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Abstract
Homozygous familial hypercholesterolaemia (HoFH) is a disorder affecting low-density lipoprotein (LDL) receptor genes. Patients typically have a triad of elevated LDL-cholesterol (LDL-C), xanthomatosis and premature atherosclerotic cardiovascular disease. Our patient, a preteen boy, presented with signs of hypertensive encephalopathy. Physical examination showed arcus cornealis, planar xanthomas and tuberous xanthomas. After appropriate investigations, a direct aetiology of the hypertension could not be elucidated; however, our patient’s hypertension resolved with the reduction in serum lipid levels. β-hydroxy β-methylglutaryl coenzyme A reductase and cholesterol absorption inhibitors were administered as first-line treatment. A significant proportion of patients with HoFH continue to have elevated LDL-C levels, thereby requiring second-line agents, such as proprotein convertase subtilisin/kexin type inhibitors (evolocumab), microsomal triglyceride transfer protein inhibitors (lomitapide) and angiopoietin-like protein inhibitors (evinacumab). This case report aimed to raise awareness among paediatricians to consider HoFH as a possible aetiology in a child presenting with hypertension and suggestive physical findings.
- Paediatrics
- Paediatric intensive care
- Headache (including migraines)
- Drugs and medicines
- Dermatology
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Background
Homozygous familial hypercholesterolaemia (HoFH) is a rare autosomal dominant disorder, affecting 1 in every 170 000–300 000 individuals worldwide. This disorder involves gene mutations that code for low-density lipoprotein (LDL) receptor, apolipoprotein B (ApoB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDL-receptor adaptor protein 1. These genes help in the normoregulation of LDL-cholesterol (LDL-C) levels.1 2 The onset of HoFH is generally within the first decade of life. The elevated LDL-C levels of patients with HoFH can cause xanthomas (erroneous deposits of lipid within the connective tissue of the skin and tendons) and cardiac diseases such as sudden myocardial infarction, valvular stenosis and premature atherosclerotic disease.1–5 Cardiac complications of HoFH often involve the aortic valve (supravalvular aortic stenosis).1 HoFH is diagnosed based on a comprehensive patient history, clinical examination and lipid studies.5 HoFH is associated with sudden cardiovascular death, which is usually seen within the second decade of life. Due to the increased mortality risk, LDL-C monitoring and administration of maximally tolerated medication should be performed in a stepwise goal-oriented approach to reduce LDL-C levels to <100 mg/dL.1 5
Case presentation
A preteen boy presented to our emergency department with complaints of altered sensorium, headache and vomiting for the past few hours. At presentation, the child was irritable, restless and spoke incoherently. The headache was intense, especially around the occipital region. The patient had two episodes of non-projectile vomiting that contained food particles. The patient also presented with eruptions over the right upper eyelid, buttocks and multiple joints, which started 3 years ago as flat lesions and have gradually increased in size.
There was no history of trauma, ingestion of any medications or toxic substances. There were no healthcare visits in the past few years. He was born to a consanguineously married couple (third degree). The patient’s grandfather died in his early 50s due to a sudden heart attack without any previously known comorbidities.
The patient had an elevated blood pressure of 150/98 mm Hg (>99th percentile). On neurological examination, there were no focal deficits or neck rigidity. Physical examinations from the head to the foot revealed the following:
Bilateral arcus cornealis and planar xanthoma (xanthelasma) over the right eyelid (figure 1A,B).
Tuberous xanthomas over both the elbows, which became prominent on flexion (figure 2A–C).
Tuberous xanthomas over the gluteal intertriginous area and planar xanthomas over the lower back (figure 3A).
Tuberous xanthomas on both knees and over both Achilles tendons (figure 3B,C).
Multiple tuberous xanthomas along the medial and lateral borders of both the feet (figure 3D).
Ocular examination showing (A) Arcus cornealis (lipid deposition in the deep corneal stroma and limbal sclera) and (B) Right-sided planar xanthoma (xanthelasma).
Examination of the extensor surfaces of the upper limbs. (A) Left elbow. (B) Right elbow. (C) Prominence on flexion. Tuberous xanthomas are indicated by black arrowheads and planar xanthomas are indicated by red arrowheads.
Examination of the lower segment of the body. (A) Gluteal intertriginous tuberous xanthomas (marked by black arrowheads) with planar xanthomas on the lower back (marked by red arrowheads). (B) Tuberous xanthomas over both knees. (C) Achilles tendon xanthomas. (D) Multiple tuberous xanthomas noted on the medial and lateral borders of both feet.
The xanthomas were located on the extensor surfaces and were soft in consistency, yellowish, non-tender and non-pruritic.
The following findings were looked for on physical examination to identify potential aetiologies for the hypertension: there was no pallor, oedema, growth abnormalities or features of rickets; no evidence of epigastric bruit or abdominal masses (renal causes); no dysmorphism; and no neurocutaneous markers (neurofibromatosis and tuberous sclerosis). There was no goitre or proptosis (hyperthyroidism); no evidence of absent or diminished femoral pulse, low leg pressure relative to arm pressure; and no murmurs, hepatomegaly or bruit over the great vessels (cardiovascular causes, such as coarctation of the aorta and arteriopathy). Angiography, arteriography and genetic studies were not performed as the family could not afford them.
Investigations
Complete lipid panel showed a total cholesterol level of 807 mg/dL (age-based cut-offs N≤170 mg/dL desirable), LDL-C levels of 677 mg/dL (N≤110 mg/dL), high-density lipoprotein levels of 60 mg/dL (N≥35 mg/dL) with a triglyceride level of 136 mg/dL (N≤150 mg/dL). The complete metabolic panel, including renal and liver function tests, was normal. Urinalysis was also within normal limits. Glycated haemoglobin and thyroid function were normal. Results of brain CT, ECG and chest X-ray were normal. Two-dimensional-echocardiography showed no evidence of valvular abnormalities. Renal doppler and ultrasound imaging findings were normal. Retinal examination showed no evidence of retinal vascular changes.
Treatment
Based on the patient’s age at presentation, classical clinical phenotype with markedly elevated plasma cholesterol levels and family history suggestive of premature heart disease, HoFH was diagnosed.
The patient was started on intravenous labetalol infusion. Blood pressure was brought under control in 48 hours, and oral nifedipine was started.6 Oral rosuvastatin 10 mg once daily, oral ezetimibe 10 mg once daily and a low cholesterol diet were started for LDL-C control. The patient’s symptoms completely resolved by day 9 of inpatient care, and he was discharged on day 11 following diet planning and parental education. The parents were advised to check the child’s blood pressure weekly at a nearby primary healthcare centre. Monthly follow-ups at our centre were planned to achieve optimal therapeutic response (LDL-C levels <100 mg/dL).
The patient’s family was consensually and sequentially tested. The patient’s sibling had notable raised lipid profiles (total cholesterol=562 mg/dL, triglycerides=103 mg/dL and LDL-C=537 mg/dL), indicating asymptomatic HoFH. The patient’s father had notably raised cholesterol levels (310 mg/dL) and raised LDL-C levels (242 mg/dL). The mother’s lipid levels (total cholesterol=174 mg/dL, LDL-C=112 mg/dL) were within normal limits.
Outcome and follow-up
The patient and his relatives with deranged lipid profiles were started on rosuvastatin and ezetimibe. On follow-up visits, given the normotension, the patient’s antihypertensives were tapered and stopped 3 weeks after initial presentation. Monthly visits during a 6-month period showed inadequate response to lowering LDL-C levels, requiring sequential uptitration of rosuvastatin from 10 mg/day to 40 mg/day (maximum tolerated dose). Over the course of 6 months, the initial LDL-C levels of 677 mg/dL decreased to 391 mg/dL. Due to the inadequate statin response (<25% fall in LDL-C monthly), PCSK9 inhibitors were considered as second-line treatment; however, the treatment added to the financial burden.1 7 8 The patient’s parents were counselled regarding the need for plasmapheresis, and we requested for a central venous canulation, to which the parents did not consent. Unfortunately, the other second-line medications were not available at our centre; we are in the process of securing alternative funding sources for PCSK9 inhibitors.
Discussion
Familial hypercholesterolaemia (FH) is divided into two subclasses: heterozygous and homozygous. The heterozygous subclass usually presents during adulthood, whereas the homozygous subclass presents within the first decade of life.9 The adult presentation of heterozygous FH can easily be managed with β-hydroxy β-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.10 The homozygous subclass generally presents with xanthomas, raised total cholesterol levels >600 mg/dL, LDL-C levels >500 mg/dL with normal triglyceride and very-low density lipoprotein (VLDL) levels. 1 9 10 Homozygous individuals are highly susceptible to sudden myocardial infarction, supravalvular aortic stenosis and premature atherosclerotic disease within the second decade of life.1 2 5 It is possible to have an overlap between homozygous and heterozygous phenotypes.
The clinical triad of HoFH classically shows elevated LDL-C, xanthomas distributed over the extensor surfaces of the arms and legs, and atherosclerotic cardiovascular disease.3 Xanthomas are yellow-tinged lipid deposits within the connective tissue of the skin and tendons. They range from soft to firm in consistency and are non-pruritic and non-tender in nature. In our patient, the xanthomas were widely distributed over the elbows, knees, feet and gluteal cleft. Additionally, lipid deposition in the deep corneal stroma and limbal sclera presented as arcus cornealis.2 4 10 11
Diagnosis of HoFH is dependent on clinical features, age at presentation and serum lipid studies.1 There may be a history of consanguinity within the family and sudden deaths without any previously known comorbidities.1 2 9 10 12 Genetic testing is not necessary to diagnose HoFH; however, it is recommended.1 5 Exhaustive evaluation in our case failed to show the aetiology for transient hypertension. In our case, hypertension could have be an outcome of hyperlipidaemia-induced hyperviscosity, which showed sequential normalisation on lowering lipid levels.13 14 Sitosterolaemia can also present with a similar clinical phenotype and blood cholesterol levels. This was unlikely in our case, considering that the patient’s father also had dyslipidaemia (likely heterozygote), and that plasma cholesterol levels in patients with sitosterolaemia are extremely sensitive to dietary modification and medications.15 The mother being asymptomatic could have been due to another possible mutation (eg, PCSK9 loss of function mutation and mutation in ApoB) moderating her phenotype.
Treatment of HoFH is done with graded goals to achieve an LDL-C <100 mg/dL. The first line of treatment includes the use of HMG-CoA reductase inhibitors (statins) and cholesterol absorption inhibitors (ezetimibe) with uptitration in dosage to maximally tolerated levels until an end goal is achieved.1 Side effects, such as statin-induced hepatitis and myopathy, may dissuade the use of high-intensity statins, which may be countered by switching over to medium-intensity or low-intensity statins.1 16 Second-line agents, such as PCSK9 inhibitors (evolocumab), microsomal triglyceride transfer protein inhibitors (lomitapide) and angiopoietin-like protein inhibitors (evinacumab), are required in most patients with HoFH as they may completely lack LDL-receptor activities, and drugs dependent on LDL-receptor activities, such as statins, may not be effective. The use of second-line agents has shown considerable therapeutic effects; however, their cost is prohibitive.1 7 17 18 In patients refractory to both treatments, plasma apheresis should be considered as it can help lower the LDL-C levels quickly.1 In patients not responding to conservative therapy, orthotopic liver transplantation is another therapeutic option, though highly invasive.1 Patients with untreated HoFH have a high risk of cardiac-associated mortality. Hence, regular cardiovascular examinations with screening for valvular stenosis may help improve patient prognosis.
Learning points
Homozygous familial hypercholesterolaemia (HoFH) is a rare autosomal dominant disorder typically presenting within the first decade of life with raised total cholesterol levels >600 mg/dL, LDL-C levels >500 mg/dL with normal triglyceride and VLDL levels.
Initial treatment includes the use of HMG-CoA reductase inhibitors and cholesterol absorption inhibitors; however, patients with HoFH are almost completely deficient in LDL-receptor activities, and drugs dependent on LDL-receptor activities, such as statins, may not be effective.
Many patients require second-line agents, such as PCSK9 inhibitors (evolocumab), microsomal triglyceride transfer protein inhibitors (lomitapide) and angiopoietin-like protein inhibitors (evinacumab), with an emphasis on multidrug therapy for improved outcomes.
Patients with untreated HoFH are at a high risk for cardiac-associated mortality; hence, regular cardiovascular examinations with screening for valvular stenosis might help patient prognosis.
In paediatric treatment, screening and management of family members play an important role in holistic care.
Ethics statements
Patient consent for publication
Footnotes
Twitter @corizot
Contributors SBM: Primary physician, identification of case, analysis of workup data, follow-up management and manuscript preparation. CJP: Literature review, follow-up management, manuscript preparation, consent for the case, figure mark-ups and overall presentation.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.