With
Special
Reference
to
the
Parathyroids
Preben Geertinger, M.D.
institute of Forensic Medicine, Goteborg, Sweden
(Received February 14; revision accepted for publication June 13, 1966.)
This study was commenced while the author worked at the University Institute of Forensic Medicine, Copenhagen. Head: Professor, M.D. Harald Gormsen.
PRESENT ADDRESS: Institute of Forensic Medicine, Cotehorg, Sweden.
PEDIATRICS, Vol. 39, No. 1, January 1967
SUDDEN,
UNEXPECTED
DEATH
IN INFANCY
T
HE PRO3LEM of sudden, unexpecleddeath in infancy (SUD) has become
in-creasingly important in recent years in fo-rensic medicine. Mortality in infancy from well defined causes has rapidly decreased, and the proportion of SUD of unknown
cause has, therefore, been still more evident.
Today SUD cannot be considered a prob-lem for forensic medicine only; many other branches of medicine have an interest in
this problem.
In the Iast SUD has been attributed to suffocation by overlaying, by aspiration of
vomitus, or by bedclothes.1 During the last
10 years it has widely been presumed that SUD is due to an overwhelming viral
infectiori. Although much effort has been
spent iii an attempt to demonstrate tile
O5-sible viral agent, the results have mainly
been negative. Flypogammaglobulinemia as
a possible cause of SUD was indicated by Harboe and Gormsen, and more recently it
was suggested that SUD results from an
anaphylatic reaction to cow’s milk inhaled
into the larynx or trachea. S Many autllors
have pointed out that SUD might be con-nected with rickets or some more obscure
kind of disorder in the calcium metabolism, and in 1962 Maresch#{176} demonstrated a
significantly low content of calcium in heart
musculature in these infants and presumed
that one and the same basal disorder of me-tabolism might lead to rickets and spasmo-philia as vell as to SUD.
However different the theories, two facts seem to be generally accepted by all
au-thors in this field. Nearly all claim that SUD
is significantly most frequent at the age of
about 3 to 4 months. Also, it seems to be an
established fact that SUI) is far more
fre-juent in tile wintertillw, although SOflJC au-thors find one more niaximum ill tile
spring.1#{176} The fact that SUD so clearly is
connected with the cold season has, of
course, constantly been considered
circum-stantial evidence by those who believe that SUD is caused by an infection of the
respi-ratory tract.
Ill a series of 409 consecutive cases of
typical SUD of infants (age 2 to 11
months),15 a cilaracteristic seasonal
distri-bution of the birthdays (Fig. 1) was found
and tllere were significantly low 1ev-els of citrate in serum, spinal fluid, and
hone of these infants. The hypothesis was
brought forward that SUD is due to a
con-genital disorder involving the calcium
me-tabolism. Therefore, a study of the
parathy-roids in SUD was found relevant.
MATERIAL
The parathyroids were examined in 122
consecutive, medico-legal autopsies on
in-fants aged 2 to 11 months. In 82 cases the
negative results of histological,
bacteriolog-ical, and virological examination as well as the anamnestic data indicated typical SUD of unknown cause. Forty cases (age 2 to 11
months) with clearly demonstrated causes
of death (homicide, accident, etc.) served as
controls.
By histological serial sections through the
thyroid region the parathyroids were found
in all but three cases in the control group. All these parathyroids were normal. In a
few cases (aberrant) thymus tissue was
found in tile vicinity of the parathyroid
thy-TABLE I
DEMONSTRATION OF THE PARATHYROIDS BY
HisToLool-CAL SERIAL SECTIONS THROUGH THE THYROID
REGION
TABLE II
RELATION OF THYMUS TISSUE TO THE PAR
THYROIDS FOUND
* Imifamits with clearly verified causes of death.
* Infants with clearly verified causes of death.
50 40 30 20 U) I-4 w Li. 0 Lii
z
4// X_X _o-aA
\
I44 SUDDEN UNEXPECTED DEATH
InfantsAge2ioll Months Number of (axes Para-thyroids pound at /0
Control group* 40 37
SUD of unknown cause 8 54
Total 91
93
66
7.5
mtis tissue never occurred (Table I and II).
In the 28 of the 82 autopsies following
SUD the parathyroids could not be found.
In the 54 others, the parathyroids were
found, but many peculiar variations in
lo-calization and morphology were observed.
Thus in 32 of these 54 masses of thymus
tis-sue occurred within the parathyroid cap-sule. In 17 cases the two tissues were total-ly fused (Table II). The fusion of the
tis-sues in all these cases were clearly convinc-ing-the epithelial cells of the parathyroid
gland invading even the Hassal’s corpusculi of the thymus (Fig. 2 to 4). Parathyroid
tis-sue never occurred in the thymus gland it-self.
Along with the histological examination
x-x Typical SUD
60 #{149} Cause of death fully clarified
10
Jon. March May July Sept. Nov.
MONTH OF BIRTH
Ftc. 1. The time of birth of 1,000 infants who died at the age of 2 to 11 months.
infants Age 2 to 11
Months rara-. thyroids Found Thym us . .
I issue in
. Relation to Para-. thyroids Number . ii’ith Complete #{149} Fusion
Control group* 37
SUD of unknown cause 54
Total 91 4 372 36 0 17 17
of the parathyroids, citrate#{176} levels in serum, spinal fluid, and dry bone of vertebrae, sternum and ribs, and calcium levels in
se-rum and spinal fluid were determined. The results are shown in Table III.
COMMENT
It was impossible to find the parathyroids
in 34% of tile cases of SUD of unknown cause, wllereas the parathyroids were easily demonstrable in nearly all cases with clear-ly verified causes of death. The many anomalies (especially the fusion of parathy-roid and thymus tissue) which were found in the group of typical SUD throw
suspi-cion on the missing glands. The parathy-roids and thymus originate from the same
site in the branchial apparatus, and it is
natural to interpret the demonstrated fu-sion of parathyroid and thymus tissue as a sign of incomplete embryologic
develop-ment. The missing glands may mean a still
higher degree of incomplete development,
i.e., they may not even have reached the nor-mal site at the thyroid capsule, and some
may not even have been developed at all.
The literature in this field gives little in-formation. In his extensive studies of
0 Method of Rehell, B. : A rapid clinical method
for the determination of calcium in serum and other
biological fluids. Scandinav. J. Clin. Lab. Invest., 6:335, 1954.
t Method of McArdle, B. : Modified method for microdetermination of citric acid. Biocheni. J., 60;
tissue with large Hassal’s bodies. Only the part just below the center of the picture is parathyroid tissue
(3-month-old boy; typical case of SUD).
Infants
l)ata
Average
Age
(no)
4.9
4.3
.11 ales C-I
(‘itrate
Controls Typical SUD
40
872
Seru in
gamma!
miii
34
10
Spinal
fiuid Dry bone
gambol in g/gmn
miii
31 11.7
721 7.4
46 SUDDEN UNEXPECTED DEATH
Fic. 4. Same as Fig. 3. Fligher magnification. Parathvroid tissue mainly at right, thvmus tissue mainly
at left. Notice the complete fusion with parathvroid “clear cells” near center.
lillITiall fetus and young infants Gilmourl ) 1’
often foulid aberrant thymus tissue (thymus
IV) in relation to the 1)arathyrOidS. In a few
cases Gilmour even observed fusion of thy-mtis dIl(l I)ar1tl1y7roicl tissue. But Gilmour’s extensive aiid precise studies were
princi-pally l)ased on series of dead peritlatal and
stillborn infants, many of whom showed
se-vere con genital anomalies (anencephali,
mi-crognathi, etc.). Furthermore, Gilmour’s
pa-pers give no information concerning tile
frequency of typical cases of SUD in his
material, although these infants with
great-est certainty must have been represented to
some eXtefl t. us, although Gilmour’s
w’ork has the character of a study of tile
normal anatomy of the human parathvroids,
his many ol)servations of incompletely
de-veloped paratiiyroids, including fusion of
these glands w’ith aberrant thymus tissue,
might not give a true Picture of the
configuration of these structures in the
per-fectly healthy human infant.
The findings in the control group of the
TABLE III
Number
of cases
(consecu-tive)
POSTMOI1TI’M LEVELS OF CALCIUM AND CITRATE IN 51])
Calciu in
Spinal Serum
ing/lOO ml fluid mg/1O() ml
572 11.1 .5.8
- 8. Parish, W. E., Barrett, A. M., Coombs, present study clearly indicate that fusion of
parathyroid and thymus tissue normally
does not occur, \\4)ereas these findings are
easily demonstrable in the cases of typical
SUD. Tile average age in tile control group was 4.9 ITlOiltilS and in the group of SUD it was 4.3 months. Therefore, difference in
age can he ruled out, and it is the author’s
conciliSioll that SUD of infants is clearly
correlated to absence of the parathyroids or
fusion of these glands with thymus tissue.
The significantly low levels of citrate in serum, spiial fluid, and bone foulld in the
typical cases of SUD indicate a disorder in
the calcium metabolism of these infants.
The abnormally high level of total calcium
in the cerebrospinal fluid-although difficult
to explain-points in the same direction.
In 1939 Friderichsen2#{176} described a case
of congenital parathyroid insufficiency in a
5-month-old infant who, without prodromal
signs, suddenly collapsed at home and was
brought to hospital moribund under
cir-cumstances identica 1 to those frequently
described in typical SUD (Geertinger’
).
This infant regained a healthy appearance
ill a few hours and showed no symptoms of
ill-health in the following weeks, although a
chronic hypocalcemia (6.7 mg/100 ml)
resis-taut to vitamin D and irradiation was
pres-ent. Friderichsen found a severe
hypercal-cemia (16 mg/100 ml) in the mother which
was caused by parathyroid adenoma and
brought forward tile hypothesis that the
de-velopment of the parathyroids of the
human fetus depends on a normal calcium
homeostasis ill tile maternal organism.
Walton’ and Bruce and Strong22 have
re-ported similar findings. Sinclair23 found an
appreciable decrease in size and weight of
the parathyroid glands of young rats if high
concentrations of serum calcium or
para-thyroid hormone were produced in the
mother during pregnancy.
It is also generally accepted that gesta-lion tends to strain the parathyroids of he
mother24 and the parathyroid activity in
man is subjected to a severe seasonal
varia-tioll; hyperfunction in Ute wilTter is the
rule.23,2 Therefore, congenital anomalies of
the parathyroids may be expected,
especial-ly in infants who are conceived in the
win-ter and born in the autumn-precisely at that time of the year when the infants who die of SUD are born (Fig. 1).
HYPOTHESIS
Some evidence is available to support the
presumption that congenital subvalidity of
the parathyroids of infants is subjectcd to
seasonal variation. In the present study tile
following characteristics of typical SUD of
infants are presented: (1) a notable seasonal
variation in the time of birth; (2) a high
fre-quency of morphologically evident anorna-lies of the parathyroids; (3) low levels of
citrate in serum, spinal fluid, and bone, and
abnormally high level of calcium in spinal
fluid pointing towards a disorder in
cal-cium metabolism; and (4) appreciable
pre-ponderance of the male sex. The author,
therefore, brings forward the hypothesis that SUD of infants is correlated to a
con-genital anomaly of the parathyroids.
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