- Philippe Joly1,
- Philippe Lacan1,
- Audrey Labalme2,
- Elodie Bonhomme1,
- Damien Sanlaville2 and
- Alain Francina1⇓
- 1 Unité de Pathologie Moléculaire du Globule Rouge, Hôpital Edouard Herriot, Lyon
- 2 Service de Cytogénétique Constitutionnelle, Centre de Biologie Est, Groupement Hospitalier Est, Bron, France
- Correspondence: Alain Francina, MD, PhD, Unité de Pathologie Moléculaire du Globule Rouge, Fédération de Biochimie et de Biologie Spécialisée, Hôpital Edouard Herriot, 69437, Lyon Cedex 03, France. Phone: +33 472110628. Fax: +33472110598. E-mail:
Many large deletions removing the entire α-globin gene cluster on the short arm of the human chromosome 16 (16p13.3) have been described.1–3 At the heterozygous state, the resulting phenotype consists in α-thalassemia (α-thal) for relatively short deletions (100 to 356 kb) while an α-thalassemia mental retardation syndrome (ATR-16 syndrome) is observed for larger deletions (> 1 Mb) which generally include the 16p telomere.4,5 We report here a new large telomeric deletion (~285 kb) associated with the common alpha-thalassemia –α3.7 deletion in trans. This genotype led to a phenotypically unusual HbH disease.
The proband was a 14-year old girl (French Caucasian mother and Algerian father) with a marked hypochromic and microcytic anemia (Hb: 9.2 g/dL; MCV: 55.0 fL; MCHC: 29.9 g/dL; MCH: 16.5 pg and reticulocyte count: 1.7%). Physical examination was normal (without hepatosplenomegaly or subicterus) except for a marked scoliosis for which surgery was considered. She presented no developmental delay and had a normal school education. The presence of HbH (~8%) was detected at routine hemoglobin analysis using isoelectric focusing and cation-exchange liquid chromatography (Variant I, Bio-Rad). Unfortunately, a new blood sample to identify Heinz inclusion bodies could not be obtained. The search for the common α-thal deletions was carried out by multiplex PCR6 and the common –α3.7 deletion was found at the homozygous state. This result could not be accepted for two reasons: (i) the father carried the –α3.7 deletion at the heterozygous state but the mother did not; (ii) a homozygosity for the –α3.7 deletion is not associated with Hb disease. We thus performed an MLPA analysis (Salsa MLPA kit P140-B2 HBA, MRC Holland) which identified, for both the proband and her mother, a large deletion of the α-globin gene cluster (Figures 1 and 2). A CGH-array analysis was then carried out to gap the deletion which appeared to be approximately 285 kb in length, spanning from the telomeric region in 5’ to the AXIN1 gene in 3’ (Figure 1). We could finally determine, by semi-quantitative PCR assays,8 that the deletion removes exons 5 to 10 of the AXIN1 gene but leaves exons 1 to 4 intact (the AXIN1 gene is orientated from 3’ to 5’ on the forward strand).
The exact α-globin genotype of our proband (– – / –α3.7) is in total accordance with her HbH disease. According to Horsley et al., monosomy for the 356 kb most telomeric region of the short arm of human chromosome 16 is not associated with the ATR-16 syndrome.3 As the deletion described in the present case report is shorter (~285 kb), it seems logical not to observe major dysmorphic features for our proband, but her very marked scoliosis remains unexplained. The AXIN1 gene has been involved in osteoclasts and osteoblast regulation.9 Thus, the deleted AXIN1 gene could potentially encode a dominant negative protein for bone synthesis. This negative effect would be potentialized by HbH disease, explaining why no scoliosis was observed for the mother. AXIN1 is also a tumor suppressor gene involved in the development of embryo abnormalities and human cancers.10–12 Genetic counseling and a clinical follow-up are thus required for our proband as mutations, loss of heterozygosity or epigenetic inactivation on the unique functional AXINI-1 gene could have severe clinical consequences.
Funding: this work was partially supported by the French Ministry of Health (DHOS, Plan Maladies Rares) and Hospices Civils de Lyon.
- Copyright© Ferrata Storti Foundation