CLINICAL REPORT
The Perinatal Presentation of Cardiofaciocutaneous Syndrome Kara N. Wong Ramsey,1* Matthew H. Loichinger,2 Thomas P. Slavin,1,3 Sheree Kuo,1,3 and Laurie H. Seaver1,3 1
Department of Pediatrics, University of Hawaii, Honolulu, Hawaii
2
Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, Hawaii Kapiolani Medical Specialists, Honolulu, Hawaii
3
Manuscript Received: 21 October 2013; Manuscript Accepted: 10 March 2014
There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras–MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii’s largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts. Ó 2014 Wiley Periodicals, Inc.
Key words: cardiofaciocutaneous syndrome (CFC); neonatal; perinatal; hyponatremia; hypertension; pleural effusion; respiratory complication; loose anagen hair; BRAF; MAP2K1; MAP2K2; rasopathies; Ras–MAP kinase
INTRODUCTION Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that shares overlapping clinical features with other conditions caused by mutations in the RAS–MAP kinase signaling pathway (rasopathies), especially Noonan and Costello syndrome. Other entities involving the Ras/MAP kinase pathway include Noonan syndrome with multiple lentigines (previously refered to as LEOPARD syndrome), gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation–arteriovenous malformation, autoimmune lymphoproliferative syndrome, and Legius syndrome [Tidyman and Rauen, 2009]. Most patients with CFC have mutations in BRAF, KRAS, MAP2K1, or MAP2K2 [Rauen, 2007]. Although, there
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Wong Ramsey KN, Loichinger MH, Slavin TP, Kuo S, Seaver LH. 2014. The perinatal presentation of cardiofaciocutaneous syndrome. Am J Med Genet Part A 9999:1–7.
is literature describing the phenotype and general clinical features of CFC [Roberts et al., 2006; Armour and Allanson, 2008; Allanson et al., 2011; Abe et al., 2012], there is little information describing the perinatal course of CFC. Prenatally, polyhydramnios is a common finding and is often associated with premature birth, reported in approximately 50% of CFC patients [Armour and Allanson, 2008; Allanson et al., 2011]. Prematurity is a potential confounding factor in examining the perinatal clinical features and course of CFC. Other prenatal ultrasound findings reported in CFC patients include hydronephrosis, cerebral ventriculomegaly, macrosomia, increased nuchal translucency, and cystic hygroma [Witters et al., 2008; Allanson et al., 2011; Abe et al., 2012]. The aim of this report is to describe the prenatal, neonatal, and infant courses of four consecutive CFC patients. This information may help guide clinicians in the management of CFC patients and in the counseling of their families.
CLINICAL REPORT A retrospective chart review identified four patients with CFC born between 2005 and 2012 at Kapi’olani Medical Center for Women Conflict of interest: none. Correspondence to: Kara Wong Ramsey, Department of Pediatrics, Kapiolani Medical Center for Women and Children, University of Hawaii, 1319 Punahou St., Honolulu, HI 96826. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36558
1
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
and Children in Honolulu, Hawaii. All had molecular confirmation of the diagnosis. See Table I for a summary of their clinical characteristics. Reported ages at the various significant time points reported in the summaries below reflect the chronological age of the patients and are not adjusted for gestational age.
Patient 1 A male infant was born prematurely by vaginal delivery at 33 weeks gestation due to premature rupture of membranes and spontaneous labor to a 45-year-old G10 P9 mother and a 52-year-old father. The prenatal course was complicated by late presentation to prenatal care, and the estimated date of confinement was estimated by an ultrasound performed at 27 weeks gestation. There was a poorly documented history of gestational diabetes type A1, but according to available records, hyperglycemia did not complicate the perinatal course. Severe polyhydramnios and unilateral hydronephrosis were detected 1 week prior to delivery. Positive pressure ventilation was given in the delivery room for poor respiratory effort. Apgar scores were 6 and 9 at 1 and 5 min. The BW was 2.174 kg (75th centile), BL was 44 cm (65th centile), and OFC was 31.5 cm (75th centile). Physical examination was significant for hypotonia, tall forehead with upslanting palpebral fissures, large ears, thickened nose, wide and flat nasal bridge with prominent anteverted tip, mild micrognathia with glossoptosis, hirsutism, and bilateral cryptorchidism.
The infant was treated in the neonatal intensive care unit (NICU) where non-invasive respiratory support was continued for respiratory distress. He sustained a left grade II intra-ventricular hemorrhage (IVH) documented by head/brain ultrasound. Brain magnetic resonance imaging (MRI) was unremarkable at age 6 weeks. A tracheostomy was placed at age 1 month due to upper airway obstruction and tracheomalacia. He was eventually transitioned to tracheostomy collar without ventilator support or supplemental oxygen by age 5 months. A gastrostomy tube was placed at age 3 months due to severe dysphagia and gastroesophageal reflux. Hyponatremia (serum sodium 127 mmol/L) was first noted at age 18 days and persisted through age 37 days, during, which time he was on full enteral feeds. Evaluation for hyponatremia included a normal serum cortisol, androstenedione, testosterone, 17ahydroxyprogesterone, renin, and aldosterone levels. Urine sodium was low at 90th centile). Physical examination revealed apparent hypertelorism, posteriorly angulated ears, redundant nuchal skin extending to upper shoulders, grade II systolic cardiac murmur, hypotonia, and undescended right testis. He was admitted to the NICU on high flow nasal cannula for respiratory distress and hypoxia, but weaned to room air within 2 days. He was able to nipple full enteral feedings. An ultrasound completed for excessive posterior nuchal skin suggested the presence of a lymphangioma. Scrotal and abdominal ultrasound showed a non-descended right testis and mild hepatomegaly. He passed his newborn hearing screen. Echocardiogram shortly after birth revealed hypertrophic cardiomyopathy involving the interventricular septum with lesser involvement of the posterior wall of the left ventricle. He was discharged home at age 8 days with a weight of 3.436 kg (75th centile), still 8.5% under his birth weight. The excess nuchal skin was resected at age 1 month; pathologic diagnosis was consistent with benign adipose tissue. Serial echocardiograms showed worsening inter-ventricular septal and left ventricular wall hypertrophy, and he was started on propanolol at age 2 months. Follow-up echocardiogram at age 1 year showed stable cardiac hypertrophy. He had feeding difficulties, gastroesophageal reflux, and failure to thrive, with weight falling below
3 the 3rd centile by age 4 months. Orchiopexy was performed at age 1 year. When last seen at age 4.5 years, he had severe global developmental delay (did not walk until after 2 years, able to vocalize babbling sounds but no words, able to follow simple commands). He wore glasses for myopia and astigmatism. Weight remained below the 3rd centile. He had scattered pigmented nevi on exam. His cardiac status was stable and he had no new health concerns. Genetic testing showed a 46,XY karyotype and a mutation in BRAF exon 6, denoted p.Gln257Arg, a mutation previously associated with CFC syndrome [Niihori et al., 2006; Abe et al., 2012].
Patient 3 A female infant was born prematurely at 29 weeks gestation (based on an 11 week ultrasound) due to spontaneous pre-term labor. The mother was a 37-year-old G6 P3 and the father was 41-year-old. The pregnancy was complicated by polyhydramnios and fetal cystic hygroma, with the latter resolved prior to delivery. Positive pressure ventilation and continuous positive airway pressure support were required at delivery. Apgar scores were 6 and 8 at 1 and 5 min. She was LGA with BW 1.738 kg (95th centile), BL 40 cm (75th centile) and OFC 31 cm (>95th centile). Physical examination was notable for generalized edema, prominent forehead, posteriorly angulated ears, anteverted nares, hypotonia, and short webbed neck with redundant nuchal skin. She was gradually weaned from non-invasive positive pressure ventilation to low flow nasal cannula by age 2 months. Nissen fundoplication and gastrostomy tube placement were performed at age 3 months due to severe gastroesophageal reflux and a significant aspiration pneumonia. She did not regain her birth weight until age 3 weeks despite high calorie fortified enteral feeding. Weight gradually fell to approximately 10th centile by age 4 months. She required sodium supplementation for hyponatremia (serum sodium 126 mmol/L) from age 1 month through age 2.5 months while relatively stable on full enteral feeds and minimal respiratory support, prior to the initiation of diuretics for chronic lung disease. No laboratory evaluation was initially performed for the hyponatremia, as it was attributed to sodium wasting from premature kidneys. Head/brain ultrasound was normal at age 1 and 6 weeks. Renal ultrasound showed mild left hydronephrosis. EEG was performed for possible seizure activity and was normal. Bilateral posterior capsular cataracts were noted at age 1 month. Echocardiogram performed at birth and age 1 month was normal, but by age 2 months, there was evidence of left lateral wall segmental hypertrophy with progressive pulmonary hypertension despite treatment with sildenafil. Hydralazine was instituted for idiopathic systemic hypertension at age 3 months (systolic blood pressure 95– 108 mmHg). Hypertrophic cardiomyopathy progressed to involve the left ventricular posterior wall and the inter-ventricular septum. She experienced respiratory deterioration at age 3 months, requiring stepwise escalation of respiratory support to mechanical ventilation by age 4 months despite therapy with diuretics and steroids for chronic lung disease. At age 4 months, she developed significant edema, renal insufficiency, hypoalbuminemia, hypotension requiring dopamine, and stress dose hydrocortisone, right pleural effusion, and mixed metabolic and respiratory acidosis.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Hyponatremia was again noted (serum sodium 120 mmol/L, with serum osmolality 258 mOsm/kg H2O, urine osmolality 350 mOsm/ kg H2O, and urine sodium
The Perinatal Presentation of Cardiofaciocutaneous Syndrome Kara N. Wong Ramsey,1* Matthew H. Loichinger,2 Thomas P. Slavin,1,3 Sheree Kuo,1,3 and Laurie H. Seaver1,3 1
Department of Pediatrics, University of Hawaii, Honolulu, Hawaii
2
Department of Obstetrics and Gynecology, University of Hawaii, Honolulu, Hawaii Kapiolani Medical Specialists, Honolulu, Hawaii
3
Manuscript Received: 21 October 2013; Manuscript Accepted: 10 March 2014
There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras–MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii’s largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts. Ó 2014 Wiley Periodicals, Inc.
Key words: cardiofaciocutaneous syndrome (CFC); neonatal; perinatal; hyponatremia; hypertension; pleural effusion; respiratory complication; loose anagen hair; BRAF; MAP2K1; MAP2K2; rasopathies; Ras–MAP kinase
INTRODUCTION Cardiofaciocutaneous syndrome (CFC) is a rare genetic disorder that shares overlapping clinical features with other conditions caused by mutations in the RAS–MAP kinase signaling pathway (rasopathies), especially Noonan and Costello syndrome. Other entities involving the Ras/MAP kinase pathway include Noonan syndrome with multiple lentigines (previously refered to as LEOPARD syndrome), gingival fibromatosis type 1, neurofibromatosis type 1, capillary malformation–arteriovenous malformation, autoimmune lymphoproliferative syndrome, and Legius syndrome [Tidyman and Rauen, 2009]. Most patients with CFC have mutations in BRAF, KRAS, MAP2K1, or MAP2K2 [Rauen, 2007]. Although, there
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Wong Ramsey KN, Loichinger MH, Slavin TP, Kuo S, Seaver LH. 2014. The perinatal presentation of cardiofaciocutaneous syndrome. Am J Med Genet Part A 9999:1–7.
is literature describing the phenotype and general clinical features of CFC [Roberts et al., 2006; Armour and Allanson, 2008; Allanson et al., 2011; Abe et al., 2012], there is little information describing the perinatal course of CFC. Prenatally, polyhydramnios is a common finding and is often associated with premature birth, reported in approximately 50% of CFC patients [Armour and Allanson, 2008; Allanson et al., 2011]. Prematurity is a potential confounding factor in examining the perinatal clinical features and course of CFC. Other prenatal ultrasound findings reported in CFC patients include hydronephrosis, cerebral ventriculomegaly, macrosomia, increased nuchal translucency, and cystic hygroma [Witters et al., 2008; Allanson et al., 2011; Abe et al., 2012]. The aim of this report is to describe the prenatal, neonatal, and infant courses of four consecutive CFC patients. This information may help guide clinicians in the management of CFC patients and in the counseling of their families.
CLINICAL REPORT A retrospective chart review identified four patients with CFC born between 2005 and 2012 at Kapi’olani Medical Center for Women Conflict of interest: none. Correspondence to: Kara Wong Ramsey, Department of Pediatrics, Kapiolani Medical Center for Women and Children, University of Hawaii, 1319 Punahou St., Honolulu, HI 96826. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36558
1
2
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
and Children in Honolulu, Hawaii. All had molecular confirmation of the diagnosis. See Table I for a summary of their clinical characteristics. Reported ages at the various significant time points reported in the summaries below reflect the chronological age of the patients and are not adjusted for gestational age.
Patient 1 A male infant was born prematurely by vaginal delivery at 33 weeks gestation due to premature rupture of membranes and spontaneous labor to a 45-year-old G10 P9 mother and a 52-year-old father. The prenatal course was complicated by late presentation to prenatal care, and the estimated date of confinement was estimated by an ultrasound performed at 27 weeks gestation. There was a poorly documented history of gestational diabetes type A1, but according to available records, hyperglycemia did not complicate the perinatal course. Severe polyhydramnios and unilateral hydronephrosis were detected 1 week prior to delivery. Positive pressure ventilation was given in the delivery room for poor respiratory effort. Apgar scores were 6 and 9 at 1 and 5 min. The BW was 2.174 kg (75th centile), BL was 44 cm (65th centile), and OFC was 31.5 cm (75th centile). Physical examination was significant for hypotonia, tall forehead with upslanting palpebral fissures, large ears, thickened nose, wide and flat nasal bridge with prominent anteverted tip, mild micrognathia with glossoptosis, hirsutism, and bilateral cryptorchidism.
The infant was treated in the neonatal intensive care unit (NICU) where non-invasive respiratory support was continued for respiratory distress. He sustained a left grade II intra-ventricular hemorrhage (IVH) documented by head/brain ultrasound. Brain magnetic resonance imaging (MRI) was unremarkable at age 6 weeks. A tracheostomy was placed at age 1 month due to upper airway obstruction and tracheomalacia. He was eventually transitioned to tracheostomy collar without ventilator support or supplemental oxygen by age 5 months. A gastrostomy tube was placed at age 3 months due to severe dysphagia and gastroesophageal reflux. Hyponatremia (serum sodium 127 mmol/L) was first noted at age 18 days and persisted through age 37 days, during, which time he was on full enteral feeds. Evaluation for hyponatremia included a normal serum cortisol, androstenedione, testosterone, 17ahydroxyprogesterone, renin, and aldosterone levels. Urine sodium was low at 90th centile). Physical examination revealed apparent hypertelorism, posteriorly angulated ears, redundant nuchal skin extending to upper shoulders, grade II systolic cardiac murmur, hypotonia, and undescended right testis. He was admitted to the NICU on high flow nasal cannula for respiratory distress and hypoxia, but weaned to room air within 2 days. He was able to nipple full enteral feedings. An ultrasound completed for excessive posterior nuchal skin suggested the presence of a lymphangioma. Scrotal and abdominal ultrasound showed a non-descended right testis and mild hepatomegaly. He passed his newborn hearing screen. Echocardiogram shortly after birth revealed hypertrophic cardiomyopathy involving the interventricular septum with lesser involvement of the posterior wall of the left ventricle. He was discharged home at age 8 days with a weight of 3.436 kg (75th centile), still 8.5% under his birth weight. The excess nuchal skin was resected at age 1 month; pathologic diagnosis was consistent with benign adipose tissue. Serial echocardiograms showed worsening inter-ventricular septal and left ventricular wall hypertrophy, and he was started on propanolol at age 2 months. Follow-up echocardiogram at age 1 year showed stable cardiac hypertrophy. He had feeding difficulties, gastroesophageal reflux, and failure to thrive, with weight falling below
3 the 3rd centile by age 4 months. Orchiopexy was performed at age 1 year. When last seen at age 4.5 years, he had severe global developmental delay (did not walk until after 2 years, able to vocalize babbling sounds but no words, able to follow simple commands). He wore glasses for myopia and astigmatism. Weight remained below the 3rd centile. He had scattered pigmented nevi on exam. His cardiac status was stable and he had no new health concerns. Genetic testing showed a 46,XY karyotype and a mutation in BRAF exon 6, denoted p.Gln257Arg, a mutation previously associated with CFC syndrome [Niihori et al., 2006; Abe et al., 2012].
Patient 3 A female infant was born prematurely at 29 weeks gestation (based on an 11 week ultrasound) due to spontaneous pre-term labor. The mother was a 37-year-old G6 P3 and the father was 41-year-old. The pregnancy was complicated by polyhydramnios and fetal cystic hygroma, with the latter resolved prior to delivery. Positive pressure ventilation and continuous positive airway pressure support were required at delivery. Apgar scores were 6 and 8 at 1 and 5 min. She was LGA with BW 1.738 kg (95th centile), BL 40 cm (75th centile) and OFC 31 cm (>95th centile). Physical examination was notable for generalized edema, prominent forehead, posteriorly angulated ears, anteverted nares, hypotonia, and short webbed neck with redundant nuchal skin. She was gradually weaned from non-invasive positive pressure ventilation to low flow nasal cannula by age 2 months. Nissen fundoplication and gastrostomy tube placement were performed at age 3 months due to severe gastroesophageal reflux and a significant aspiration pneumonia. She did not regain her birth weight until age 3 weeks despite high calorie fortified enteral feeding. Weight gradually fell to approximately 10th centile by age 4 months. She required sodium supplementation for hyponatremia (serum sodium 126 mmol/L) from age 1 month through age 2.5 months while relatively stable on full enteral feeds and minimal respiratory support, prior to the initiation of diuretics for chronic lung disease. No laboratory evaluation was initially performed for the hyponatremia, as it was attributed to sodium wasting from premature kidneys. Head/brain ultrasound was normal at age 1 and 6 weeks. Renal ultrasound showed mild left hydronephrosis. EEG was performed for possible seizure activity and was normal. Bilateral posterior capsular cataracts were noted at age 1 month. Echocardiogram performed at birth and age 1 month was normal, but by age 2 months, there was evidence of left lateral wall segmental hypertrophy with progressive pulmonary hypertension despite treatment with sildenafil. Hydralazine was instituted for idiopathic systemic hypertension at age 3 months (systolic blood pressure 95– 108 mmHg). Hypertrophic cardiomyopathy progressed to involve the left ventricular posterior wall and the inter-ventricular septum. She experienced respiratory deterioration at age 3 months, requiring stepwise escalation of respiratory support to mechanical ventilation by age 4 months despite therapy with diuretics and steroids for chronic lung disease. At age 4 months, she developed significant edema, renal insufficiency, hypoalbuminemia, hypotension requiring dopamine, and stress dose hydrocortisone, right pleural effusion, and mixed metabolic and respiratory acidosis.
4
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
Hyponatremia was again noted (serum sodium 120 mmol/L, with serum osmolality 258 mOsm/kg H2O, urine osmolality 350 mOsm/ kg H2O, and urine sodium
