Here, we focus on the differential diagnosis of hypertension in early childhood, while reporting the diagnosis, evaluation, and treatment of a 3-year-old Asian patient with GACI which is a rare genetic disease that affects the circulatory system in general, and the large and medium-sized arteries in particular, throughout the body. We summarize the following aspects of this case next.

Gene mutations and pathogenesis of GACI

GACI is a rare autosomal recessive genetic disorder caused mostly by mutations in the ENPP1 or ABCC6 genes, which cause GACI type 1 and GACI type 2, respectively. The number of affected individuals with ABCC6 variants was small versus affected individuals with ENPP1 variants (9% versus 67%) [7, 10]. Our case had GACI type 2, due to ABCC6 compound heterozygous mutations. So far, only a dozen ABCC6 gene mutations associated with GACI have been reported [11, 12], including missense mutation c.3340C > T, while c.4404-1G > A is a novel mutation site. ABCC6 is responsible for coding the protein of ATP-binding cassette subfamily C, member 6 (ABCC6), whose function is not yet clear [13]. It is assumed that ABCC6 is a transmembrane transporter expressed primarily in hepatocytes and proximal tubular epithelial cells of the kidney [14, 15]. ABCC6 has been shown to influence extracellular ATP levels and therefore plays a role in the pyrophosphate (PPi) generating pathway [15, 16]. PPi inhibits the crystallization and the growth of calcium phosphate crystalline phases such as hydroxyapatite. Patients with GACI as well as Abcc6−/− mice have a reduced plasma PPi level which promotes the deposition of hydroxyapatite in arteries and organs [17].

Clinical features of GACI and the new manifestations of this case

GACI is characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels, resulting in cardiovascular findings (including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly) [8, 18,19,20]. Additional findings can include typical pseudoxanthoma elasticum (PXE)-like skin and retinal manifestations, periarticular calcifications, nephrocalcinosis, development of rickets after infancy, cervical spine fusion, and hearing loss [7, 19]. There is a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 mutations, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively) [21]. But in contrast to the ABCC6 mutations, the incidence of ENPP1 mutations was higher in terms of mortality, rickets, joint calcification, hearing complications, and neurological complications [21].

The majority of GACI patients had an onset during fetal life or within 1 year of birth, and the median age of onset was 3 months [6]. The case in this paper had a late onset age of 45 months. Late-onset (≥ birth 1 week) GACI most commonly involved the coronary, renal, and pulmonary arteries [6]. However, in our patient, arterial calcification occurs first in the lower extremities and in the cervical arteries, which may be related to different genetic phenotypes. During follow-up, she gradually developed scattered calcifications in the aorta abdominalis, superior mesenteric artery, arteria mesenterica inferior, bilateral iliac artery, bilateral upper limb arteries, bilateral subclavian arteries, bilateral lower limb arteries, aortic valve, mitral valve, pulmonary valve, left ventricular endocardium, and the circumflex branch of the coronary artery as measured by vascular B-scan, echocardiography, and coronary artery CTA examination (Table 4). Her left ventricular hypertrophy gradually eased (Table 5) which may be related to smooth blood pressure control. Arterial stenosis, which has been reported, does not necessarily occur at the same time as arterial calcification, and can occur over time in the same vessels as calcification [22]. Our patient also had no evidence of arterial stenosis at the time of diagnosis. However, at the fourth month after the diagnosis of GACI, coronary CTA reexamination revealed the stenosis of the anterior descending coronary artery, circumflex branch and right coronary artery, and the stenosis degree was less than 50% (Table 4). At the same time, the vascular B-scan also found that the flow rate and resistance of both renal arteries increased (Table 5) which further confirmed the possibility of renal microvascular stenosis. In addition, the middle and distal lumen of her right profunda femoral artery were occluded. The cardiovascular complications of GACI (ABCC6 mutation) are mostly reported as heart failure, hypertension, and respiratory failure, while severe hypertension like our case has only been reported in rare cases. We speculate that BP may not be severely elevated in patients with concurrent heart failure. In addition, in terms of organ calcification, we identified some previously unreported abnormalities, including thyroid calcification with abnormal thyroid function and kidney crystallization with hypercalciuria, but found no joint calcification commonly reported in the literature [7]. At the beginning of the disease, B-scan revealed multiple calcifications of the thyroid, accompanied by abnormal thyroid function, showing elevated FT3 and FT4 levels but normal TSH levels, and after a short period of BP control, her thyroid function improved spontaneously. As a result, thyroid dysfunction may be a secondary alteration of GACI for hypertension or organ calcification.

Table 4 Manifestations of coronary CTATable 5 Manifestations of echocardiography and renal artery B-scanGACI and kidney disease

To date, which specific area of the kidney is affected by GACI has been scarcely reported. To our knowledge, in patients with GACI, kidney disease mainly presents as nephrocalcinosis, renovascular hypertension, and kidney failure. Acute kidney failure commonly occurs in infancy [8, 23], while in adulthood it is indicated by a decline in renal tubular reabsorption function [19]. In our case, there was a slightly decreased eGFR and an increase in serum creatinine and proteinuria, which returned to the normal range after antihypertensive therapy. Therefore, we consider that these abnormalities may be related to hypertension and hypoperfusion caused by minor renal vessel stenosis, which is a chronic progressive process. Despite the fact that severe forms of chronic kidney diseases (CKD) have not been described as a consequence of GACI, we still cannot ignore the risk of CKD in adulthood of GACI. Second, the kidney is one of the most common sites of organ calcification in GACI. In addition to renal artery calcification, renal calcification can also manifest as nephrocalcinosis [11]. While medullary nephrocalcinosis is likely a complication from treatment of rickets, cortical nephrocalcinosis likely represents a consequence of ischemia [7]. When Abcc6−/− and Enpp1−/− mice (two established mouse models of ectopic mineralization) were placed on the acceleration diet, they revealed extensive mineralization in the kidney interstitium, primarily affecting the medullary tubules as well as arcuate and renal arteries, whereas when on standard rodent diet, developed nephrocalcinosis only at very late age [24], which may explain why nephrocalcinosis rarely occurs in infants. Of note, in our case, we did not find nephrocalcinosis but did find multiple crystals in the bilateral calyces, which has not been reported in the previous literature and is indeed considered to be one of the common features of another ABCC6 mutant disease, pseudoxanthoma elasticum (PXE) [25]. In addition, this patient had hypercalciuria, which had also not been described previously. Mutations in ENPP1 or ABCC6 lead to the deposition of excess hydroxyapatite particles in the Henle basement membrane of the renal tubules. These particles then grow extending into the medullary interstitium and further towards the papillary surface. The mineral syncytium can lie beneath the uroepithelium and may become exposed to the urinary environment after the loss of uroepithelial integrity [24]. Hypercalciuria could therefore be involved first in the deposition of excess hydroxyapatite particles [24]. The patient was treated with bisphosphonates at a later period and the urinary calcium levels returned to normal for a time, but there was no significant change in the crystallization of the calyces. Regarding the proteinuria of the patient, we considered the following factors to be relevant: her proteinuria gradually normalized as her BP decreased, and it was assumed that hypertension was also involved in the production of proteinuria; CTA showed uneven and delayed local perfusion of the renal parenchyma, and increased renal arterial resistance was found during follow-up, thought to be associated with stenosis of minor arteries in the kidneys, causing ischemic nephropathy.

The differential diagnosis of GACI (ABCC6 mutations)

ABCC6 mutations can manifest as two different diseases, GACI and PXE, which overlap in phenotype and need to be distinguished. Classic PXE, caused by ABCC6 variants, appears as soon as the second decade of life with skin changes and is characterized by mineralization and fragmentation of elastic fibers in the skin, eyes, and cardiovascular system. In contrast, GACI has a younger onset age, a higher mortality rate, an earlier onset of arterial calcification, and a lower incidence of skin and eye lesions. The most commonly calcified arteries in GACI are thoracic and abdominal arteries such as coronary, renal, pulmonary, and aortic arteries. Whereas, PXE has a moderate onset and most affected individuals live a normal life span. Skin and eye lesions occur mostly in the first or second decade of life. Vascular signs (except for claudication) usually become apparent years after the onset of skin and ocular changes. The primary clinical expression of the arterial wall mineralization is intermittent claudication in both lower and upper limbs and peripheral artery disease [26]. In our case, the patient was diagnosed with GACI due to her early age, arterial calcification, and lack of skin and eye lesions. She may, of course, develop PXE-like skin and eye lesions over time, which we should continue to watch.

Treatment and follow-up for GACI

Up to now, there is no curative treatment for GACI. The goal of early diagnosis and treatment in children with GACI is to promote the regression of arterial calcifications and cessation of the development of arterial stenoses. Arterial calcifications may decrease or disappear spontaneously, after treatment, but arterial stenoses usually persist that can cause significant clinical ischemic complications [22]. Classic drugs that promote the regression of arterial calcification are bisphosphonates such as etidronate, pamidronate, and risedronate. This patient had no calcifications in the thoracic and abdominal arteries and no evidence of calcification on a coronary artery CTA performed 1 month after her GACI diagnosis; therefore, no bisphosphonate therapy was initiated immediately. However, 3 months after the diagnosis of GACI, coronary artery calcification was detected during follow-up monitoring, and intravenous pamidronate was initiated. The first day was 0.25 mg/kg, and second and third days were 0.5 mg/kg. After that, treatment was every 2 months as a course of treatment (0.5 mg/kg /d × 3 days) for 4 consecutive courses. Repeated coronary artery CTA, performed 1 year after diagnosis, and compared to the previous coronary artery CTA, reported less coronary calcification. However, bisphosphonates improve calcium salt deposition but do not delay the progression of arterial stenosis, as also shown in our case (Table 4), which was treated with aspirin at the cardiologist’s recommendation. During the bisphosphonate administration, the patient did not develop rickets and only showed a transient decrease in blood calcium, which quickly returned to normal upon administration of calcium supplements. In addition, arterial hypertension is also prominent in GACI. Since hypertension in GACI is most likely caused by stenosis of the renal arteries, it may be beneficial to use ACEI or ARB. Moreover, ectopic arterial calcification can manifest in any systemic organ, thus requiring individualized treatment for each organ dysfunction such as cardiac failure, rickets, PXE-like eye lesions, and hearing loss. These systemic diseases need to be tracked by a comprehensive medical team involving multiple specialties for their management.