BACKGROUND

CHARGE syndrome is a genetic birth defect, which occurs in about one in every 9–10 000 births worldwide.1 It is a complex syndrome, involving medical and physical disabilities that differ from child to child. Cardinal features of CHARGE syndrome are coloboma, heart anomalies, choanal atresia, retardation of growth and development, genitourinary anomalies, and ear anomalies. There are various other less associated features but haematological association with myelodysplastic syndrome (MDS) has not been reported in the literature. Here we report a very interesting case of CHARGE syndrome with MDS.

CASE PRESENTATION

An 8-month-old malnourished (weight 4.5 kg, crown–heel length (CHL) 68.2 cm, and mid arm circumference 12.2 cm) mentally retarded girl presented to the outpatient department with fever and cough for the previous 10 days. Fever was in the range of 102–104°F (39–40°C) with non-productive cough, which was persisting throughout the day. She had refused to feed and had breathing difficulties in the form of rapid breathing and chest indrawing for 3 days. She had a past history of recurrent cough, fever, and dyspnoea since birth. On examination, her respiratory rate was 84/min and pulse 118/min, which was normal in volume and character. She had bilateral deformed upturned pinna with a groove at the helix and left sided microphthalmia and microcornea (fig 1). Examination of chest revealed vesicular breath sounds with bilateral crepts and rhonchi. An ejection systolic murmur with fixed splitting of the second heart sound was heard at the left lateral parasternal area in the second left second intercostal space. There was no hepatosplenomegaly and lymphadenopathy.

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Figure 1

Photograph showing deformed and upturned helix with microphthalmia and microcornia.

INVESTIGATIONS

Chest x ray showed bilateral infiltrates with right upper lobe consolidation. Ultrasonography of the abdominal and pelvic organs was normal. On ophthalmological evaluation, colobomas were present in both eyes with retinal detachment in the left eye (fig 2). On echocardiography, a 10 mm ostium primum atrial septal defect was found. There was no sensorineuronal or conductive deafness in brain stem auditory evoked response assay (BAERA).

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Figure 2

Fundal photograph showing coloboma and retinal detachment.

The examination of blood revealed pancytopenia, with a haemoglobin value of 47 g/l (haematocrit 14.3%, mean corpuscular volume 63 fl), total leucocyte count 3.2×10⁹/l (neutrophils 0.8×10⁹/l, lymphocytes 2.4×10⁹/l), platelet count 75×10⁹/l, and the proportional circulating blasts were 9% (fig 3). The serum ferritin, vitamin B12 and folate values were normal. Bone marrow aspiration showed trilineage dysplasia with 13% of blast cells (fig 4). The blast morphology was not characteristic of any particular cell lineage. Cytochemical stains including myeloperoxidase, Sudan Black B, and periodic acid Schiff were negative. The findings were diagnostic of MDS with refractory anaemia with excess of blasts (RAEB) in accordance with the World Health Organization criteria modified for paediatric age group.1 Chromodomain helicase DNA binding protein 7 (CHD7) mutation analysis confirmed the case as CHARGE syndrome.2

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Figure 3

Peripheral smear of blood showing blasts.

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Figure 4

Bone marrow aspirate examination showing blasts and trilineage dysplasia.

TREATMENT

The patient was treated with packed cell transfusion and antimicrobials (cefotaxime and vancomycin) for 10 days. Retinal detachment was treated with laser photocoagulation. The patient was finally sent for bone marrow transplantation.

DISCUSSION

CHARGE syndrome, an autosomal dominant condition, is mostly due to mutation or deletion of the CHD7 gene. A developmental defect involving the midline structures of the body occurs, specifically affecting the craniofacial structures leading to arrest in embryologic differentiation in the second month of gestation, when the organs affected are in the formative stages (choanae at 35–38 days post-conception, eye fifth week, cardiac septum 32–38 days, cochlea 36 days, external ear sixth week). Cardinal features of CHARGE syndrome are coloboma, heart anomalies, choanal atresia, retardation of growth and development, genitourinary anomalies, and ear anomalies.3 No single feature is universally present or sufficient for diagnosis, and the severity is variable. Other frequently occurring features of significance include characteristic facies, hypotonia, orofacial clefting, and tracheoesophageal anomalies.4 The clinical diagnosis requires the presence of at least three cardinal features. Our patient had growth retardation, ear anomalies, colobomas of both eyes, and a cardiac anomaly in the form of an atrial septal defect.

MDS is a rare clonal haematological disorder in children characterised by dysplastic haematopoiesis and progression to leukaemia. The preleukaemic phase is usually short and the disease rapidly evolves into overt leukaemia. Marrow cellularity is normal or increased in MDS, with hypocellular marrow being a rare feature. According to the paediatric modification of the WHO classification, MDS patients are classified into three groups: refractory cytopenia (RC), refractory anaemia with excess of blasts (RAEB), and RAEB in transformation (RAEB-T). Minimal diagnostic criteria for paediatric MDS as suggested by Hasle et al5 are sustained, unexplained cytopenia and/or at least bilineage morphological myelodysplasia and/or acquired clonal cytogenetic abnormality in haematopoietic cells and/or increased blasts >5%. It may be incidental but requires further research to detect any increase in incidence of MDS in CHARGE syndrome, as both are associated with microdeletion of chromosome.

Families of patients with CHARGE syndrome require education regarding the disease manifestations and potential complications. A discussion of the genetic basis of the disorder should include recurrence risks (1–2% for unaffected parents, up to 50% for affected individuals). Genetic counselling should be made available for individuals at increased risk for affected offspring to explain the options for future pregnancies, including prenatal and preimplantation genetic diagnosis.