A number sign (#) is used with this entry because transient neonatal cyanosis is caused by heterozygous mutation in the HBG2 gene (142250) on chromosome 11p15.5.
Neonatal cyanosis is characterized by symptoms in the fetus and neonate that gradually abate by 5 to 6 months of age. The disorder is caused by a defect in the fetal hemoglobin chain, which causes reduced affinity for oxygen due to steric inhibition of oxygen binding and/or due to increased oxidation of the fetal hemoglobin molecule to methemoglobin (Hb FM), which has decreased oxygen-binding capacity. Some patients develop anemia resulting from increased destruction of red cells containing abnormal or unstable hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months of age or earlier, as the adult beta-globin chain (HBB;141900) is produced and replaces the fetal gamma-globin chain (summary byCrowley et al., 2011).
Hayashi et al. (1980) reported a premature Japanese baby with severe cyanosis and jaundice.
Priest et al. (1989) reported a well newborn who was cyanotic at birth. He was found to have a mutant gamma-globin chain, leading to functionally abnormal fetal hemoglobin. This patient showed no clinical evidence of cyanosis at 5 weeks of age as gamma-chain synthesis was replaced by beta-chain synthesis. A sib born 20 months later was also affected.
Urabe et al. (1996) described a full-term baby who was cyanotic from birth but did not require special treatment.
Prehu et al. (2003) reported a newborn male in southwest France who presented at birth with marked cyanosis. He was of normal weight and was born uneventfully at 41 weeks from a 28-year-old mother. Studies excluded a cardiovascular origin of the cyanosis, which persisted under oxygen therapy. The intensity of cyanosis decreased after a few months.
Dainer et al. (2008) reported a male with neonatal cyanosis. The patient's oxygen saturation was 85% on room air and he required supplemental oxygen. His 4-year-old sister had a similar neonatal course and had required supplemental oxygen for the first 4 to 5 months of life, at which time she became asymptomatic. High performance liquid chromatography of the male infant's blood showed 68.4% HbF, 17.5% HbA, and 14.0% HbX, eluting between HbF and HbA. Spectroscopic analysis was not performed.
Crowley et al. (2011) reported a female infant with cyanosis and moderate hepatomegaly at birth. Hemoglobin oxygen saturation in ambient air was 30 to 50%. She also had moderate anemia with reticulocytosis, but methemoglobin levels were normal. Electrophoresis showed that total hemoglobin consisted of about 90% HbF and 10% HbA, with no variant bands. She received transfusions, which raised the hemoglobin oxygen saturation levels. By 2 months of age, her hemoglobin oxygen saturation was consistently higher than 95%. The patient's father also had transient neonatal cyanosis, which resolved within 1 to 2 months.
A methemoglobinemic (M) variant of fetal hemoglobin (HbF), known as Hb FM-Osaka (H63Y;142250.0025), was found in a premature Japanese baby with severe jaundice and cyanosis (Hayashi et al., 1980). The Osaka variant was also found in newborns with cyanosis byGlader et al. (1989),Urabe et al. (1996), andPrehu et al. (2003).
Glader (1989) identified Hb FM-Fort Ripley, caused by a heterozygous mutation in the HBG2 gene (H92Y;142250.0034), in a healthy but cyanotic newborn girl. The patient reported byPriest et al. (1989) had the Hb FM-Fort Ripley variant.
Kohli-Kumar et al. (1995) reported a term infant with mild cyanosis. Standard hemoglobin electrophoresis, including isoelectric focusing, was normal. However, by reverse-phase HPLC on a C(4) column, they detected an abnormal globin chain. Amino acid and DNA sequencing revealed a heterozygous F41S (142250.0041) substitution in the HBG2 chain. This substitution, designated hemoglobin F-Cincinnati, presumably decreased oxygen affinity of the hemoglobin. The corresponding substitution in the beta-globin gene is found in hemoglobin Denver (HBB;141900.0441) and is associated with cyanosis.
In 2 sibs with neonatal transient cyanosis,Dainer et al. (2008) identified a heterozygous mutation in the HBG2 gene (H63L;142250.0050), which was termed Hb F-Circleville. The heterozygous mutation was found in the father, who had no recollection of neonatal cyanosis. Position his63 in HBG2 coordinates with heme iron and is mutant in Hb FM-Osaka (H63Y;142250.0025).Dainer et al. (2008) noted that the presence of a tyrosine at codon 63 in Hb FM-Osaka causes the formation of a covalent link with heme iron, so that the iron is stabilized in the ferric (3+) form. When this occurs, methemoglobin is formed, oxygen can no longer bind to heme, and cyanosis occurs.
In a female infant with neonatal cyanosis and anemia,Crowley et al. (2011) identified a heterozygous mutation in the HBG2 gene (V67M;142250.0051). The variant was named Hb-Toms River. This mutation modified the ligand-binding pocket of fetal hemoglobin via 2 mechanisms. First, the relatively large side chain of methionine decreases both the affinity of oxygen for binding to the mutant hemoglobin subunit via steric hindrance and the rate at which it does so. Second, the mutant methionine is converted to aspartic acid posttranslationally, probably through oxidative mechanisms. The presence of this polar amino acid in the heme pocket was predicted to enhance hemoglobin denaturation, causing anemia. The patient's father, who was also heterozygous for the mutation, had transient neonatal cyanosis, which resolved within 1 to 2 months.
Crowley, M. A., Mollan, T. L., Abdulmalik, O. Y., Butler, A. D., Goodwin, E. F., Sarkar, A., Stolle, C. A., Gow, A. J., Olson, J. S., Weiss, M. J.A hemoglobin variant associated with neonatal cyanosis and anemia. New Eng. J. Med. 364: 1837-1843, 2011. Note: Erratum: New Eng. J. Med. 365: 281 only, 2011. [PubMed:21561349,images,related citations] [Full Text]
Dainer, E., Shell, R., Miller, R., Atkin, J. F., Pastore, M., Kutlar, A., Zhuang, L., Holley, L., Davis, D. H., Kutlar, F.Neonatal cyanosis due to a novel fetal hemoglobin: Hb F-Circleville [G-gamma-63(E7)his-to-leu, CAT-CTT]. Hemoglobin 32: 596-600, 2008. [PubMed:19065339,related citations] [Full Text]
Glader, B. E.Hemoglobin, FM-Fort Ripley: another lesson from the neonate. Pediatrics 83: 792-793, 1989. [PubMed:2470018,related citations]
Glader, B. E., Zwerdling, D., Kutlar, F., Kutlar, A., Wilson, J. B., Huisman, T. H. J.Hb F-M-Osaka or gamma63(E7)his-to-tyr in a Caucasian male infant. Hemoglobin 13: 769-773, 1989. [PubMed:2483933,related citations] [Full Text]
Hayashi, A., Fujita, T., Fujimura, M., Titani, K.A new abnormal fetal hemoglobin, Hb FM-Osaka (gamma 63 his-to-tyr). Hemoglobin 4: 447-448, 1980. [PubMed:6158500,related citations] [Full Text]
Kohli-Kumar, M., Zwerdling, T., Rucknagel, D. L.Hb F-Cincinnati, alpha-2-G-gamma-2-41(C7) phe-to-ser in a newborn with cyanosis. Am. J. Hemat. 49: 43-47, 1995. [PubMed:7741137,related citations] [Full Text]
Prehu, C., Rhabbour, M., Netter, J. C., Denier, M., Riou, J., Galacteros, F., Wajcman, H.Hb F-M-Osaka [G-gamma-63(E7)his-to-tyr] in a newborn from southwest France. Hemoglobin 27: 27-30, 2003. [PubMed:12603090,related citations] [Full Text]
Priest, J. R., Watterson, J., Jones, R. T., Faassen, A. E., Hedlund, B. E.Mutant fetal hemoglobin causing cyanosis in a newborn. Pediatrics 83: 734-736, 1989. [PubMed:2470017,related citations]
Urabe, D., Li, W., Hattori, Y., Ohba, Y.A new case of Hb F-M-Osaka [G-gamma-63(E7)his-to-tyr] showed only benign neonatal cyanosis. Hemoglobin 20: 169-173, 1996. [PubMed:8811323,related citations] [Full Text]
ORPHA: 280615;
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key | Gene/Locus | Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.4 | Cyanosis, transient neonatal | 613977 | Autosomal dominant | 3 | HBG2 | 142250 |
A number sign (#) is used with this entry because transient neonatal cyanosis is caused by heterozygous mutation in the HBG2 gene (142250) on chromosome 11p15.5.
Neonatal cyanosis is characterized by symptoms in the fetus and neonate that gradually abate by 5 to 6 months of age. The disorder is caused by a defect in the fetal hemoglobin chain, which causes reduced affinity for oxygen due to steric inhibition of oxygen binding and/or due to increased oxidation of the fetal hemoglobin molecule to methemoglobin (Hb FM), which has decreased oxygen-binding capacity. Some patients develop anemia resulting from increased destruction of red cells containing abnormal or unstable hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months of age or earlier, as the adult beta-globin chain (HBB; 141900) is produced and replaces the fetal gamma-globin chain (summary by Crowley et al., 2011).
Hayashi et al. (1980) reported a premature Japanese baby with severe cyanosis and jaundice.
Priest et al. (1989) reported a well newborn who was cyanotic at birth. He was found to have a mutant gamma-globin chain, leading to functionally abnormal fetal hemoglobin. This patient showed no clinical evidence of cyanosis at 5 weeks of age as gamma-chain synthesis was replaced by beta-chain synthesis. A sib born 20 months later was also affected.
Urabe et al. (1996) described a full-term baby who was cyanotic from birth but did not require special treatment.
Prehu et al. (2003) reported a newborn male in southwest France who presented at birth with marked cyanosis. He was of normal weight and was born uneventfully at 41 weeks from a 28-year-old mother. Studies excluded a cardiovascular origin of the cyanosis, which persisted under oxygen therapy. The intensity of cyanosis decreased after a few months.
Dainer et al. (2008) reported a male with neonatal cyanosis. The patient's oxygen saturation was 85% on room air and he required supplemental oxygen. His 4-year-old sister had a similar neonatal course and had required supplemental oxygen for the first 4 to 5 months of life, at which time she became asymptomatic. High performance liquid chromatography of the male infant's blood showed 68.4% HbF, 17.5% HbA, and 14.0% HbX, eluting between HbF and HbA. Spectroscopic analysis was not performed.
Crowley et al. (2011) reported a female infant with cyanosis and moderate hepatomegaly at birth. Hemoglobin oxygen saturation in ambient air was 30 to 50%. She also had moderate anemia with reticulocytosis, but methemoglobin levels were normal. Electrophoresis showed that total hemoglobin consisted of about 90% HbF and 10% HbA, with no variant bands. She received transfusions, which raised the hemoglobin oxygen saturation levels. By 2 months of age, her hemoglobin oxygen saturation was consistently higher than 95%. The patient's father also had transient neonatal cyanosis, which resolved within 1 to 2 months.
A methemoglobinemic (M) variant of fetal hemoglobin (HbF), known as Hb FM-Osaka (H63Y; 142250.0025), was found in a premature Japanese baby with severe jaundice and cyanosis (Hayashi et al., 1980). The Osaka variant was also found in newborns with cyanosis by Glader et al. (1989), Urabe et al. (1996), and Prehu et al. (2003).
Glader (1989) identified Hb FM-Fort Ripley, caused by a heterozygous mutation in the HBG2 gene (H92Y; 142250.0034), in a healthy but cyanotic newborn girl. The patient reported by Priest et al. (1989) had the Hb FM-Fort Ripley variant.
Kohli-Kumar et al. (1995) reported a term infant with mild cyanosis. Standard hemoglobin electrophoresis, including isoelectric focusing, was normal. However, by reverse-phase HPLC on a C(4) column, they detected an abnormal globin chain. Amino acid and DNA sequencing revealed a heterozygous F41S (142250.0041) substitution in the HBG2 chain. This substitution, designated hemoglobin F-Cincinnati, presumably decreased oxygen affinity of the hemoglobin. The corresponding substitution in the beta-globin gene is found in hemoglobin Denver (HBB; 141900.0441) and is associated with cyanosis.
In 2 sibs with neonatal transient cyanosis, Dainer et al. (2008) identified a heterozygous mutation in the HBG2 gene (H63L; 142250.0050), which was termed Hb F-Circleville. The heterozygous mutation was found in the father, who had no recollection of neonatal cyanosis. Position his63 in HBG2 coordinates with heme iron and is mutant in Hb FM-Osaka (H63Y; 142250.0025). Dainer et al. (2008) noted that the presence of a tyrosine at codon 63 in Hb FM-Osaka causes the formation of a covalent link with heme iron, so that the iron is stabilized in the ferric (3+) form. When this occurs, methemoglobin is formed, oxygen can no longer bind to heme, and cyanosis occurs.
In a female infant with neonatal cyanosis and anemia, Crowley et al. (2011) identified a heterozygous mutation in the HBG2 gene (V67M; 142250.0051). The variant was named Hb-Toms River. This mutation modified the ligand-binding pocket of fetal hemoglobin via 2 mechanisms. First, the relatively large side chain of methionine decreases both the affinity of oxygen for binding to the mutant hemoglobin subunit via steric hindrance and the rate at which it does so. Second, the mutant methionine is converted to aspartic acid posttranslationally, probably through oxidative mechanisms. The presence of this polar amino acid in the heme pocket was predicted to enhance hemoglobin denaturation, causing anemia. The patient's father, who was also heterozygous for the mutation, had transient neonatal cyanosis, which resolved within 1 to 2 months.
Crowley, M. A., Mollan, T. L., Abdulmalik, O. Y., Butler, A. D., Goodwin, E. F., Sarkar, A., Stolle, C. A., Gow, A. J., Olson, J. S., Weiss, M. J.A hemoglobin variant associated with neonatal cyanosis and anemia. New Eng. J. Med. 364: 1837-1843, 2011. Note: Erratum: New Eng. J. Med. 365: 281 only, 2011. [PubMed: 21561349] [Full Text: https://doi.org/10.1056/NEJMoa1013579]
Dainer, E., Shell, R., Miller, R., Atkin, J. F., Pastore, M., Kutlar, A., Zhuang, L., Holley, L., Davis, D. H., Kutlar, F.Neonatal cyanosis due to a novel fetal hemoglobin: Hb F-Circleville [G-gamma-63(E7)his-to-leu, CAT-CTT]. Hemoglobin 32: 596-600, 2008. [PubMed: 19065339] [Full Text: https://doi.org/10.1080/03630260802507915]
Glader, B. E.Hemoglobin, FM-Fort Ripley: another lesson from the neonate. Pediatrics 83: 792-793, 1989. [PubMed: 2470018]
Glader, B. E., Zwerdling, D., Kutlar, F., Kutlar, A., Wilson, J. B., Huisman, T. H. J.Hb F-M-Osaka or gamma63(E7)his-to-tyr in a Caucasian male infant. Hemoglobin 13: 769-773, 1989. [PubMed: 2483933] [Full Text: https://doi.org/10.3109/03630268908998852]
Hayashi, A., Fujita, T., Fujimura, M., Titani, K.A new abnormal fetal hemoglobin, Hb FM-Osaka (gamma 63 his-to-tyr). Hemoglobin 4: 447-448, 1980. [PubMed: 6158500] [Full Text: https://doi.org/10.3109/03630268008996225]
Kohli-Kumar, M., Zwerdling, T., Rucknagel, D. L.Hb F-Cincinnati, alpha-2-G-gamma-2-41(C7) phe-to-ser in a newborn with cyanosis. Am. J. Hemat. 49: 43-47, 1995. [PubMed: 7741137] [Full Text: https://doi.org/10.1002/ajh.2830490108]
Prehu, C., Rhabbour, M., Netter, J. C., Denier, M., Riou, J., Galacteros, F., Wajcman, H.Hb F-M-Osaka [G-gamma-63(E7)his-to-tyr] in a newborn from southwest France. Hemoglobin 27: 27-30, 2003. [PubMed: 12603090] [Full Text: https://doi.org/10.1081/hem-120018433]
Priest, J. R., Watterson, J., Jones, R. T., Faassen, A. E., Hedlund, B. E.Mutant fetal hemoglobin causing cyanosis in a newborn. Pediatrics 83: 734-736, 1989. [PubMed: 2470017]
Urabe, D., Li, W., Hattori, Y., Ohba, Y.A new case of Hb F-M-Osaka [G-gamma-63(E7)his-to-tyr] showed only benign neonatal cyanosis. Hemoglobin 20: 169-173, 1996. [PubMed: 8811323] [Full Text: https://doi.org/10.3109/03630269609027925]
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