Hematopathology / Pelger-Hut Anomaly

Understanding and Recognizing the Pelger-Hut Anomaly

Rita Colella, PhD,1 and Sandra C. Hollensead, MD2
Key Words: Pelger-Hut anomaly; PseudoPelger-Hut anomaly; Polymorphonuclear leukocyte; Lamins; Lamin B receptor;
Myelodysplasia; Leukemoid reaction

CME/SAM

DOI: 10.1309/AJCP3G8MDUXYSCID

Upon completion of this activity you will be able to:

list the characteristics and functions of the lamin B receptor (LBR).
list the characteristics of the gene encoding the LBR.
distinguish the Pelger-Hut anomaly (PHA) from leukemoid reaction
and myelodysplasia by morphology on peripheral blood smear.
relate the clinical importance of the PHA.

Abstract
The Pelger-Hut anomaly (PHA) is a recognized
morphologic variant affecting all granulocytes but
is most evident in polymorphonuclear neutrophils
(PMNs). PHA is caused by a decreased amount of
the lamin B receptor (LBR). Recognition of PHA
morphologic features serves as a marker for mutations
in the LBR gene. This review summarizes the history of
PHA and the current knowledge of the functions of the
LBR. Guidance is given for distinguishing PHA from
other hematologic disorders in which granulocytes
may show similar changes. Recognition of PHA in
the laboratory should prompt communication to
the patients physician about the possible clinical
significance of this finding and the recommended
screening for the anomaly in other family members by
CBC and review of a peripheral blood smear.

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This activity qualifies as an American Board of Pathology Maintenance of
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The authors of this article and the planning committee members and staff
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The human polymorphonuclear leukocyte (PMN) is

unusual among eukaryotic cells in that it has a lobulated nucleus containing condensed chromatin. The segmented nucleus
allows for rapid diapedesis through vessel walls and chemotaxis
through interstitial spaces. The shape of the interphase nucleus
Figure 1 is partly determined by the nuclear envelope (NE),
a complex structure consisting of 2 unit membranes, the outer
nuclear membrane (ONM) and the inner nuclear membrane
(INM). The ONM faces the cytoplasm and is continuous with
membranes of the rough endoplasmic reticulum, whereas the
INM faces the nucleoplasm. The ONM and INM are continuous at nuclear pores, channels that allow communication and
transport between the nucleoplasm and cytoplasm. The INM
is supported by the nuclear lamina (NL), which consists of a
network of intermediate filaments known as lamins. In humans
there are A- and B-type lamins encoded by 3 genes; at least 7
different lamin proteins are produced through alternative splicing of these genes.1 It is believed that the B-type lamins are the
building blocks of the NL since they are essential for survival,
whereas the A-type lamins have more specialized functions.2
The NL forms a layer between the INM and membraneassociated heterochromatin, but also provides a structural link
between chromatin and the INM. In doing so, the NL is responsible for organizing the interphase nucleus and for dissolving
and reforming the NE during cell division. The NL also ensures
correct positioning of nuclear pore complexes within the NE.
Evidence supports a role for the NL in organizing the cytoskeleton as well. This additional role for the NL is important for cells
that lack a cell wall, where the NL functions as the load-bearing
structure with the ability to withstand forces of deformation.1
The NL performs its various functions through associations with a number of chromatin-associated proteins and NE
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transmembrane proteins. The dynamics of the NL and its

associated proteins have gained intense scrutiny in recent
years owing to the discoveries of a number of mutations in
the lamins and/or associated proteins that are responsible for
at least 20 different diseases encompassing striated muscle
disorders, peripheral neuropathies, lipodystrophy, premature
aging, and developmental abnormalities resulting in prenatal
death.2 The diseases are known collectively as laminopathies
(reviewed by Broers et al1 and Prokocimer et al3).
The lamin B receptor (LBR) is an INM protein that binds
B-type lamins and heterochromatin; its role in nuclear segmentation of PMNs was demonstrated in retinoic acidinduced
granulocytic maturation of the human myeloblastic HL-60
cells.4 Mutations in the LBR gene are responsible for the morphologic changes seen in leukocytes known as the Pelger-Hut
anomaly (PHA).5 Current knowledge regarding the structure
and function of LBR tentatively links LBR aberrations as
laminopathies.6 Different mutations in the LBR gene have been
linked to various phenotypes in humans ranging from benign
disorders of abnormal nuclear shape, as in heterozygous PHA,
to more serious consequences, as occurs in hydrops, ectopic
calcifications, and moth-eaten (HEM)/Greenberg skeletal dysplasia, a prenatal lethal condition resulting from homozygous
null mutations in the LBR gene.7,8 Therefore, the ability to correctly diagnose PHA from morphologic features, distinguishing
it from pseudo-PHA, and to communicate the possible implications for the patient is important. A review of the history of
PHA, the functions of the LBR, and morphologic distinction
between PHA and similar-appearing cells in other hematologic
disorders, known as pseudo-PHA cells, follows.

History
An anomaly of PMNs as being short and compact
was described in 1928 by Karl Pelger in 2 patients with disseminated tuberculosis. Pelger believed that the anomaly was
associated with a poor prognosis in patients with tuberculosis
because both patients died.9 However, Pelgers conclusions
were refuted in 1932 by G.J. Hut, a Dutch pediatrician, who
recognized the Pelger anomaly in a 7-year-old girl with
tuberculosis who recovered from her illness. Furthermore,
examination of peripheral blood smears revealed the Pelger
anomaly in several of the childs relatives, including the girls
aunt who was one of the patients originally described by Pelger. Hut concluded that the aberrant PMN morphology, later
termed the Pelger-Hut anomaly, was a benign autosomal
dominant inherited trait rather than an acquired change associated with a poor prognosis for tuberculosis.10 It is now known
that heterozygous mutations of LBR result in hyposegmented
PMN nuclei known as PHA.5 The worldwide occurrence of
PHA varies from 0.01% to 0.1% in diverse populations, with
higher percentages (0.6% and 1.0%, repectively) in northeast

Figure 1 Diagrammatic representation of the associations

of the nuclear envelope, nuclear lamina (NL), the lamin B
receptor (LBR), and other nuclear-associated structures. C and
N, carboxyl and amino terminals, respectively, of LBR; ER,
endoplasmic reticulum; H, heterochromatin; INM, inner nuclear
membrane; NP, nuclear pore; ONM, outer nuclear membrane.

Sweden and southeast Germany.5 Subsequent population

studies showed PHA to be present with a prevalence rate of 1
in 4,785 in the United Sates and 1 in 6,000 in Great Britain.6
In the heterozygous state, PHA presently serves as a
marker for the carrier state of an LBR mutation with no
adverse symptoms; patients exhibiting this anomaly are
clinically normal with respect to neutrophil function.8 In vitro,
PHA granulocytes exhibit no significant differences when
compared with normal granulocytes regarding cytoplasmic
granular enzymes, nitroblue tetrazolium reduction, superoxide production, phagocytosis, and chemotaxis,7 although
a study by Park et al11 showed that PHA granulocytes from
persons in the same family had slower migration through
structural barriers than normal granulocytes.
In 1952, a Dutch girl was described as having homozygous
PHA with no overt skeletal abnormalities other than a mild
short stature.12 In a review of 11 reported cases of homozygous
PHA in humans, variable clinical conditions were described
in some cases, while others had no observed anomalies.
Described clinical conditions included psychomotor retardation, disproportionate body stature, macrocephalus, ventricular
septal defect, polydactyly, and short metacarpals.13 In contrast,
homozygous PHA in rabbits and mice is associated with skeletal abnormalities, early lethality, and ichthyosis (the latter
occurring in mice).8 Definitive characteristics of the clinical
spectrum cannot be made in human homozygous PHA because
molecular data are lacking compared to the animal studies.
In 2003, a lethal phenotype attributed to homozygous
mutations in the LBR gene was reported following studies on
the autosomal recessive HEM/Greenberg dysplasia.14 Greenberg dysplasia is characterized by in utero lethality, severe
hydrops, defects in chondro-osseous calcification, shortlimbed dwarfism, polydactyly, and other skeletal malformations. The phenotypic manifestations of Greenberg dysplasia
are similar to those present in homozygous PHA in rabbits.13

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To date, there are fewer reported cases of PHA homozygosity in humans than would be predicted by the prevalence of
heterozygous PHA, raising the question of increased fetal loss
in humans as observed in rabbits and mice. The question is
currently not resolved, as the causes for the variability in the
clinical manifestations in humans reported with homozygous
PHA need clarification. Currently, 11 different mutations of
the LBR gene have been discovered leading to human PHA,
and the differences in genetic background, site of the mutation, and severity of the mutation may explain the lack of
one specific phenotype associated with PHA.8 Until more is
known about LBR and its functions, patients exhibiting PHA
may benefit from counseling about the possible genetic consequences of this anomaly.

The Lamin B Receptor

The LBR is a multifunctional protein containing 2 subdomains. The amino terminal of approximately 200 amino acids
faces the nucleoplasm and binds to the B-type lamins and
HP-1 type chromatin. The amino terminal of LBR is important
for the reassembly of the NE at the end of mitosis, in nuclear
and chromatin organization, and in gene expression. The carboxyl terminal, composed of approximately 400 amino acids,
is reputed to contain 8 transmembrane segments.15 Its gene
sequence bears strong sequence similarities to 2 human sterol
reductase genes and demonstrates C-14 sterol reductase activity. Therefore, the LBR protein belongs to the sterol reductase
family of proteins.16 Sequence analysis of the human LBR
gene indicates that the LBR gene has 13 exons; exons 1
through 4 encode the amino terminal, and exons 5 through
13 encode the C-terminus. The intron between exons 4 and 5
is large, suggesting that the LBR gene came from 2 separate
primordial genes having different functions.17
Possible Functions of LBR
The advent of tissue staining techniques in the second half
of the 19th century enabled Paul Ehrlich to probably be the
first to describe the neutrophil nucleus as being polymorphous
in appearance. Further advances in ultrastructural techniques
confirmed that the neutrophil nucleus is multilobulated with
an abundance of peripheral heterochromatin.7 The distinctive
nuclear shape is the differentiated result of 6 morphologically
identified stages of granulopoiesis, beginning with the myeloblast containing a spherical, euchromatic nucleus that ends
with the neutrophil displaying a heterochromatic, multilobulated nucleus.18 It is now well established that the presence
of intact LBR is essential for normal neutrophil morphologic
development, together with an intact microtubular network.7
Furthermore, the degree of nuclear segmentation depends on
the number of functional copies of the LBR gene.19 Hence
persons with PHA have hyposegmented nuclei corresponding
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to reduced amounts of functional LBR. Increased expression

of LBR during granulopoiesis is implicated in the downregulation of lamin A/C, thereby contributing to the less
rigid nuclear structure needed for the granulocytes ability of
diapedisis.20 LBR may also be involved in the maintenance
of the structure of the endoplasmic reticulum since a number
of cell lines transfected with vectors containing mutant LBR
constructs demonstrated profound changes in the morphology
of the endoplasmic reticulum and the NE.21
The mechanisms whereby LBR mutations maintain nuclear shape are not known. LBR, together with chromatin, lamins,
and the INM, forms distinct microdomains in the nucleus,
which are altered in heterozygous LBR-mutant mice.15 One
can speculate that LBR, by virtue of its association with chromatin and other nuclear structures, may indirectly regulate gene
expression, and this regulation may be tissue-specific depending on the LBR-associated proteins unique to that tissue.
As mentioned, a second function of LBR is that of its
sterol reductase activity in human cholesterol biosynthesis.22
This was a surprising function since, to date, all enzymes
involved in cholesterol biosynthesis localize to the endoplasmic reticulum.14 Currently, it is debated whether diseases
associated with LBR mutations, especially Greenberg dysplasia, should be classified as laminopathies23 or whether the
phenotypic and pathologic symptoms result from aberrant
sterol reductase activity separate from the role of LBR in
nuclear morphology.24
Classifying mutations in LBR as laminopathies is supported by the presence of 2 analogous sterol reductases in
the endoplasmic reticulum that could substitute for the lack
of sterol reductase activity resulting from aberrant or null
existence of LBR.23 On the other hand, symptoms associated
with Greenberg dysplasia are similar to other inherited skeletal
dysplasias associated with aberrant cholesterol biosynthesis
in humans.24,25 It is not known how compromised function of
LBRs sterol reductase activity contributes to Greenberg dysplasia; accumulation of abnormal or intermediate cholesterol
metabolites can affect other nuclear and cytoplasmic structural
and metabolic functions. It is now well established that mutations in the LBR gene that result in complete loss of its sterol
reductase function is developmentally lethal in humans. In
addition, the expression pattern of LBR during mouse prenatal
development and the finding that LBR is expressed in human
osteoclasts and osteoblasts indicate a role for LBR in cartilage
and bone development.24 It should be noted that not all mutations in the LBR gene result in PHA, further supporting a separation of the structural and sterol reductase functions of LBR.24
This brief summary on the history and functional
aspects of LBR and PHA underscores the importance of
correct clinical diagnosis of PHA. The following presents
our findings on distinguishing PHA from other conditions
resembling this anomaly.
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Morphologic Discrimination of PHA From

Pseudo-PHA and Leukemoid Reaction
in Peripheral Blood Smears
Although PHA has been known as a morphologic variant
of WBCs for decades, the anomaly can, at times, be confused
with other hematologic disorders having similar WBC changes.
Recent case reports have included the misinterpretation of PHA
as a possible myeloproliferative disorder, leading to a bone
marrow procedure26 and the initiation of clinical workup and
treatment for suspected sepsis in a newborn with tachypnea
and unrecognized PHA.27 In the latter case, a WBC differential
count performed on a peripheral blood smear from the infant
yielded an impression of a shift to the left in granulocytes. This
observation, along with the initial tachypnea in the newborn,
led to clinical initiation of a septic workup, including lumbar

puncture and initiation of antibiotics. The anomaly was recognized after a family history was provided that the father, grandfather, and paternal uncle of the infant had PHA. Familiarity
with the classic morphologic changes in the granulocytes of
PHA Table 1 can help avoid laboratory misinterpretation of
granulocyte morphology as a leukemoid reaction, myeloproliferative neoplasm, or myelodysplastic syndrome.
The nuclei in patients with congenital PHA are characterized by a lower nuclear/cytoplasmic ratio, and the nuclear
chromatin is coarse, densely clumped, and darkly stained. In
the heterozygous phenotypes, 55% to 93% of the neutrophils
show a bilobed nucleus. The lobes are symmetrical with a
dumbbell or pince-nez appearance and are connected
by a thin filament of chromatin Image 1. The PMN nuclei
appear shorter and thicker than usual. Some cells may closely

Table 1
Nuclear Characteristics of PHA Granulocytes and Possible Cell Misidentification
Variants of PHA PMNs

Possible Misidentification

PHA unilobed variant: Ovoid nucleus but chromatin more compact,

condensed, and darkly stained than typical myelocyte; lower N/C
ratio than typical myelocyte
PHA indented nucleus (peanut shape): Chromatin more dense
than expected for apparent nuclear stage; nucleus more compact
and smaller than typical metamyelocyte or band form
Bilobed PHA: Classic bilobed pince-nez appearance in some
PMNs; lobes may be perfectly symmetrical or slightly asymmetric;
neutrophils with more than 2 lobes rare
PHA monocyte: Nucleus round to oval or has membrane irregularities
PHA eosinophil: Unilobed nucleus

Neutrophil myelocyte: Ovoid nucleus with smooth nuclear contours;

chromatin pattern more open and lightly staining than PHA
unilobed variant; higher N/C ratio
Neutrophil metamyelocyte or band form: Chromatin pattern more
open and lightly staining than in PHA
Pseudo-PHA: Bilobed nucleus, but lobes asymmetrical; bilobed cells
in minority; hypogranular; dysplasia may also be present in
platelets and RBCs; blasts may be present
Dysplastic monocyte: Horseshoe-shaped or bizarre nuclear lobations
Dysplastic eosinophil: Immature-appearing hypolobated nucleus;
decreased and irregularly spaced granules

N/C, nuclear/cytoplasmic; PHA, Pelger-Hut anomaly, PMN, polymorphonuclear leukocyte.

Image 1 A, Pelger-Hut anomaly (PHA) with classic bilobed polymorphonuclear leukocyte (PMN) on left and indented variant
on right with a short, thick nucleus and dense, darkly staining chromatin most consistent with a mature PMN. This variant may
be misidentified as a band (Wright-Giemsa, 100, oil immersion). B, Typical band on the left and PMN on the right. Note that
the nucleus is larger in the typical band than in the PHA band-like variant with lighter staining and more open chromatin, while
the PMN displays more areas of constriction than the classic PHA PMN (Wright-Giemsa, 100, oil immersion).

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resemble myelocytes or metamyelocytes owing to an indented

nuclear shape, but they differ in that overall the cells are smaller
than usual and the nuclear chromatin pattern is markedly dense
within a smaller-than-usual nucleus, as seen in a mature granulocyte Image 2. A small population (up to 4%) of neutrophils,
known as Stodtmeister cells Image 3, may be present and
are characterized by a nonlobulated or peanut-shaped nucleus.
Overall cell size, appearance of cytoplasm, and staining quality

of granules in PHA cells are similar to normal mature neutrophils. In homozygous PHA, Stodtmeister cells predominate,
making up 94% to 96% of the total neutrophils.8
The nuclei of all leukocytes are affected in PHA, including the suppression of segmentation of granulopoiesis, along
with changes in the nuclei of lymphocytes, monocytes,
eosinophils, and basophils Image 4 and Image 5.8 When
a high band count is seen in a WBC differential count, or

Image 2 A, Pelger-Hut anomaly (PHA) with a unilobed ovoid nucleus. This may be confused with a myelocyte, but the
nucleus is smaller, with more compact and densely staining chromatin than a typical myelocyte (Wright-Giemsa, 100, oil
immersion). B, A typical myelocyte with an eccentric ovoid nucleus, a higher nuclear/cytoplasmic ratio, and a chromatin pattern
more open than in a unilobed PHA variant (Wright-Giemsa, 100, oil immersion).
A

Image 3 A, A slightly indented nucleus in Pelger-Hut anomaly (PHA). These cells may be confused with metamyelocytes,
but the nucleus is smaller and the nuclear chromatin is dense and compact (Wright-Giemsa, 100, oil immersion). B, A typical
metamyelocyte. Note the higher nuclear/cytoplasmic ratio than in the PHA variant and the more open and lightly staining
chromatin pattern (Wright-Giemsa, 100, oil immersion).

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when bands, myelocytes, and metamyelocytes are reported in

a patient without inflammation or other known causes for the
appearance of immature granulocytes in the peripheral blood,
careful analysis of the peripheral smear should be undertaken
to assess for possible PHA.
Bilobed neutrophils are also seen in acquired conditions
and are known as pseudo-PHA. These acquired conditions
include leukemoid reactions during severe bacterial infections, HIV, tuberculosis and Mycoplasma pneumoniae infections, some medications, myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemia.28 Thus,
A

the distinction of PHA from pseudo-PHA is clinically important. Knowledge of morphology and correlation with clinical
history can permit this distinction in most cases. Dhle bodies, cytoplasmic vacuoles, and toxic granulations common to
granulocytes in leukemoid reactions Image 6 may be present
in PHA when concomitant inflammation is present. Review of
the clinical history usually explains the presence of immature
granulocytes in the peripheral blood during a leukemoid reaction. In these cases, lymphocytes and monocytes may also
appear reactive, along with large platelets as a sign of bone
marrow response.
B

Image 4 A, A hypolobated eosinophil in Pelger-Hut anomaly. The nucleus is indented rather than displaying 2 distinct lobes
and may be interpreted as dysplastic (Wright-Giemsa, 100, oil immersion). B, Typical bilobed eosinophils (Wright-Giemsa,
100, oil immersion).
A

Image 5 A, A reactive monocyte with an irregular nuclear membrane contour in Pelger-Hut anomaly. Such changes, along
with bilobed polymorphonuclear leukocytes, may be confused with myelodysplasia (Wright-Giemsa, 100, oil immersion). B, A
typical reactive monocyte with a convoluted but smooth nuclear membrane (Wright-Giemsa, 100, oil immersion).

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Acquired pseudo-PHA cell nuclei in the myeloproliferative neoplasms and myelodysplastic syndromes may be distinguished from congenital PHA by noting marked heterogeneity
in nuclear lobations, which are not symmetrical Image 7.
Other findings of myelodysplasia will also be present, including hypogranulation and an increased nuclear/cytoplasmic ratio
of granulocytes, while the nuclear chromatin is not as condensed and dark as in PHA. Hypersegmented neutrophils and
large granulocytes may be seen, and the pseudo-PHA cells are
less than 25% of granulocytes.6 Another important clue is the
presence of cytopenias and anemia that are found in the myelodysplastic syndromes, together with circulating blasts and
nucleated RBCs frequently seen on a peripheral blood smear
Image 8. Platelet and RBC anisocytosis may be prominent.
The cause of the pseudo-PHA morphology in myelodysplasia
is thought to be acquired clonal LBR mutations or reduced LBR
expression in myelodysplasia.8 Another theory is that pseudoPHA is a type of apoptotic neutrophil, as ultrastructurally, the
cells resemble mature granulocytes undergoing apoptosis.6
In acute care facilities, a patient with PHA can be experiencing an associated leukemoid reaction with true shift to
the left in granulocytes, confounding the recognition of the
concomitant disorders. In these cases (personal observation), more typical myelocytes and metamyelocytes may be
observed Image 9 and Image 10, but more mature cells
appearing as bands and neutrophils demonstrate typical PHA
nuclear changes, notably dense, dark nuclear chromatin.
Nuclei in these cells will appear more mature than the nuclear

Image 7 PseudoPelger-Hut anomaly in myelodysplastic

syndrome. The lobes are not symmetrical, and the
membrane outline is irregular. Bilobed cells were a minority
of the polymorphonuclear leukocyte population, and dysplasia
was noted in other myeloid cells as well (Wright-Giemsa,
100, oil immersion).

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Image 6 PseudoPelger-Hut anomaly in leukemoid

reaction. Note the nonsymmetrical lobes. Presence of toxic
granulations, Dhle bodies, and cytoplasmic vacuoles are
morphologic hallmarks of inflammation, particularly sepsis.
The majority of polymorphonuclear leukocytes had more than
2 lobes (Wright-Giemsa, 100, oil immersion).

shape suggests, and the nuclear chromatin will be hyperchromatic and densely clumped. The majority of the segmented
neutrophils will show symmetrical bilobed nuclei or, less
frequently, the unilobed variants of homozygous PHA.

Image 8 PseudoPelger-Hut anomaly with a myeloblast

in acute myeloid leukemia (Wright-Giemsa, 100, oil
immersion).

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Image 9 Pelger-Hut anomaly polymorphonuclear leukocyte

with leukemoid reaction. Dhle bodies and toxic granulation
were present, and bilobed forms predominated (WrightGiemsa, 100, oil immersion).

To distinguish the morphologic features of PHA and

pseudo-PHA, a well-prepared and well-stained smear of
peripheral blood is critical. Smears should be prepared
promptly following collection because specimens older than
12 hours may show degenerated neutrophils with round, pyknotic nuclei, making assessment difficult.29
Identification of PHA necessitates thorough analysis of
all peripheral blood cell morphologic features and review
of patient clinical and family history to separate PHA from
pseudo-PHA. When heterozygous or homozygous PHA is
identified and pseudo-PHA excluded, the finding should be
communicated to the clinician and noted on a CBC or consultative report. A comment can be made that heterozygous PHA
is usually clinically benign but may serve as a morphologic
marker of defects in the LBR,6 and family screening for the
disorder is recommended. This can be done by a pathologist
or a hematologist familiar with granulocyte morphologic features to identify other affected family members, including the
more uncommon homozygous PHA with possible associated
clinical findings.
Future studies of LBR may lead to the explanation of
abnormalities of WBC morphologic features in other hematologic disease states, such as hypersegmentation of neutrophils
in megaloblastic anemia7 and marked nuclear condensation
and clumping in chronic lymphocytic leukemia. Further
understanding of the pathophysiology of these morphologic
variants may lead to more accurate diagnosis and improved
treatment of hematologic disorders.

Image 10 Metamyelocyte in Pelger-Hut anomaly (PHA) with

leukemoid reaction. The chromatin is more condensed, and
the nucleus is smaller than a usual metamyelocyte but not
as dark and condensed as the indented PHA nucleus. Classic
bilobed and indented nuclear forms predominated. When the
patients condition improved, these true metamyelocytes
disappeared from the peripheral blood (Wright-Giemsa, 100,
oil immersion).
From the Departments of 1Anatomical Sciences and Neurobiology
and 2Pathology and Laboratory Medicine, University of Louisville
School of Medicine, Louisville, KY.
Address reprint requests to Dr Hollensead: Dept of
Pathology and Laboratory Medicine, University of Louisville
School of Medicine, Louisville, KY 40292.
Acknowledgments: We thank Ronald Elin, MD, PhD,
for review of the manuscript, and Marsha Baugher-Cattaneo,
MLS(ASCP)CM for assistance in preparation of images for
publication.

References
1. Broers JLV, Ramaekers FCS, Bonne G, et al. Nuclear lamins:
laminopathies and their role in premature ageing. Physiol Rev.
2006;86:967-1008.
2. Hutchison CJ, Alvarez-Reyes M, Vaughan OA. Lamins in
disease: why do ubiquitously expressed nuclear envelope
proteins give rise to tissue-specific disease phenotypes? J Cell
Sci. 2001;114:9-19.
3. Prokocimer M, Davidovich M, Nissim-Rafinia M, et al.
Nuclear lamins: key regulators of nuclear structure and
function. J Cell Mol Med. 2009;13:1059-1085.
4. Olins AL, Ernst A, Zwerger M, et al. An in vitro model for
Pelger-Hut anomaly: stable knockdown of lamin B receptor
in HL-60 cells. Nucleus. 2010;1:506-512.
5. Hoffmann K, Dreger CK, Olins AL, et al. Mutations in
the gene encoding the lamin B receptor produce an altered
nuclear morphology in granulocytes (Pelger Hut anomaly).
Nat Genet. 2002;31:410-414.

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Am J Clin Pathol 2012;137:358-366

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DOI: 10.1309/AJCP3G8MDUXYSCID

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365

Colella and Hollensead / Pelger-Hut Anomaly

6. Cunningham JM, Patnaik MM, Hammerschmidt DE, et al.

Historical perspective and clinical implications of the PelgerHut cell. Am J Hematol. 84;2009:116-119.
7. Hoffmann K, Sperling K, Olins AL, et al. The granulocyte
nucleus and lamin B receptor: avoiding the ovoid.
Chromosoma. 2007;116:227-235.
8. Speeckaert MM, Verhelst C, Koch A, et al. Pelger-Hut
anomaly: a critical review of the literature. Acta Haematol.
2009;21:202-205.
9. Pelger K. Demonstratie van een paar zeldzaam voorkomende
typen van bloedlichaampjes en bespreking der patinten. Ned
Tijdschr Geneeskd. 1928;72:1178.
10. Hut GJ. Uber eine bisher unbekannte familiare anomalie
der leukocyten. Klin Wochenschr. 1932;2:1264-1266.
11. Park BH, Dlen J, Snyder B. Defective chemotactic
migration of polymorphonuclear leukocytes in Pelger-Hut
anomaly. Proc Soc Exp Biol Med. 1977;155:51-54.
12. Haverkamp BN, Van Lookeren CA. Homozygous form
of Pelger-Huts nuclear anomaly in man. Acta Haematol.
1952;7:295-303.
13. Oosterwijk JC, Mansour S, van Noort G, et al. Congenital
abnormalities reported in Pelger-Hut homozygosity as
compared to Greenberg/HEM dysplasia: highly variable
expression of allelic phenotypes. J Med Genet. 2003;40:937941.
14. Waterham HR, Koster J, Mooyer P, et al. Autosomal
recessive HEM/Greenberg skeletal dysplasia is caused
by 3-hydroxysterol 14-reductase deficiency due to
mutations in the lamin B receptor gene. Am J Hum Genet.
2003;72:1013-1017.
15. Makatsori D, Kourmouli N, Polioudaki H, et al. The inner
nuclear membrane protein lamin B receptor forms distinct
microdomains and links epigenetically marked chromatin to
the nuclear envelope. J Biol Chem. 2004;279:25567-25573.
16. Silve S, Duprey PH, Ferrara P, et al. Human lamin B receptor
exhibits sterol C14-reductase activity in Saccharomyces
cerevisiae. Biochim Biophys Acta. 1998;1392:233-244.
17. Schuler E, Lin F, Worman HJ. Characterization of the
human gene encoding LBR, an integral protein of the nuclear
envelope inner membrane. J Biol Chem. 1994;269:1131211317.

366
366

Am J Clin Pathol 2012;137:358-366

DOI: 10.1309/AJCP3G8MDUXYSCID

18. Ross MH, Pawlina W. Histology: A Text and Atlas.

Philadelphia, PA: Lippincott William & Wilkins; 2006.
19. Graveman S, Schnipper N, Meyer H, et al. Dosage effect
of zero to three functional LBR-genes in vivo and in vitro.
Nucleus. 2010;1:179-189.
20. Herrmann H, Zwerger M. The danger of multi-tasking:
LBR out of control. Nucleus. 2010;1:319-324.
21. Zwerger M, Kolb T, Richter K, et al. Induction of a massive
endoplasmic reticulum and perinuclear space expansion
by expression of lamin B receptor mutants and the related
sterol reductases TM7SF2 and DHCR7. Mole Biol Cell.
2000;21:354-368.
22. Holmer L, Pezhman A, Worman HJ. The human lamin
B receptor/sterol reductase multigene family. Genomics.
1998;54:469-476.
23. Wassif CA, Brownson KE, Sterner AL, et al. HEM dysplasia
and ichthyosis are likely laminopathies and not due to
3-hydroxysterol 14-reductase deficiency. Hum Mol Genet.
2007;16:1176-1187.
24. Clayton P, Fischer B, Mann A, et al. Mutations causing
Greenberg dysplasia but not Pelger anomaly uncouple
enzymatic from structural functions of a nuclear membrane
protein. Nucleus. 2010;1:354-366.
25. Konstantinidou A, Karadimas C, Waterham HR, et al.
Pathologic, radiographic and molecular findings in three
fetuses diagnosed with HEM/Greenberg skeletal dysplasia.
Prenat Diagn. 2008;28:309-312.
26. Arnand M, Kumar R, Raina V. Pelger Hut anomaly: a case
report. Indian J Pathol Microbiol. 2007;50:661-662.
27. Mohamed ISI, Wynn RJ, Cominsky K, et al. White blood cell
left shift in a neonate: a case of mistaken identity. J Perinatol.
2006;26:378-380.
28. Dusse LMS, Moreira AMB, Vieira LM, et al. Acquired
Pelger-Hut: what does it really mean? Clin Chim Acta.
2010;411:1587-1590.
29. Constantino BT. Pelger-Hut anomaly: morphology,
mechanism, and significance in the peripheral blood film.
Lab Med. 2005;36:103-107.

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