1Division of Pediatric Endocrinology, 2Laboratory of Medical Genetics, Department of Pediatrics, University of Patras, Patras, Greece
45,X/46,XY mosaicism is associated with a broad spectrum of phenotypes ranging from apparently normal male development to individuals with incomplete sexual differentiation and clinical signs of Turner syndrome in both males and females. The most common presentation among individuals with a 45,X/46,XY karyotype is sexual ambiguity, accounting for approximately 60% of cases, while the least common category of 45,X/46,XY patients consists of those with bilaterally descended testes, found in 11-12%. We report on two patients with an apparently normal male phenotype and 45,X/46,XY mosaicism who were diagnosed postnatally because of short stature. Both of these boys presented at the age of 15 years with short stature, minor Turner-like stigmata, normal male external genitalia and spontaneous pubertal development. One of them had coarctaction of the aorta with bicuspid aortic valve, an uncommon clinical feature in boys with mosaicism. The same patient underwent a trial of GH replacement therapy with poor response and his sperm analysis revealed azoospermia. Like our patients, most mosaic 45,X/46,XY children with bilateral scrotal testes go unrecognised at birth and throughout childhood unless they have somatic features of Turner syndrome or significant growth retardation. We recommend that boys with otherwise unexplained short stature, being short for their families, should be karyotyped routinely as is recommended in short-stature girls. In addition, boys with 45,X/46,XY mosaicism require a thorough clinical evaluation similar to that performed in girls with Turner syndrome and must be routinely followed up for their potential to respond favorably to GH treatment and for late onset abnormalities, such as infertility and gonadal tumors.
45,X/46,XY mosaicism, Male, Short stature
CASE REPORT 1
The
first patient presented at the age of 15 years and 2 months with short stature.
The patient's height was 150.5cm (-2.6 SD), sitting height was 82cm (-1.77SD),
his weight was 55.1Kg and his BMI was 24.3 (+1.65 SD). Mid-parental height
(MPH) was 187cm (+1.42SD), thus the patient was 36.5cm shorter than his target
height. Pregnancy and neonatal history was unremarkable and his birth weight
was 2900gr. From his past medical history a severe cardiac malformation with
coarctaction of the aorta and bicuspid aortic valve was discovered and operated
on at 12 years of age. Non-verbal learning disabilities, mainly in mathematics,
were reported and a tendency for low self-esteem. He was supported with an
individualized education plan tailored to his school requirements.
On
physical examination he had scoliosis, hallus
valgus, mild nail dysplasia, high arched palate and Turner-like appearance
(broad chest with widely spaced nipples). The boy had normal male phenotype and
normal male external genitalia, marked pubic hair (Tanner stage V) and enlarged
testes with testicular volume 15ml
bilaterally, with soft consistency. Renal and testicular ultrasound were
normal. Hearing testing was normal.
Laboratory
analysis demonstrated basal levels of FSH 10,7mIU/ml, LH 10,2mIU/ml,
Testosterone 471.5ng/dl, Estradiol 15pg/ml,Cortisol 16.3μg/dl,
Prolactin 14.2ng/ml, DHEAS 178.6μg/dl, Δ4-androstenedione
2.30ng/ml, 17-hydroxy progesterone 1.90ng/ml, all within the normal range.
Levels of carcinoembryonic antigen (CEA) 0.85ng/ml, a-fetoprotein 3.36ng/ml and
β-hCG 0.01IU/ml were also normal. Bone age was
estimated at 14 years 6 months. Laboratory evaluation showed normal levels of
insulin-like growth factor 1 (IGF-I 224mg/dl). A GnRH test revealed a normal
pubertal pattern (FSH level of 4.2, 9.6,
17.3, and 20.1 mIU/ml and LH level of <0.1, 6.1, 41.8,
and 42.8 mIU/ml at 0, 15, 30, 45 minutes, respectively).Sperm
analysis showed azoospermia. Cytogenetic analysis of peripheral blood revealed
a karyotype with mos 45,X [5]/46,XY [65].
Because
of the diagnosis of 45,X/46,XY mosaicism, treatment with growth hormone (GH)
was initiated at the age of 15 years and 9 months at a dose of 0.025 mg/kg per
day. During the first 4 months of GH replacement the patient's body height
increased only 1.8cm, bone age was advanced at 16 years and, based on the poor
response, a decision to discontinue GH replacement therapy was made.
CASE REPORT 2
The
second patient, a 15 year and one month old male, was short in stature and
severely obese. The patient's height was 141.5cm (-3.55 SD), sitting height was
78.2cm (-2.52 SD), his weight was 80.2Kg and his BMI was 40.1 (+3.64 SD).
Mid-parental height (MPH) was 179cm (+0.9 SD), thus the patient was 37.5cm
shorter than his target height. Past medical history, including pregnancy and
neonatal history, was unremarkable and his birth weight was 3300gr. Our second
patient also had non-verbal learning disabilities and was supported with an
individualized education plan tailored to his school requirements. On physical
examination he had mild dysmorphic features, with mild
nail dysplasia, low posterior hairline, inverted nipples,
borderline short fourth metacarpal and cubitus
valgus.
The boy had normal male external genitalia, no pubic hair (Tanner stage I) and
testicular volume was 10 ml (right) and 6 ml (left).
Echocardiography and renal sonography revealed no abnormalities. Laboratory
analysis revealed basal levels of FSH 3.8mIU/ml, LH 2.8mIU/ml, Testosterone
45.46ng/dl, Cortisol 5.6μg/dl,
Prolactin 5.9ng/ml, DHEAS 206μg/dl,
all within the normal range. Levels of carcinoembryonic antigen (CEA)
1.05ng/ml, a-fetoprotein 2.17ng/ml and β-hCG
<0.01IU/ml were also normal.
Bone
age was delayed at 13 years 6 months and laboratory evaluation showed low
levels of insulin-like growth factor 1 (IGF- I 59mg/dl). GH provocative testing
gave laboratory evidence of GH deficiency (0.64ng/ml and 1.0ng/ml maximum GH
rise after combined betaxolole/clonidine stimulation and L-Dopa stimulation,
normal >10ng/ml). Cytogenetic analysis of peripheral blood revealed a
karyotype with mos 45,X [7]/46,XY [43].
Because
of the diagnosis of 45,X/46,XY mosaicism, treatment with growth hormone (GH)
was initiated at the age of 15 years and 8 months at a dose of 0.018 mg/kg per
day.
DISCUSSION
45,X/46,XY
children present as Turner-like syndrome having bilateral streak gonads with
mullerian structures and TS stigmata, as mixed gonadal dysgenesis with a
unilateral testis, a contralateral streak gonad and mullerian structures, as
males having bilateral testes (any combination of dysgenetic or normal testes)
but with mullerian structures and signs of decreased virilization, or
as normal males having bilaterally descended testes and normal male genitalia.1-4
45,X/46,XY
mosaicism is considered a postzygotic
mitotic error. Loss of the Y chromosome by 'non-disjunction' after normal
disomic fertilization leads to the 45,X cell line. If the error (Y loss) occurs
in early postzygotic cell division, more cells and hence tissues will be affected.
Generally, it is a random event that can take place at any time of the embryo
development and can affect one or several tissues. The number and distribution
of the 45,X cells differs amongst patients, thus producing a spectrum of
phenotypic features.
The
most common presentation for individuals with a 45,X/46,XY karyotype is sexual
ambiguity, accounting for ~60%,
and the least common category of 45,X/46,XY patients consists of those with
bilaterally descended testes, found in 11-12%.3 The
true incidence of a 45,X/46,XY karyotype in males with bilaterally descended
testes is unknown.
Like
our patients, most mosaic 45,X/46,XY children with bilateral
scrotal testes go unrecognised at birth and throughout childhood because they
usually display minor dysmorphic features of Turner syndrome. The most striking
feature of these patients is the unexplained significantly short stature, which
raises the suspicion of the diagnosis. According to the literature, all of
these boys who have reached adult height have had short stature relative to
mid-parental height (MPH) and only few of them had physical stigmata of Turner
syndrome.1,3-7 Both of our patients had minor dysmorphic features of
TS, mainly unremarkable unless associated with the extremely short stature.
Our
first patient had coarctaction of the aorta with bicuspid aortic valve, a very
characteristic cardiac anomaly in girls with Turner syndrome. However, in boys
with 45,X/46,XY karyotype, this is a unique finding, as the review of the
literature identifies only one mosaic 45,X/46,XY male patient with aortic
coarctation, reported by Telvi et al.3 Additionally, both of our
patients had learning difficulties, another rare finding in boys with
45,X/46,XY karyotype. Generally, the phenotype of our patient confirms the
finding that both physical stigmata of TS and congenital anomalies known to be
associated with TS (including congenital cardiac and renal anomalies, recurrent
otitis media, hearing defects and visual defects) are more predominant in X/XY
female children compared to X/XY male children.4 On the other hand,
the extremely rare cardiac anomaly and uncommon learning difficulties found in
our patients argues for the phenotypic variability of 45,X/46,XY mosaicism,
partly explained by the relative distribution of 45X and 46XY cell lines in
different organ-systems. This justifies a thorough clinical evaluation of males
with a 45,X/46,XY karyotype similar to that performed in Turner syndrome,
including evaluation of cardiac, renal and autoimmune conditions, recurrent
otitis media, hearing deficit, ophthalmological deficit, learning disability
and behavioral evaluation.
A
wide spectrum of abnormal gonadal development including gonadal dysgenesis,
infertility, low testosterone level and azoospermia may occur in patients
presenting with 45,X/46,XY mosaicism as well as an apparently normal male
phenotype, which can probably be explained by the predominance of the 45,X or
46,XY cell lines in the gonads.1,3 Our patients had normal
development of male internal and external genitalia, which indicates sufficient
secretion of fetal testosterone. They both went spontaneously into a fairly
normal puberty, which happens in most mosaic 45,X/46,XY boys. Leydig cell
function is at least partially preserved in 45,X/46,XY males and often allows
spontaneous pubertal development. But later on in adulthood, these patients
usually develop infertility because of azoospermia or oligospermia, and
elevated gonadotropins.4,7,8 Our first patient had azoospermia with
elevated gonadotropins, which are clearly signs of primary gonadal failure.
According
to the literature, men with the 45,X/46,XY karyotype are at increased risk for
germ-cell neoplasia of the gonads, especially gonadoblastoma and carcinoma in
situ. Tumor risk is significantly higher in patients with marked genital
ambiguity as compared to patients with mild undervirilisation or with a female
phenotype.1,9,10 There is not an exact prediction of tumor risk in
normal males with 45,X/46,XY constitution, but based on the study of Cools et
al, the risk is low because the clinical picture of a normal external
masculinisation score and bilaterally descended testes suggests a (close to)
normal testicular differentiation and maturation process.9 Although
our patients belong to the lower tumor risk category, close follow-up for
development of gonadal tumors is mandatory, including physical examination and
laboratory investigation with ultrasonography and serum tumor markers. The
possibility of testicular biopsy after puberty should be strongly considered in
45,X/46,XY males with cryptorchism and/or hypospadias.9,10
The
growth pattern of 45,X/46,XY female and male children recently described by
Tosson et al. revealed growth deceleration at the time of puberty and adult
height compromised relative to mid-parental height.7 Early GH
treatment should be considered to be part of the management of short stature in
45,X/46,XY male children because, like girls with Turner syndrome, a good
linear growth response to GH therapy was observed in these boys who started GH
therapy early in life.5-7 Similar to other reports, laboratory
evaluation in our first patient showed normal levels of IGF-I, making GH
deficiency unlikely.6,7 In accordance with the current guidelines of
GH treatment in 45,X/46,XY male children, we offered him a trial of GH therapy,
but unfortunately he had a poor response. GH treatment may have started too
late to exert a significant influence on the final height of our patient. On
the other hand, laboratory evaluation in our second patient revealed GH
deficiency (low levels of IGF-I, abnormal GH provocative tests)
and, taking into account the diagnosis of 45,X/46,XY mosaicism, GH replacement
therapy was initiated.
In conclusion, 45,X/46,XY mosaicism is
underdiagnosed or late-diagnosed in phenotypic males with short stature. We
recommend that boys with otherwise unexplained short stature, being short for
their families, should be karyotyped routinely, as is recommended in
short-stature girls. In addition, boys with 45,X/46,XY mosaicism require a thorough
clinical evaluation similar to that performed in girls with Turner syndrome and
must be routinely followed up for their potential to respond favorably to GH
treatment and for late onset abnormalities, such as infertility and gonadal
tumors.
REFERENCES
1. Knudtzon J, Aarskog D, 1987 45,X/46,XY mosaicism: a clinical review and report of ten cases. Eur J Pediatr 146: 266-271.
2. Rosenburg C, Frota-Pessoa O, Vianna-Morgante AM, Chu TH, 1987 Phenotypic spectrum of 45,X/46,XY individuals. Am J Med Genet 27: 553-559.
3. Telvi L, Lebbar A, Del Pino O, Barbet JP, Chaussain JL, 1999 45,X/46,XY mosaicism: report of 27 cases. Pediatrics 104: 304-308.
4. Tosson H, Rose SR, Gartner LA, 2011 Description of children with 45,X/46,XY karyotype. Eur J Pediatr 171: 521-529.
5. Lee C-F, Su P-H, Chen S-J, Yang K-C, Lin L-L, 2006 Short stature in patients with 45,X/46,XY mosaicism: report of three cases. Acta Paediatr Tw 47: 312-316.
6. Richter-Unruh A, Knauer-Fischer S, Kaspers S, Albrecht B, Gillessen-Kaesbach G, Hauffa BP, 2004 Short stature in children with an apparently normal male phenotype can be caused by 45,X/46,XY mosaicism and is susceptible to growth hormone treatment. Eur J Pediatr 163: 251-256.
7. Tosson H, Rose SR, Gartner L, 2010 Children with 45,X/46,XY karyotype from birth to adult height. Horm Res Paediatr 74: 190-200.
8. Layman LC, Tho SPT, Clark AD, Kulharya A, McDonough PG, 2009 Phenotypic spectrum of 45,X/46,XY males with ring Y chromosome and bilaterally descended testes. Fertil Steril 91: 791-797.
9. Cools M, Pleskacova J, Stoop H, et al, 2011 Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46,XY mosaicism. J Clin Endocrinol Metab 96: E1171-E1180.
10. Müller J, Ritzén EM, Ivarsson S-A, Rajpert-De Meyts E, Norjavaara E, Skakkebæk NE, 1999 Management of males with 45,X/46,XY gonadal dysgenesis. Horm Res 52: 11-14.
Address for correspondence:
Dr Alexandra Efthymiadou, Division of Pediatric Endocrinology, Department of Pediatrics, University Hospital of Patras, 26504 Rion Patras, Greece,
Tel.: +302610999546, Fax: +302610994711, e-mail: eythymiadou@upatras.gr
Received 19-01-12, Revised 12-03-12, Accepted 10-04-12