Severe neuroglycopenic symptoms due to nonketotic hypoglycemia in children with cardio‐facio‐cutaneous syndrome

• Published in: American journal of medical genetics. Part A 2022-12, Vol.188 (12), p.3505-3509
• Main Authors: Shiohama, Tadashi, Fujii, Katsunori, Kosaki, Rika, Watanabe, Yoshimi, Uchida, Tomoko, Hagiwara, Sho, Kinoshita, Kaori, Sugita, Katsuo, Aoki, Yoko, Shimojo, Naoki
• Format: Article
• Language: English
• Subjects: Basal ganglia; BRAF; CFC syndrome; Child; Child, Preschool; Children; Choreoathetosis; Complications; Convulsions; Ectodermal Dysplasia - diagnosis; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - pathology; Facies; Failure to Thrive - genetics; Failure to Thrive - pathology; Growth hormones; Heart Defects, Congenital - diagnosis; Humans; Hypoglycemia; Hypoglycemia - complications; Hypoglycemia - genetics; Magnetic resonance imaging; Male; MAP2K1; Mitochondria; Nervous System Diseases; Neuroimaging; nonketotic hypoglycemia; Proto-Oncogene Proteins B-raf; Putamen; Raf protein; RASopathy; Seizures; Thalamus
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62926

Cardio‐facio‐cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4‐year‐old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3‐year‐old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left‐hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2‐elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co‐occurrence of mitochondrial HMG‐CoA synthase deficiency and HMG‐CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia.