- Email: [email protected]
10p12.1 deletion: HDR phenotype without DGS2 features
Experimental and Molecular Pathology 86 (2009) 74–76
Contents lists available at ScienceDirect
Experimental and Molecular Pathology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / yex m p
Case Report
10p12.1 deletion: HDR phenotype without DGS2 features Elisa Benetti a,⁎, Luisa Murer a,b, Andrea Bordugo c, Barbara Andreetta a, Lina Artifoni b a b c
Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Pediatrics, University of Padua, Via Giustiniani, 3, 35128 Padua, Italy Laboratory of Pediatric Nephrology, Department of Pediatrics, University of Padua, Italy Department of Pediatrics, Ospedale Santa Maria degli Angeli, Pordenone, Italy
a r t i c l e
i n f o
Article history: Received 21 October 2008 Available online 31 October 2008 Keywords: GATA3 gene HDR syndrome DiGeorge syndrome Chromosome deletion 10p chromosome Gene deletion Renal hypodysplasia Deafness Hypoparathyroidism Chronic renal failure
a b s t r a c t GATA3 gene encodes a transcription factor expressed during thymus, liver, kidney, adrenal gland, central and peripheral nervous systems, placenta and T lymphocytes embryonic development. Mutations of GATA3 cause Hypoparathyroidism, sensorineural Deafness and Renal dysplasia syndrome (HDR). We report the case of a girl with a terminal deletion of the short arm of chromosome 10 (10p12.1-pter), including both HDR locus and the DiGeorge critical region 2 (DGCR2), with HDR phenotype but not DiGeorge syndrome 2 features. The girl developed chronic renal failure during the first year of life, associated with sensorineural hearing loss, facial dysmorphic features and psychomotor development. She had hypodysplastic kidneys and bilateral grade 3-vesicoureteric reflux. Her karyotype was 46,XX,del(10)(p12.1-pter). Quantitative analysis by Real Time PCR on blood DNA confirmed the lack of one copy of GATA3 gene. She underwent renal transplantation at the age of 11. Our patient is the first case with a large deletion of the short arm of chromosome 10 - that certainly involves DGCR2 - with the HDR phenotype but without the clinical features of DGS2. This peculiarity suggests the hypothesis that the mechanisms underlying this syndrome may be more complex. It is therefore possible that DGS2 may be determined by locus heterogeneity. © 2008 Elsevier Inc. All rights reserved.
Introduction GATA3 gene localizes on 10p14-15 and is a transcription factor belonging to a family of six zinc fingers-proteins that are involved in different organs development. In animal models, gata3 is expressed during thymus, liver, kidney, adrenal gland, central and peripheral nervous systems, placenta and T lymphocytes embryonic development. In humans, GATA3 plays an important role in T lymphocytes differentiation by activating genes for the CD8alfa chain and for T-cells receptors, but it is also involved in kidney, inner ear, parathyroids and central nervous system embryogenesis. In adults, its expression is restricted to T lineage (Debacker et al., 1999). In kidney development, GATA3 is expressed in the mesonephros from the 4th week of gestation (WG). In the metanephros, the gene is intensely expressed in the ureteric bud (UB) from the 7th WG, when the Wolffian duct has penetrated into the metanephric blastema and ureteric branching and mesenchymal differentiation occur. Later, GATA3 expression remains high in the UB and in epithelial cells of the collecting duct until the 32nd WG (Labastie et al., 1995). Mutations or deletions of GATA3 cause Hypoparathyroidism, sensorineural Deafness and Renal dysplasia syndrome (HDR; MIM
⁎ Corresponding author. Fax: +39 0498211401. E-mail address: [email protected] (E. Benetti). 0014-4800/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2008.10.003
146255), an autosomal dominant disorder, characterized by hypoparathyroidism, moderate to severe bilateral sensorineural hearing loss and various renal anomalies, including renal hypoplasia/dysplasia, pelvicalyceal deformity and vesicoureteral reflux. HDR was also reported in patients who carried 10p deletions and showed clinical features of DiGeorge Syndrome (DGS). Thus a DiGeorge-like (DGS2) locus was placed on 10p13-14 and called DiGeorge Critical Region 2 (Lichtner et al., 2000; Hernández et al., 2007). Herein we report the case of a girl with a terminal deletion of the short arm of chromosome 10, resulting in a complete haploinsufficiency of GATA3 gene, with HDR phenotype but not DGS2 features. Case report The girl was delivered at term after caesarean section for podalic presentation. Ultrasound examinations during her prenatal course showed intrauterine growth restriction and decreased fetal movements since the 5th week of gestation (WG). Her birth weight and length were 2160 g and 44 cm respectively (both b3rd percentile), but head circumference was 34 cm (50th percentile). Family history was non-contributory. During the first weeks of life, she presented feeding difficulties with poor weight gain and recurrent respiratory tract infections. At the age of 8 months, she was admitted to another hospital to undergo an evaluation for three urinary tract infection episodes. Physical
E. Benetti et al. / Experimental and Molecular Pathology 86 (2009) 74–76
examination was remarkable for somatic growth (weight, height and head circumference b3rd percentile) and psychomotor development retardation with facial dysmorphic features and axial hypotonia. Laboratory studies showed a serum creatinine level of 380 μmol/L, which later decreased to 80 μmol/L. Technetium-99 m-labeled dimercaptosuccinic acid (DMSA) scan revealed one scar on the upper pole of the right kidney and two scars on the left. On follow up analyses performed at 15 months of age, serum creatinine level was 106 μmol/L (creatinine clearance according to Schwartz formula 20 ml/min/1.73 mq), with no other remarkable findings (serum calcium and parathyroid hormone were normal). Urinalysis was negative. Renal ultrasonography showed hypodysplastic kidneys, with left mild hydroureteronephrosis. Bilateral grade 3-vesicoureteric reflux was observed on contrast voiding cystography. The girl presented sensorineural hearing loss and malformed ears, with tympanic cavity hypoplasia and external auditory canal atresia. Brain ultrasound was normal but brain CT revealed cerebral atrophy and left basal nuclei calcification. EEG showed slow brain waves but no paroxystical activity. The girl later developed epilepsy and valproic acid therapy was started. Ophthalmological examination and visual evoked potential were normal. ECG and echocardiography were normal and no anomalies to other organs were found in further investigations. A high resolution cytogenetic analysis detected a deletion of the short arm of chromosome 10. The girl's karyotype was 46,XX,del (p12.1-pter). Parents' karyotype was normal. About 131 genes were identified in the deleted region. Among these genes, GATA3 drew our attention for its important role in nephrogenesis and in renal developmental disorders. Therefore, a quantitative analysis by Real Time PCR on patient blood DNA was performed and confirmed the lack of one copy of GATA3 gene. By age 10 years, creatinine and BUN levels were 601 μmol/L (creatinine clearance 10 mL/min/1.73 mq) and 47.3 mmol/L, respectively, with a serum calcium level of 2.89 mmol/L and parathyroid hormone (PTH) of 161 ng/L. Immunological function was normal. The girl started renal replacement therapy (peritoneal dialysis) and she underwent renal transplantation from a deceased donor at the age of 11. On recent investigations conducted at 12 years of age, serum creatinine and BUN level were 100 μmol/L (creatinine clearance 62 mL/min/1.73 mq) and 8.1 mmol/dL respectively, serum calcium was 2.31 mmol/L and PTH 290 ng/L. Discussion We report a case of a large terminal deletion of the short arm of chromosome 10 in a girl with renal hypodysplasia and VUR, deafness and mental retardation. The deleted chromosomal region includes GATA3 gene, whose mutations or deletions are associated with HDR syndrome, a rare congenital disease, first described by Barakat et al. (1977). However, the detected deletion also included the so called DiGeorge Critical Region 2 (DGCR2), localized on chromosome 10p13-14. DiGeorge Syndrome (DGS; MIM 188400) is characterized by distinct facial features, hypoplasia or aplasia of the thymus with immunodeficiency, hypoplasia or aplasia of parathyroid glands with hypocalcemia and hypoparathyroidism, and conotruncal cardiac defects. Molecular analyses demonstrated that nearly 90% of patients with the clinical features of DGS had a chromosomal rearrangement resulting in 22q11 deletion. In some cases, a DiGeorge-like phenotype (DGS2) has been associated with the deletion 10p13-14 (Daw et al., 1996; Schuffenhauer et al., 1998; Gottlieb et al., 1998). Some authors suggested that DGS2 could be considered as a contiguous gene syndrome owing to haploinsufficiency of genes localized on 10p13-14 or more distally (Lichtner et al., 2000; Gottlieb et al., 1998). Alternatively, others placed DGCR2 in 10p13-14 and HDR locus in 10p14-15 (Van Esch and Devriendt, 2001). While the disease causing-gene for HDR was identified in GATA3, no genes were
75
found for DGS2. Thus, in order to identify a disease causing-gene, a mutation analysis of two candidate genes, BRUNOL3 and nebulette gene (NEBL) was performed in DGS2 patients, but no alterations were detected (Lichtner et al., 2002; Villanueva et al., 2002). Our patient showed the phenotypic characteristics of HDR, namely deafness and renal disease. As a matter of fact, she did not show hypoparathyroidism. It is known that this is the component of the HDR triad which shows the higher variability and patients with a late-onset or without hypoparathyroidism were reported (Hernández et al., 2007; Muroya et al., 2001). Furthermore, the development of chronic renal failure in the first year of life in our patient may have influenced calcium and PTH levels, confusing the assessment of a potential hypoparathyroidism. Besides, the girl did not present the clinical features of DGS2 (heart defects nor immunodeficiency). This makes our patient the only case with a large deletion of the short arm of chromosome 10 (p12.1-pter) – that certainly involves DGCR2 – without any of the clinical features of DGS2. In patients with such a large deletion, renal involvement was reported in 54% of cases with DGS2 phenotype, whereas it was constant in patients with HDR phenotype (Van Esch et al., 1999). This suggests that GATA3 locus must be involved to determine a renal disorder. A further evidence of GATA3 role in renal disease development is the association between GATA3 mutations and renal illness (Ali et al., 2007). Even though we cannot exclude that our patient may represent a case of incomplete penetrance of DGS2, we hypothesize that the mechanisms underlying this syndrome may be more complex. As well as trisomies or deletions of different chromosomal segments are described to be associated with DGS phenotype (Fernández et al., 2008), it is possible that this syndrome is determined by locus heterogeneity. References Ali, A., Christie, P.T., Grigorieva, I.V., Harding, B., Van Esch, H., Ahmed, S.F., BitnerGlindzicz, M., Blind, E., Bloch, C., Christin, P., Clayton, P., Gecz, J., GilbertDussardier, B., Guillen-Navarro, E., Hackett, A., Halac, I., Hendy, G.N., Lalloo, F., Mache, C.J., Mughal, Z., Ong, A.C., Rinat, C., Shaw, N., Smithson, S.F., Tolmie, J., Weill, J., Nesbit, M.A., Thakker, R.V., 2007. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum. Mol. Genet. 16, 265–275. Barakat, A.Y., D'Albora, J.B., Martin, M.M., Jose, P.A., 1977. Familial nephrosis, nerve deafness, and hypoparathyroidism. J. Pediatr. 91, 61–64. Daw, S.C., Taylor, C., Kraman, M., Call, K., Mao, J., Schuffenhauer, S., Meitinger, T., Lipson, T., Goodship, J., Scambler, P., 1996. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat. Genet. 13, 458–460. Debacker, C., Catale, M., Labastie, M.C., 1999. Embryonic expression of the human GATA-3 gene. Mech. Dev. 85, 183–187. Fernández, L., Lapunzina, P., Pajares, I.L., Palomares, M., Martínez, I., Fernández, B., Quero, J., García-Guereta, L., García-Alix, A., Burgueros, M., Galán-Gómez, E., Carbonell-Pérez, J.M., Pérez-Granero, A., Torres-Juan, L., Heine-Suñer, D., Rosell, J., Delicado, A., 2008. Unrelated chromosomal anomalies found in patients with suspected 22q11.2 deletion. Am. J. Med. Genet. A 146A, 1134–1141. Gottlieb, S., Driscoll, D.A., Punnett, H.H., Sellinger, B., Emanuel, B.S., Budarf, M.L., 1998. Characterization of 10p deletions suggests two nonoverlapping regions contribute to the DiGeorge syndrome phenotype. Am. J. Hum. Genet. 62, 495–498. Hernández, A.M., Villamar, M., Roselló, L., Moreno-Pelayo, M.A., Moreno, F., Del Castillo, I., 2007. Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am. J. Med. Genet. A 143, 757–762. Labastie, M.C., Catala, M., Gregoire, J.M., Peault, B., 1995. The GATA-3 gene is expressed during human kidney embryogenesis. Kidney Int. 4, 1597–1603. Lichtner, P., König, R., Hasegawa, T., Van Esch, H., Meitinger, T., Schuffenhauer, S., 2000. An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J. Med. Genet. 37, 33–37. Lichtner, P., Attié-Bitach, T., Schuffenhauer, S., Henwood, J., Bouvagnet, P., Scambler, P.J., Meitinger, T., Vekemans, M., 2002. Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. J. Mol. Med. 80, 431–442. Muroya, K., Hasegawa, T., Ito, Y., Nagai, T., Isotani, H., Iwata, Y., Yamamoto, K., Fujimoto, S., Seishu, S., Fukushima, Y., Hasegawa, Y., Ogata, T., 2001. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J. Med. Genet. 38, 374–380.
76
E. Benetti et al. / Experimental and Molecular Pathology 86 (2009) 74–76
Schuffenhauer, S., Lichtner, P., Peykar-Derakhshandeh, P., Murken, J., Haas, O.A., Back, E., Wolff, G., Zabel, B., Barisic, I., Rauch, A., Borochowitz, Z., Dallapiccola, B., Ross, M., Meitinger, T., 1998. Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2). Eur. J. Hum. Genet. 6, 213–225. Van Esch, H., Devriendt, K., 2001. Transcription factor GATA3 and the human HDR syndrome. Cell. Mol. Life Sci. 58, 1296–1300.
Van Esch, H., Groenen, P., Fryns, J.P., Van de Ven, W., Devriendt, K., 1999. The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Genet. Counsel. 10, 59–65. Villanueva, M.P., Aiyer, A.R., Muller, S., Pletcher, M.T., Liu, X., Emanuel, B., Srivasta, D., Reeves, R.H., 2002. Genetic and comparative mapping of genes dysregulated in mouse hearts lacking the Hand2 transcription factor gene. Genomics 80, 593–600.
Contents lists available at ScienceDirect
Experimental and Molecular Pathology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / yex m p
Case Report
10p12.1 deletion: HDR phenotype without DGS2 features Elisa Benetti a,⁎, Luisa Murer a,b, Andrea Bordugo c, Barbara Andreetta a, Lina Artifoni b a b c
Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Pediatrics, University of Padua, Via Giustiniani, 3, 35128 Padua, Italy Laboratory of Pediatric Nephrology, Department of Pediatrics, University of Padua, Italy Department of Pediatrics, Ospedale Santa Maria degli Angeli, Pordenone, Italy
a r t i c l e
i n f o
Article history: Received 21 October 2008 Available online 31 October 2008 Keywords: GATA3 gene HDR syndrome DiGeorge syndrome Chromosome deletion 10p chromosome Gene deletion Renal hypodysplasia Deafness Hypoparathyroidism Chronic renal failure
a b s t r a c t GATA3 gene encodes a transcription factor expressed during thymus, liver, kidney, adrenal gland, central and peripheral nervous systems, placenta and T lymphocytes embryonic development. Mutations of GATA3 cause Hypoparathyroidism, sensorineural Deafness and Renal dysplasia syndrome (HDR). We report the case of a girl with a terminal deletion of the short arm of chromosome 10 (10p12.1-pter), including both HDR locus and the DiGeorge critical region 2 (DGCR2), with HDR phenotype but not DiGeorge syndrome 2 features. The girl developed chronic renal failure during the first year of life, associated with sensorineural hearing loss, facial dysmorphic features and psychomotor development. She had hypodysplastic kidneys and bilateral grade 3-vesicoureteric reflux. Her karyotype was 46,XX,del(10)(p12.1-pter). Quantitative analysis by Real Time PCR on blood DNA confirmed the lack of one copy of GATA3 gene. She underwent renal transplantation at the age of 11. Our patient is the first case with a large deletion of the short arm of chromosome 10 - that certainly involves DGCR2 - with the HDR phenotype but without the clinical features of DGS2. This peculiarity suggests the hypothesis that the mechanisms underlying this syndrome may be more complex. It is therefore possible that DGS2 may be determined by locus heterogeneity. © 2008 Elsevier Inc. All rights reserved.
Introduction GATA3 gene localizes on 10p14-15 and is a transcription factor belonging to a family of six zinc fingers-proteins that are involved in different organs development. In animal models, gata3 is expressed during thymus, liver, kidney, adrenal gland, central and peripheral nervous systems, placenta and T lymphocytes embryonic development. In humans, GATA3 plays an important role in T lymphocytes differentiation by activating genes for the CD8alfa chain and for T-cells receptors, but it is also involved in kidney, inner ear, parathyroids and central nervous system embryogenesis. In adults, its expression is restricted to T lineage (Debacker et al., 1999). In kidney development, GATA3 is expressed in the mesonephros from the 4th week of gestation (WG). In the metanephros, the gene is intensely expressed in the ureteric bud (UB) from the 7th WG, when the Wolffian duct has penetrated into the metanephric blastema and ureteric branching and mesenchymal differentiation occur. Later, GATA3 expression remains high in the UB and in epithelial cells of the collecting duct until the 32nd WG (Labastie et al., 1995). Mutations or deletions of GATA3 cause Hypoparathyroidism, sensorineural Deafness and Renal dysplasia syndrome (HDR; MIM
⁎ Corresponding author. Fax: +39 0498211401. E-mail address: [email protected] (E. Benetti). 0014-4800/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2008.10.003
146255), an autosomal dominant disorder, characterized by hypoparathyroidism, moderate to severe bilateral sensorineural hearing loss and various renal anomalies, including renal hypoplasia/dysplasia, pelvicalyceal deformity and vesicoureteral reflux. HDR was also reported in patients who carried 10p deletions and showed clinical features of DiGeorge Syndrome (DGS). Thus a DiGeorge-like (DGS2) locus was placed on 10p13-14 and called DiGeorge Critical Region 2 (Lichtner et al., 2000; Hernández et al., 2007). Herein we report the case of a girl with a terminal deletion of the short arm of chromosome 10, resulting in a complete haploinsufficiency of GATA3 gene, with HDR phenotype but not DGS2 features. Case report The girl was delivered at term after caesarean section for podalic presentation. Ultrasound examinations during her prenatal course showed intrauterine growth restriction and decreased fetal movements since the 5th week of gestation (WG). Her birth weight and length were 2160 g and 44 cm respectively (both b3rd percentile), but head circumference was 34 cm (50th percentile). Family history was non-contributory. During the first weeks of life, she presented feeding difficulties with poor weight gain and recurrent respiratory tract infections. At the age of 8 months, she was admitted to another hospital to undergo an evaluation for three urinary tract infection episodes. Physical
E. Benetti et al. / Experimental and Molecular Pathology 86 (2009) 74–76
examination was remarkable for somatic growth (weight, height and head circumference b3rd percentile) and psychomotor development retardation with facial dysmorphic features and axial hypotonia. Laboratory studies showed a serum creatinine level of 380 μmol/L, which later decreased to 80 μmol/L. Technetium-99 m-labeled dimercaptosuccinic acid (DMSA) scan revealed one scar on the upper pole of the right kidney and two scars on the left. On follow up analyses performed at 15 months of age, serum creatinine level was 106 μmol/L (creatinine clearance according to Schwartz formula 20 ml/min/1.73 mq), with no other remarkable findings (serum calcium and parathyroid hormone were normal). Urinalysis was negative. Renal ultrasonography showed hypodysplastic kidneys, with left mild hydroureteronephrosis. Bilateral grade 3-vesicoureteric reflux was observed on contrast voiding cystography. The girl presented sensorineural hearing loss and malformed ears, with tympanic cavity hypoplasia and external auditory canal atresia. Brain ultrasound was normal but brain CT revealed cerebral atrophy and left basal nuclei calcification. EEG showed slow brain waves but no paroxystical activity. The girl later developed epilepsy and valproic acid therapy was started. Ophthalmological examination and visual evoked potential were normal. ECG and echocardiography were normal and no anomalies to other organs were found in further investigations. A high resolution cytogenetic analysis detected a deletion of the short arm of chromosome 10. The girl's karyotype was 46,XX,del (p12.1-pter). Parents' karyotype was normal. About 131 genes were identified in the deleted region. Among these genes, GATA3 drew our attention for its important role in nephrogenesis and in renal developmental disorders. Therefore, a quantitative analysis by Real Time PCR on patient blood DNA was performed and confirmed the lack of one copy of GATA3 gene. By age 10 years, creatinine and BUN levels were 601 μmol/L (creatinine clearance 10 mL/min/1.73 mq) and 47.3 mmol/L, respectively, with a serum calcium level of 2.89 mmol/L and parathyroid hormone (PTH) of 161 ng/L. Immunological function was normal. The girl started renal replacement therapy (peritoneal dialysis) and she underwent renal transplantation from a deceased donor at the age of 11. On recent investigations conducted at 12 years of age, serum creatinine and BUN level were 100 μmol/L (creatinine clearance 62 mL/min/1.73 mq) and 8.1 mmol/dL respectively, serum calcium was 2.31 mmol/L and PTH 290 ng/L. Discussion We report a case of a large terminal deletion of the short arm of chromosome 10 in a girl with renal hypodysplasia and VUR, deafness and mental retardation. The deleted chromosomal region includes GATA3 gene, whose mutations or deletions are associated with HDR syndrome, a rare congenital disease, first described by Barakat et al. (1977). However, the detected deletion also included the so called DiGeorge Critical Region 2 (DGCR2), localized on chromosome 10p13-14. DiGeorge Syndrome (DGS; MIM 188400) is characterized by distinct facial features, hypoplasia or aplasia of the thymus with immunodeficiency, hypoplasia or aplasia of parathyroid glands with hypocalcemia and hypoparathyroidism, and conotruncal cardiac defects. Molecular analyses demonstrated that nearly 90% of patients with the clinical features of DGS had a chromosomal rearrangement resulting in 22q11 deletion. In some cases, a DiGeorge-like phenotype (DGS2) has been associated with the deletion 10p13-14 (Daw et al., 1996; Schuffenhauer et al., 1998; Gottlieb et al., 1998). Some authors suggested that DGS2 could be considered as a contiguous gene syndrome owing to haploinsufficiency of genes localized on 10p13-14 or more distally (Lichtner et al., 2000; Gottlieb et al., 1998). Alternatively, others placed DGCR2 in 10p13-14 and HDR locus in 10p14-15 (Van Esch and Devriendt, 2001). While the disease causing-gene for HDR was identified in GATA3, no genes were
75
found for DGS2. Thus, in order to identify a disease causing-gene, a mutation analysis of two candidate genes, BRUNOL3 and nebulette gene (NEBL) was performed in DGS2 patients, but no alterations were detected (Lichtner et al., 2002; Villanueva et al., 2002). Our patient showed the phenotypic characteristics of HDR, namely deafness and renal disease. As a matter of fact, she did not show hypoparathyroidism. It is known that this is the component of the HDR triad which shows the higher variability and patients with a late-onset or without hypoparathyroidism were reported (Hernández et al., 2007; Muroya et al., 2001). Furthermore, the development of chronic renal failure in the first year of life in our patient may have influenced calcium and PTH levels, confusing the assessment of a potential hypoparathyroidism. Besides, the girl did not present the clinical features of DGS2 (heart defects nor immunodeficiency). This makes our patient the only case with a large deletion of the short arm of chromosome 10 (p12.1-pter) – that certainly involves DGCR2 – without any of the clinical features of DGS2. In patients with such a large deletion, renal involvement was reported in 54% of cases with DGS2 phenotype, whereas it was constant in patients with HDR phenotype (Van Esch et al., 1999). This suggests that GATA3 locus must be involved to determine a renal disorder. A further evidence of GATA3 role in renal disease development is the association between GATA3 mutations and renal illness (Ali et al., 2007). Even though we cannot exclude that our patient may represent a case of incomplete penetrance of DGS2, we hypothesize that the mechanisms underlying this syndrome may be more complex. As well as trisomies or deletions of different chromosomal segments are described to be associated with DGS phenotype (Fernández et al., 2008), it is possible that this syndrome is determined by locus heterogeneity. References Ali, A., Christie, P.T., Grigorieva, I.V., Harding, B., Van Esch, H., Ahmed, S.F., BitnerGlindzicz, M., Blind, E., Bloch, C., Christin, P., Clayton, P., Gecz, J., GilbertDussardier, B., Guillen-Navarro, E., Hackett, A., Halac, I., Hendy, G.N., Lalloo, F., Mache, C.J., Mughal, Z., Ong, A.C., Rinat, C., Shaw, N., Smithson, S.F., Tolmie, J., Weill, J., Nesbit, M.A., Thakker, R.V., 2007. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum. Mol. Genet. 16, 265–275. Barakat, A.Y., D'Albora, J.B., Martin, M.M., Jose, P.A., 1977. Familial nephrosis, nerve deafness, and hypoparathyroidism. J. Pediatr. 91, 61–64. Daw, S.C., Taylor, C., Kraman, M., Call, K., Mao, J., Schuffenhauer, S., Meitinger, T., Lipson, T., Goodship, J., Scambler, P., 1996. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat. Genet. 13, 458–460. Debacker, C., Catale, M., Labastie, M.C., 1999. Embryonic expression of the human GATA-3 gene. Mech. Dev. 85, 183–187. Fernández, L., Lapunzina, P., Pajares, I.L., Palomares, M., Martínez, I., Fernández, B., Quero, J., García-Guereta, L., García-Alix, A., Burgueros, M., Galán-Gómez, E., Carbonell-Pérez, J.M., Pérez-Granero, A., Torres-Juan, L., Heine-Suñer, D., Rosell, J., Delicado, A., 2008. Unrelated chromosomal anomalies found in patients with suspected 22q11.2 deletion. Am. J. Med. Genet. A 146A, 1134–1141. Gottlieb, S., Driscoll, D.A., Punnett, H.H., Sellinger, B., Emanuel, B.S., Budarf, M.L., 1998. Characterization of 10p deletions suggests two nonoverlapping regions contribute to the DiGeorge syndrome phenotype. Am. J. Hum. Genet. 62, 495–498. Hernández, A.M., Villamar, M., Roselló, L., Moreno-Pelayo, M.A., Moreno, F., Del Castillo, I., 2007. Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am. J. Med. Genet. A 143, 757–762. Labastie, M.C., Catala, M., Gregoire, J.M., Peault, B., 1995. The GATA-3 gene is expressed during human kidney embryogenesis. Kidney Int. 4, 1597–1603. Lichtner, P., König, R., Hasegawa, T., Van Esch, H., Meitinger, T., Schuffenhauer, S., 2000. An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J. Med. Genet. 37, 33–37. Lichtner, P., Attié-Bitach, T., Schuffenhauer, S., Henwood, J., Bouvagnet, P., Scambler, P.J., Meitinger, T., Vekemans, M., 2002. Expression and mutation analysis of BRUNOL3, a candidate gene for heart and thymus developmental defects associated with partial monosomy 10p. J. Mol. Med. 80, 431–442. Muroya, K., Hasegawa, T., Ito, Y., Nagai, T., Isotani, H., Iwata, Y., Yamamoto, K., Fujimoto, S., Seishu, S., Fukushima, Y., Hasegawa, Y., Ogata, T., 2001. GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J. Med. Genet. 38, 374–380.
76
E. Benetti et al. / Experimental and Molecular Pathology 86 (2009) 74–76
Schuffenhauer, S., Lichtner, P., Peykar-Derakhshandeh, P., Murken, J., Haas, O.A., Back, E., Wolff, G., Zabel, B., Barisic, I., Rauch, A., Borochowitz, Z., Dallapiccola, B., Ross, M., Meitinger, T., 1998. Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2). Eur. J. Hum. Genet. 6, 213–225. Van Esch, H., Devriendt, K., 2001. Transcription factor GATA3 and the human HDR syndrome. Cell. Mol. Life Sci. 58, 1296–1300.
Van Esch, H., Groenen, P., Fryns, J.P., Van de Ven, W., Devriendt, K., 1999. The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Genet. Counsel. 10, 59–65. Villanueva, M.P., Aiyer, A.R., Muller, S., Pletcher, M.T., Liu, X., Emanuel, B., Srivasta, D., Reeves, R.H., 2002. Genetic and comparative mapping of genes dysregulated in mouse hearts lacking the Hand2 transcription factor gene. Genomics 80, 593–600.