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Case report
peer-reviewed

Hypertension With Brachydactyly Syndrome: A Case Report



Abstract

We describe the case of a 23-year-old African American male who presented to the emergency department complaining of unremitting dyspepsia for the last four months. His blood pressure was incidentally found to be 230/157 mm Hg. The initial admitting diagnosis in the intensive care unit was hypertensive “emergency” as he had also displayed acute kidney injury that was deemed to be superimposed on chronic kidney disease. While the diagnostic work-up of his hypertension was inconclusive, physical examination was impressive for the presence of brachydactyly of the bilateral hands, especially the fourth digits. His feet appeared grossly normal. X-rays (XRs) of the bilateral hands revealed absent distal phalanges and fused middle and distal phalanges of the second digits. XRs of the bilateral feet showed similar findings in addition to the absence or hypoplasia of the lateral cuneiform bones. His family medical history was unknown as the patient was adopted and did not have contact with his biological parents. Given these findings in the setting of uncontrolled hypertension in a young adult, he was diagnosed with hypertension with brachydactyly syndrome.

Introduction

Hypertension with brachydactyly (HTNB) or Bilginturan syndrome is a rare autosomal dominant condition with multiethnic predominance that results in age-dependent and salt-independent hypertension [1]. If left untreated, it results in recurrent strokes in patients less than 50 years of age and a subsequent high mortality rate. Cases of HTNB have been described in North American and Middle Eastern families (i.e., Turkish) [1]. Such patients, if regularly followed by a primary care provider, can be diagnosed and treated during childhood and adolescence. Genetic testing for this syndrome in patients with a supportive phenotype can facilitate family screening and pre-pregnancy genetic counseling.

Case Presentation

A 23-year-old African American male with a medical history of chronic migraines presented to the emergency department complaining of unremitting dyspepsia for the last four months. He also complained of fatigue, ataxia, and orthopnea. He denied diplopia, chest pain, exertional dyspnea, palpitations, lightheadedness, nausea, vomiting, hematemesis, or hematochezia. The patient denied smoking, alcohol, illicit drug use, non-steroidal anti-inflammatory drug (NSAID) use, and recent intravenous (IV) contrast exposure. His family medical history was unknown as the patient was adopted and had no contact with his biological parents. His blood pressure was incidentally found to be 230/157 mm Hg. The patient was admitted to the intensive care unit with the initial diagnosis of hypertensive emergency for which nicardipine drip was instituted. Lab results also showed acute kidney injury (AKI) that was deemed to be superimposed on chronic kidney disease (CKD), among other findings (Table 1).

Test Results  
WBC 10.1 x 103/mL  
Hemoglobin 13.3 g/dL (L)  
Hematocrit 39.2% (L)  
Platelets 268 x 103/uL  
MCV  82.2 fL  
RDW 14.2%  
MCHC 33.9 g/dL  
Glucose  90 mg/dL  
Blood urea nitrogen 21 mg/dL  
Creatinine  1.8 mg/dL (H)  
Creatinine clearance 74 cc/min (L)  
Sodium (mmol/L)  134 mEq/L (L)  
Potassium (mmol/L)  2.9 mEq/L (L)  
Chloride (mmol/L)  98 mEq/L  
Cortisol  27.3 mcg/dL (H)  
TSH  1.51 uIU/mL  
NT-proBNP  5,510 pg/mL (H)  
Urine drug screen  Negative  
Urinalysis 20 ketones, 50 glucose, > 500 protein  
Urine specific gravity  1.1015  
Troponin (ng/mL)  0.16 ng/mL -> 0.12 ng/mL -> 0.35 ng/mL (H)  
 

Acute coronary syndrome was ruled out using several serial electrocardiograms (ECGs) (Figure 1). A transthoracic echocardiogram (TTE) yielded a left ventricular ejection fraction (LVEF) of 40-45% and mild-to-moderate left ventricular wall thickness, among other findings (Figure 2). Cardiac enzyme (troponin) levels were marginally elevated (Table 1). Left heart catheterization showed normal coronary arteries. Optimum medical therapy was instituted with a statin, beta-blocker, renin-angiotensin-aldosterone system (RAAS) antagonist, and arteriolar vasodilator. The aforementioned cardiac enzyme elevation was attributed to demand ischemia secondary to uncontrolled hypertension.

Given the presence of AKI on CKD stage II, a work-up of his non-nephrotic range proteinuria ensued. The nephrology service was consulted. A renal ultrasound showed an echogenic cortex bilaterally suggestive of chronic renal disease. A work-up for glomerulonephritis and secondary hypertension came up negative (Table 2). A subsequent renal artery angiogram was negative for any occlusion or vascular anomaly that could compromise renal blood flow. A renal biopsy revealed focal segmental glomerulosclerosis with microangiopathic changes, severe arteriolosclerosis, interstitial fibrosis, and atrophy. The diagnostic work-up of his uncontrolled hypertension itself was inconclusive given these findings.

Test Results
IgA 65 mg/dL (L)
IgG 702 mg/dL (L)
IgM 72 mg/dL
Acute hepatitis panel Negative
HIV Negative
TPEP 5.5 (L)
SPEP Hypogammaglobulinemia with no monoclonal proteins
Albumin 3.34 g/dL (L)
Alpha-1 globulin 0.35 g/dL
Alpha-2 globulin 0.59 g/dL
Beta globulin 0.62 g/dL
Gamma globulin 0.60 g/dL (L)
Renin 16.9 μIU/mL (H)
Aldosterone 47.5 ng/dL (H)
ANA Negative
C3 11 mg/dL (L)
C4 27 mg/dL
Glomerular basement membrane antibodies Negative
Urine 24-hour protein 766 (H)

Physical examination was impressive for the presence of brachydactyly of the bilateral hands, especially the fourth digits (Figure 3). His feet appeared grossly normal (Figure 4). X-rays (XRs) of the bilateral hands revealed absent distal phalanges in the third through fifth rays and fused middle and distal phalanges of the second digits (Figure 5). XRs of the bilateral feet showed absent distal phalanges of the second through fifth rays and spade configuration of the middle phalanx, in addition to the absence or hypoplasia of the lateral cuneiform bones bilaterally (Figure 6). As an aside, the patient did not have papilledema, and his pupils were equal and reactive to light and accommodation. He also had no appreciable murmur on cardiac examination. His neurologic examination was normal, including cranial nerves.

Given these findings in the setting of uncontrolled hypertension in a young adult, our patient was diagnosed with HTNB syndrome. The patient was discharged home. Genetic work-up could not be initiated since the patient failed to establish a follow-up visit in the clinic.

Discussion

HTNB or Bilginturan syndrome is a rare autosomal dominant condition that was initially described by Bilginturan et al. in 1973 in a Turkish family [1]. Later cases have been found in Canadian and American families, both of English descent [2]. The disease itself is known to cause severe salt-independent, age-dependent hypertension beginning in childhood, which results in significant cerebrovascular disease before the age of 50 [2-3]. It is monogenic for which mutant gene is mapped to the short arm of chromosome 12. The resultant defective gene results in enhanced phosphorylation of the phosphodiesterase 3A (PDE3A) enzyme that results in accelerated vascular smooth muscle proliferation that causes peripheral vasoconstriction [3]. This sustained increase in systemic vascular resistance ultimately causes the uncontrolled hypertension described herein. Additionally, this defective enzyme results in dysregulated PTH-related protein (PTHrP) secretion yielding a pseudohypoparathyroidism-like state and subsequent brachydactyly and short stature [3-4]. Undiagnosed patients are very young and succumb to recurrent strokes. Unlike in our patient, hypertension-related end-organ damage is usually not apparent. An alternative pathophysiological mechanism for the uncontrolled hypertension component of this syndrome has been described. It has been suggested that a neurovascular anomaly in the posterior cranial fossa involving the posterior inferior cerebellar artery and vertebral arteries yields hypersensitivity of carotid and renal baroreceptors [5-6]. These anomalous vessels come directly into contact with the roots of cranial nerves IX and X, resulting in this heightened level of baroreceptor sensitivity [3,5-6]. CT and MRI studies did not show any such culprit vascular anomalies in our patient. Our patient’s uncontrolled hypertension was successfully managed with a beta-blocker, RAAS antagonist, and arteriolar vasodilator.

Conclusions

HTNB or Bilginturan syndrome is a multiethnic disease. Clinicians should screen adolescents or young adults with secondary hypertension for brachydactyly. Early detection and treatment of HTNB will decrease the risk of detrimental end-organ damage and long-term debility in the form of recurrent cerebrovascular accidents such as strokes. Additionally, genetic testing should be considered in patients with suggestive HTNB phenotypes in order to facilitate family screening and pre-pregnancy genetic counseling.


References

  1. Bilginturan N, Zileli S, Karacadag S, Pirnar T: Hereditary brachydactyly associated with hypertension. J Med Genet. 1973, 10:253-259. 10.1136/jmg.10.3.253
  2. Toka HR, Bähring S, Chitayat D, et al.: Families with autosomal dominant brachydactyly type E, short stature, and severe hypertension. Ann Intern Med. 1998, 129:204-208. 10.7326/0003-4819-129-3-199808010-00008
  3. Toka O, Maass PG, Aydin A, et al.: Childhood hypertension in autosomal-dominant hypertension with brachydactyly. Hypertension. 2010, 56:988-994. 10.1161/HYPERTENSIONAHA.110.156620
  4. Levanovich PE, Diaczok A, Rossi NF: Clinical and molecular perspectives of monogenic hypertension [Online ahead of print]. Curr Hypertens Rev. 2019, 10.2174/1573402115666190409115330
  5. Lee CG, Kang K, Yoon RG, Seo JY, Park JM: PDE3A variant associated with hypertension and brachydactyly syndrome in a patient with ischemic stroke caused by spontaneous intracranial artery dissection: a review of the clinical and molecular genetic features. Eur J Med Genet. 2020, 63:103781. 10.1016/j.ejmg.2019.103781
  6. Fan P, Zhang D, Yang KQ, et al.: Hypertension and brachydactyly syndrome associated with vertebral artery malformation caused by a PDE3A missense mutation. Am J Hypertens. 2020, 33:190-197. 10.1093/ajh/hpz151
Case report
peer-reviewed

Hypertension With Brachydactyly Syndrome: A Case Report


Author Information

Rizwan Asim Corresponding Author

Internal Medicine, Texas Tech University Health Sciences Center at Permian Basin, Odessa, USA

Anand Reddy

Nephrology, Medical Center Health System, Odessa, USA

Olga Grigorieva Olson

Internal Medicine, Texas Tech University Health Sciences Center at Permian Basin, Odessa, USA

Joshua A. Ronen

Internal Medicine, Texas Tech University Health Sciences Center at Permian Basin, Odessa, USA

Vivek Prasad

Internal Medicine, Permian Internal Medicine Associates, Odessa, USA


Ethics Statement and Conflict of Interest Disclosures

Human subjects: Consent was obtained by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.


Case report
peer-reviewed

Hypertension With Brachydactyly Syndrome: A Case Report


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