Macroglossia and elevated lactate as initial presenting features for cardiofaciocutaneous syndrome
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Macroglossia is a distinctive feature often identified early in the neonatal period. While it has a broad diagnostic differential, it is recommended to rule out Beckwith-Wiedemann Syndrome (BWS) even in isolated cases. Elevated lactate is a common feature of mitochondrial and other metabolic conditions, and individuals with RASopathies may exhibit secondary mitochondrial dysfunction. Cardiofaciocutaneous (CFC) syndrome is an autosomal dominant condition characterized by cardiac abnormalities, distinctive craniofacial features, and cutaneous anomalies. Additional features include poor growth, developmental delays, feeding issues, sparse hair, hypotonia, vomiting, dysmotility, hip dysplasia, and joint contractures.
Case Presentation
The proband, a female infant conceived via in vitro fertilization, was delivered at 32 weeks gestation by cesarean section due to severe preeclampsia. She had birth weight of 1.42 kg (97.4th centile), length of 47 cm(22.37th centile), and head circumference of 36 cm (100th centile). She was admitted to the NICU for apnea and required intubation for 5 days due to respiratory distress.
A dysmorphology exam revealed macroglossia, dolichocephaly, sparse hair, down-slanting palpebral fissures, absent eyebrows with mild ulerythema, coarse facial features, ulnar hand deviation, and decreased muscle bulk with bilateral hip and knee contractures. Initial laboratory results showed elevated lactate at 3.5 mmol/L (reference range: 0.5–2.2 mmol/L), peaking at 4.2 mmol/L.
Her clinical course was complicated by poor weight gain, dysphagia, and feeding difficulties requiring gastrostomy tube (g-tube) placement. She experienced recurrent, unexplained fevers and elevated white blood cell counts without identifiable infections.. The proband also had episodes of perioral cyanosis and desaturation, which resolved with repositioning, potentially related to macroglossia. An EEG showed occasional isolated bilateral multifocal sharp activity but no clinical seizures. She was discharged from the NICU at 10 weeks old.
Diagnostic Workup
Genetic testing for BWS, including methylation studies and CDKN1C sequencing, was negative, though the broad spectrum of BWS and associated malignancy risks necessitate ongoing surveillance. Abdominal and renal ultrasounds ruled out hepatoblastoma and nephroblastoma. Elevated lactate levels suggested a possible mitochondrial disorder. Rapid exome sequencing (ES) identified heterozygous de novo variants of uncertain significance in MAP2K1 (c.333_335del,p.Ile112del), HNF4A (c.1291G>A, p.Val431Ile), and NRXN1 (c.345C>G, p.His115Gln). The mitochondrial genome revealed a homoplasmic MT-CO1 variant.
Outcome and Follow-Up
At 17 months, outpatient evaluation in the RASopathy clinic confirmed a phenotype consistent with CFC syndrome. The proband exhibited poor growth (weight: 54. kg[CR1] , Z = -6.82; head circumference: 43.9. cm, Z = -18.31) and significant global delays. She could sit with support but was unable to stand or walk, andspeech was limited to a single inconsistent word. No episodes of developmental regression were reported. She is monitored by multiple specialties, including pulmonology (chronic aspiration), orthopedics (hip dysplasia and leg contractures), gastroenterology, endocrinology (failure to thrive), and immunology (recurrent fevers and persistent elevated white blood cell counts).
Discussion
Exome sequencing revealed a de novo in-frame deletion in MAP2K1. Although in-frame deletions in MAP2K1 have not been reported in CFC syndrome, similar cases involving MAP2K2 suggest a phenotype overlap. Individuals with MAP2K2-related CFC syndrome typically have less severe neurodevelopmental delays and lower epilepsy risk compared to those with MAP2K1 mutations. MAP2K1 in-frame deletions have also been reported in tumors, such as melanoma, with strong RAS pathway activation.
Conclusion
This case expands the phenotype (macroglossia and mildly elevated lactate) and molecular variant spectrum of MAP2K1, suggesting a severe phenotype associated with this in-frame deletion. Further studies are necessary to determine whether secondary mitochondrial dysfunction is a component of CFC syndrome. While the MAP2K1 variant likely accounts for the proband’s clinical features, ongoing monitoring and segregation studies of the MT-CO1 and other variants are essential for a comprehensive understanding of her condition.
Macroglossia is a distinctive feature often identified early in the neonatal period. While it has a broad diagnostic differential, it is recommended to rule out Beckwith-Wiedemann Syndrome (BWS) even in isolated cases. Elevated lactate is a common feature of mitochondrial and other metabolic conditions, and individuals with RASopathies may exhibit secondary mitochondrial dysfunction. Cardiofaciocutaneous (CFC) syndrome is an autosomal dominant condition characterized by cardiac abnormalities, distinctive craniofacial features, and cutaneous anomalies. Additional features include poor growth, developmental delays, feeding issues, sparse hair, hypotonia, vomiting, dysmotility, hip dysplasia, and joint contractures.
Case Presentation
The proband, a female infant conceived via in vitro fertilization, was delivered at 32 weeks gestation by cesarean section due to severe preeclampsia. She had birth weight of 1.42 kg (97.4th centile), length of 47 cm(22.37th centile), and head circumference of 36 cm (100th centile). She was admitted to the NICU for apnea and required intubation for 5 days due to respiratory distress.
A dysmorphology exam revealed macroglossia, dolichocephaly, sparse hair, down-slanting palpebral fissures, absent eyebrows with mild ulerythema, coarse facial features, ulnar hand deviation, and decreased muscle bulk with bilateral hip and knee contractures. Initial laboratory results showed elevated lactate at 3.5 mmol/L (reference range: 0.5–2.2 mmol/L), peaking at 4.2 mmol/L.
Her clinical course was complicated by poor weight gain, dysphagia, and feeding difficulties requiring gastrostomy tube (g-tube) placement. She experienced recurrent, unexplained fevers and elevated white blood cell counts without identifiable infections.. The proband also had episodes of perioral cyanosis and desaturation, which resolved with repositioning, potentially related to macroglossia. An EEG showed occasional isolated bilateral multifocal sharp activity but no clinical seizures. She was discharged from the NICU at 10 weeks old.
Diagnostic Workup
Genetic testing for BWS, including methylation studies and CDKN1C sequencing, was negative, though the broad spectrum of BWS and associated malignancy risks necessitate ongoing surveillance. Abdominal and renal ultrasounds ruled out hepatoblastoma and nephroblastoma. Elevated lactate levels suggested a possible mitochondrial disorder. Rapid exome sequencing (ES) identified heterozygous de novo variants of uncertain significance in MAP2K1 (c.333_335del,p.Ile112del), HNF4A (c.1291G>A, p.Val431Ile), and NRXN1 (c.345C>G, p.His115Gln). The mitochondrial genome revealed a homoplasmic MT-CO1 variant.
Outcome and Follow-Up
At 17 months, outpatient evaluation in the RASopathy clinic confirmed a phenotype consistent with CFC syndrome. The proband exhibited poor growth (weight: 54. kg[CR1] , Z = -6.82; head circumference: 43.9. cm, Z = -18.31) and significant global delays. She could sit with support but was unable to stand or walk, andspeech was limited to a single inconsistent word. No episodes of developmental regression were reported. She is monitored by multiple specialties, including pulmonology (chronic aspiration), orthopedics (hip dysplasia and leg contractures), gastroenterology, endocrinology (failure to thrive), and immunology (recurrent fevers and persistent elevated white blood cell counts).
Discussion
Exome sequencing revealed a de novo in-frame deletion in MAP2K1. Although in-frame deletions in MAP2K1 have not been reported in CFC syndrome, similar cases involving MAP2K2 suggest a phenotype overlap. Individuals with MAP2K2-related CFC syndrome typically have less severe neurodevelopmental delays and lower epilepsy risk compared to those with MAP2K1 mutations. MAP2K1 in-frame deletions have also been reported in tumors, such as melanoma, with strong RAS pathway activation.
Conclusion
This case expands the phenotype (macroglossia and mildly elevated lactate) and molecular variant spectrum of MAP2K1, suggesting a severe phenotype associated with this in-frame deletion. Further studies are necessary to determine whether secondary mitochondrial dysfunction is a component of CFC syndrome. While the MAP2K1 variant likely accounts for the proband’s clinical features, ongoing monitoring and segregation studies of the MT-CO1 and other variants are essential for a comprehensive understanding of her condition.