Nina Saeed1, Khulood Al-Saad2, David Shome3, Huda Jamsheer4

Author affiliations
1RCSI medical student
2Department of Pediatrics, MD, Salmaniya Medical Complex, Kingdom of Bahrain
3Department of Pathology, MD, Salmaniya Medical Complex and Arabian Gulf University, Kingdom of Bahrain
4Department of Pathology, MD, Salmaniya Medical Complex, Kingdom of Bahrain

Royal College of Surgeons in Ireland Student Medical Journal 2012;5: 47-49.

Chédiak-Higashi Syndrome (CHS) is a rare and usually fatal autosomal recessive disease1 that was first described over 50 years ago.2

Although its exact incidence is unknown, fewer than 200 people have been reported to have the condition worldwide.1 CHS is caused by defects in the lysosomal trafficking regulator (LYST) gene, whose gene product regulates intracellular protein trafficking to and from the lysosome.3,4 Impaired function of this protein disrupts the size, structure and function of lysosomes in the body, resulting in the accumulation of large intracellular vesicles within granulocytes, platelets and melanocytes.3,4

Patients with CHS may present with an increased incidence of bacterial infection, as the phagolysosome fails to properly form in immune phagocytic cells.5 Affected individuals typically have fair skin and silver hair, since faulty intracellular transportation of melanin and the presence of giant melanosomes in the melanocytes may lead to partial oculo-cutaneous albinism.5,6 Due to abnormalities in protein trafficking in their platelets, patients with CHS also tend to suffer from coagulopathies, and may present with easy bruising and bleeding diathesis.4 They may also present with sensory and/or motor neurological disorders or nystagmus.7
The mean age of survival for CHS patients is 10 years, but the oldest patient is currently 39 years of age.7,8 Approximately 50-80% of children with CHS reach the accelerated phase – a lymphoma-like syndrome characterised by the lympho-histiocytic infiltration of the bone marrow, liver and spleen.7 The accelerated phase is usually triggered by a viral infection, and the patient may present with a haemophagocytic syndrome with pancytopaenia, liver dysfunction and coagulopathy, for which he/she would require a bone marrow transplant (BMT).4 Without transplantation, CHS in the accelerated lymphoproliferative phase is usually fatal.9

Here, we present a child with CHS and trisomy 21 syndrome who presented in the accelerated phase. To our knowledge, these two syndromes have never before been encountered simultaneously in the literature.

Case report
A baby boy was born to first-degree consanguineous parents at 36 weeks’ gestation by spontaneous vaginal delivery after an uneventful pregnancy. He was born with dysmorphic features suggestive of trisomy 21 syndrome – low-set ears, upward slanting eyes, a short neck and a protruding tongue (Figure 1). This diagnosis was confirmed by cytogenetic studies and karyotyping. On further inspection, the baby was extremely fair with silver hair, in stark contrast to his Middle Eastern parents. At two months, the baby underwent surgical intervention to correct a duodenal atresia and a patent ductus arteriosus (Figure 2).

FIGURE 1: A two-year-old child with dysmorphic features suggestive of trisomy 21 syndrome. Note the low-set ears, upward slanting eyes, short neck and protruding tongue.

FIGURE 2: Patient with CHS and trisomy 21. A healed scar is evident on the left aspect of the thoracic cage – the site of surgical intervention for patent ductus arteriosus ligation.

At the age of six months, the baby boy was referred to the Salmaniya Medical Complex (SMC) with pancytopaenia, coagulopathy and cholestasis. On examination, the baby was pale and lethargic. He had fair skin and hair suggestive of albinism. Examination of his oral cavity revealed gingivitis with a bleeding tendency, and hepato-splenomegaly was detected on abdominal percussion. Significant generalised hypotonia and delayed developmental milestones were also noted. On questioning, the mother revealed that two of his half siblings died in early childhood, one of whom had been given a confirmed diagnosis of CHS. Investigations ordered for the boy included a chest x-ray, full blood count (FBC), a peripheral blood smear and a bone marrow study. The FBC revealed a significant pancytopaenia, and abnormal giant granules within the neutrophils with prominent secondary granules were detected on blood smear. The bone marrow study demonstrated pancytopaenia and evidence of haemophagocytosis (Figure 3), and it was confirmed that the patient was in the accelerated phase of CHS. The patient was commenced on an immunosuppressive regime consisting of dexamethasone and cyclosporine to control the accelerated phase of disease. BMT was ruled out for him as a therapy option due to severe psychomotor retardation secondary to trisomy 21 syndrome. The baby boy responded well to treatment and recovered from the accelerated phase, but remained on maintenance treatment.

FIGURE 3: Bone marrow aspirate: bone marrow smear of CHS patient demonstrating polymorphonuclear cells with giant lysosomal granules.

During his hospital stay, the baby boy was diagnosed with bronchial asthma, and subsequently required several re-admissions in the following months for acute asthmatic exacerbations and an episode of pneumonia. Two years and four months after his diagnosis was confirmed, the patient presented to the Accident & Emergency Department at SMC with a two-week history of fever, poor feeding, lethargy, hypotonia and frequent bouts of dark brown-to-black diarrhoea, which was occasionally speckled with blood and mucus. On inspection, the boy was conscious and well hydrated, but pale, lethargic and hypotonic. Closer examination revealed gingivitis, a soft abdomen and an enlarged spleen 3cm below the left costal margin. No lymphadenopathy or meningeal signs were detected and capillary refill was within normal limits. Scattered rhonchi and crepitations were audible on auscultation of the chest. The first and second heart sounds were present, and a soft systolic murmur was appreciated at the left lower sternal edge.

An FBC was ordered, and the results of the investigation are reproduced below:

Given these results, the boy was diagnosed with re-activation of the accelerated phase of CHS secondary to a viral infection. The patient was commenced once again on cyclosporine and dexamethasone, and antibiotics, intravenous immunoglobulin (IVIG) and bronchodilators were added to his drug regime. He was also given blood transfusions to replace blood lost to gastrointestinal bleeding. Despite these measures, the boy was unresponsive to treatment. His parents agreed to continue palliative care and to avoid aggressive resuscitation measures. Sadly, despite best efforts, the boy passed away at the age of two years and ten months.

The diagnosis of CHS is based on the identification of abnormal neutrophil, lymphocyte and eosinophil granules on peripheral blood smears and in bone marrow aspirates.4,6 Ophthalmological findings and platelet aggregation studies may also be used. The definitive diagnostic test is molecular genetic analysis of the LYST locus; however, this investigation is expensive and technically difficult, as several mutations have been linked to CHS.6 Other immunodeficiency syndromes, particularly Griscelli and Hermansky-Pudlak syndromes, may present similarly to CHS and should be excluded before arriving at a definitive diagnosis.2 Both these conditions are characterised by partial oculo-cutaneous albinism, immunodeficiency and bleeding diathesis.2 However, patients with Griscelli or Hermansky-Pudlak syndromes lack the hallmark giant cytoplasmic granules seen within polymorphonuclear cells in CHS, and thus can be ruled out on blood or bone marrow smear.10 The prognosis of CHS is poor. Death usually results from frequent and recurrent bacterial infection, haemorrhage or the development of the accelerated lymphoma-like phase.6 The key to improving patient survival is the early diagnosis of CHS by careful inspection of peripheral blood and bone marrow smears. BMT is currently the only option for the treatment of haematologic and immune disease in CHS, but does not improve neurological deficiencies caused by the condition.7,10 Corticosteroids, IVIG and chemotherapy are indicated in the management of the accelerated lymphoproliferative phase of CHS; however, this treatment regime is thought to induce only temporary remission.10 In this case, despite early diagnosis of CHS, the patient’s condition was complicated by significant psychomotor retardation secondary to trisomy 21 syndrome. It was decided that the best option for the patient was palliative treatment with immunosuppressive drugs, since the incidence of life-threatening toxicity due to BMT is significantly higher in patients with trisomy 21 syndrome and thus contraindicated.11,12 Patients with trisomy 21 syndrome also have an increased risk for acute pulmonary and infectious complications of BMT.12 Familial consanguinity has been described in 50% of CHS cases in the literature, yet there have been many reports of CHS in children of unrelated parents.7 Prenatal diagnosis is a technically difficult process, but can be made by measuring acid phosphatase-positive lysosomes from cultures of amniotic fluid cells, chorionic villous cells, or leukocytes isolated from foetal blood.10 In this case, it was not clear why the parents did not receive genetic counselling or were not offered prenatal testing.

This case demonstrates the clinical course of CHS in an infant who concurrently had trisomy 21 syndrome. In arriving at the diagnosis of CHS, other immunodeficient conditions must be considered and ruled out by a blood smear.

The prognosis for CHS is poor, with most patients passing away in childhood. In this patient, the accelerated lymphoproliferative phase was managed effectively at first with immunosuppressive therapy, but recurred two years later.

The patient was not a candidate for BMT as the incidence of complications and mortality following a BMT in patients with trisomy 21 syndrome is considerably high.


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