TO THE EDITOR
Cyanosis is an abnormal bluish discoloration of the skin and mucous membranes. It
is most commonly seen in conditions associated with cardiovascular and respiratory
insufficiency that lead to hypoxemia. A rare cause of lifelong cyanosis is methemoglobinemia
occurring due to either an enzymatic deficiency or the presence of abnormal hemoglobin
variants known as hemoglobin M (Hb-M) [1]. Herein, we report the case of a 2-year-old
child who was found to have a rare Hb-M variant resulting from a de novo mutation.
The proband was a 2-year-old girl who presented at the pediatric hematology clinic
with anemia and a bluish discoloration of the lips. Her parents indicated a history
of fever and respiratory infection dating to three months ago and she was found to
have pallor and cyanosis. All these findings were ascribed to the respiratory tract
infection, and she was treated accordingly. The infection subsided; however, cyanosis
continued for several weeks. The child had no history of fatigue or exertional dyspnea
and no significant history of any recent drug intake. She was the first child born
from the non-consanguineous marriage of the parents, had a birth weight of 3 kg, and
had an uneventful neonatal period. The family history was unremarkable. Clinically,
the child was active and playful but had pallor; her lips and nails showed bluish
discoloration due to cyanosis (Fig. 1A). However, no clubbing or organomegaly was
found. Her vital parameters were within normal limits. Echocardiogram revealed normal
parameters. Other systems were also unremarkable.
A peripheral blood sample was sent for routine hematological and biochemical investigation.
Complete blood count showed the following findings: hemoglobin (Hb), 10.1 g/dL; red
blood cell count, 4.14×106/μL; hematocrit, 32.0%; mean corpuscular volume, 77.3 fL;
mean corpuscular hemoglobin (MCH), 24.4 pg; MCH concentration (MCHC), 31.6 g/dL; red
cell distribution width, 16.9%; total leucocyte count, 13.2×103/μL; platelets, 496×103/μL;
reticulocyte count, 1.1%. Biochemical tests such as serum iron profile, liver function
test, and G6PD assay showed normal results. Oxygen saturation measured by pulse oximetry
was 57%, while SaO2 was 98.1%. However, the methemoglobin level was high at 6.7% (normal,
<1%). The blood sample also showed a distinct dark brown color (Fig. 1B).
To investigate the possibility of anemia, high-performance liquid chromatography (HPLC)
was performed; the results revealed an unknown Hb peak of 14.3% in the C-window at
a retention time (RT) of 5.06 min with increased Hb F levels (3.1%; normal, 0.1–1.2%)
and elevated Hb A2 (4.0%; normal, 2.0–3.3%) (Fig. 2A). Considering the levels of Hb
A2, Hb F, and abnormal hemoglobin, HPLC was carried out in samples collected from
the parents, which showed normal levels. Thus, gene sequencing of the child and her
parents was performed. Automated DNA sequence analysis of the beta globin gene in
the patient showed a C>T substitution at codon 92 (Fig. 2B). This heterozygous point
mutation leads to the substitution of histidine (CAC) by tyrosine (TAC) at the b 92
position, which is seen in Hb-M Hyde Park (also known as Hb Milwaukee 2). However,
parent gene sequencing analysis showed normal results. Moreover, no other mutations
for beta thalassemia trait were seen in both the child and her parents.
Considering the negative family history for cyanosis and the normal parental HPLC
and DNA mutational analysis, the patient was diagnosed with Hb-M Hyde Park due to
a de novo mutation.
Methemoglobinemia is a disorder in which there are increased levels of methemoglobin
(MetHb) in the circulation. The iron in MetHb is present in the ferric state, which
is much more stable than the ferrous state, and thus, it has a decreased ability to
bind to O2 [1]. The most common cause of methemoglobinemia is the intake of certain
drugs and chemical agents including local anesthetic agents such as lidocaine, procaine,
and benzocaine; aniline dyes, nitrates, sulfonamides, primaquine, dapsone, and acetaminophen,
among others. Some inherited conditions such as cytochrome B5 reductase deficiency
and NADPH-methemoglobin reductase deficiency can also lead to this disorder [1, 2].
Methemoglobinemia may arise due to mutations in globin chains—alpha, beta, or gamma—leading
to the formation of abnormal hemoglobin, Hb-M [1
-3]. Hb-M displays an autosomal dominant inheritance pattern. It is a rare hemoglobinopathy
in which the proximal or distal histidine in the alpha, beta, or gamma subunit is
replaced by a tyrosine residue [1].
Hb-M Hyde Park/Hb-M Milwaukee2/Hb-M Akita is a rare beta globin chain variant of hemoglobin
M wherein the mutation is present at codon 92 by C>T substitution leading to the replacement
of histidine by tyrosine (His>Tyr) [1]. Patients with Hb-M Hyde Park are usually asymptomatic
but present with cyanosis. This is an unstable hemoglobin resulting in a mild hemolytic
picture with anemia and reticulocytosis. Owing to the prominent cyanosis, patients
are frequently misdiagnosed for cyanotic heart disease [1].
The first case of Hb-M Hyde Park was reported in 1966 by Heller et al. [4] in black
patient in the USA. Since then, very few cases have been reported worldwide. In 1968,
Shibata et al. discovered a new variant of Hb-M in a family with hereditary cyanosis
in the Akita province of Japan. It was named as Hb-M Akita but was later found to
have the same primary hemoglobin structure as in Hb-M Hyde Park [5, 6]. Hutt et al.
[7] in 1998 found Hb-M Milwaukee 2 in a patient with Hb E trait. They also found that
the mutation in this case was identical to Hb-M Akita and Hb-M Hyde Park.
Most of these reported cases had a hereditary pattern in which the patient’s parents,
siblings, or both had similar symptoms and were found to have Hb-M Hyde Park. However,
only two cases of Hb-M Hyde Park arising from a de novo mutation have been described
thus far. Stamato-yannopoulas et al. [8] in 1976 reported a case of a 10-year-old
child who had cyanosis and Hb-M Hyde Park. However, none of the parents showed any
symptoms or positivity for this Hb variant. Another case occurred in a 6-year-old
girl who was diagnosed with Hb-M Hyde Park in 1992. Rotoli et al. [9] reported that
neither the parents nor the sibling showed any abnormalities.
In India, only few cases of Hb-M have been reported, which includes Hb-M Iwate, Hb-M
Ratnagiri, and Hb-M Boston [10
-12]. However, only a single case of hereditary Hb-M Hyde Park has been reported in
India to date. Upadhye et al. [12], in 2014, reported the case of a 26-year-old man
who was incidentally found to have low oxygen saturation and cyanosis. On further
investigation, he was found to have elevated methemoglobin levels. HPLC and DNA sequence
analysis confirmed a diagnosis of Hb-M Hyde Park. Subsequently, his mother was also
found to have similar complaints [12].
Therefore, to the best of our knowledge, this study is the first to report a case
of Hb-M Hyde Park arising due to a de novo mutation in India. The patient in our case
presented with the classical history of anemia with cyanosis: dark colored blood and
elevated methemoglobin levels. HPLC and DNA sequencing results were indicative of
Hb-M Hyde Park. Our patient showed elevated levels of HbF and HbA2, which was also
observed by Loong et al. [13]. Although elevated levels of HbF and HbA2 are found
in individuals with the beta thalassemia trait, our patient and her parents did not
show any such mutation in their DNA sequencing. The cause of the elevated HbF and
HbA2 in this patient remains unknown and needs further study. Hb-M Hyde Park patients
are usually asymptomatic and thus require no further treatment. However, because Hb-M
shows greatly decreased oxygen affinity compared to normal hemoglobin and this affects
the oxygen saturation, its significance increases under general anesthesia [14].
To conclude, Hb-M Hyde Park is a rare hemoglobinopathy and should be considered as
the underlying cause of cyanosis, especially when the search for other common causes
has been unproductive. However, the importance of HPLC and DNA gene sequencing in
the identification of abnormal hemoglobin variants is indispensable. Generally, the
clinical course of such patients is unremarkable. However, owing to low oxygen affinity
of hemoglobin M, these patients require special attention by an anesthetist when undergoing
any surgery.