2 Rare form Rapid neurodegenerative course with extensive visceral involvement and death within the first years of life. Presents in infancy with increased tone, strabismus, hepatosplenomegaly Failure to thrive and stridor Psychomotor regression. Death typically occurs secondary to respiratory compromise

TYPE 3 Presents with clinical manifestations that are intermediate to those seen in types 1 and 2, with presentation in childhood and death by age 10-15 years. More common among the Swedish population Neurologic involvement is present.

INVESTIGATIONS Bone marrow. Will reveal Gaucher cells. Enzyme assays. Glucocerebrosidase activity in isolated leucocytes or cultured fibroblasts. Gene mutation identification

WHAT IS A GAUCHER CELL The Gaucher cell results from the accumulation of excessive glucocerebroside in cells of the monocyte-macrophage system.  Pushes the nucleus to the periphery

TREATMENT Enzyme replacement therapy. Recombinant human glucocerebrosidase. 60IU/kg IV infusion every other week. Reverses most symptoms ( organomegaly, hematologic indices, bone pain) Velaglucerase alfa Taliglucerase alfa Enzyme replacement does not alter the neurologic progression of patients with Gaucher disease types 2 and 3. Oral substrate reduction agents- miglustat Bone marrow transplantation. Curative but associated with significant morbidity.