Hemoglobin Kansas: First Korean Family and Literature Review.

Dear Editor,

Hb variants may lower oxygen saturation levels and induce cyanosis. One such variant, Hb Kansas, is unstable with a tendency for dissociation. We present the first Korean family with Hb Kansas, and review the literature related to Hb variants in the Korean population.

A 34-yr-old woman experienced low oxygen saturation during her first pregnancy. At that time, her complete blood count was normal. Oxygen saturation was 65.8% according to a pulse oximeter; however, arterial blood gas analysis was normal. After ruling out cardiac and respiratory causes, no further evaluation was conducted. Eight years later, she was transferred to our hospital for a recurrence of low oxygen saturation during pregnancy before delivery. Since other vital signs were normal, her delivery was safely achieved without intervention. However, the oxygen saturation of her newborn fell to 92%. After oxygen supply, the saturation increased to 98%. Once discontinuing the oxygen supply, the saturation went up and down with normal vital signs. The pediatrician suspected hemoglobinopathy, which causes low oxygen affinity.

The history of low oxygen saturation of the patient's family is shown in Fig. 1. She recalled that her grandmother (I-2) and father (II-2) had experienced low oxygen saturation. Her Hb electrophoresis showed an increased Hb F level to 41.1% of total Hb; Hb A1 was 57.8%, and Hb S was 0%. The result of Hb electrophoresis allowed us to suspect thalassemia or hemoglobinopathy. Therefore, we conducted direct Sanger sequencing of HBB.

Fig. 1

(A) Pedigree of a family with low oxygen saturation. Black symbols indicate clinically affected family members and white symbols indicate unaffected family members. The black arrowhead indicates the proband with the HBB variant. (B) Sequencing chromatogram of the proband demonstrating the HBB c.308A>C (p.Asn103Thr) variant (NM_000518.4 version of the HBB reference sequence).

We found a c.308A>C point variant of HBB exon 2, which results in a change of the 103th amino acid from asparagine to threonine. This single point variant causes Hb Kansas. It is associated with low oxygen affinity and it rarely causes cyanosis or other signs. The patient did not want genetic evaluation of HBB of her baby and the clinically affected family members.

Hb Kansas was first reported in 1961 [1]. Since then, four more patients with Hb Kansas have been reported worldwide, in Japan, Brazil, and Turkey. This is the first case of Hb Kansas in Korea.

Since 1992, several Hb variants have been reported in Korea (Table 1). There were total 12 variants of Hb and details of each variants were described in the Table 1. The first Hb variant in Korea was Hb Queens which was detected from family members of β-thalassemia minor in 1992 [2]. After that, two more Hb variants were founded in hemolytic anemia patients [34]. In 2001, a Korean family with β-thalassemia due to Hb Durham-N.C./Brescia was reported [5]. Hb G Coushatta, Hb Hoshida, Hb Beckman and Hb Yamagata have been revealed through ion-exchange HPLC during measurements of the HbA1c [5678]. Similar to these cases, some Hb variants can induce a falsely low or high level of glycohemoglobin when using the ion-exchange HPLC assay. Other variants of Hb were also reported in patients of thalassemia minor and severe hemolytic anemia [910]. The latest Hb variant, Hb Seoul, was reported in Korea in 2016, causing congenital erythrocytosis [11].

Table 1

Summary of 12 cases of Hb variants in the Korean population

Year	Sex/Age	Hb variant	Amino acid change	Associated condition	Reference
1992	M/43	Hb Queens	p.Arg34Leu (α-chain)	family members of β-thalassemia minor	[2]
1999	M/23	Hb Köln	p.Val99Met (β-chain)	hemolytic anemia	[3]
2000	M/17	Hb Madrid	p.Ala115Pro (β-chain)	chronic hemolytic anemia	[4]
2001	F/59	Hb Durham-N.C./Brescia	p.Leu114Pro (β-chain)	β-thalassemia	[5]
2006	N/A	Hb G Coushatta	p.Glu22Ala (β-chain)	underestimation of HbA1c	[6]
	N/A	Hb Queens	p.Arg34Leu (α-chain)	abnormal peak at the S window in HPLC*
	N/A	Hb Hoshida	p.Glu43Gln (β-chain)	abnormal peak at the E, D window in HPLC*
2008	M/61	Hb Beckman	p.Ala135Asp (β-chain)	failure of measuring an HbA1c value	[7]
2009	M/70	Hb Yamagata	p.Lys133Asn (β-chain)	overestimation of HbA1c	[8]
2010	M/5	Hb Gγ-β Ulsan	Hybrid Gγ-β	thalassemia minor	[9]
2011	F/6	Hb Koriyama	p.Cys94_His98dup (β-chain)	severe hemolytic anemia	[10]
2016	M/33	Hb Seoul	p.Ala86Thr (β-chain)	congenital erythrocytosis	[11]
2016	F/34	Hb Kansas	p.Asn103Thr (β-chain)	low oxygen saturation	present study

*ion-exchange HPLC.

Although Hb Kansas is a neutral substitution, it differs from normal Hb with respect to its equilibrium with oxygen and chromatographic behavior [12]. The amino acid substitution removes the only hydrogen bond that stabilizes the oxygenated quaternary conformation of the Hb molecule, thereby shifting the equilibrium between the oxy and deoxy conformation toward deoxy. Moreover, isolated β-chains of Hb Kansas have low oxygen affinity [1213]. In general, patients with Hb of low oxygen affinity have slightly decreased Hb levels [13], including the cases of Hb Kansas reported in 1961 [1] and 1983 [14]. This trend might be due to the enhanced oxygen release that diminishes the erythropoietin-mediated stimulus to erythropoiesis. However, the cases in Japan and Brazil showed Hb Kansas with polycythemia, whose cause has not yet been revealed. In the present case, the patient showed an Hb level of 10.9 g/dL and an Hct level of 33.7%, in line with the earlier cases. None of the previous cases showed signs or symptoms except for cyanosis.

Some Hb variants might be screened in the presence of signs or symptoms, but not all variants can be detected through Hb electrophoresis. Therefore, sequencing based on genetic analysis would be helpful to discover or confirm Hb variants, including novel variants. We report the first Korean family with Hb Kansas who had low oxygen saturation, using direct sequencing of HBB.