The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 28-2017: A 13-Month-Old Girl

with Pneumonia and a 33-Year-Old Woman
with Hip Pain
Steven M. Holland, M.D., Virginia M. Pierce, M.D., Randheer Shailam, M.D.,
Krzysztof Glomski, M.D., and Jocelyn R. Farmer, M.D., Ph.D.​​

Pr e sen tat ion of C a se

Dr. Virginia M. Pierce: A 13-month-old girl was admitted to this hospital because of From the National Institute of Allergy
pneumonia. and Infectious Diseases, National Insti‑
tutes of Health, Bethesda, MD (S.M.H.);
Nine days before admission, fever and vomiting developed in the child. The and the Departments of Pediatrics
vomiting resolved after 2 days, but fever (with a maximum temperature of 39.7°C) (V.M.P.), Pathology (V.M.P., K.G.), Radiol‑
continued, and the child was fussier than usual. On the fourth day of illness, ogy (R.S.), and Medicine (J.R.F.), Massa‑
chusetts General Hospital, and the De‑
cough developed. Her parents administered acetaminophen and ibuprofen, but partments of Pathology (V.M.P., K.G.),
her condition did not improve. On the seventh day of illness, her parents brought Radiology (R.S.), and Medicine (J.R.F.),
her to the emergency department of this hospital for evaluation. Harvard Medical School — both in Boston.
In the emergency department, the parents reported that the child’s appetite had N Engl J Med 2017;377:1077-91.
decreased but she had been drinking well and had a normal volume of urine out- DOI: 10.1056/NEJMcpc1706097
Copyright © 2017 Massachusetts Medical Society.
put. On examination, the child was fussy but consolable and appeared mildly ill.
The temperature was 37.0°C, the pulse 145 beats per minute, the respiratory rate
32 breaths per minute, and the oxygen saturation 100% while she was breathing
ambient air. The weight was 9.1 kg (46th percentile). Multiple discrete, mobile,
mildly enlarged, superficial cervical lymph nodes were present bilaterally; the re-
mainder of the examination was normal. Testing for influenza virus was negative.
Urinalysis revealed yellow, slightly cloudy urine, with a specific gravity of 1.017, a
pH of 6.0, and 1+ ketones. Blood and urine samples were sent for culture; results
of other laboratory tests are shown in Table 1.
Dr. Randheer Shailam: Chest radiography revealed dense consolidation of the left
upper lobe and, to a lesser extent, the left lower lobe. There was no pleural effusion
(Fig. 1A).
Dr. Pierce: One dose of ceftriaxone was administered intravenously, and cefdinir
was prescribed. The family was advised to follow up with the primary pediatrician
2 days later.
During the next 2 days, fevers persisted despite administration of cefdinir,
acetaminophen, and ibuprofen. The cough increased, tachypnea developed, and

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 Table 1. Laboratory Data.*

1078
Variable Child Mother

Reference Range, 2 Days before

Age-Adjusted† Admission On Admission Hospital Day 3 Hospital Day 5 On Presentation
Hematocrit (%) 33.0–39.0 30.9 30.1 27.2 26.2 35.5 (ref 36.0–46.0)
Hemoglobin (g/dl) 10.5–13.5 9.9 9.8 8.9 8.6 10.9 (ref 12.0–16.0)
White-cell count (per μl) 6000–17,500 34,780 35,940 26,670 29,640 13,160 (ref 4500–11,000)
Differential count (%)
Neutrophils 25–49 63.4 61.0 72.0 69.0 72.2 (ref 40–70)
Lymphocytes 60–67 26.1 24.0 18.0 22.0 17.5 (ref 22–44)
Monocytes 4–11 3.5 11.0 3.0 6.0 6.0
Eosinophils 0–8 6.1 4.0 7.0 3.0 3.7
The

Basophils 0.1 (ref 0–3)

Metamyelocytes 0 0.9
Platelet count (per μl) 150,000–450,000 361,000 297,000 277,000 263,000 316,000 (ref 150,000–
400,000)
Red-cell count (per μl) 3,700,000–5,300,000 4,510,000 4,400,000 3,980,000 3,850,000 4,140,000
Mean corpuscular volume (fl) 70.0–86.0 68.5 68.4 68.3 68.1 85.7
Mean corpuscular hemoglobin (pg) 23.0–31.0 22.0 22.3 22.4 22.3 26.3
Mean corpuscular hemoglobin concentration (g/dl) 30.0–36.0 32.0 32.6 32.7 32.8 30.7
Red-cell distribution width (%) 11.5–16.0 15.0 15.3 15.9 16.1 14.6
Description of peripheral-blood smear Toxic granulation, Toxic granulation, Toxic granulation, Toxic granulation,
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

polychroma‑ vacuolated vacuolated Döhle bodies,
of

sia, burr cells, neutrophils, neutrophils, large platelets

target cells, polychroma‑ large platelets
large platelets sia, schisto‑
cytes, target

n engl j med 377;11 nejm.org  September 14, 2017

cells, large

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

platelets
m e dic i n e

Erythrocyte sedimentation rate (mm/hr) 0–20 98 82

Sodium (mmol/liter) 135–145 133 135 136 138
Potassium (mmol/liter) 3.4–5.0 5.3 (slightly hemo‑ 4.3 4.4 4.2
lyzed)

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Chloride (mmol/liter) 98–108 97 100 99 99
Carbon dioxide (mmol/liter) 23–32 18 19 22 26
Anion gap (mmol/liter) 3–17 18 16 15 13
 Variable Child Mother

Reference Range, 2 Days before

Age-Adjusted† Admission On Admission Hospital Day 3 Hospital Day 5 On Presentation
Calcium (mg/dl) 8.5–10.5 9.8 9.9 9.8 9.1
Phosphorus (mg/dl) 2.6–4.5 3.3
Magnesium (mg/dl) 1.7–2.4 2.1
Glucose (mg/dl) 70–110 90 102 83 103
Urea nitrogen (mg/dl) 5–20 14 14 14 18 (ref 8–25)
Creatinine (mg/dl) 0.30–1.00 0.37 0.31 0.32 0.68 (ref 0.60–1.50)
Protein (g/dl)
Total 6.0–8.3 7.9 7.3 7.9
Albumin 3.3–5.0 3.3 3.1 3.5
Globulin 1.9–4.1 4.6 4.2 4.4
Aspartate aminotransferase (U/liter) 9–80 47 (hemolyzed) 20 30 (ref 9–32)
Alanine aminotransferase (U/liter) 7–33 81 (hemolyzed) 25
Alkaline phosphatase (U/liter) 15–350 473 345 231 (ref 30–100)
Bilirubin (mg/dl)
Total 0–1.0 0.3 0.2 0.5
Direct 0–0.4 <0.2 <0.2 <0.2
C-reactive protein (mg/liter) <8.0 92.0 111.8 81.3 81.4 28.9
Lactate dehydrogenase (U/liter) 110–210 474 164
Uric acid (mg/dl) 2.3–6.6 2.4
Venous blood gases

The New England Journal of Medicine

n engl j med 377;11 nejm.org  September 14, 2017
Fraction of inspired oxygen Unspecified
pH 7.30–7.40 7.46
Partial pressure of carbon dioxide (mm Hg) 38–50 31
Case Records of the Massachuset ts Gener al Hospital

Partial pressure of oxygen (mm Hg) 35–50 73

Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Base excess (mmol/liter) 0–3.0 −2.0
Human immunodeficiency virus type 1 and 2 anti‑ Nonreactive Nonreactive
bodies and type 1 p24 antigen
Interferon-γ release assay for Mycobacterium tuber- Negative Negative
culosis

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IgG antibodies (mg/dl) 332–1164 1318
IgA antibodies (mg/dl) 14–105 137
IgM antibodies (mg/dl) 41–163 521
IgE antibodies (IU/ml) 0–100 27
Tetanus IgG antibodies (IU/ml) ≥0.01 (vaccinated) 0.05

1079
 The n e w e ng l a n d j o u r na l of m e dic i n e

* The term ref denotes the reference range for the mother; these ranges are listed when they differ from those for the child. To convert the values for calcium to millimoles per liter, multi‑
ply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to millimoles per liter, multiply by 0.4114. To convert

to micromoles per liter, multiply by 88.4. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for uric acid to micromoles per liter, multiply
Figure 1 (facing page). Imaging Studies in the Child.

† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are age-adjusted
the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine
A frontal radiograph of the chest (Panel A) shows right‑
On Presentation
ward tracheal deviation (arrow) and airspace opacity in
Mother

the left upper lung zone (asterisk), a finding that most

likely represents pneumonia. An ultrasound image of
the spleen (Panel B) shows numerous hypoechoic lesions
throughout the splenic parenchyma (arrowheads) and
enlarged splenic hilar lymph nodes (arrows) with hypo­
echoic foci. A contrast-enhanced axial CT image of the

and for patients who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
Hospital Day 5

abdomen (Panel C) shows multiple splenic lesions

­(arrowheads), an enlarged splenic hilar lymph node
2726
1910

1192
70.0

43.7

27.3
744 (white arrow), a retrocaval lymph node (red arrow),
and an enlarged peripancreatic lymph node (asterisk).
Contrast-enhanced axial CT images of the chest (Panels
D and E) show consolidation of the left upper lobe
(Panel D, asterisk), paratracheal lymphadenopathy
Hospital Day 3

(Panel D, arrows), and a 3-mm nodule in the right up‑

per lobe (Panel E, arrow). A contrast-enhanced coronal
CT image of the chest (Panel F) shows paratracheal
lymphadenopathy (red arrows), subcarinal lymphadenop­
athy (white arrows), narrowing of the left main-stem
bronchus (arrowhead), and consolidation of the left
upper lobe (asterisk).
On Admission
Child

the use of accessory muscles in the neck and

chest was noted. Oral intake and urine output
decreased. The child was brought back to the
2 Days before

emergency department for evaluation.

Admission

The history was obtained from the child’s

mother. The child had been born after a full-
term gestation. The results of newborn blood-
spot screening tests (i.e., a panel of tests for
multiple congenital diseases, primarily inborn
Reference Range,

errors of metabolism) had been normal. The

Age-Adjusted†
980–2967
616–2183

348–1456

148–1173

child had been well until 4 months before ad-

59–88

21–64

9–48

mission, when a diagnosis of pneumonia was

made; she was treated as an outpatient with a
10-day course of an unspecified oral antibiotic
agent. Six weeks before admission, she was seen
in the emergency department because of vomit-
ing and diarrhea; a diagnosis of viral gastroen-
teritis was made. Four weeks before admission,
she returned to the emergency department be-
cause of fever and was again thought to have a
CD3+CD4+ lymphocyte count (per μl)

CD3+CD8+ lymphocyte count (per μl)

Absolute lymphocyte count (per μl)

CD3+CD4+ lymphocyte count (%)

CD3+CD8+ lymphocyte count (%)

viral illness. Three weeks before admission, she

CD3+ lymphocyte count (per μl)

received a diagnosis of acute otitis media and

CD3+ lymphocyte count (%)

was treated with an unspecified oral antibiotic.

During the 4 months before admission, the child
reportedly did not gain any weight. Medications
included acetaminophen, ibuprofen, and cefdinir.
She had no known allergies, and immunizations
by 59.48.

were reportedly current. She was of Brazilian

Variable

ancestry, was born in New England, and had

not traveled. She lived in an urban area of New

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 Case Records of the Massachuset ts Gener al Hospital

A B

C D

*
*

E F

England with her parents and 5-year-old sister;
her mother was a homemaker and her father
was a carpenter. The family kept canaries in the
home as pets; they had previously had pet cats
but not during the 2 months before admission.
The child’s maternal grandmother had asthma.
In the child’s mother, an ipsilateral axillary mass
had developed after she had received the bacille
Calmette–Guérin (BCG) vaccine during infancy
in Brazil; the mass had been resected, and anti-
biotics had been administered for many months.
While the mother was pregnant with the child,

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 The n e w e ng l a n d j o u r na l
a tuberculin skin test was positive and a chest
radiograph was normal.
On examination, the child was in mild respi-
ratory distress. The temperature was 37.8°C, the
pulse 193 beats per minute, the respiratory rate
60 breaths per minute, and the oxygen satura-
tion 97% while she was breathing ambient air.
The lips were dry. Nasal flaring and suprasternal,
intercostal, and subcostal retractions were pres-
ent. The remainder of the examination was un-
changed. Tests for respiratory syncytial virus,
adenovirus, parainfluenza virus, and metapneu-
movirus were negative. A blood sample was sent
for culture; other laboratory test results are
shown in Table 1. Findings on a chest radio-
graph appeared unchanged from 2 days earlier.
Intravenous fluids, ceftriaxone, azithromycin, and
acetaminophen were administered. The child was
admitted to the hospital.
During the next 2 days, the administration of
intravenous fluids, ceftriaxone, and azithromycin
was continued. Fever and cough persisted, and
emesis occurred intermittently. On the third
hospital day, vancomycin therapy was added.
Laboratory tests results are shown in Table 1.
Dr. Shailam: Ultrasonography of the chest was
performed, and incidental findings in the spleen
prompted extension of the study to include the
abdomen and pelvis. The spleen was enlarged
and contained numerous hypoechoic lesions mea-
suring up to 1 cm in diameter (Fig. 1B). There
were multiple enlarged peripancreatic, periportal,
and perisplenic lymph nodes, some of which
were centrally hypoechoic.
Dr. Pierce: A tuberculin skin test was placed,
and airborne precautions were instituted.
Dr. Shailam: The next day, computed tomogra-
phy of the chest, abdomen, and pelvis was per-
formed after the administration of intravenous
contrast material. The findings included left
supraclavicular, left hilar, mediastinal, upper ab-
dominal, and mesenteric lymphadenopathy, as
well as splenomegaly with multiple hypodense
splenic lesions, consolidation with air broncho-
grams involving the majority of the left upper
lobe, scattered pulmonary nodules (measuring
2 to 4 mm in diameter), and narrowing of the
left main-stem bronchus due to bulky lymphade-
nopathy (Fig. 1C through 1F).
Dr. Pierce: Azithromycin therapy was discon-
tinued. On the fifth hospital day, bronchoscopy
revealed marked external compression of the left
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of m e dic i n e
main-stem bronchus and left upper lobe and
scant secretions in the airways. Bronchoalveolar
lavage (BAL) was performed; acid-fast staining
of the BAL fluid revealed rare acid-fast bacilli,
and a nucleic-acid amplification test for Mycobac-
terium tuberculosis was negative. Induration (8 mm
in diameter) was noted at the site of the tuber-
culin skin test. Laboratory test results are shown
in Table 1. Diagnostic tests were performed, and
management decisions were made.
Three months later, the child’s 33-year-old
mother was admitted to this hospital because of
pain in the right hip. The mother had been well
until 6 weeks before admission, when pain in
the right groin developed. The pain was initially
intermittent and then became more constant,
with radiation to the right buttock. She was seen
in an urgent care clinic; radiographs of the hip
that were obtained during that visit were report-
edly normal. A limp developed, and during the
3 weeks before admission, the pain progressed
in severity and she began to hold onto objects to
support herself as she walked. During this time,
she returned to the urgent care clinic and was
also seen by her primary care physician. She took
ibuprofen, diclofenac, prednisone, and another
unspecified medication, but her symptoms did not
improve. On the day of admission, the mother
presented to the emergency department of this
hospital because of progressive pain and diffi-
culty walking.
In the emergency department, the mother re-
ported that no trauma had preceded the onset of
pain. She had lost 4.5 kg in weight during the
previous 2 months while dieting. She had no
fevers, chills, or night sweats. On examination,
the vital signs were normal. The gait was antalgic.
There was tenderness on palpation of the right
hip, and a log-roll test was positive; the active
and passive ranges of motion of the right hip were
limited by pain. The remainder of the examina-
tion was normal. A urinalysis was normal; other
laboratory test results are shown in Table 1.
Dr. Shailam: Radiography of the pelvis revealed
an ill-defined lytic region in the superior aspect
of the right femoral neck (Fig. 2A). Magnetic
resonance imaging of the right hip, performed
with and without the administration of intrave-
nous contrast material, revealed a large lesion at
the junction of the right femoral head and neck
that had extended through the femoral neck and
had caused cortical destruction. There were de-
 Case Records of the Massachuset ts Gener al Hospital
structive changes at the femoroacetabular joint,
as well as a small joint effusion, exuberant intra-
muscular edema throughout the upper thigh,
markedly enlarged right external and common
iliac lymph nodes, and foci of abnormal marrow
signal in both iliac wings (Fig. 2B through 2F).
Dr. Pierce: Viscous, serosanguineous fluid was
aspirated from the right hip joint. Analysis of
the synovial fluid revealed a nucleated-cell count
of 34 per microliter (reference range, 0 to 200).
Gram’s staining, acid-fast staining, and calco-
fluor white staining of a wet-mount preparation
revealed no organisms.
The mother was admitted to the hospital. Ad-
ditional diagnostic studies were performed, and
a diagnosis was made.
Differ en t i a l Di agnosis
Dr. Steven M. Holland: This 13-month-old girl, who
had normal development and a history of “pneu-
monia” that had lasted for at least 4 months
despite treatment with conventional therapies,
presented to this hospital with an ill appearance
and involvement of multiple organ systems, in-
cluding the lungs, spleen, and lymph nodes; dur-
ing bronchoscopy, a nontuberculous mycobac-
terium was recovered. Three months later, the
child’s mother, who had had regional BCG dis-
ease during infancy, presented with presumed
chronic, progressive osteomyelitis. In developing
a differential diagnosis for these two patients,
we must first consider whether the mother and
the child have the same disease process, and if
they do, we must then consider whether a unify-
ing underlying disorder, such as an immunode-
ficiency syndrome, explains this family’s story.
Immunodeficiency
Do these two patients have an underlying immu-
nodeficiency syndrome that increases their sus-
ceptibility to infection? To approach this ques-
tion, we first must assume that they both had an
infection that would suggest an impairment of
normal immune function. Immunodeficiency is
not typically associated with rare and unusual
infections; rather, it is associated with infections
that often go unnoticed because they are con-
trolled by normal immunity. Thus, invasive, severe,
or persistent infections with low-grade pathogens
are characteristic of immunodeficiency. Dissemi-
nated nontuberculous mycobacterial infections
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are not part of normal development and always
require explanation.
The number of species of nontuberculous
(environmental) mycobacteria, which is current-
ly higher than 150, is increasing; these species
are overwhelmingly nonpathogenic. M. avium
complex has been associated with complications
and death in patients with advanced human im-
munodeficiency virus (HIV) infection who have
CD4+ T-cell counts below 50 per cubic millime-
ter; establishment of this association led to the
understanding that control of disseminated non-
tuberculous mycobacterial infection is immune-
mediated. Subsequently, at least 10 genes that
control susceptibility to nontuberculous myco-
bacterial infection have been identified, most of
which are directly involved in the synthesis and
response pathways of interferon-γ and interleu-
kin-12 (Fig. 3). Depending on the specific muta-
tion, the inheritance of a disorder caused by a
mutation in one of these genes can be autosomal
recessive, autosomal dominant, or X-linked.1
Autoantibodies to interferon-γ itself can mimic
these genetic lesions, since they can potently
neutralize interferon-γ.2
Is the Mother’s Story Relevant?
The mother had regional BCG infection during
infancy and now has slowly progressive osteomy-
elitis. If the problems seen in the mother and the
child are related, which seems likely, then their
susceptibility to nontuberculous mycobacterial in-
fection could be due to an autosomal dominant
gene. The six candidate autosomal dominant genes
that increase such susceptibility are IRF8, GATA2,
IKBKB (NEMO), IFNGR1, IFNGR2, and STAT1.
On the basis of the history and clinical pre-
sentation of these two patients, can we narrow
down the list of autosomal dominant genes? IRF8
deficiencies have been mostly described in per-
sons who have disseminated BCG disease and
do not have osteomyelitis, and this child does
not have BCG infection.3 Patients with GATA2
haploinsufficiency do not typically present with
mycobacterial infection when they are as young
as this child.4 IKBKB (NEMO) is X-linked and
does not cause this sort of disseminated invasive
disease in females.5 Anti–interferon-γ autoanti-
bodies could easily explain the mother’s disease,
and although maternal IgG antibodies are trans-
ferred transplacentally, this child is 13 months
of age, which is too old for the maternal anti–
1083
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

*
*

C D

*
*

E F

*
*

*
* *
*

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 Case Records of the Massachuset ts Gener al Hospital
Figure 2 (facing page). Imaging Studies in the Mother.
An anteroposterior radiograph of the pelvis (Panel A)
shows lytic and destructive changes involving the right
femoral neck and right ilium (arrows). Coronal short-
tau inversion recovery images (Panels B and C) show
hyperintense signal in the proximal right femur and
­bilateral iliac bones (arrows), as well as extensive ab‑
normal signal in the soft tissues and muscles surround‑
ing the proximal right femur and hemipelvis (asterisks).
A coronal T1-weighted image (Panel D) shows low sig‑
nal (arrows) in the proximal right femur that involves
the neck and proximal diaphysis. A coronal T2-weighted
image (Panel E) shows heterogeneous hyperintense
signal in the proximal right femur (arrows) and joint
fluid (arrowhead) and hyperintense signal in the mus‑
cles surrounding the right hip (asterisks). A contrast-
enhanced coronal T1-weighted image with fat saturation
(Panel F) shows enhancement of the proximal right
­femur (white arrows), nonenhancing foci in the medul‑
lary bone of the intertrochanteric region and soft tissues
medial to the proximal right femur (red arrows), enhanc‑
ing thickened synovium (arrowhead), and enhance‑
ment of muscles surrounding the right hip (asterisks).
interferon-γ autoantibodies to have persisted in
the child and resulted in the child’s infection.2
Therefore, we are left with three candidate auto-
somal dominant genes that are associated with
susceptibility to nontuberculous mycobacterial
infection: IFNGR1, IFNGR2, and STAT1. Dominant
negative STAT1 mutations can cause dissemi-
nated nontuberculous mycobacterial disease or
osteomyelitis, but these manifestations do not
typically first occur in adulthood. IFNGR2 haplo-
insufficiency is rare, and patients typically pre­
sent with a mild BCG infection, which would not
explain the child’s disease, since she did not re-
ceive the BCG vaccine.6 Only the IFNGR1 gene is
left to provide a unifying diagnosis in these two
patients.
Complete loss-of-function recessive mutations
in IFNGR1 typically lead to severe disseminated
disease early in life, especially among those who
receive the BCG vaccine.7 In contrast, the most
common mutations in this gene are heterozy-
gous four-base-pair deletions that lead to intra-
cellular truncations of interferon-γ receptor 1
(IFNγR1); these truncations still permit receptor
display and interferon-γ binding but destroy the
activation site of STAT1 (signal transducer and
activator of transcription 1) and the receptor
recycling site.7,8 The consequence is that the pro-
tein still binds interferon-γ extracellularly but
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cannot signal or be recycled, which leads to the
overaccumulation of a mutant IFNγR1 on the cell
surface and dominant-negative interference (Fig. 3).
For our understanding of this case, it is impor-
tant to note that, in patients with dominant
IFNγR1 deficiency, a wild-type allele remains that
continues to support reduced but clinically im-
portant residual interferon-γ signaling, which
allows for better long-term survival and contain-
ment of infection than can be seen in associa-
tion with recessive IFNγR1 deficiency.7 For reasons
that are unclear, autosomal dominant IFNγR1
deficiency is very commonly associated with non-
tuberculous mycobacterial osteomyelitis, which
is seen in the mother in this case. In addition, in
patients with dominant IFNγR1 deficiency, myco-
bacterial infections are typically limited to infec-
tions with BCG and slow-growing mycobacteria,
such as M. avium complex.7 Therefore, for such
patients, I would consider the administration of
empirical therapy with azithromycin, ethambutol,
and rifampin. However, it is important to remem-
ber that the same intracellular killing defect that
is caused by this immunodeficiency also confers
a predisposition to salmonellosis and endemic
mycoses, such as coccidioidomycosis and histo-
plasmosis.9,10
The child and the mother most likely have a
mutation in exon 6 of IFNGR1, which causes a
truncation that removes the signal transduction
and receptor recycling domains and thus leads
to autosomal dominant IFNγR1 deficiency. The
most common mutation is 818del4, but several
other mutations that occur around the same re-
gion yield similar phenotypes. To confirm this
diagnosis, the simplest test would be flow cy-
tometry to detect surface expression of IFNγR1
(CD119) on monocytes; the expression of CD119
is characteristically 5 to 10 times as high in a
patient with autosomal dominant IFNγR1 defi-
ciency as in an unaffected patient.7 The most
definitive diagnostic test would be DNA sequenc-
ing of IFNGR1 exon 6, which is the region in
which the majority of mutations that cause this
dominant disease are found.8 The 818del4 muta-
tion is a hotspot mutation, and it has been de-
tected in patients worldwide.
Dr. Eric S. Rosenberg (Pathology): Dr. Pierce, what
were the impressions of the clinical teams when
these patients were evaluated?
Dr. Pierce: Our principal diagnostic consider-
1085
 The n e w e ng l a n d j o u r na l of m e dic i n e

Interleukin-2 T-cell receptor

IL-2R

Gene
transcription Type 1 helper T cell
or natural killer cell
P P

Active
STAT4
JAK2
IL-12R Interferon-γ
P
β2 P

β1 STAT4
TYK2

Interferon-γ

Interleukin-15 Interleukin-18

IFNγR

ISG15 JAK1 JAK2

Macrophage
STAT1

NADPH
STAT1
CD14
P P Active TLR4
NRAMP1 STAT1
Mycobacteria

IRF8
P P

? TNFα
Interleukin-12
Gene
transcription GATA2

NEMO
NF-κB
NF- B
TNFαR
Interleukin-12

ations in the child included lymphoma compli-
cated by postobstructive pneumonia and dis-
seminated mycobacterial infection due to either
M. tuberculosis or a nontuberculous mycobacterium
in the context of immunodeficiency. The suspi-
cion of mycobacterial disease was reinforced by
the results of the tuberculin skin test in the child,
the maternal history of BCG disease during in-
fancy, and ultimately, the detection of acid-fast
bacilli in BAL fluid and gastric aspirates. These
organisms appeared shorter (i.e., more coccoba-
cillary) than would be typical for M. tuberculosis,
and a nucleic-acid amplification test for M. tuber-
culosis was negative. An interferon-γ release assay
for M. tuberculosis was also negative, although its
sensitivity is not well established in very young

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 Case Records of the Massachuset ts Gener al Hospital
Figure 3 (facing page). Interferon-γ–Interleukin-12
­Signaling Pathway.
Immunity against mycobacteria requires an intact
interferon-γ–interleukin-12 pathway, which signals
­between type 1 helper T cells or natural killer cells and
effector phagocytes. Interferon-γ binds as a homodimer
to its cognate receptor (IFNγR), which is composed of
interferon-γ receptor 1 (IFNγR1; encoded by IFNGR1)
and interferon-γ receptor 2 (IFNγR2; encoded by IFNGR2).
When interferon-γ binds, the receptors aggregate, and
the intracellular portions of the receptor chains and their
associated Janus kinase molecules (JAK1 and JAK2) are
brought into apposition. This process eventually leads
to signal transducer and activator of transcription 1
(STAT1) phosphorylation, dimerization, nuclear trans‑
location, and interferon-γ–mediated gene transcription.
Interleukin-12 is released from macrophages and acti‑
vates its cognate receptor (IL-12R). This process leads
to STAT4 phosphorylation and thus leads to production
of interferon-γ. Other critical actors in this pathway in‑
clude GATA2, ISG15, tumor necrosis factor α (TNFα)
and its receptor (TNFαR), interleukin-15, interleukin-18,
and the NADPH oxidase. The natural resistance-asso‑
ciated macrophage protein 1 (NRAMP1) is involved in
the killing of mycobacteria and other intracellular para‑
sites. A critical feature of receptor proteins is that they
need specific signals to target them to the Golgi appara‑
tus and the cell surface, as well as intracellular sequenc‑
es to allow their recycling away from the cell surface af‑
ter activation. The mutation seen in this patient affects
the ability of IFNγR1 to signal and to recycle off the cell
surface, which leads to overaccumulation of mutant
IFNγR1 molecules on the cell surface. IRF8 denotes
­interferon regulatory factor 8, NF-κB nuclear factor κB,
TLR4 toll-like receptor 4, and TYK2 tyrosine kinase 2.
children.11,12 In view of these findings, we
thought that nontuberculous mycobacterial in-
fection in the context of underlying immunode-
ficiency was the most likely diagnosis in the
child. Broad-range polymerase-chain-reaction
(PCR) analysis of the BAL fluid that targeted the
16S rRNA gene sequence ultimately identified
the organism as M. genavense.
An extremely fastidious mycobacterium,
M. genavense was first described in patients with
advanced HIV disease,13-16 and infections have
subsequently been reported in patients with other
types of profound immunosuppression.17-31 The
importance of the interferon-γ–interleukin-12
pathway in resistance to M. genavense infections
has been shown.32-35 This child was negative for
HIV and her lymphocyte subset counts and
percentages were normal, so investigations for
a defect in interferon-γ immunity were begun.
M. genavense has been described as a common
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cause of avian mycobacteriosis among pet birds,
including canaries.36-42 We were concerned that
the canaries in this patient’s home might have
served as a reservoir, although we recognized
that zoonotic transmission of the organism has
not been described and that humans and animals
might instead acquire M. genavense infection
through exposure to a common source.43
While the child’s immunologic evaluation was
underway, the mother presented with a 6-week
history of hip pain and a destructive lesion in
the right femoral neck. After additional history
was obtained that revealed that the daughter
had begun treatment for M. genavense infection
3 months earlier, nontuberculous mycobacterial
disease and an inborn error of interferon-γ im-
munity were strongly suspected in the mother,
as well. Biopsies of the femoral lesion and an
enlarged pelvic lymph node were performed.
Cl inic a l Di agnosis
Child
Disseminated Mycobacterium genavense infection
due to an underlying inborn error of interferon-γ
immunity.
Mother
Disseminated nontuberculous mycobacterial in-
fection, complicated by osteomyelitis, due to an
inborn error of interferon-γ immunity.
Dr . S te v en M. Hol l a nd’s
Di agnosis
Autosomal dominant IFNγR1 deficiency, most
likely due to an 818del4 mutation.
Pathol o gic a l Discussion
Dr. Krzysztof Glomski: A biopsy specimen of the
femoral lesion was obtained from the mother.
On microscopic examination, the specimen con-
sisted of blood and a mixed inflammatory infil-
trate that was composed of lymphocytes, neutro-
phils, and loosely clustered histiocytes that most
likely represented ill-formed or disrupted gran-
ulomas (Fig. 4A). Grocott methenamine–silver
staining was negative for fungal forms (not
shown), whereas both Ziehl–Neelsen staining and
Fite staining showed acid-fast coccobacilli in
histiocytes (Fig. 4B and 4C). Despite the absence
1087
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

N
N

Figure 4. Biopsy Specimens from the Mother.

Hematoxylin and eosin staining of the femoral lesion (Panel A) shows mixed lymphohistiocytic inflammation and
loose histiocytotic aggregates that are suggestive of granulomas (dashed ellipse) in the absence of bone. Ziehl–
Neelsen staining (Panel B) shows acid‑fast intrahistiocytic coccobacilli; modified acid‑fast Fite staining (Panel C)
confirms this finding. Hematoxylin and eosin staining of the inguinal lymph node (Panel D) shows histiocytic granu‑
lomas (one delineated by a dashed ellipse) with central necrosis (N) and associated lymphocytes (arrowhead).

of bone in the biopsy material, the clinical, radio-
graphic, and histopathological findings were
highly suggestive of mycobacterial osteomyelitis
with associated replacement or destruction of bone
by a mixed inflammatory infiltrate. Histopatho-
logical examination of the lymph node–biopsy
specimen showed confluent necrotizing granu-
lomas (Fig. 4D), and Ziehl–Neelsen staining
showed acid-fast coccobacilli in histiocytes (not
shown); these features are diagnostic of myco-
bacterial lymphadenitis. Broad-range PCR analy-
sis that targeted the 16S rRNA gene sequence,
which was performed at a reference laboratory,
identified the mycobacterium as M. genavense, the
same species that had been identified in the
patient’s daughter.
Discussion of Gene t ic Di agnosis
a nd M a nagemen t
Dr. Jocelyn R. Farmer: Functional flow cytometry
was conducted in both patients to screen for
defects in the interferon-γ–interleukin-12 path-
way, which account for approximately 77% of
the cases of mendelian susceptibility to myco-
bacterial disease that have been described.44 In-
tact surface expression of the interleukin-12 re-
ceptor β1 (IL12Rβ1) on lymphocytes and IFNγR1
on monocytes was observed in both the child
and the mother; the density of the surface ex-
pression of IFNγR1 was not analyzed. However,
in vitro treatment of monocytes with interferon-γ
produced an atypical response in both patients;
in cells obtained from the child, interferon-γ–
induced cell death was observed during two con-
secutive trials, whereas in cells obtained from
the mother, the level of interferon-γ–induced
STAT1 phosphorylation was lower than the level
seen in normal cells, but cell viability was pre-
served. These data suggested a defect in the
interferon-γ–interleukin-12 pathway that was
localized between the interferon-γ receptor and
STAT1. Subsequent targeted exome sequencing
of IFNGR1 revealed a heterozygous mutation
(c.819_822delTAAT) in both the child and the
mother. This mutation is in a known hotspot
for IFNGR1 mutagenesis.8 The mutant truncated
IFNγR1 does not have the intracytoplasmic do-

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 Case Records of the Massachuset ts Gener al Hospital
main that contains motifs associated with recy-
cling, Janus kinase 1 binding, and STAT1 binding.
Thus, it acts in a dominant-negative fashion by
accumulating at the cell surface and outcompet-
ing the wild-type receptor for interferon-γ binding
while blunting signaling downstream. Although
unique toxic effects were observed in the child
in response to in vitro treatment of the mono-
cytes with interferon-γ, when both patients under-
went further targeted exome sequencing of genes
associated with mendelian susceptibility to myco-
bacterial disease,44 these genes were found to be
wild-type in both patients. Whole-exome sequenc-
ing was not clinically indicated to establish the
diagnoses in this case; however, it may have
provided additional insight into genetic modifi-
ers of the interferon-γ–interleukin-12 pathway
that perhaps led to the different clinical presen-
tations in the child and the mother.
A diagnosis of autosomal dominant IFNγR1
deficiency has direct clinical implications. Be-
cause expression of the wild-type receptor is re-
tained, the autosomal dominant form is associ-
ated with an overall better clinical prognosis
than the autosomal recessive form. Mycobacterial
osteomyelitis, which was seen in the mother in
this case, is a frequent primary manifestation of
autosomal dominant IFNγR1 deficiency.7 This
disease is also characteristically responsive to
high-dose interferon-γ therapy.45,46 In this case,
the decision was made to reserve interferon-γ
for second-line therapy, because both patients had
clinical stabilization with antimicrobial therapy
(along with surgical débridement in the mother).
The child’s older sister underwent screening by
means of flow cytometry, which revealed normal
function of the interferon-γ pathway, a finding
inconsistent with inheritance of mendelian sus-
ceptibility to mycobacterial disease.
Dr. Rosenberg: Dr. Madhavan, would you tell us
what happened with the child?
Dr. Vandana Madhavan (Pediatrics): On the basis
of the limited published data on the antimicro-
bial susceptibility of M. genavense and clinical out-
comes related to M. genavense infections, therapy
with oral azithromycin, rifampin, and moxifloxa-
cin and parenteral amikacin was begun. The
fever, cough, and work of breathing improved,
and the patient was discharged home on the
17th hospital day. After 2 months of treatment,
acid-fast staining of gastric aspirate specimens
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was negative. Currently, after 10 months of treat-
ment, the patient has gained weight, and labora-
tory markers of inflammation have slowly im-
proved. The ultimate duration of therapy will
depend on the findings on imaging studies and
ongoing laboratory monitoring, the occurrence
of medication-related toxic effects, and multi-
specialty input.
Dr. Rosenberg: Dr. Sen, would you tell us what
happened with the mother?
Dr. Pritha Sen (Medicine): To reduce the burden
of bony infection, resection arthroplasty and
radical débridement of the hip were performed.
The joint contained purulent, necrotic debris.
The femoral head and neck were resected, an
abscess that tracked along the psoas muscle and
obturator foramen was débrided, and a cement
spacer that was impregnated with amikacin and
azithromycin was placed. Once M. genavense was
definitively identified, therapy with oral azithro-
mycin, rifampin, and moxifloxacin and paren-
teral amikacin was initiated. By the 10th postop-
erative day, the patient was able to walk and was
discharged home. The timing of the second stage
of total hip replacement will depend on clinical
response; she will receive antimycobacterial treat-
ment for a minimum 12 months (including par-
enteral amikacin for 3 months) before implanta-
tion of a metal prosthetic hip.
Although the family’s canaries were not spe-
cifically tested to determine whether they carried
M. genavense, it was thought that the birds were a
possible environmental reservoir of this myco-
bacterium, and the family elected to remove them
from their home.
Fina l Di agnose s
Child and Mother
Autosomal dominant heterozygous IFNγR1 defi-
ciency.
Disseminated Mycobacterium genavense infection.
This case was presented at Medical Grand Rounds.
Supported in part by the McNeely Case Records of the MGH
Visiting Professor Series and the Division of Intramural Re-
search, National Institute of Allergy and Infectious Diseases,
National Institutes of Health.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org
We thank Dr. Gunnlaugur Petur Nielsen for his help with
preparation for the conference.
1089
 The n e w e ng l a n d j o u r na l
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