Noonan syndrome (NS) is a heterogenous condition characterized by distinctive craniofacial features, cardiac defects, and neurodevelopmental changes and is caused by variants in one of seven genes coding for proteins within the Ras-MAPK pathway. Pathogenic variants in RAF1 account for approximately 3-17% of cases and are associated with a high prevalence of severe hypertrophic cardiomyopathy (HCM) and pulmonary hypertension (PHTN). Cerebrovascular and Chiari I malformations, although rare, have also been described in individuals with RAF-1 NS. To our knowledge, the presence of congenital occipital alopecia in an individual with NS has not been previously reported. We report a patient with a de novo pathogenic heterozygous RAF1 gene sequence variant, c.770C>T (p.Ser257Leu), with atypical scalp findings. Our proband was a 4-week-old female dichorionic, diamniotic twin born at 35 weeks 2 days gestation to nonconsanguineous parents. At birth, her length was 45.7 cm (14th centile), weight was 2656 g (69th centile), and head circumference was 34.5 cm (97th centile). The mother was 38 at the time of birth. There was no history of maternal or gestational diabetes. Prenatal ultrasound was concerning for cystic hygroma. The immediate neonatal course was complicated by acute respiratory failure, left ventricular outflow tract obstruction with concern for coarctation on echocardiogram, poor feeding, and failed newborn hearing screen which prompted transfer to a tertiary NICU for further management. At the time of consultation, the following problems had been identified: bilateral cataracts, significant redundant posterior neck folds that showed fatty soft tissue neck mass without a cystic component, and hypertrophic cardiomyopathy with elevated pulmonary arterial pressures. Physical exam was notable for relative macrocephaly with turricephaly, lowset, posteriorly rotated ears, redundant posterior neck folds, and a focal, 1cm circular area of alopecia at the midline occipital region. These findings were concerning for a RASopathy. Imaging of her superficial midline scalp defect with brain MRI showed a suspected atretic encephalocele, but CT did not reveal any occipital bony defects. After re-evaluation, it was confirmed that there was no intracranial connection or bony defect at the area of the congenital alopecia nor at the level of the suboccipital skin thickening/redundancy. Chromosomal microarray was nondiagnostic and thus exome sequence analysis was preformed which detected the pathogenic RAF1 variant. The diagnosis of RAF1 NS accounts for nearly all of the physical changes seen in our patient, particularly the severe degree of PHTN and HCM, with the exception of her occipital alopecia. Since our initial consultation, the patient continues to grow along NS-specific curve, has persistent mild bilateral hearing loss, and has had interval placement of gastric tube secondary to oral feeding difficulties. There has been mild improvement in cardiac function, septal hypertrophy, and PHTN. She remains seizure-free. This report expands the phenotype of RAF1 Noonan syndrome to include congenital focal alopecia. We recommend that NS should be added to the differential when this same scalp finding is present. Although the presence of this physical finding in our patient was not definitively associated with any underlying structural CNS or bony changes, this case highlights the importance of investigating with detailed cranial and spinal imaging to better characterize cerebral morphology and guide genetic testing in suspected RASopathy cases. Additional cases with this finding are needed to better understand potential associations.
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Apr 21, 2023
Telford Yeung + 7
Open Access