We
report
here
two
cases
of
significant
symptomatic hypoglycemia in children
receiv-ing propranolol for cardiac disease. Both
chil-dren
became
hypoglycemic
after
prolonged
pe-nods of decreased oral intake. Neither child had a known hypoglycemic tendency or
diffi-culty while receiving propranolol and a normal
diet although carbohydrate balance studies
have
not
been
done.
With
the
increasing
use
of
propranolol in children, it is important to be aware of this apparent association of
hypo-glycemia and propranolol during periods of
low
oral
intake.
J
OHN T. MCBRIDE, M.D.MARGARET
C.
MCBRIDE, M.D.PETER
H.
VILE5, M.D.Department of Pediatrics
University of Rochester School of Medicine Rochester, New York 14642
REFERENCES
1. Cumming, C. R. : Propranolol in tetralogy of
Fallot. Circulation, 41 : 13, 1970.
2. Linde, L. M., Turner, S. W., and Awa, S.:
Present status and treatment of paroxysmal
supraventricular tachycardia. PEDIATRICS, 50: 127, 1972.
3. Huff, B. B., ed : Physicians Desk Reference to Pharmaceutical Specialties and Biologicals. Oradell, New Jersey: Charles B. Baker, 1972, p.571.
4. Kotler, M. N., Berman, L., and Rubenstein, A. H. : Hypoglycemia precipitated by
pro-pranolol. Lancet, 2: 1389, 1966.
5. Mackintosh, T. F. : Propranolol and hypoglyce-mia. Lancet, 1:104, 1967.
6. Adibi, S. A.: Influence of dietary deprivations
on plasma concentrations of free amino acids in man.
J.
Appl. Physiol., 25:52, 1968.7. Huinninghake, D. B., Azarnoff, D. L., and
Waxman, D. : Drug inhibition of
catechola-mine-induced metabolic effects in humans.
Ann. New York Acad. Sci., 139:971, 1967.
8. Abramson, E. A., and Arky, R. A. : Role of B-adrenergic receptors in counter-regulation to insulin-induced hypoglycemia. Diabetes, 17:
141, 1968.
9. Salvador, R. A., April, 5. A., and Lemberger,
L. : Inhibition by butoxamine, propranolol
and MJ 1999 of the glcogenolvtic action of the catecholamines in the rat. Biochem. Pharmacol., 16:2037, 1967.
10. Narahara, H. T., and Con, C. F. : Hormonal control of carbohydrate metabolism in mus-cle. In Dickens, F., Randle, P.
J.,
andWhe-land,
W.J.,
eds: Carbohydrate Metabolismand Its Disorders, I. New York: Academic Press, 1968, pp. 375-395.
Achondrogenesis
Until recently the newborn infant with a large head and short limbs who died soon after birth was assumed to have achondroplasia. This assumption has been shown to be incorrect by the delineation of at least
two
additionaldis-orders,
thanatophoric
dwarfism1
and
achondro-genesis,2 which also cause this physical appear-ance. Of the two, achondrogenesis has more definite genetic significance to the family in that it is an autosomal recessive disorder. Re-cent reviews4’5 indicate that at least 22 infants with achondrogenesis have been reported.
Be-cause
of the importance of proper recognitionFIG. 1. Large head, markedly shortened limbs,
;J’
.‘;
. , I . . ..
;
‘,, . ., I .‘ .S_t.,..
‘:
.‘. ‘
‘. ,
.. ..v
,% .‘
:
..
,:.t
#{149}. 1,,
. .‘ ..)
.‘.
,
‘. .FIG. 2. Lumbar vertebra. Irregular outline of cartilage model, extensive vas-cularization of cartilage, minimal enchondral bone formation, and abnormally
small ossification centr
(
central black area)
are demonstrated. Arrows point to intervertebral disk (hematoxylin-eosin, original magnificationx
11).1088
ACHONDROGENESIS
of this disorder by pediatricians, this additional
case
of achondrogenesis
is being
reported.
CASE PRESENTATION
This male infant was born after a term
preg-nancy. At the time of his birth his mother was 27
years old and his father 30. They have
subse-quently had a normal male infant. The parents are
not related. At birth the infant weighed 2.8 kg,
was 35.6 cm long, and had a head circumference
of 36.6 cm. His Apgar score at one minute was 3.
He had slow, irregular respirations and a strong
heart rate. His physical features were a large head,
a short neck, markedly shortened limbs, and a
dis-tended
abdomen and scrotum( Fig.
1). Hisbreathing remained labored and he died at 13 hours of age. The autopsy findings included small,
but not hypoplastic lungs, elevated diaphragms, a
large indirect inguinal hernia and hydronephrosis
of the right kidney due to a ureteropelvic stricture. Only vertebrae and ribs from the autopsy were
available for reevaluation. The cartilage, which
serves as the preformed model for enchondral
ossi-fication, shows striking abnormalities. Large
chon-drocytes are arranged in (liSOrderlv and haphazard groups
( Fig.
2 ).The cartilage matrix stains irregu-larly for mucopolysaccharides .The subsequenten-chondral sequence is retarded in all of its phases; the resulting bone trabeculae are disorganized and abnormally thickened. Periosteal bone formation is
normal. The lumbar ossification is less developed
than is normal for a 24-week fetus. The ribs show
similar enchondral abnormalities.
Radiographs
( Fig.
3) show a large calvariumwith wormian bones but normal suture diastasis.
The craniofacial ratio, mandible, and clavicles are
normal. The scapulae are small with indistinct
me-dial borders.
The rib cage is bell-shaped. There is progressive
lengthening of the ribs from the first to the ninth ribs and thereafter there is marked progressive shortening. The anterior ends of the ribs are
ex-panded and cupped. The thoracic cavity is
uni-formly dense.
The spine is relatively short and poorly ossified. The striking finding is the almost complete absence
of ossification of the vertebral bodies. The pedi-cules are identified down to the first sacral verte-bra. However, most neural arches are indistinct.
The sacrum is not ossified.
The iliac wings are square. The medial borders are sharp and concave. The other borders are
in-distinct. The acetabular roofs are horizontal. Both ischia are represented by a single area of
ossifica-ion. There is no ossification of the pubic bones to be found.
The long bones of the extremities are shortened and relatively widened. The ends of the bones are flared. This finding is especially remarkable in the
ends of the humeri and femora. The talus and cal-caneus are not ossified.
DISCUSSION
The physical, pathologic, and radiographic findings in our patients are identical to those reported by Saldino and Houston. The basis
for suggesting autosomal recessive inheritance
is that three authors have reported affected
siblings
born
to phenotypically normal parentsand that in one family the parents were second cousins. In a family4 with four children there was an affected male and female and two nor-mal children. In another family with nine
chil-dren
there
were
three
affected
males
and
one
affected female.
There
are
two problems with the termachondrogenesis used to describe this disorder.
First, the same term has been used to describe entirely different 2.3 Our patient
repre-sents the Parenti-Fraccaro type which is always lethal in the newborn period.2 This is distinct from the Crebe or Brazilian type of
achondro-genesis which is a separate autosomal recessive
disorder. The Crebe type is not lethal; the affected children have marked shortening of the
limbs,
tiny
digits,
and
a normal
head
and
trunk.
The second problem is that the term
achondro-genesis is inaccurate as it implies that cartilage
is not made. As is shown in our patients (Fig.
2
)
and those reported by Saldino, the cartilageis present hut markedly abnormal. Possibly further understanding of this disease will lead
to a more accurate and specific designation. This experience underscores the importance
of a careful examination of the newborn infant
with short limbs and a large head. Radiographic
examination appears to he the most
discrimi-nating study at the present time. By contrast
histologic examination, using routine
light-microscopic methods, confirms the presence of
abnormal cartilage as a principal defect in the
disorder but does not permit specific differen-tiation from similar chondrodysplasias at this time.
ROBERTO B. JIMENEZ, M.D. LE\vls B. HOLsfE5, M.D.
J
OlIN S. KAISER, M.D.ALFRED L. WEBER, M.D.
Departments of Radiology,
Pediatrics,
and PathologyHarvard
Medical
School,
and Departments of Radiology and Pathology Children’s Service
FIG. 3. Anteroposterior view of the infant shows the markedly deficient ossification of the vertebrae,
sacrum and pubis; the bell-shape rib cage; and the
shortened limbs with flared metaphvses.
Massachusetts General Hospital
Fruit
Street
Boston, Mas.sach usetts 021 14
Supported in part by N.I.H. Special F’ellowship
1 F03 HD-53, 606-01 and a grant from the
Charles H. Hood Foundation, Boston,
Massachu-setts.
AmmEss FOR REPRINTS:
(
L.B.H. ) Genetics Unit,Massachusetts General Hospital, Boston,
Massa-chusetts 02114.
REFERENCES
1. Maroteaux, P., Lamv, M. E., and Robert,
J.
M.: Le Nanismes thanatophore. Presse \I#{233}dicale,75:2519, 1967.
1090
ACHONDROGENESIS
Discussion of hereditary disorders of bones.
Birth
Defects:
Original
Article
Series.
Vol.
V,No. 4, April 1969, pp. 14-16.
3. McKusick, V. A. : Mendelian inheritance in man, ed. 3. Baltimore: The Johns Hopkins Press, 1971.
4. Saldino, R. M. : Achondrogenesis and
thanato-phoric
dwarfism.
Amer.
J.
Roentgen.,
112:185, 1971.
5. Houston, C. S., Awen, C. F., and Kent, H. P.: Fatal neonatal dwarfism. Canad.
J.
Radio!.,23:45, 1972
6. Silverman, F. : Personal communication cited by McKusick, op. cit., p. 298.
“The medieval alchemists
( actually
much
ma-ligned)
were accused of Black Magic. Theirpro-pensity for evil was far less than the best-intentioned scientists of today because the latter are far too
in-nocent to foresee the abuse of their discoveries . .
Scientists are the trustees of knowledge but ‘Quis
CUStO(liet ipsOI custodes?’-who indeed watches the
watchman? The answer is that no one does. We still
have nobody of wisdom which can adjudge what
in the science of medicine can best be applied in the present and future interests of mankind.”
Lord Ritchie-Calder, in The Center Magazine,
