- Email: [email protected]
Pfeiffer syndrome: the importance of prenatal diagnosis
Letters to the Editor—Brief Communications / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 338–346
stage 2 and sparse axillary and pubic hair. The external genitalia were pre pubertal in appearance. Other anthropometric measurements were normal. Hematological investigations revealed a normal blood count, serum prolactin levels of 10 ng/ml (normal range 3–25 ng/ml), high FSH (180 mIU/ml) and LH (94 mIU/ml). Ultrasonography of abdomen & pelvis demonstrated a hypoplastic uterus of size 32 mm 12 mm 8 mm with empty ovarian fossae. Bilateral kidneys and ureters were reported normal. Twenty metaphases obtained from peripheral blood leucocytes analysed by GTG Banding technique demonstrated a balanced reciprocal translocation between long arm of X chromosome and short arm of chromosome 1 with a pattern of 46,X,t(X;1)(q22;p32) (Fig. 1). The girl was started on combined oral pills after she failed to have withdrawal bleeding on progesterone challenge test. She menstruated after 3 months of therapy. X-autosome translocations occur in 1/10,000 to 3/10,000 live births [1]. The carriers of unbalanced translocations usually present with multiple congenital anomalies and mental retardation (MCA–MR) syndromes. Primary amenorrhoea is the presenting feature in 0.5–1.6% cases of X-autosome translocations [2]. Translocations resulting in deletion or breakage of a gene responsible for gonadal development could account for the gonadal dysfunction. Alternately, hemizygous status of a recessive gene consequent upon inactivation of the normal X chromosome could also result in inhibition of development of gonads. The latter theory is supported by the observation that the normal X chromosome is usually found to be late replicating in individuals with balanced X; autosome translocations [2]. Third, a position effect mutation may also contribute to the phenotypic features in a few. The X-autosome translocations are usually of maternal origin or arise denovo [3]. All the denovo balanced X-autosome translocations reported so far are of paternal origin and are more likely to be associated with abnormal outcome, suggesting that denovo status versus breakpoint location is the most important risk factor in defining the phenotype [4]. Therman et al. noted that 45 of the 118 translocation carriers in whom the breakpoint was in the critical region (Xq13–q22, Xq22–q26) had gonadal dysgenesis [5]. This critical region is the fifth brightest segment in the human genome and consist mainly of Q-bright material. It contains two ‘supergenes’ which are responsible for normal ovarian development. The effect exerted by this region is independent of the breakpoint within the region and of the chromosome bands to which the broken ends are attached [5]. This may account for the amenorrhoea and gonadal dysgenesis observed in cases where the translocation involved Xq13 to Xq28. Altered gene dosage caused by the X;1 translocation along with X chromosome inactivation in our patient could have contributed to her phenotypic abnormality. It is suggested that the novel abnormal karyotype probably did not interrupt any genes or highly conserved genes even though a position effect mutation was not tested in our patient. References [1] Binkert F, Spreiz A, Ho¨ckner M, et al. Parental origin and mechanism of formation of a 46,X,der(X)(pter ! q21.1:: p11.4 ! pter)/45,X karyotype in a woman with mild Turner syndrome. Fertil Steril 2010;94(1). 350.e12-5. [2] Therman E, Patau K. Abnormal X chromosomes in man: origin, behavior and effects. Humangenetik 1974;25(1):1–16. [3] Kalz-Fuller B, Sleegers E, Schwanitz G, Schubert R. Characterization: phenotypic manifestations and X-inactivation pattern in 14 patients with X-autosomal translocations. Clin Genet 1999;55(5):362–6. [4] Waters JJ, Campbell PL, Crocker AJM, Campbell CM. Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories. Hum Genet 2001;108(4):318–27. [5] Therman E, Laxova R, Susman B. The critical region on the human Xq. Hum Genet 1990;85(5):455–61.
339
Nirmala Duhan* Roopa Malik Manisha Upadhyaya Department of Obstetrics and Gynecology, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India *Corresponding author. Tel.:+91 9896016348; fax: +0091 1262 211301 E-mail addresses: [email protected], [email protected] (N. Duhan). Received 30 July 2014 Accepted 7 August 2014 http://dx.doi.org/10.1016/j.ejogrb.2014.08.018
Pfeiffer syndrome: the importance of prenatal diagnosis Dear Editors, We found that Pfeiffer Syndrome (PS) was first described in 1964 and has an incidence of 1/100.000 neonates. Conventionally, PS is classified into three types. All types demonstrate craniofacial anomalies (craniosynostosis, midface retrusion, hypertelorism, proptosis) and limb deformities (brachydactyly, syndactyly, broad thumbs/great toes). Type 1 is the mildest phenotype with normal intelligence and generally good outcome. Type 2 has a poor prognosis and is characterized by a cloverleaf skull. Type 3 is an intermediate form with a very short skull base, severe proptosis, but without the cloverleaf skull. PS is an autosomal dominant condition, genetically heterogeneous with mutations in the FGFR1 or FGFR2 gene [1–5]. In our clinic we saw a 31-year-old primi-gravida, known with PS caused by a FGFR1 mutation. She was referred to our level 3 unit at 25 6/7 weeks of gestation. She was known to have the classical limb deformities: broad abducted thumbs and great toes (Fig. 1D). Her medical history was otherwise uneventful. Prenatal diagnosis comprising first trimester screening revealed no increased risk for trisomy 13, 18 and 21. She did not opt for amniocentesis. At 20 weeks of gestation advanced ultrasound examination was performed and showed no structural anomalies, normal growth and amount of amniotic fluid. She was referred because of threatened preterm labor. Ultrasound examination at admittance showed polyhydramnios and broad, deviated big toes of the fetus (Fig. 1A). Shortly afterwards she delivered of a daughter [weight 1.030 kg (+1SD), head circumference 25 cm (+1SD)]. Apgar scores were 8 and 9 after, respectively, 1 and 5 min. Umbilical cord blood gas analysis was normal. Physical examination showed a clinically normal skull shape. Both thumbs and big toes were broad and deviated in varus position (Fig. 1B). There was no syndactyly. Postnatal DNA-analysis confirmed the P252R (FGFR1 ex5) mutation. Previously the family of the index patient was investigated at the department of Clinical Genetics. DNA-analysis showed the FGFR1 mutation in the index patient, a sister and her mother. The index patient was born at term. During this pregnancy her mother had 25 weeks of bed rest because of premature contractions. Her sister was born at 32 weeks of gestation. It is not known at what
Letters to the Editor—Brief Communications / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 338–346
340
literature review and the preparation of the article. AJMH was as clinical geneticist responsible for writing down the genetic disorder of the individuals who are described. LSS was as pediatrician-neonatologist responsible for the correct description of the examination of the newborn. RH was the referring gynecologist and delivered a critical look at writing down the correct patient data. All authors were responsible for manuscript editing and had a final approval of the version to be submitted. Ethical approval Written consent of the patients described were obtained. Acknowledgement There are no other persons than the authors who had a contribution to this case report. References Fig. 1. (A) Prenatal right foot child. (B) Left and (C) right foot child. (D) Left foot mother. (E) Left and right foot grandmother.
term the mother of the index patient is born. Clinically her mother has limb deformities (Fig. 1E). She delivered thrice and all her children have the known hand and foot abnormalities. Two children are identified with the P252R mutation. Her third child is not tested. To our knowledge this is the first reported case of a relationship between PS type 1 and polyhydramnios and consequent premature birth. In only one article a case of PS type 2 and polyhydramnios is described [3]. In our case, in retrospect at least two people with PS type 1 were born prematurely. During pregnancies in the first and second generation ultrasound examination was not performed. In the third generation, ultrasound examination was performed at 20 weeks of gestation and no fetal anomalies or polyhydramnios were seen. Five weeks later polyhydramnios was found. The importance of prenatal diagnosis is already known because of the poor prognosis of PS type 2 and 3 [5]. This case emphasizes the need for a complete fetal sonographic survey and a frequent check of the amniotic fluid index when there is an increased risk for PS type 1. In our case the rapidly developing polyhydramnios eventually resulted in early preterm birth. In conclusion, we report a family affected by PS due to a pathogenic FGFR1 mutation and premature delivery most likely due to polyhydramnios. Our report emphasizes the need for prenatal diagnosis and close monitoring of pregnancy in case of PS with special attention to developing polyhydramnios.
[1] Cohen Jr MM. Pfeiffer syndrome update: clinical subtypes and guidelines for differential diagnosis. Am J Med Genet 1993;45:300–7. [2] Jones KL. Pfeiffer syndrome. In: Smith’s recognizable patterns of human malformation. Philadelphia: WB Saunders Company; 1997. p. 416–7. [3] Plomp AS, Hamel BCJ, Cobben JM, et al. Pfeiffer syndrome type 2: further delineation and review of the literature. Am J Med Genet 1998;75:245–51. [4] Robin NH, Scott JA, Arnold JE, et al. Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification. Am J Med Genet 1998;75:240–4. [5] Gorincour G, Rypens F, Grignon A, et al. Prenatal diagnosis of cloverleaf skull: watch the hands! Fetal Diagn Ther 2005;20:296–300.
Gatske M. Nieuwenhuyzen-De Boer* Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, The Netherlands A. Jeannette M. Hoogeboom Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, The Netherlands Liesbeth S. Smita,b Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands b Department of Neurology, Division of Pediatric Neurology, Erasmus MC, University Medical Center Rotterdam, The Netherlands a
Roger Heydanus Department of Obstetrics and Gynecology, Amphia Hospital, Breda, The Netherlands Alex J. Eggink Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
Funding There is no funding. Conflict of interest The authors report no conflict of interest.
*Corresponding author at: Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 7040704 E-mail address: [email protected] (G.M. Nieuwenhuyzen-De Boer). Received 28 July 2014
Contribution to authorship All authors had a substantial contribution to conception of this article. GMN and AJE were responsible for data collection,
http://dx.doi.org/10.1016/j.ejogrb.2014.08.006
stage 2 and sparse axillary and pubic hair. The external genitalia were pre pubertal in appearance. Other anthropometric measurements were normal. Hematological investigations revealed a normal blood count, serum prolactin levels of 10 ng/ml (normal range 3–25 ng/ml), high FSH (180 mIU/ml) and LH (94 mIU/ml). Ultrasonography of abdomen & pelvis demonstrated a hypoplastic uterus of size 32 mm 12 mm 8 mm with empty ovarian fossae. Bilateral kidneys and ureters were reported normal. Twenty metaphases obtained from peripheral blood leucocytes analysed by GTG Banding technique demonstrated a balanced reciprocal translocation between long arm of X chromosome and short arm of chromosome 1 with a pattern of 46,X,t(X;1)(q22;p32) (Fig. 1). The girl was started on combined oral pills after she failed to have withdrawal bleeding on progesterone challenge test. She menstruated after 3 months of therapy. X-autosome translocations occur in 1/10,000 to 3/10,000 live births [1]. The carriers of unbalanced translocations usually present with multiple congenital anomalies and mental retardation (MCA–MR) syndromes. Primary amenorrhoea is the presenting feature in 0.5–1.6% cases of X-autosome translocations [2]. Translocations resulting in deletion or breakage of a gene responsible for gonadal development could account for the gonadal dysfunction. Alternately, hemizygous status of a recessive gene consequent upon inactivation of the normal X chromosome could also result in inhibition of development of gonads. The latter theory is supported by the observation that the normal X chromosome is usually found to be late replicating in individuals with balanced X; autosome translocations [2]. Third, a position effect mutation may also contribute to the phenotypic features in a few. The X-autosome translocations are usually of maternal origin or arise denovo [3]. All the denovo balanced X-autosome translocations reported so far are of paternal origin and are more likely to be associated with abnormal outcome, suggesting that denovo status versus breakpoint location is the most important risk factor in defining the phenotype [4]. Therman et al. noted that 45 of the 118 translocation carriers in whom the breakpoint was in the critical region (Xq13–q22, Xq22–q26) had gonadal dysgenesis [5]. This critical region is the fifth brightest segment in the human genome and consist mainly of Q-bright material. It contains two ‘supergenes’ which are responsible for normal ovarian development. The effect exerted by this region is independent of the breakpoint within the region and of the chromosome bands to which the broken ends are attached [5]. This may account for the amenorrhoea and gonadal dysgenesis observed in cases where the translocation involved Xq13 to Xq28. Altered gene dosage caused by the X;1 translocation along with X chromosome inactivation in our patient could have contributed to her phenotypic abnormality. It is suggested that the novel abnormal karyotype probably did not interrupt any genes or highly conserved genes even though a position effect mutation was not tested in our patient. References [1] Binkert F, Spreiz A, Ho¨ckner M, et al. Parental origin and mechanism of formation of a 46,X,der(X)(pter ! q21.1:: p11.4 ! pter)/45,X karyotype in a woman with mild Turner syndrome. Fertil Steril 2010;94(1). 350.e12-5. [2] Therman E, Patau K. Abnormal X chromosomes in man: origin, behavior and effects. Humangenetik 1974;25(1):1–16. [3] Kalz-Fuller B, Sleegers E, Schwanitz G, Schubert R. Characterization: phenotypic manifestations and X-inactivation pattern in 14 patients with X-autosomal translocations. Clin Genet 1999;55(5):362–6. [4] Waters JJ, Campbell PL, Crocker AJM, Campbell CM. Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories. Hum Genet 2001;108(4):318–27. [5] Therman E, Laxova R, Susman B. The critical region on the human Xq. Hum Genet 1990;85(5):455–61.
339
Nirmala Duhan* Roopa Malik Manisha Upadhyaya Department of Obstetrics and Gynecology, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India *Corresponding author. Tel.:+91 9896016348; fax: +0091 1262 211301 E-mail addresses: [email protected], [email protected] (N. Duhan). Received 30 July 2014 Accepted 7 August 2014 http://dx.doi.org/10.1016/j.ejogrb.2014.08.018
Pfeiffer syndrome: the importance of prenatal diagnosis Dear Editors, We found that Pfeiffer Syndrome (PS) was first described in 1964 and has an incidence of 1/100.000 neonates. Conventionally, PS is classified into three types. All types demonstrate craniofacial anomalies (craniosynostosis, midface retrusion, hypertelorism, proptosis) and limb deformities (brachydactyly, syndactyly, broad thumbs/great toes). Type 1 is the mildest phenotype with normal intelligence and generally good outcome. Type 2 has a poor prognosis and is characterized by a cloverleaf skull. Type 3 is an intermediate form with a very short skull base, severe proptosis, but without the cloverleaf skull. PS is an autosomal dominant condition, genetically heterogeneous with mutations in the FGFR1 or FGFR2 gene [1–5]. In our clinic we saw a 31-year-old primi-gravida, known with PS caused by a FGFR1 mutation. She was referred to our level 3 unit at 25 6/7 weeks of gestation. She was known to have the classical limb deformities: broad abducted thumbs and great toes (Fig. 1D). Her medical history was otherwise uneventful. Prenatal diagnosis comprising first trimester screening revealed no increased risk for trisomy 13, 18 and 21. She did not opt for amniocentesis. At 20 weeks of gestation advanced ultrasound examination was performed and showed no structural anomalies, normal growth and amount of amniotic fluid. She was referred because of threatened preterm labor. Ultrasound examination at admittance showed polyhydramnios and broad, deviated big toes of the fetus (Fig. 1A). Shortly afterwards she delivered of a daughter [weight 1.030 kg (+1SD), head circumference 25 cm (+1SD)]. Apgar scores were 8 and 9 after, respectively, 1 and 5 min. Umbilical cord blood gas analysis was normal. Physical examination showed a clinically normal skull shape. Both thumbs and big toes were broad and deviated in varus position (Fig. 1B). There was no syndactyly. Postnatal DNA-analysis confirmed the P252R (FGFR1 ex5) mutation. Previously the family of the index patient was investigated at the department of Clinical Genetics. DNA-analysis showed the FGFR1 mutation in the index patient, a sister and her mother. The index patient was born at term. During this pregnancy her mother had 25 weeks of bed rest because of premature contractions. Her sister was born at 32 weeks of gestation. It is not known at what
Letters to the Editor—Brief Communications / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 338–346
340
literature review and the preparation of the article. AJMH was as clinical geneticist responsible for writing down the genetic disorder of the individuals who are described. LSS was as pediatrician-neonatologist responsible for the correct description of the examination of the newborn. RH was the referring gynecologist and delivered a critical look at writing down the correct patient data. All authors were responsible for manuscript editing and had a final approval of the version to be submitted. Ethical approval Written consent of the patients described were obtained. Acknowledgement There are no other persons than the authors who had a contribution to this case report. References Fig. 1. (A) Prenatal right foot child. (B) Left and (C) right foot child. (D) Left foot mother. (E) Left and right foot grandmother.
term the mother of the index patient is born. Clinically her mother has limb deformities (Fig. 1E). She delivered thrice and all her children have the known hand and foot abnormalities. Two children are identified with the P252R mutation. Her third child is not tested. To our knowledge this is the first reported case of a relationship between PS type 1 and polyhydramnios and consequent premature birth. In only one article a case of PS type 2 and polyhydramnios is described [3]. In our case, in retrospect at least two people with PS type 1 were born prematurely. During pregnancies in the first and second generation ultrasound examination was not performed. In the third generation, ultrasound examination was performed at 20 weeks of gestation and no fetal anomalies or polyhydramnios were seen. Five weeks later polyhydramnios was found. The importance of prenatal diagnosis is already known because of the poor prognosis of PS type 2 and 3 [5]. This case emphasizes the need for a complete fetal sonographic survey and a frequent check of the amniotic fluid index when there is an increased risk for PS type 1. In our case the rapidly developing polyhydramnios eventually resulted in early preterm birth. In conclusion, we report a family affected by PS due to a pathogenic FGFR1 mutation and premature delivery most likely due to polyhydramnios. Our report emphasizes the need for prenatal diagnosis and close monitoring of pregnancy in case of PS with special attention to developing polyhydramnios.
[1] Cohen Jr MM. Pfeiffer syndrome update: clinical subtypes and guidelines for differential diagnosis. Am J Med Genet 1993;45:300–7. [2] Jones KL. Pfeiffer syndrome. In: Smith’s recognizable patterns of human malformation. Philadelphia: WB Saunders Company; 1997. p. 416–7. [3] Plomp AS, Hamel BCJ, Cobben JM, et al. Pfeiffer syndrome type 2: further delineation and review of the literature. Am J Med Genet 1998;75:245–51. [4] Robin NH, Scott JA, Arnold JE, et al. Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification. Am J Med Genet 1998;75:240–4. [5] Gorincour G, Rypens F, Grignon A, et al. Prenatal diagnosis of cloverleaf skull: watch the hands! Fetal Diagn Ther 2005;20:296–300.
Gatske M. Nieuwenhuyzen-De Boer* Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, The Netherlands A. Jeannette M. Hoogeboom Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, The Netherlands Liesbeth S. Smita,b Department of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands b Department of Neurology, Division of Pediatric Neurology, Erasmus MC, University Medical Center Rotterdam, The Netherlands a
Roger Heydanus Department of Obstetrics and Gynecology, Amphia Hospital, Breda, The Netherlands Alex J. Eggink Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
Funding There is no funding. Conflict of interest The authors report no conflict of interest.
*Corresponding author at: Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 7040704 E-mail address: [email protected] (G.M. Nieuwenhuyzen-De Boer). Received 28 July 2014
Contribution to authorship All authors had a substantial contribution to conception of this article. GMN and AJE were responsible for data collection,
http://dx.doi.org/10.1016/j.ejogrb.2014.08.006