Reversal of cardiac and renal damage in a teenager with hypertension: A case report

Abstract

The authors describe the case of a 16‐year‐old male who was incidentally found to have a blood pressure of 200/? mmHg 6 months previously due to blurred vision and was diagnosed with “high risk of hypertension grade 3, renal insufficiency, hypertensive encephalopathy, hypertensive heart disease, and fundus hemorrhage” after relevant examinations were performed. His blood pressure fluctuated around 120/90 mmHg after beginning antihypertensive treatment. While the diagnostic work‐up of his hypertension was inconclusive, he had severe hypertension with brachydactyly type E and short stature on physical examination. The patient's cardiac damage and renal insufficiency ultimately returned to normal after strict blood pressure control, suggesting that hypertension and brachydactyly syndrome alone do not cause cardiac and renal damage.

1. BACKGROUND

In 1973, Bilginturan was the first to describe a new syndrome in a large nonconsanguineous Turkish family. ¹ Hypertension and brachydactyly syndrome (HTNB), also known as Bilginturan syndrome (Online Mendelian Inheritance in Man (OMIM) #112410), is a rare autosomal dominant genetic disease, a form of monogenic inherited hypertension, and its pathogenic gene is phosphodiesterase 3A (PDE3A). HTNB is characterized by brachydactyly type E (BDE), small stature, severe salt‐independent but age‐dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral‐ventrolateral medulla, altered baroreflex blood pressure regulation, and death from stroke before 50 years of age when untreated. ² Here, we report a case with reversal of cardiac and renal damage in a teenager with HTNB to improve the awareness of this disease and the ability to diagnose and treat it.

2. CASE REPORT

A student, a 16‐year‐old Chinese male with a more than half a year history of hypertension, presented to the clinic of Henan Province People's Hospital in April 2022. Seven months prior, the patient visited a local hospital because of “blurred vision,” and his blood pressure was incidentally measured to be high, at 200/? mmHg, without any accompanying symptoms.

In July 2021, in the untreated state, supine RAS: renin 76.109 pg/mL, aldosterone 190.853 pg/mL, angiotensin II 92.399 pg/mL, ARR 2.51; Orthostatic RAS: renin 89.207 pg/mL, aldosterone 431.197 pg/mL, angiotensin II 90.202 pg/mL, ARR 4.83. 3‐methoxytyramine, metanephrine, and normetanephrine were all in the normal ranges. Cardiac ultrasound indicated left ventricular wall thickening 14 mm and EF 62%. Serum creatinine 116 μmol/L. Fundus photography showed bilateral retinal vein occlusion and bilateral hypertensive retinopathy. Renal dynamic imaging showed that GFR was 23.9 mL/min on the left side and 28.5 mL/min on the right side, indicating poor blood perfusion and impaired function of both kidneys. Oral antihypertensive medication had been started, but he had forgotten the medication. However, his blood pressure remained poorly controlled.

In August 2021, he was referred to another hospital, and relevant examinations were performed. His renal function test results were as follows: total 24‐hour urine protein, 0.75 g; urine microalbumin/urine creatinine (UACR), 16.94. Cardiac ultrasound indicated uniform thickening of the interventricular septum and left ventricular wall, consistent with hypertensive cardiac changes. Cranial magnetic resonance imaging (MRI) + magnetic resonance angiography (MRA) showed multiple abnormal signals in the right temporal lobe; bilateral insula; and bilateral periventricular, occipitoparietal, and left frontal lobes, and hypertensive encephalopathy was a possible diagnosis. The right anterior cerebral artery, segment A1, was fibrous. CT scan of bilateral adrenal glands and kidneys showed no abnormalities. Renal artery MRA showed stiffness of both renal arteries, uneven lumen, and focal stenosis at the beginning of the left renal artery bifurcation, which suggested the possibility of arteriosclerosis. He was diagnosed with “high risk of hypertension grade 3, renal insufficiency, hypertensive encephalopathy, hypertensive heart disease, and fundus hemorrhage.” The patient was given benidipine 8 mg qd, Entresto 200 mg bid, terazosin 2 mg tid, and bisoprolo 2.5 mg qd. His blood pressure fluctuated at 110−130/80–95 mmHg after discharge from the hospital.

In April 2022, his re‐examination results were good. Dynamic blood pressure results were as follows: the daily average was 128/69 mmHg, the daytime average was 130/71 mmHg, and the nighttime average was 117/61 mmHg. The most important blood biochemistry parameters, including renal function, cardiac ultrasound, total 24‐h urine protein, liver function, blood lipids, glycosylated hemoglobin, routine blood tests, urine tests, and sex hormones, were within the normal ranges. The ACTH rhythm: 39.6 pg/mL (08:00), 21.9 pg/mL (16:00), 10.9 pg/mL (00:00). The Cortisol rhythm: 10.89 μg/dL (08:00), 5.7 μg/dL (16:00), 0.8 μg/dL (00:00). The 24 h urine free cortisol 206.48 μg/24 h. On cardiac ultrasound, all cardiac chambers showed average internal diameters, the left ventricular wall thickness was moderate, and the pulmonary artery indicated mild reflux. Renal dynamic imaging showed that GFR was 43.98 mL/min on the left side and 56.9 mL/min on the right side, indicating the blood perfusion and function of the right kidney were normal, while the blood perfusion of the left kidney was normal and the function of the left kidney was slightly reduced (Table 1).

TABLE 1.

Changes in the four examinations of the patient.

	Cardiac ultrasound							Renal dynamic imaging
Time	Left ventricular wall thickness/mm	Interventricular septal thickness/mm	Left Atrium Diameter/mm	Left Ventricular Diameter/mm	EF/%	Serum creatinine /μmol/L	Total 24‐h urine protein/g	Right side GFR/mL/min	Left side GFR/mL/min
July 2021	14↑	14↑			62	116↑
August 2021	16↑	16↑	28	39	64	96	0.75 g↑	23.9↓	28.5↓
February 2022	12↑	12↑			63
April 2022	9	8	33	29	66	86	0.06 g	56.9	43.98

The patient had no extraordinary personal history, he was born full term; he was unmarried and childless. In addition, his family history was not remarkable; his father had hypertension, and his mother and two sisters were all healthy. However, in the clinic, the patient and his mother presented with short stature; the patient had a height of 160 cm, a weight of 66.6 kg, a body mass index (BMI) of 26.02 kg/m², E‐shaped short fingers on both hands, and normal intellectual and mental development (Figure 1).

FIGURE 1.

Hand picture (from left to right, the patient's mother, the patient, and the doctor).

Improved orthopantomograms of the hands and feet suggested the presence of metacarpal shortening. The orthopantomogram of the patient's hands showed no obvious abnormality in the bone quality of either hand; the 5th metacarpal bone of the left hand was shorter, and the bone age reached the level of early male youth. Anteroposterior radiographs of the feet showed no obvious abnormalities in the left and right feet. (Figure 2) The orthopantomogram of the patient's mother's hand showed that the 4th and 5th metacarpals on the left hand and the 3rd and 5th metacarpals on the right hand were shortened. Her feet orthopantomograms also normal.

FIGURE 2.

Orthopantomogram of the patient's hands and feet.

We collected 4 mL of peripheral blood from the patient and sent it for next‐generation sequencing (NGS) + Sanger sequencing to screen for monogenic hypertension. The results showed that the patient carries a mutation in the PDE3A gene, c.374C > T, a heterozygous missense variant (PDE3A:p.Ala125Val het) highly suspected to be causative for HTNB, which is consistent with the subject's clinical features. Family verification showed that this mutation was inherited from the patient's mother (N2200214‐2); his younger sister (N2200214‐4) also carries this variant. Neither the patient's father (N2200214‐1) nor elder sister (N2200214‐3) harbored this variant (Figure 3).

FIGURE 3.

Sanger sequencing results and family tree.

The patient's medication regimen was amlodipine 5 mg bid, Entresto 200 mg qd, and terazosin 2 mg tid. In July 2023, we conducted a telephone follow‐up, and the patient reported that his blood pressure was usually controlled at 130/80 mmHg or lower, with no other particular discomfort. His re‐examination results at the local hospital were normal.

3. DISCUSSION

Software predicts that this patient's variant may exert an influence on protein function; the amino acids at this position are highly conserved in vertebrates, and a mutation at a nearby locus has been repeatedly reported to be causative for HTNB. HTNB is a rare autosomal dominant genetic disease, a form of monogenic inherited hypertension. ³ HTNB is caused by gain‐of‐function mutations in the PDE3A gene. PDE3A plays a prominent role in the heart, vascular smooth muscle cells (VSMCs), oocytes, and platelets. ⁴ The mutated PDE3A enzymes are highly active, the phosphorylation mode changes, they participate in abnormal protein‒protein interactions, and their location is abnormal. ⁵ PDE3A controls blood pressure independent of the renin‐angiotensin‐aldosterone system and salt reabsorption by the kidney by influencing VSMC signaling and proliferation. ⁶

Surprisingly, despite lifelong severe hypertension, HTNB is not associated with hypertension‐induced cardiac or kidney damage. In addition, hypertensive retinopathy is also absent in this form of inherited hypertension. ⁷ The encoded superactive PDE3A enzymes have dual functions: on the one hand, they increase peripheral vascular resistance and cause hypertension through vascular smooth muscle; on the other hand, through cardiomyocytes, they protect against heart damage caused by hypertension. ⁸ Animal model data also suggest that the PDE3A mutations did not affect the kidney, cause proteinuria, or perturb renal function in the mutant animals. ⁶ Thus, the transgenic mouse models resemble patients, who aside from stroke also had little evidence of target‐organ damage, and hardly deviate from values observed in patients with essential hypertension. ⁹

At present, there is no radical cure for HTNB. Treatment aims to alleviate patient symptoms, control the development of complications, and improve appearance characteristics. Most treatments involve antihypertensive drugs to control blood pressure, bone surgery, and other symptomatic treatments. A prospective clinical trial showed that the blood pressure reduction in this monogenic form of hypertension was similar to that of other single‐drug trials in essential hypertension. Beta‐blockers, calcium antagonists, alpha blockers, and angiotensin‐converting enzyme (ACE) inhibitors all improved blood pressure without significant differences. Multidrug therapy is necessary for the treatment of patients. ¹⁰

4. CONCLUSIONS

We treated a HTNB patient with reversal of cardiac and renal damage. We hope to use this case to enrich our understanding of HTNB, and studies of more patients with follow‐up are necessary.

AUTHOR CONTRIBUTIONS

Huiyu Du takes primary responsibility for this paper. Shilei Gao, Wenyong Dong, Qi Huang, Huiyun Qu, Chen Zhang, Linya Guo, Zhilan Liu, and Min Liu reviewed this manuscript. Huiyu Du: Data curation, writing–original draft preparation, and investigation. Yalei Shi: Data curation, writing‐original draft preparation, and visualization. Wenyong Dong: Formal analysis and writing–review & editing. Qi Huang: Writing‐original draft preparation and investigation. Huiyun Qu: Data curation. Chen Zhang: Writing–review & editing. Linya Guo: Writing‐review & editing. Zhilan Liu: Data curation. Min Liu: Writing–review & editing.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

Du H, Gao S, Dong W, et al. Reversal of cardiac and renal damage in a teenager with hypertension: A case report. J Clin Hypertens. 2024;26:295–298. 10.1111/jch.14769

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study. This article has been approved by the Ethics Committee of Henan Provincial People's Hospital. There were no clinical trials in this case report.