Persistent hypercholesterolemia in child with homozygous autosomal recessive hypercholesterolemia: A decade of lipid management.

Autosomal recessive hypercholesterolemia (ARH) is a rare form of genetic hypercholesterolemia caused by mutations in low density lipoprotein receptor adaptor protein 1 (LDLRAP1). The proband first presented with linear eruptive xanthomas over her ankles, knees and elbows, with low density lipoprotein cholesterol (LDL-C) of 16.0 mmol/L (618.7 mg/dL), at 2.5 years old. Next generation sequencing revealed a novel homozygous mutation in LDLRAP1 exon 5 (c.466delG). In the first year, drug regimens of either cholestyramine or simvastatin, reduced her LDL-C to 10.5 mmol/L (406 mg/dL) and 11.7 mmol/L (452.4 mg/dL), respectively. Combination simvastatin and ezetimibe was the mainstay of therapy from age 5 - 10 years. Her lowest achieved LDL-C was 6.3 mmol/L (243.6 mg/dL). Switching to atorvastatin did not lead to further reduction. Carotid intima-media thickness was 0.47 mm (> 97th percentile) and 0.32 mm (75 - 95th percentile) at ages 8 years and 11 years, respectively. Addition of monthly injections of evolocumab for 3 months, led to an increase in LDL-C, from 7.0 mmol/L (270.7 mg/dL) to a range of [(8.4 - 9.1) mmol/L or (324.8 - 351.9) mg/dL]. In this report, a decade-long lipid management is described in a patient with ARH. Residual activity of LDLRAP1 is a likely determinant of her response. Clinical management remains sub-optimal and options for the paediatric population are limited. Novel classes of cholesterol-lowering medications are needed for this ultra-rare and severe hypercholesterolemia.

MIRAGE Syndrome Caused by a De Novo c.3406G>C (p. Glu1136Gln) Mutation in the SAMD9 Gene Presenting With Neonatal Adrenal Insufficiency and Recurrent Intussusception: A Case Report.

Introduction: Primary adrenal insufficiency (PAI) presenting in the neonatal period can be life threatening and requires early recognition, diagnosis, and management. PAI due to adrenal hypoplasia (syndromic/non-syndromic) is a rare disorder. MIRAGE is a recently described syndrome with PAI and multisystem involvement. Case Presentation: A preterm female neonate presenting with PAI and persistent severe thrombocytopenia was diagnosed to have MIRAGE syndrome due to a de novo pathogenic variant c.3406G>C (p. Glu1136Gln) in the SAMD9 gene. In the first year of life, she had recurrent respiratory and gastrointestinal infection causing failure to thrive. At 17 months, she suffered recurrent intussusception requiring treatment with parenteral nutrition and high-dose steroids. Subsequently, she established oral feeds with hydrolysed formula and demonstrated good weight gain. Conclusion: In neonates presenting with PAI and associated multisystem involvement, a thoughtful approach and genetic testing is valuable in discerning an etiological diagnosis. This case of MIRAGE adds to the spectrum of reported cases and is the first to report on recurrent intussusception and its management with high-dose steroids.

Influence of red blood cell indices on HbA1c performance in detecting dysglycaemia in a Singapore preconception cohort study.

Abnormalities of red blood cell (RBC) indices may affect glycated haemoglobin (HbA1c) levels. We assessed the influence of haemoglobin (Hb) and mean corpuscular volume (MCV) on the performance of HbA1c in detecting dysglycaemia among reproductive aged women planning to conceive. Women aged 18-45 years (n = 985) were classified as normal (12 ≤ Hb ≤ 16 g/dL and 80 ≤ MCV ≤ 100 fL) and abnormal (Hb < 12 g/dL and/or MCV < 80 fL). The Area Under the Receiver Operating Characteristic (AUROC) curve was used to determine the performance of HbA1c in detecting dysglycaemic status (prediabetes and diabetes). There were 771 (78.3%) women with normal RBC indices. The AUROCs for the normal and abnormal groups were 0.75 (95% confidence interval 0.69, 0.81) and 0.80 (0.70, 0.90), respectively, and were not statistically different from one another [difference 0.04 (- 0.16, 0.08)]. Further stratification by ethnicity showed no difference between the two groups among Chinese and Indian women. However, Malay women with normal RBC indices displayed lower AUROC compared to those with abnormal RBC indices (0.71 (0.55, 0.87) vs. 0.98 (0.93, 1.00), p = 0.002). The results suggest that the performance of HbA1c in detecting dysglycaemia was not influenced by abnormal RBC indices based on low Hb and/or low MCV. However, there may be ethnic variations among them.

Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature.

Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1_941-1) (1845 + 1_1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose.