6 Med Genet 1992; 29: 652-655

Cartilage-hair hypoplasia in Finland:
epidemiological and genetic aspects of 107
patients

Outi Makitie

Abstract
Cartilage-hair hypoplasia (CHH) is an
autosomal recessive form of metaphyseal
chondrodysplasia characterised by short
limbed short stature, hypoplastic hair
growth, and impaired cell mediated
immunity and erythrocyte production.
The syndrome is exceptionally prevalent
among the Finns and among the Old Ord-
er Amish in the United States; sporadic
cases have been reported from other
countries. An epidemiological and genetic
study of CHH in Finland showed 107
patients, 46 males and 61 females, in 85
families. Eighteen ofthem had died, seven
before the age of 1 year. The living patients
ranged in age from 1 to 51 years, median
21 years. The incidence was estimated to
be 1:23 000 live births. Consanguinity was
found in two families and interfamilial
relationships in 20 families. Geographical
distribution of the birth places of the
patients and their great grandparents
showed accumulation in a small area in
western Finland and regional clusters
were seen in other parts of the country as
well. The result ofthe segregation analysis
was in accordance with recessive inherit-
ance with reduced penetrance.
(J Med Genet 1992;29:652-5)

Department of
Medical Genetics, and
Children's Hospital,
University of Helsinki,
Helsinki, Finland.
O MMkitie

Correspondence to
Dr Makitie, Department of
Medical Genetics, Helsinki
University Hospital,
Tukholmankatu 8 F,
SF-00290 Helsinki, Finland.
Received 3 February 1992.
Accepted 17 February 1992.

Cartilage--hair hypoplasia (CHH) is a form of
metaphyseal chondrodysplasia characterised
by disproportionate short limbed short stature
and fine and sparse hair.'2 Skeletal growth is
retarded from birth; the median adult height is
131 cm for males and 123 cm for females.'
Cellular immunity is impaired as indicated by
lymphopenia and decreased in vitro lympho-
cyte reactivity; humoral immunity is intact.45
Deficient erythrocyte production often leads to
mild transient macrocytic anaemia, and, on
occasion, to congenital hypoplastic anaemia.6
The disease was first described among the Old
Order Amish in the United States2 and it has
also been found in the Finns in exceptionally
high numbers.7 Sporadic cases have been
reported in other countries. McKusick et aP
concluded that the mode of inheritance is
autosomal recessive with reduced penetrance,
since the number of patients in the families
was smaller than expected.
As part of a multidimensional project on

CHH, an epidemiological and genealogical
study was carried out in Finland.

Patients and methods
The material consisted of CHH patients dia-
gnosed and followed at the Department of
Medical Genetics or the Children's Hospital,
Helsinki University Hospital, which is the
major national centre for studying children
with growth failure. In addition, a question-
naire study was carried out in 1988 to 1989 in
each of Finland's 21 health care districts in
order to attain complete ascertainment. The
questionnaire was sent to the senior physicians
of paediatric, medical genetic, internal medi-
cine, and orthopaedic units of all central hospi-
tals (n = 21) and district hospitals (n = 29) as
well as to physicians in charge in health centres
(n = 216). The questionnaire consisted of de-
scriptions and illustrations of CHH, diastro-
phic dysplasia, and achondroplasia, the three
most common chondrodysplasias in Finland.
Information was requested on any such
patients. In case of positive answers, the
patients were contacted by their own doctors,
and medical records, radiographs, and detailed
information on the growth failure were
obtained. A clinical study was performed at the
Children's Hospital if CHH was suspected.
Furthermore, CHH patients were looked for
and personally contacted at the meetings of the
Association of Little People in Finland.
The diagnosis of CHH was based on short

limbed short stature, generalised laxity of joint
ligaments and, in childhood radiographs, meta-
physeal flaring and irregularities of the growth
plates. Hair hypoplasia was used only as a
positive criterion; normal hair does not exclude
CHH (Makitie and Kaitila, unpublished data).
There were seven patients who had normal hair
but otherwise typical features of CHH. Two of
them had a sib, and another two a relative, all
with typical features of CHH.

Since present urbanisation has mixed the
possible regional clusters, differences in re-
gional gene frequencies were assessed by the
great grandparents' birth places. The patients'
and their great grandparents' birth places and
the great grandparents' identity were confirmed
from the population register. Detailed genea-
logy was available for some families. For the
incidence calculation the number of annual live
births was obtained from the Statistical Year-
book.8 Information on abortions was obtained
from parents and hospital records and was
compared with the abortion frequency in the
normal population.9 If the family had not been
contacted recently, the number of sibs was
verified from the population register. Heights of
the sibs were recorded from the child health

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Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients

centres to find possible undiagnosed patients.
Segregation analysis was performed with the
'singles method"' and the 'a priori method'," 12
which both assume truncate complete ascer-
tainment, and with the 'sib method'," which
assumes single incomplete ascertainment.
The study was approved by the ethical com-

mittee of the Children's Hospital.

Results
The epidemiological study showed a total of
107 Finnish CHH patients, 46 males and 61
females, in 85 families. Eighty patients had
been followed at the Department of Medical
Genetics or the Children's Hospital. Eighteen
families with 26 CHH patients were added
through the questionnaire study and one
patient through the Association of Little
People. Eighteen of the 107 patients had died,
seven of them under the age of 1 year. The
living patients ranged in age from 1 to 51 years,
median 21 years. The incidence of CHH calcu-
lated for the 10 year period 1977 to 1986 was
1:23 000 live births, which means about three
new patients yearly (fig 1). The frequency of
spontaneous abortions was 8%, which is not
higher than the abortion frequency in the
normal population. There was no apparent
relationship between the birth order and
occurrence of CHH.
Two female patients from two Finnish fami-

lies lived in Sweden. Since adequate informa-
tion on their sibs or ancestors could not be
obtained, they were not included in the segre-
gation analysis. Thus, the series consisted of
105 Finnish CHH patients in 83 families (fig
2). Fourteen families had two affected sibs and
four families had three. Altogether there were
157 unaffected sibs in the families. Using the
correction for the 'singles method', the ratio of
the affected sibs was 0-203 (SE 0 036). By the
'a priori method' the observed number of
patients (105) was lower than expected on the
basis of recessive inheritance (111, SE 5-0).
The 'sib method' resulted in a ratio of 0-123
(SE 0 025) of the affected sibs.
The patients' and their great grandparents'

birth places showed an accumulation in a small
area in western Finland, Southern Ostroboth-
nia. Furthermore, the gene was more frequent
in three other areas: the south-eastern corner
of the country, Northern Savonia, and the
most southern part of Lapland (fig 3). The
incidence in the high frequency area of South-

22
20 a Alive (n = 89)
18 E Dead (n= 18)
16

e14-
12-
CLloH

H
H

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H.

00

0 0*0

0 0

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0

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0 0* o

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U.0 0
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flUE

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O- '

* 0 0

0 0 0,

,0
0 0 0

.E. O

0H *,o0ioDi o

oo00,Sob o o
0 * 0 0 0

ow'0 0
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0ojz(i

0 000 Z'0 0jzfo.ooZOUO
Ho0*000*HA
o00*,o'a0o0o

* * Affected
O 0 Unaffected
* Spontaneous abortion

Figure 2 The 83 sibships with 105 affected, 157
unaffected, and 22 spontaneous abortions.

em Ostrobothnia was 1:3000 live births. Con-
sanguinity, not closer than third cousins, was
found within two families, and interfamilial
relationships in 20 families (fig 4). In more
cases, however, possible remote relationships
between the families could not be detected,
since the ancestors were not traced back
further than the great grandparents.

Six female patients were married to unaffec-
ted males. Two of these couples had two
children and two had one child. All the chil-
dren had been delivered by caesarean section
and were healthy. None of the male patients
was married or had children.

Discussion
Cartilage-hair hypoplasia (CHH) is a rare
inherited form of metaphyseal osteochondro-
dysplasia which results in severe growth fail-
ure. It is overrepresented among the religious
sect of the Old Order Amish in the United
States and among the Finns. At least 113 CHH
patients have been recognised among the
Amish.214 The present study showed a total of
107 CHH patients among the Finns. The
number of CHH patients among other natio-
nalities is low: seven patients have been
reported among the English,"-" eight among
the Dutch (van der Burgt, personal communi-
cation), and sporadic cases among the
French, 1-22 Germans,23-26 Danes 27 Algerians,20
Italians,2'30 Polish (van der Burgt, personal
communication), Spanish," and Mexicans.'2 A
study of 403 children with bone dysplasia in
Nigeria found no patients with CHH."
The specific pattern of rare hereditary dis-

eases in Finland, that is, overrepresentation of

1940 -50 -60 -70 -80 -90
-45 -55 -65 -75 -85

Year of birth
Figure I Cartilage-hair hypoplasia patients born in
1939 to 1991.

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Makitie

A

Patients' birth

Figure 3 Geographical distribution of birth places of (A) the patients and (B) the
great grandparents (one dot =family or great grandparent). The area denoted by the
broken line belonged to Finland before the second world war.

some 30 rare autosomal recessive disorders and
lack of some others, is the result of national and
regional isolation of the small population.3435
Most of the ancestors of CHH families origi-
nated from a small area in western Finland with
some regional clusters in a few eastern and
south-eastern communities. These are sparsely
inhabited rural areas which were permanently
settled as late as the sixteenth century and are
still isolated.35 Even today most native inhabit-
ants of these communities are descendants of
a few settlers from 15 to 20 generations back
and are therefore remotely related to one
another.3536 The break up of isolates by increas-
ing migration to towns will in the future slowly
even out the clustering of recessive genes and
thereby result in a decrease in the incidence of
CHH. The patients' birth places, however, still
gave evidence of accumulations similar to their
great grandparents' birth places. Calculated
using the Hardy-Weinberg coefficient, the gene
frequency for the whole country was 0-0066 and

for the high frequency area of Southern Ostro-
bothnia 0-018, and the carrier frequencies were
1:76 and 1:29, respectively. However, this
method is partly invalidated by uneven distri-
bution of the gene in the Finnish population.
The present study showed consanguinity in
two families and interfamilial relationships in
20 families. However, by tracing the ancestors
back further than the great grandparents,
several other remote relationships within and
between CHH families would certainly have
emerged.

In the study of CHH among the Amish, the
number of affected was higher for females than
for males (46 v 31).2 Similarly, females were
overrepresented among the Finnish patients
(61 v 46). When the two groups are combined,
the sex ratio is 1:1 4 (X2=2214, NS).
Autosomal recessive inheritance was estab-

lished in a study of CHH in 53 Amish sibships.
However, as the number of affected patients
was significantly lower than expected on the
basis of the recessive hypothesis (72 v 98-5, SE
6 8), reduced penetrance of about 70% was
suggested.2 The other possible explanations
discussed were contamination of the series
by numerous sporadic, mimicking dominant
conditions, non-random chromosome segrega-
tion, gametic selection, and increased mortality
in utero.2 The segregation analysis of 83 Fin-
nish CHH families was performed by methods
of complete and incomplete ascertainment. The
ascertainment was probably close to complete
among young patients, but incomplete in the
older age groups, since no patients over 51 years
of age were ascertained. As the ascertainment
was somewhere between complete and incom-
plete, the corrected ratio of affected patients lies
between those derived by the two extreme
methods, that is, between 0-203 (SE 0 036) and
0-123 (SE 0025). The result is in accordance
with reduced penetrance. Five more patients in
these families would have resulted in a ratio of
0-25 ('singles method'). The abortion frequency
among the Finnish CHH families does not
support increased mortality in utero. The lack
of affected patients is too great to be explained

Figure 4 Pedigrees of CHHfamilies with consanguinity (two families) or interfamilial relationships (20 families).

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Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients

by contamination by new dominant mutations
and contamination by another recessive dis-
order should not lead to lack of affected. The
other explanations, non-random chromosome
segregation and gametic selection, are hypo-
thetical and highly improbable, but difficult to
prove or disapprove.
The reduced penetrance in CHH may be

explained by some homozygotes being so
mildly affected that they are presumed to be
healthy.37 Among the Amish this was found in
two cases: very mild CHH, only found radio-
logically, in three children of affected parents,
and thin hair, short and pudgy hands, and
contracted pelvis in a female who was 157 cm
tall.2 Furthermore the hair diameter in some
healthy sibs overlapped that of the patients.2 In
another study, lymphopenia and low response
to lymphocyte stimulation were observed in a
healthy sib who had no other clinical features
of CHH.38 In order to find mildly affected,
undiagnosed persons among the Finnish CHH
families, the relative height (deviation ofheight,
in SD units, from mean height for age and sex)
of 84 healthy sibs was compared with the mid-
parent relative height: no difference of more
than 2-0 SD was observed. Also, the midparent
relative height was always within the mean (2.0
SD) of the normal population. The relative
heights of the patients, in contrast, were always
more than 3 0 SD below the midparent relative
height, and the adult relative heights ranged
from -11 4 SD to -4 9 SD. Childhood radio-
graphs of the left knee were obtained from 13
healthy sibs; none of them showed metaphyseal
changes. One healthy sister had poor hair
growth and wore a wig; her adult height was
169 cm and her sitting height normal. No child-
hood radiographs were available for her. More
thorough clinical and biochemical studies of
healthy sibs are needed to settle the question of
reduced penetrance.
The results of this study were consistent

with those of studies of the Amish CHH
patients.2 The number of affected persons in
the families was lower than expected on the
basis of a recessive hypothesis, and the affected
females slightly outnumbered the affected
males. No definite explanation was found and
these features of the recessive CHH syndrome
remain to be elucidated further.

I am grateful to Professor Reijo Norio, Dr
Ilkka Kaitila, and Professor Jaakko Perheen-
tupa for their comments on the manuscript.
This study was supported by grants from the
University of Helsinki, the Finnish Medical
Foundation, the Paulo Foundation, and the
Paivikki and Sakari Sohlberg Foundation,
Helsinki, Finland.

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