The chromosome 9p syndrome with microgenitalia
Takeshi MATSUISHI, Anne MILLAR
Name and Address for Correspondence:
Name: Dr.Takeshi Matsuishi
Yokohama National University
Faculty of Education and Human Sciences
Department of Special Education
Address: 79-2,Tokiwadai, Hodogayaku, Yokohama
City, 240-8501 , Japan
ABSTRACT
We report an 18 year old male with monosomy
9p syndrome. Clinical features included microgenitalia,
mental retardation with microcephaly and
dysmorphic features consistent with those
of the known 9p syndrome. Endocrinological
investigations indicated gonadal failure
with raised FSH and LH concentrations and
a low testosterone level. On examination
the SRY gene was found to be normal hence
we support previous reports which suggest
that there is a gene on 9p involved in early
testes development. Furthermore agenesis
of the corpus callosum is reported for the
first time in 9p syndrome,
INTRODUCTION
Monosomy 9p syndrome is a well delineated chromosomal syndrome
with cardinal features including psychomotor
retardation, trigonocephaly, flat nasal bridge,
long philtrum, and a short, broad and webbed
neck. Due to a high prevalence of impaired
sexual development in genetic males with
9p syndrome a gene for testis formation has
been suggested to be on the distal part of
9p:9p24 (Hoo et al.1989). In this paper we
present an adult male with 9p syndrome including
microgenetalia. Findings from cytogenetic,
molecular and endocrinological studies are
presented and we review the literature on
the involvement of 9p in testis development.
CASE REPORT
An 18- year -old male is the third child
of healthy and unrelated parents. The mother
and father were 28 and 31 years old respectively
at birth. The proband has twin elder sisters
both of whom are healthy. The third pregnancy
was terminated by elective abortion.The proband
was born at 42 weeks after an uneventful
pregnancy. Birth weight was 4000g , length
was 53cm and head circumferance was 37cm.
Early developmental milestones were slightly
delayed : Head control was achieved at 6
months, sitting at 8 months, and first step
taken at 1 year and 3 months. Medical history
reports undescended testes which resolved
spontaneously . The proband attended a remedial
class in both elementary and junior high
school. For high school he transferred to
a special school.
On evaluation at 18 years old he scored 30
on the Tanaka Binet Intelligence test, this
is the Japanese version of the Binet test.
On examintion at age 18 he presented with
a head circumferance of 56cm. Morphological
anomalies included webbed neck, flat occiput,
broad nasal bridge, anteverted nostrils,
narrow palpeberal fissures, hyperteleorism
and epicanthic folds. His mouth was small
with a protruding lower lip, thin upper lip
and a high arched palate. His ears were low
set ears with abnormal lobules. Other dysmorphic
features included long philtrum, micrognatia
and retrognatia (Fig 1,2)*. He had a thoracic
kyphosis and a long middle phalanx. Microgenitalia
was characterized by a small penis (4cm stretched),
small testis and sparse pubic hair.
Neurological findings included hypotonia,
intention tremor, dysarthria, and exaggerated
deep tendon reflexes particularly on the
left side. CT scan revealed agenesis of the
corpus callosum .
* Fig 1 & 2 are available on request of
a reprint.
ENDOCRINE INVESTIGATIONS
Endocrine investigations were consistent
with gonadal failure with a raised FSH of
40 mIU/ml (normal range 2.9-8.2mIU/ml) and
an LH of 14mIU/ml ( normal range 1.8-5.2
mIU/ml). After LHRH stimulation a normal
response in the LH value was observed, the
LH value rose to 79mIU/ml. base value. Similarly
following FSHRH stimulation a normal response
in the FSH value, the FSH value rose to 84mIU/ml.
The concentration of testosterone was 307ng/dl
( normal range 250- 1100 ng/dl).
CYTOGENETIC AND MOLECULAR ANALYSIS
Chromosome analysis, performed on 20 cultured lymphocytes with high resolution
banding, showed an abnormal chromosome 9 with a terminal deletion of the
short arm,46,XY,del(9)(p22.3).FISH method cofirmed the absence of a translocation
with the following result obtained; 46, XY,del (9)(p22.3).ish del (9)(wcp9+).
The parental chromosomes were normal. The SRY gene was amplified by the
polymerase chain reaction, cloned and sequenced and no mutation found (Sinclair
et al.1990, Koopman et al. 1991, Reijo et al. 1995).
DISCUSSION
The case presented with micropenis and underdeveloped testis in addition
to dysmorhic features consistent with 9p syndrome. Endocrinological analysis
indicated gonadal failure as opposed to a hypothalamic hypophyseal disorder.
Thus it can be inferred that the hypoplastic testis was incapable of producing
sufficient androgen resulting in microgenitalia.
This case is similar to three previously
reported genetic male patients with 9p and
impaired male sexual development. Monaghan
et al (1981) described a 20 month old boy
with small penis, partly descended testis,
and underdeveloped scrotum. Results of endocrinological
analysis were also consistent with a primary
gonadal disorder. Kadotani et al (1984) reported
an 8 year old boy with cryptorchism, small
penis, hypoplastic scrotum and hypospadias.
Finally, Szymansky et al. (1984) reported
a 10 month old boy with a small penis. Hoo
et al.(1989) suggest that a recessive gene
on the 9p24 locus is important in the early
development of testis, all of the above 4
cases presented with monosomy of 9p24 .
Considerable variability has been reported regarding impairment of male
sex development in cases of 9p. Abnormal genitalia ranging from complete
sexual reversal (Bennett et al. 1993) to ambiguous genitalia (Ogata et
al. 1997), or to microgenitalia (Monaghan et al. 1981) have been reported
in approximately 70% of 46 XY 9p deletion patients. This variability may
be related to the time of influence of the defective gene relative to the
critical period in testis development. It has been suggested that defective
androgen production during the critical period usually results in female
external genitalia or ambiguous genitalia while defective androgen production
post critical period usually leads to male external genitalia with microgenitalia
(Ogata et al.1997).
While an increasing number of reports of 9p syndrome and impaired male
sexual development provide more support for a role for 9p in early testis
development the mechanisms to explain the sexual impairment remain unclear.
From the genetic point of view haploinsufficieny has been suggested as
one possible mode of action (Veitia et al. 1997). Haploinsufficiency syndromes
tend to show a wide variety of phenotypes between individuals. Furthermore
it is thought that developmental pathways are particularly susceptible
to haploinsufficiency (Fisher & Scambler 1994). However it is unlikely
that haploinsufficiency alone can explain the wide range of expressivity
seen in relation to sexual development in 9p cases and it may be that both
genetic and nongenetic factors are responsible for this phenomenon. Two
other possible mechanisms cited are prezygotic mutation of the testis forming
gene on the normal 9p and postzygotic somatic mutation of the normal 9p
gene in developing testicular cells (Ogata et al 1997).
Finally the authors wish to highlight the
previously unreported finding of agenesis
of the corpus callosum. The only other relationship
that could be found between abnormality of
the corpus callosum and 9p was that of atrophy
of the corpus callosum in a case of 9p trisomy
(Stern 1996).
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(Journal of Faculty of Education and Human
Sciences,Yokohama National University,Sec.
I, No 1, 157-162, November,1998)