Diet-Responsive Hypercholesterolemia With Cardiofaciocutaneous Syndrome Type 3

Background: Molecular basis of diet responsive hypercholesterolemia remains unclear. We report diet-responsive severe hypercholesterolemia in a young female with cardiofaciocutaneous syndrome type 3 (CFC3) due to a heterozygous pathogenic MAP2K1 variant, suggesting a role of common MAPK variants in LDL-cholesterol (LDL-C) response to diet. Clinical case: A 3-year-old Caucasian female with CFC3 (macrocephaly, frontal bossing, wide nasal root with depressed bridge, anteverted nares, low set fleshy ears, congenital pulmonic valve stenosis, postnatal growth deficiency, hypotonia, and neurocognitive impairment) due to a de novo heterozygous c.389A>G, p.Tyr130Cys pathogenic variant in MAP2K1, presented with extremely elevated serum total cholesterol of 446 mg/dL, triglycerides of 239 mg/dL, HDL-cholesterol of 53 mg/dL, LDL-C of 335 mg/dL (normal range < 110 mg/dL) and serum apolipoprotein B level 219 mg/dL (normal range < 90 mg/dL). Her LDL-C was 252 mg/dL a year ago and 215 mg/dL one month prior to presentation. Reducing total dietary fat to 20–25% of total energy and saturated fat to <6% of total energy over the next 4 months lowered LDL-C to 104 mg/dL. However, her weight decreased by 0.5 kg and liberalization of fat intake again increased LDL-C to 222 mg/dL. Her father has mildly elevated LDL-C of 160 mg/dL and her mother had normal LDL-C of 80 mg/dL. Her plasma phytosterol levels were normal and she had ApoE3/E3 genotype. Targeted genetic testing of the patient and parents showed a benign heterozygous LDL receptor (LDLR) variant c.2242G>A; p.Asp748Asn, (Minor allele frequency 0.00008) in the patient and her father. Whole exome sequencing of the patient and both parents showed no known disease-causing variants in LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, LIPA, ABCG5, ABCG8 and other known hyperlipidemia-related genes. There are no previous reports of hypercholesterolemia in patients with CFC3. MAP2K1 stimulates various MAP kinases upon wide variety of extra- and intracellular signal and is involved in cell proliferation, differentiation, transcription regulation and development. Previous studies of the relationship between p42/44MAPK activation and LDLR expression in human hepatoma HepG2-derived cell line showed that that activation of the Raf-1/MEK/p42/44MAPK cascade induces LDLR expression and modulation of the Raf-1 kinase signal strength can determine LDLR expression levels. Thus, extent of MAPK activation can alter signaling of LDLR, resulting in hypercholesterolemia. Conclusion: Our case report suggests that MAP2K1 may play a significant role in LDLR signaling, and some MAP2K1 variants may be associated with diet-responsive hypercholesterolemia. Larger studies are required to assess dietary response to LDL-C in subjects with MAP2K1 variants.

RASopathies in multidisciplinary pediatric hospita

RAS-патии - группа наследственных заболеваний, возникающая вследствие нарушения регуляции функции RAS/MAPK внутриклеточных путей (Ras/mitogen-activated protein kinase). Суммарная частота заболеваний данной группы - 1 случай на 1000 новорожденных. Наиболее часто среди RAS-патий встречается синдром Нунан. В настоящее время описано 13 генов, мутации которых отвечают за развитие данного заболевания, включая ген SHOC2, ассоциированный с Нунан-подобным синдромом и измененной структурой волос (Noonan-like syndrome with loose anagen hair) и ген LZTR1, мутации в котором приводят к развитию синдрома Нунан, тип 2 с аутосомно-рецессивным типом наследования. RASopathies - group of inherited diseases, caused by mutations in genes, encoding components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. We identified 28 patients with inherited diseases from RASopathies: 61% - with Noonan syndrome, 14 % - with Cardiofaciocutaneous syndrome, 14% - with Costello syndrome - 11% - Noonan syndrome-like with loose anagen hair. Mutation c.770C>T, p.S257L in RAF1gene is most common in hypertrophic cardiomyopathy patients with Noonan syndrome. All patients with Noonan syndrome-like with loose anagen hair have mutation c.4A>G , p.S2G in SHOC2 gene.

Chondroblastoma-like mass of the temporal bone, secondary aneurysmal bone cyst, and intracerebral hemorrhage in a patient with cardiofaciocutaneous syndrome: case report

Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder that is phenotypically similar to Noonan syndrome and is associated with mutations in BRAF, MEK1, MEK2, and KRAS. The relationship between malignancy risk and CFCS is unclear with few cases published in the literature. The purpose of this paper is to describe the case of a patient with CFCS presenting in extremis as a result of a large intracerebral hemorrhage arising from a temporal bone mass with histopathology most consistent with chondroblastoma and secondary aneurysmal bone cyst. This is the first case to document an association between CFCS and chondroblastoma.

Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.