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Congenital hemihypertrophy Oncogenic potential of the hypertrophic side.

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HeGihypertroph y :
Oncogenic Potential
of the Hypertrophic Side
Tetsuo Furukawa, M D , and Tamiko Shinohara, P h D
Congenital hemihypertrophy is a rare condition, occasionally associated with neoplasms on the affected side
of the body. Investigation of three cases disclosed increased growth rate of cultured skin keratinocytes and
fibroblasts and high skin temperature on the hypertrophic side. These observations suggest the oncogenic
potential of the affected side in the condition.
Furukawa T , Shinohara T: Congenital
hemihypertrophy: oncogenic
potential of the hypertrophic side.
Ann Neurol 10:199-201, 1981
Congenital hemihypertrophy is a rare condition characterized by overgrowth of one side of the body. The
disease is occasionally associated with neoplasms on
the affected side [ l , 3-7, 91. Three patients with this
condition were investigated with regard to the potential for development of neoplasms.
Case Histories
PATIENT 1 . A 32-year-old man had been the product of a
normal pregnancy and delivery. Since infancy the left side
of his body had been slightly hypertrophic. His milestones
were normal. At 18 years he developed fever up to 4 0 T ,
sustained for a few days. His left leg became much longer at
this time, and he noticed that the left knee rested at a
higher position than the right when h e sat on a chair. His
body asymmetry was unchanged thereafter. He was lefthanded, 170 cm tall, and 78 kg in weight. T h e left side of
his body, including the face, was hypertrophic; his left hand
was larger than the right and the left leg was 5.0 cm longer
than the right. Nevus verrucosus systematicus was found
on the left abdomen. His hair was slightly kinky o n the
right but was straight on the left. O n palpation his skin was
warmer o n the left, hypertrophic side compared with the
right. Axillary temperature was 0.2" to 0.4"C higher on the
hypertrophic side. Muscle power was normal bilaterally.
Neurological examination revealed n o abnormality except
for the body asymmetry. Laboratory studies including
From the Departments of Neurology and Human Cytogenerics,
Japan Red Cross Medical Center, Tokyo, Japan.
Received Oct 27, 1980, and in revised form Jan 23, 1981. Accepted for publication Jan 28, 1981.
Address reprint requests to Dr Furukawa, Department of Neurology, Tokyo Medical and Dental University, 1-5-45 Yushima,
Bunkyo-ku, Tokyo 113, Japan.
blood cell counts, serum biochemistry, urinalysis, cerebrospinal fluid, electrocardiogram, and brain CT scan were
within normal limits. Intravenous pyelography revealed a
larger left than right kidney.
PATIENT 2. The right hand and arm of a 31-year-old
woman had been longer than the left since childhood, but
with no motor or sensory disturbance. O n examination the
right side of her body was hypertrophic; her right shoulder,
arm, and hand were longer than the left, and the right thenar and hypothenar muscles were enlarged. Muscle power
was normal, grip power being 34 kg in the right hand and
22 kg in the left. Skin temperature was higher on the right
arm than the left. Neurological examination revealed no
abnormality except for the body asymmetry.
PATIENT 3. A 47-year-old man had noticed since childhood that the right side of his face was hypertrophic. The
condition was not progressive. At age 40 he developed
right occipital headache and ataxia. Vertebral angiography
showed a hemangioblastoma of the right cerebellar hemisphere, which was surgically removed. Ataxia almost disappeared after operation. At that time a chest roentgenogram
revealed a coinlike, 1 x 1 cm shadow in the right middle
lobe. His condition has remained stationary. Details of the
case have been reported [ 5 ] .
Results of Special Studies
Thermograms of Patient 1 are shown in Figure 1.
Skin temperature was diffusely higher on the entire
left side of the body than on the nonhypertrophic
side. No focal concentration was observed. Thermograms of Patient 3 disclosed increased skin temperature on the hypertrophic side of the face [>I.
Skin biopsies were obtained from both elbows and
knees in Patient 1, the elbows in Patient 2, and bilateral preauricular areas in Patient 3. Specimens were
incubated under the same conditions. The culture
medium contained 70% Leibowitz L-15 medium,
10% TC-109, and 20% calf serum at 37°C with a
constant flow of 5% carbon dioxide in air. Growth of
keratinocytes and fibroblasts was observed under
phase-contrast microscopy.
Figure 2 shows cultured skin samples obtained
from the elbows of Patient 1. The specimen from the
left, hypertrophic side developed keratinocytes on
the third day of culture, and on the sixth day abundant keratinocytes were observed. A small group of
keratinocytes was detected on the sixth day in the
right, normal skin. The same phenomenon was observed in skin samples from the knees. In Patients 2
and 3, keratinocytes took 5 to 7 days to appear in
normal skin, while growing keratinocytes were detected as early as the second or third day of culture in
hypertrophic skin. The keratinocytes were followed
by abundant fibroblasts in all samples. Fibroblasts
were increased in growth rate and number in skin
from the hypertrophic sides. No morphological dif-
0364-5 134/81/080199-03$0l.25 @ 1980 by the American Neurological Association
F i g I. Thermograms of Patient 1 (A,face; 3,face and trunk;
C , lower extremities). Skin temperature is higher on the left,
hypertrophic side of the body.
ferences in fibroblasts were detected between the
two sides. Karyotypes of peripheral lymphocytes and
skin fibroblasts from both sides were normal.
Congenital hemihypertrophy was originally described by Boeck [2, 121 in 1836. Although the cause
of the condition is obscure. the disease is occasionally
associated with neoplasms on the affected side [ l ,
3-7, 91, as in Patient 3.
Skin temperature was 1" to 2°C higher o n the
hypertrophic side compared with the normal side in
all the present cases. Keratinocytes usually take 5 to
7 days to appear in cultured skin of normal subjects.
No difference was observed between normal sub-
200 Annals of Neurology
Vol 10 No 2
August 1981
F i g 2. Cultured skin samples from both elbows of Patient I.
The specimen from the left, hypertrophic side developed
keratinocytes as early as the third day of culture (A),and on
the sixth day abundant keratinocytes were observed (B). I t was
not until the sixth day of culture that a smallgroup of
keratinocytes appeared in the normal skin (C). (The large central line was a j a w on the culture bottle.) (A and B x 10, C
~ 2 5all
, before 10% reduction.)
jects and the normal side of the body in subjects with
congenital hemihypertrophy. On the other hand,
abundant keratinocytes were seen as early as the second or third day of culture in biopsies from the
hypertrophic side. Furthermore, fibroblasts were
greatly increased in growth rate and number in skin
from the hypertrophic side.
Patients with familial intestinal polyposis are susceptible to the development of cancer. Pfeiffer et a1
[8] demonstrated increased ability of skin fibroblasts
of affected individuals to grow in vitro. Their observation is similar to ours on cells from the affected
side in congenital hemihypertrophy. The RussellSilver syndrome [lo, 111 consists of short stature,
low birth weight, and “hemihypertrophy.” We examined an 8-month-old boy with this syndrome;
thermography and skin culture showed no difference
between the two sides of his body and no difference
from a normal infant. Patients with the Russell-Silver
syndrome have no tendency to develop neoplasms.
The so-called hemihypertrophy in this syndrome is
quite different from that in congenital hemihypertrophy, and asymmetry is a more appropriate term.
The increased growth rate of skin fibroblasts and
high skin temperature of the hypertrophic side are
considered intimately related to an increased susceptibility to neoplasms in congenital hemihypertrophy.
The condition not only is a hemiovergrowth, but also
has oncogenic potential with accelerated cell growth.
Studies on this point may cast light on the relationship between congenital anomalies and neoplasms.
Thermograms of the patients were kindly performed by the Department of Medical Electronics, University of Tokyo.
1. Benson PE, Vulliamy DG, Taubman JO: Congenital hemihypertrophy and malignancy. Lancet 1:468-469, 1963
2. Boeck: Abnorme Grosse des Daumens und des Zeigefingers
der rechten Hand. Meditinische Annalen von Puchelt,
Chelius und Nagele (Heidelberg) 2:89, 1836 (cited by Ziehl
3. Fraumeni JF Jr, Geiser CF, Manning M D Wilms’ tumor and
congenital hemihypertrophy: report of five new cases and review of literature. Pediatrics 40:886-899, 1967
4. Fraumeni JF Jr, Miller RW: Adrenocortical neoplasms with
hemihypertrophy, brain tumors, and other disorders. J Pediatr
70~129-138, 1967
5. FurukawaT, Shimizu T, Toyokura Y:Facial hemihypertrophy
and cerebellar hemangioblastoma. Neurology (Minneap) 23:
1324-1328, 1973
6. Geiser CF, Baez A, Schindler AM, Shih VE: Epithelial
hepatoblastoma associated with congenital hemihypertrophy
and cystathionuria: presentation of a case. Pediatrics 4 6
66-73, 1970
7. Haicken BN, Schulman NH, Schneider KM: Adrenocortical
carcinoma and congenital hemihypertrophy. J Pediatr 83:
284-285, 1973
8. Pfeiffer L, Lipkin M, Stutman 0, Kopelovich L: Growth abnormalities of cultured human skin fibroblasts derived from
individuals with hereditary adenomatosis of the colon and
rectum. J Cell Physiol 8929-37, 1976
9. Roth F: Zur Kenntnis und Auffassung der Lebermischgeschwiilste und des halbseitigen Riesenwuchses. Frankfurt
Z Pathol 52:163-196, 1938
0. Russell A: A syndrome of “intra-uterine” dwarfism recognizable at birth with cranio-facial dysostosis, disproportionately
short arms, and other anomalies ( 5 examples). Proc R SOC
Med 47:1040-1044, 1954
1. Silver HK, Kiyasu W, George J, Deamer WC: Syndrome
of congenital hemihypertrophy, shortness of stature, and
elevated urinary gonadotropins. Pediatrics 12:368-376,
12. Ziehl F: Ein Fall von congenitaler halbseitiger Gesichtshypertrophie. Virchows Arch 91:92-105, 1883
Case Report: Furukawa and Shinohara: Congenital Hemihypertrophy
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potential, hemihypertrophy, side, hypertrophic, congenital, oncogenic
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