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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, unexpecled

death 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

(2)

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-a

A

\

I

44 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;

(3)

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).

(4)

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

(5)

- 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.

REFERENCES

1. Barrett, A. vI. : Sudden death in infimcy. In

Girdner, D., ed. Recent Advances in

Pedi-atrics. London: J. and A. Churchill, 1954.

2. Garrw, I., and Werne, J.: Pathologic findings

in infants dying immediately after violence

contrasted with those after sudden

ap-parently unexplained death. Amer. J. Path.,

29:833, 1953.

3. Adelson, L., and Kinney, E. R.: Sudden and

urtexpected death in infancy and childhood.

PEDIATRICS, 17:663, 1956.

4. Cormsen, H., and Rosendal, K.: Sudden and

unexpected infant death. III.

Bacteriologi-cal and histological examinations in 50

con-secutive cases. Acta Med. Leg. Soc. (Liege),

9:161, 1956.

5. Muller, C. : Der pl#{246}tzliche Kindstod.

Patho-logische Anatomie und Dynamik. Stuttgart:

Georg Thieme Verlag, 1963.

6. Harboe, N., and Cormsen, H. : Sudden and

unexpected infant death. IV. A preliminary

report on electrophoretic serum studies. Acta.

Med. Leg. Soc. (Liege), 9: 173, 1956.

7. Parish, W. E., Barrett, A. M., and Coombs,

R. R. A.: Inhalation of cow’s milk by

sensi-tized guinea-pigs in the conscious and

anaestheUzed state. Immunology, 3:307,

(6)

48

SUDDEN UNEXPECTED DEATH

R. R. A., Gunther M., and Camps, F. E.: Hypersensitivity to milk and sudden death

in infancy. Lancet, 2: 1 106, 1960.

9. Maresch, W.: Die Bedeutung der

Elektrolyt-bestimmungen des Herzmuskels zur Klarung

plotzlicher Todesf#{228}lle im Sauglingsalter. Wien. Klin. Wschr., 74:21, 1962.

10. Weyrich, G.: Erfahrungen #{252}berden pl#{246}tz-lichen Tod aus innerer Ursach bei Kindern und Jugendlichen. Deutsch. Z. Ges. Gerichtl.

Med., 22:116, 1933.

1 1. Abramson, H. : Accidental mechanical suffo-cation in infants. J. Pediat., 25:404, 1944.

12. Jacobsen, T., and Voigt, J.: Sudden and

un-expected infant death II. Result of medico-legal autopsies of 356 infants aged 0-2

years. Acta Med. Leg. Soc. (Liege), 9: 133,

1956.

13. Coe, J. I., and Hartman, E. E. : Sudden, ur-expected death in infancy. J. Pediat., 56:

786, 1960.

14. Rominger, E.: Zur Frage ungeklarter, plotz-licher Todesf#{228}lle im fr#{252}hen Kindesalter. Arch. Kinderheilk., 164:209, 1961.

15. Geertinger, P.: Pludselig, uventet spaedbarns-d#{248}di K#{248}benhavn. Dissertation. (Danish with an English summary). Copenhagen:

1965.

16. Gilmour, J. R.: Embryology of parathyroid

glands, thymus and certain associated

rudi-ments. J. Path. Bact., 45:507, 1937. 17. Gihnour, J. R.: The gross anatomy of the

parathyroid glands. J. Path. Bact., 46:133, 1938.

18. Gilmour, J. R.: Normal histology of parathy-roid glands. J. Path. Bact., 48: 187, 1939. 19. Cilmour, J. R.: Some developmental

abnor-malities of thymus and parathyroids. J. Path. Bact., 52:213, 1941.

20. Friderichsen, C. : Tetany in a ‘uckling with

latent osteitis fibrosa in the mother. Lancet, 236:85, 1939.

21. Walton, R. L.: Neonatal tetany in 2 siblings:

Effect of maternal hyperparathyroidism.

PEDIATRICS, 13:227, 1954.

22. Bruce, J., and Strong, J. A.: Maternal

hyper-parathyroidism and parathyroid deficiency

in the child with an account of the effect of parathyroidectomy on renal function and

of an attempt to transplant part of the

tumor. Quart. J. Med. (New Series), 24:307,

1955.

23. Sinclair, J. G.: Size of the parathyroid glands of albino rats as affected by pregnancy and

controlled diets. Anat. Rec., 80:479, 1941.

24. Talbot, N. B., Sobel, E. H., McArthur, J. W.,

and Crawford, J. D. : Functional endocri-nology from birth through adolescence. Cam-bridge, Massachusetts : Harvard University

Press, 1952.

25. Iwanami, N., Osiba, S., Yamada, T., and Yoshimura, H.: Seasonal variations in serum inorganic phosphate and calcium with spe-cial reference to parathyroid activity. J.

Physiol., 149:23, 1959.

-26. Fanconi, G.: Physiology and pathology of calcium and phosphate metabolism.

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1967;39;43

Pediatrics

Preben Geertinger

Parathyroids

SUDDEN, UNEXPECTED DEATH IN INFANCY: With Special Reference to the

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(8)

1967;39;43

Pediatrics

Preben Geertinger

Parathyroids

SUDDEN, UNEXPECTED DEATH IN INFANCY: With Special Reference to the

http://pediatrics.aappublications.org/content/39/1/43

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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