J Pediatr Endocrinol Metab 2016; aop
Case Report Isabel Periquito*, Catarina Carrusca, Joana Morgado, Brígida Robalo, Carla Pereira and Maria de Lurdes Sampaio
Familial Turner syndrome: the importance of information DOI 10.1515/jpem-2015-0277 Received July 15, 2015; accepted December 14, 2015
Abstract: Turner syndrome is a common genetic d isorder with an incidence of 1 in 2500 live births. Spontaneous fertility is rare in such patients and is most likely in women with mosaicism or very distal Xp deletions. The authors report an unusual case of familial Turner syndrome in a woman with mosaicism 45,X/46,Xdel(Xp) karyotype with three documented spontaneous pregnancies, which resulted in two daughters with 46,Xdel(X) (p11.4)mat karyotype and a healthy son. The mother was first diagnosed by the age of 11 and did not receive contraceptive medication, due to information that she would be infertile. Both daughters were referred to an endocrinology unit and are now under growth hormone treatment, and have been growing in the 3rd percentile. This family illustrates the complexity and difficulties in counseling, follow-up and treatment in Turner syndrome, namely referring to a tertiary center, fertility and treatment such as growth hormone and hormonal replacement, due to the heterogeneity of the clinical spectrum. Keywords: familial; information; Turner syndrome.
Introduction Turner syndrome (TS) is a genetic disorder occurring in females, characterized by a single X chromosome
*Corresponding author: Isabel Periquito, Pediatrics Department, Centro Hospitalar de Setúbal, Setúbal, Portugal, E-mail: [email protected] Catarina Carrusca: Pediatrics Department, Hospital de Vila Franca de Xira, Vila Franca de Xira, Portugal Joana Morgado: Pediatrics Department, Hospital do Espírito Santo de Évora, Évora, Spain Brígida Robalo, Carla Pereira and Maria de Lurdes Sampaio: Pediatric Endocrinology Unit, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
or absence of all or part of the second sex chromosome (X or Y) [1, 2]. The estimated prevalence of TS is 1 in 2500 to 1 in 3000 live births, making it one of the most frequent chromosomal abnormalities [1]. Approximately half of the patients have monosomy X (45,X), while the remainder have mosaicism for 45,X with one or more cell lines containing a second sex chromosome, which usually corresponds to a normal or structurally abnormal X [1, 3]. The diagnosis of TS also implies the presence of characteristic physical changes in a phenotypic female patient [4, 5]. The key features are growth retardation, gonadal dysgenesis, frequently coexisting with other congenital malformations, such as lymphedema, webbed neck, cardiovascular, renal, orthopedic, ear, nose and throat abnormalities, among others [5]. Ovarian follicles appear to develop normally in TS women, however, an accelerated process of follicular atresia ensues, hence spontaneous puberty only occurs in 5%–20% of TS girls and only 5%–16% will have menses [3, 6]. Spontaneous pregnancies are therefore rare, occurring in about 2%–8% of all TS women, being most frequent in mosaics with a normal cell line or very distal Xp deletions [3, 6, 7]. The authors describe the case of a woman with TS who has a 45,X/46,Xdel(Xp) karyotype and three documented spontaneous pregnancies, two daughters with TS and a healthy son.
Case presentation Patient 1 The first patient is a 46-year-old Caucasian female, the first child of unrelated parents, born after an unremarkable pregnancy. She had slow growth during infancy, normal cognitive development and a physical exam revealing webbed neck, low posterior hairline and short upper limbs. At 11 years of age, she was diagnosed with TS karyotype 45,X/46,Xdel(Xp), with 64% mosaicism for
Brought to you by | University of California - San Diego Authenticated Download Date | 2/3/16 4:26 PM
2 Periquito et al.: Familial Turner syndrome
77 – 195 75 – 190 73 – 185 71 – 180 69 – 175 67 – 170
95
65 – 165 63 – 160
50
61 – 155 59 – 150
5
57 – 145 55 – 140 Height
45,X. Her puberty progressed normally without estrogen replacement therapy and spontaneous menarche occurred at the age of 13. Growth hormone (GH) treatment was not administered and she reached the final height of 140 cm (under the 3rd percentile, 25–50th percentile in the TS growth chart) and weight of 47 kg (10th percentile). She did not receive contraceptive medication, due to information that she would not be able to get pregnant. However, she had three spontaneous pregnancies (the first one was unplanned), resulting in two daughters with a 46,Xdel(X) (p11.4)mat karyotype and a son with a 46XY normal karyotype.
95 90 75
53 – 135 51 – 130
50 25 10 5
49 – 125 47 – 120 45 – 115 43 – 110 41 – 105 39 – 100
Patients 2 and 3 Both daughters were born from uneventful pregnancies, with prenatal diagnosis of a 46,Xdel(X)(p11.4)mat karyotype and had caesarian sections performed at 38 weeks’ gestation due to fetal dystocia. Post-natal echocardiograms, renal ultrasounds, ophthalmologic and in otorhinolaryngology observations were normal in the two patients. The first daughter was initially referred to our outpatient clinic by the age of 9, due to prior information that GH treatment would only be administered during puberty. Her initial weight was 32.6 kg, height 119.9 cm, body mass index (BMI) 22.7 kg/m2 and the physical exam revealed low posterior hairline, webbed neck, high-arched palate, shield chest, cubitus valgus and short upper limbs. She started GH treatment 5 months later and has been steadily growing. Menarche occurred spontaneously by the age of 12. She is currently 13 years old, weighs 50.6 kg (50th percentile), has a height of 145.5 cm (5th percentile, above percentile 95 in the TS growth chart) and is still under GH treatment (0.035 mg/kg/day) (Figure 1). After realizing that the second daughter was also not being assessed in a pediatric endocrinology unit during her sibling’s evaluation, she was then referred to our outpatient clinic by the age of 4. Her initial weight was 13.4 kg, height 95 cm, BMI 14.8 and the physical exam exhibited broad short neck, low posterior hair line and high arched palate. GH treatment was initiated 10 months later and she has been growing in the 50th percentile of the TS growth chart. She is now 8 years old, has a weight of 21.3 kg (3rd percentile) and a height of 116.5 cm (5th percentile, 75th percentile in the TS chart), under GH treatment (0.035 mg/ kg/day) (Figure 2). Both girls maintain a multidisciplinary follow-up with regular endocrinologist and cardiologist consults.
37 – 95 35 – 90 33 – 85 31 – 80 29 – 75 27 – 70 25 – 65 In cm
Girls without TS Untreated girls with TS
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 Age, years
Figure 1: Growth chart of the first daughter. Growth hormone treatment was initiated when she was 9 years plus 9 months old. Source: Ref. [2].
Discussion TS is a frequent genetic disorder in female patients and the most common cause of hypergonadotropic hypogonadism in women [6]. Around 90% of adolescents with TS will have gonadal failure and require hormone replacement therapy to initiate puberty and maintain sexual development [1, 4]. Current recommendations state that lowdose estradiol can be initiated by 12 years of age, without interfering with the positive effect of GH therapy on final height [4]. Nevertheless, some women achieve spontaneous pregnancies, particularly those with a karyotype of 45,X/46,XX or 45,X/47,XXX and very distal Xp deletions [1, 8]. It is, however, not possible to predict phenotypic manifestations, based solely on karyotype in patients with TS [1]. This implies that the information provided by healthcare professionals has to be clearly transmitted and appropriate to both the child and the parents [9, 10]. It is recommended that counseling for patients who achieve spontaneous menarche should also include the potential for spontaneous unintentional pregnancy, contraception
Brought to you by | University of California - San Diego Authenticated Download Date | 2/3/16 4:26 PM
Periquito et al.: Familial Turner syndrome 3
77 – 195 75 – 190 73 – 185 71 – 180 69 – 175 67 – 170
95
65 – 165 63 – 160
50
61 – 155 59 – 150
5
Height
57 – 145 55 – 140
95 90 75
53 – 135 51 – 130
50 25 10 5
49 – 125 47 – 120 45 – 115 43 – 110 41 – 105 39 – 100 37 – 95 35 – 90 33 – 85 31 – 80 29 – 75 27 – 70 25 – 65 In cm
Girls without TS Untreated girls with TS
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 Age, years
Figure 2: Growth chart of the second daughter. Growth hormone treatment was initiated when she was 5 years plus 7 months old. Source: Ref. [2].
and also the complications associated with pregnancy in women with TS. Pregnancies in women with TS are related to increased morbidity and mortality, due to heart failure, aortic dissection, and sudden death, even in patients without prior known risk factors [8]. Most recent clinical practice guidelines recommend a thorough cardiovascular evaluation, and an MRI of the cardiac anatomy and aortic dimensions before conception [4]. In this case, patient 1 did not receive contraceptive medication due to incorrect information which resulted in an unplanned pregnancy, without adequate initial follow-up in a tertiary center. Many TS patients are diagnosed prenatally due to specific ultrasound findings, such as increased nuchal translucency or cystic hygroma, in such cases the classic phenotypic characteristics are more likely [11, 4]. However, when a prenatal diagnosis is made incidentally, based on other reasons such as advanced maternal age, false positive results may occur. On the other hand, if a mosaic karyotype is discovered the fetus may not have any of the features of TS, hence not being predictive of the severity of TS phenotype [11, 12]. Therefore, a postnatal karyotype reevaluation is recommended in patients with a prenatal diagnosis [4].
Some reports suggest that spontaneous pregnancies in TS patients are associated with an increase in miscarriage, congenital malformations and chromosomal defects such as trisomy 21. However, recent studies particularly in the Swedish population have shown more favorable results than had been previously documented [3, 6, 7]. Specific maternal karyotype should be taken into account in genetic counseling regarding potential risks for offspring, for instance, in TS women with a structurally abnormal X chromosome, there is a risk of transmission to their children, thus having a phenotype similar to the mother, as was the case with these patients [6]. Currently, many pregnancies diagnosed with TS are electively terminated. However, given the wide clinical spectrum of TS, physicians must counsel parents about the different features, quality of life and prognosis of such patients, as well as the possibility that an incidental finding of TS karyotype may be a poor predictor of outcome, thus allowing parents to make an informed decision [4, 11]. Short stature is the most common characteristic in TS women, occurring in 95%–100% of patients, and is characterized by a tendency for intrauterine growth restriction, slow growth during infancy and adult short stature (average 20 cm below the controls) [5, 13]. Although the etiology of short stature is not completely clarified, multiple causes appear to be contributing factors for growth restriction [14]. One of the mechanisms is a pseudoautosomal deletion resulting in haploinsufficiency of the SHOX gene (short stature homeobox-containing gene on the X chromosome), which is expressed exclusively in developing limbs and the first and second pharyngeal arches, thus causing growth failure and other skeletal characteristics seen in TS, such as cubitus valgus, high arched palate, micrognatia, among others [5, 15]. Recent studies have shown that adults with TS have an increase in IGF binding protein-3 proteolytic activity, low IGF-I, but are not usually GH deficient in comparison to age matched controls [11, 16]. Numerous reports have shown that treatment with GH is effective in increasing final adult height and also has beneficial effects in other areas, such as lower diastolic blood pressure, total cholesterol, low-density lipoprotein and insulin resistance [11]. Current recommendations state that GH treatment in TS patients should be considered when growth failure is demonstrated (decreasing height percentile on the normal curve) and its risks and benefits have been discussed with the family. Treatment should be discontinued when there is a small growth potential (bone age ≥ 14 years or growth velocity
Case Report Isabel Periquito*, Catarina Carrusca, Joana Morgado, Brígida Robalo, Carla Pereira and Maria de Lurdes Sampaio
Familial Turner syndrome: the importance of information DOI 10.1515/jpem-2015-0277 Received July 15, 2015; accepted December 14, 2015
Abstract: Turner syndrome is a common genetic d isorder with an incidence of 1 in 2500 live births. Spontaneous fertility is rare in such patients and is most likely in women with mosaicism or very distal Xp deletions. The authors report an unusual case of familial Turner syndrome in a woman with mosaicism 45,X/46,Xdel(Xp) karyotype with three documented spontaneous pregnancies, which resulted in two daughters with 46,Xdel(X) (p11.4)mat karyotype and a healthy son. The mother was first diagnosed by the age of 11 and did not receive contraceptive medication, due to information that she would be infertile. Both daughters were referred to an endocrinology unit and are now under growth hormone treatment, and have been growing in the 3rd percentile. This family illustrates the complexity and difficulties in counseling, follow-up and treatment in Turner syndrome, namely referring to a tertiary center, fertility and treatment such as growth hormone and hormonal replacement, due to the heterogeneity of the clinical spectrum. Keywords: familial; information; Turner syndrome.
Introduction Turner syndrome (TS) is a genetic disorder occurring in females, characterized by a single X chromosome
*Corresponding author: Isabel Periquito, Pediatrics Department, Centro Hospitalar de Setúbal, Setúbal, Portugal, E-mail: [email protected] Catarina Carrusca: Pediatrics Department, Hospital de Vila Franca de Xira, Vila Franca de Xira, Portugal Joana Morgado: Pediatrics Department, Hospital do Espírito Santo de Évora, Évora, Spain Brígida Robalo, Carla Pereira and Maria de Lurdes Sampaio: Pediatric Endocrinology Unit, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
or absence of all or part of the second sex chromosome (X or Y) [1, 2]. The estimated prevalence of TS is 1 in 2500 to 1 in 3000 live births, making it one of the most frequent chromosomal abnormalities [1]. Approximately half of the patients have monosomy X (45,X), while the remainder have mosaicism for 45,X with one or more cell lines containing a second sex chromosome, which usually corresponds to a normal or structurally abnormal X [1, 3]. The diagnosis of TS also implies the presence of characteristic physical changes in a phenotypic female patient [4, 5]. The key features are growth retardation, gonadal dysgenesis, frequently coexisting with other congenital malformations, such as lymphedema, webbed neck, cardiovascular, renal, orthopedic, ear, nose and throat abnormalities, among others [5]. Ovarian follicles appear to develop normally in TS women, however, an accelerated process of follicular atresia ensues, hence spontaneous puberty only occurs in 5%–20% of TS girls and only 5%–16% will have menses [3, 6]. Spontaneous pregnancies are therefore rare, occurring in about 2%–8% of all TS women, being most frequent in mosaics with a normal cell line or very distal Xp deletions [3, 6, 7]. The authors describe the case of a woman with TS who has a 45,X/46,Xdel(Xp) karyotype and three documented spontaneous pregnancies, two daughters with TS and a healthy son.
Case presentation Patient 1 The first patient is a 46-year-old Caucasian female, the first child of unrelated parents, born after an unremarkable pregnancy. She had slow growth during infancy, normal cognitive development and a physical exam revealing webbed neck, low posterior hairline and short upper limbs. At 11 years of age, she was diagnosed with TS karyotype 45,X/46,Xdel(Xp), with 64% mosaicism for
Brought to you by | University of California - San Diego Authenticated Download Date | 2/3/16 4:26 PM
2 Periquito et al.: Familial Turner syndrome
77 – 195 75 – 190 73 – 185 71 – 180 69 – 175 67 – 170
95
65 – 165 63 – 160
50
61 – 155 59 – 150
5
57 – 145 55 – 140 Height
45,X. Her puberty progressed normally without estrogen replacement therapy and spontaneous menarche occurred at the age of 13. Growth hormone (GH) treatment was not administered and she reached the final height of 140 cm (under the 3rd percentile, 25–50th percentile in the TS growth chart) and weight of 47 kg (10th percentile). She did not receive contraceptive medication, due to information that she would not be able to get pregnant. However, she had three spontaneous pregnancies (the first one was unplanned), resulting in two daughters with a 46,Xdel(X) (p11.4)mat karyotype and a son with a 46XY normal karyotype.
95 90 75
53 – 135 51 – 130
50 25 10 5
49 – 125 47 – 120 45 – 115 43 – 110 41 – 105 39 – 100
Patients 2 and 3 Both daughters were born from uneventful pregnancies, with prenatal diagnosis of a 46,Xdel(X)(p11.4)mat karyotype and had caesarian sections performed at 38 weeks’ gestation due to fetal dystocia. Post-natal echocardiograms, renal ultrasounds, ophthalmologic and in otorhinolaryngology observations were normal in the two patients. The first daughter was initially referred to our outpatient clinic by the age of 9, due to prior information that GH treatment would only be administered during puberty. Her initial weight was 32.6 kg, height 119.9 cm, body mass index (BMI) 22.7 kg/m2 and the physical exam revealed low posterior hairline, webbed neck, high-arched palate, shield chest, cubitus valgus and short upper limbs. She started GH treatment 5 months later and has been steadily growing. Menarche occurred spontaneously by the age of 12. She is currently 13 years old, weighs 50.6 kg (50th percentile), has a height of 145.5 cm (5th percentile, above percentile 95 in the TS growth chart) and is still under GH treatment (0.035 mg/kg/day) (Figure 1). After realizing that the second daughter was also not being assessed in a pediatric endocrinology unit during her sibling’s evaluation, she was then referred to our outpatient clinic by the age of 4. Her initial weight was 13.4 kg, height 95 cm, BMI 14.8 and the physical exam exhibited broad short neck, low posterior hair line and high arched palate. GH treatment was initiated 10 months later and she has been growing in the 50th percentile of the TS growth chart. She is now 8 years old, has a weight of 21.3 kg (3rd percentile) and a height of 116.5 cm (5th percentile, 75th percentile in the TS chart), under GH treatment (0.035 mg/ kg/day) (Figure 2). Both girls maintain a multidisciplinary follow-up with regular endocrinologist and cardiologist consults.
37 – 95 35 – 90 33 – 85 31 – 80 29 – 75 27 – 70 25 – 65 In cm
Girls without TS Untreated girls with TS
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 Age, years
Figure 1: Growth chart of the first daughter. Growth hormone treatment was initiated when she was 9 years plus 9 months old. Source: Ref. [2].
Discussion TS is a frequent genetic disorder in female patients and the most common cause of hypergonadotropic hypogonadism in women [6]. Around 90% of adolescents with TS will have gonadal failure and require hormone replacement therapy to initiate puberty and maintain sexual development [1, 4]. Current recommendations state that lowdose estradiol can be initiated by 12 years of age, without interfering with the positive effect of GH therapy on final height [4]. Nevertheless, some women achieve spontaneous pregnancies, particularly those with a karyotype of 45,X/46,XX or 45,X/47,XXX and very distal Xp deletions [1, 8]. It is, however, not possible to predict phenotypic manifestations, based solely on karyotype in patients with TS [1]. This implies that the information provided by healthcare professionals has to be clearly transmitted and appropriate to both the child and the parents [9, 10]. It is recommended that counseling for patients who achieve spontaneous menarche should also include the potential for spontaneous unintentional pregnancy, contraception
Brought to you by | University of California - San Diego Authenticated Download Date | 2/3/16 4:26 PM
Periquito et al.: Familial Turner syndrome 3
77 – 195 75 – 190 73 – 185 71 – 180 69 – 175 67 – 170
95
65 – 165 63 – 160
50
61 – 155 59 – 150
5
Height
57 – 145 55 – 140
95 90 75
53 – 135 51 – 130
50 25 10 5
49 – 125 47 – 120 45 – 115 43 – 110 41 – 105 39 – 100 37 – 95 35 – 90 33 – 85 31 – 80 29 – 75 27 – 70 25 – 65 In cm
Girls without TS Untreated girls with TS
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 Age, years
Figure 2: Growth chart of the second daughter. Growth hormone treatment was initiated when she was 5 years plus 7 months old. Source: Ref. [2].
and also the complications associated with pregnancy in women with TS. Pregnancies in women with TS are related to increased morbidity and mortality, due to heart failure, aortic dissection, and sudden death, even in patients without prior known risk factors [8]. Most recent clinical practice guidelines recommend a thorough cardiovascular evaluation, and an MRI of the cardiac anatomy and aortic dimensions before conception [4]. In this case, patient 1 did not receive contraceptive medication due to incorrect information which resulted in an unplanned pregnancy, without adequate initial follow-up in a tertiary center. Many TS patients are diagnosed prenatally due to specific ultrasound findings, such as increased nuchal translucency or cystic hygroma, in such cases the classic phenotypic characteristics are more likely [11, 4]. However, when a prenatal diagnosis is made incidentally, based on other reasons such as advanced maternal age, false positive results may occur. On the other hand, if a mosaic karyotype is discovered the fetus may not have any of the features of TS, hence not being predictive of the severity of TS phenotype [11, 12]. Therefore, a postnatal karyotype reevaluation is recommended in patients with a prenatal diagnosis [4].
Some reports suggest that spontaneous pregnancies in TS patients are associated with an increase in miscarriage, congenital malformations and chromosomal defects such as trisomy 21. However, recent studies particularly in the Swedish population have shown more favorable results than had been previously documented [3, 6, 7]. Specific maternal karyotype should be taken into account in genetic counseling regarding potential risks for offspring, for instance, in TS women with a structurally abnormal X chromosome, there is a risk of transmission to their children, thus having a phenotype similar to the mother, as was the case with these patients [6]. Currently, many pregnancies diagnosed with TS are electively terminated. However, given the wide clinical spectrum of TS, physicians must counsel parents about the different features, quality of life and prognosis of such patients, as well as the possibility that an incidental finding of TS karyotype may be a poor predictor of outcome, thus allowing parents to make an informed decision [4, 11]. Short stature is the most common characteristic in TS women, occurring in 95%–100% of patients, and is characterized by a tendency for intrauterine growth restriction, slow growth during infancy and adult short stature (average 20 cm below the controls) [5, 13]. Although the etiology of short stature is not completely clarified, multiple causes appear to be contributing factors for growth restriction [14]. One of the mechanisms is a pseudoautosomal deletion resulting in haploinsufficiency of the SHOX gene (short stature homeobox-containing gene on the X chromosome), which is expressed exclusively in developing limbs and the first and second pharyngeal arches, thus causing growth failure and other skeletal characteristics seen in TS, such as cubitus valgus, high arched palate, micrognatia, among others [5, 15]. Recent studies have shown that adults with TS have an increase in IGF binding protein-3 proteolytic activity, low IGF-I, but are not usually GH deficient in comparison to age matched controls [11, 16]. Numerous reports have shown that treatment with GH is effective in increasing final adult height and also has beneficial effects in other areas, such as lower diastolic blood pressure, total cholesterol, low-density lipoprotein and insulin resistance [11]. Current recommendations state that GH treatment in TS patients should be considered when growth failure is demonstrated (decreasing height percentile on the normal curve) and its risks and benefits have been discussed with the family. Treatment should be discontinued when there is a small growth potential (bone age ≥ 14 years or growth velocity
