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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 37-39

Cantu and alport syndrome in a young girl

1 Department of Paediatrics, Caritas Medical Centre, Kowloon, Hong Kong, China
2 Department of Pediatrics, The Hong Kong Children's Hospital, Kowloon, Hong Kong, China
3 Department of Health, Clinical Genetic Service, Kowloon, Hong Kong, China

Date of Submission06-Feb-2021
Date of Decision19-May-2021
Date of Acceptance16-Feb-2022
Date of Web Publication28-Jun-2022

Correspondence Address:
Chi San Wai
Department of Paediatrics, Caritas Medical Centre, 111 Wing Hong Street, Sham Shui Po, Kowloon, Hong Kong
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajpn.ajpn_9_21

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We report a 9-year-old girl with nephritis, dysmorphism, and short stature. She was diagnosed to have Cantu syndrome and Alport syndrome by whole-exome sequencing. Diagnosis of patients with two or more syndromes is challenging due to blended phenotypes. This case illustrates the clinical utility of exome testing in patients with medical complexity.

Keywords: Adrenal insufficiency, exome sequencing, hematuria, proteinuria

How to cite this article:
Wai CS, Alison Ma LT, Lee LK, Luk HM, Lau WL. Cantu and alport syndrome in a young girl. Asian J Pediatr Nephrol 2022;5:37-9

How to cite this URL:
Wai CS, Alison Ma LT, Lee LK, Luk HM, Lau WL. Cantu and alport syndrome in a young girl. Asian J Pediatr Nephrol [serial online] 2022 [cited 2022 Aug 18];5:37-9. Available from: https://www.ajpn-online.org/text.asp?2022/5/1/37/348538

  Introduction Top

The 9-year-old girl presented with nephritis and dysmorphism with short stature. Renal biopsy showed features of Alport syndrome. Further investigations revealed growth hormone deficiency and adrenal insufficiency, which is uncommon in Alport syndrome. Whole-exome sequencing was performed in view of atypical presentation and showed genotype of both Alport and Cantu syndromes. Dual molecular diagnosis is recognized in around 1%–2% of genome-wide testing. The blended phenotype in patients complicates the diagnosis and this case illustrates the use of whole-exome sequencing in this group of patients.

  Case Report Top

A 9-year-old girl was presented to the pediatric unit for abdominal distension, puffy eyes, and frothy urine for 2 weeks. She was noted to have poor growth for 2 years. Her mother had chronic kidney disease of unknown cause for 30 years of age. The patient weighed 24.5 kg (25th percentile), and her height was 121 cm (below 3rd percentile). She was prepubertal with a growth velocity of 3.8 cm in 1 year (−1.56 standard deviation scores, SDS). Her blood pressure was 120/84 mm Hg, at 99th percentile. She had broad nasal bridge, wide mouth, anteverted nares, big tongue, and gum hypertrophy [Figure 1]. She also had finger clubbing, generalized hypertrichosis, and joint hyperlaxity. She had periorbital swelling, distended abdomen with ascites. Urinalysis showed proteinuria 3+ and microscopic hematuria.
Figure 1: Clinical photographs of the patient show dysmorphic and coarse facial features, gum hypertrophy, and finger clubbing

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Urine examination showed nephrotic range proteinuria with spot protein to creatinine ratio of 10.25 mg/mg and over 10% dysmorphic red blood cells. Blood tests showed hypoalbuminemia (24 g/L), creatinine 0.42 mg/dL, and cholesterol 305.5 mg/dL. Complement C3 and C4 levels were 115 mg/dL and 22 mg/dL, respectively. Antinuclear antibodies and antinuclear cytoplasmic antibodies were negative. Ultrasound scan revealed increased renal parenchymal echogenicity in normal-sized kidneys, with left side 10 cm and right side 9.7 cm. Kidney biopsy showed focal segmental glomerulosclerosis with interstitial foam cells, diffuse splitting, and reduplication of basement membrane with basket-weave-like appearance and electron-dense dot-like structures, consistent with Alport syndrome. Liver, kidney, and thyroid function tests and electrolytes levels were normal. The radiograph of the left hand and wrist showed bone age of 7 year and 10 months. Skeletal survey did not show features of osteochondrodysplasia. Insulin-like growth factor 1 level was low at 42 μg/L. Glucagon stimulation test showed inadequate peak growth hormone at 2.7 μg/L and cortisol level at 240 nmol/L, which was confirmed with clonidine stimulation test (peak growth hormone level: 4 μg/L) and low-dose synacthen stimulation test (peak cortisol 356 nmol/L; reference cutoff 440 nmol/L). Magnetic resonance imaging of the pituitary showed an increased pituitary gland height of 8.4 mm (normal 5.09 ± 1.36 mm for her age) without intraglandular defect or mass.

Echocardiogram was normal without evidence of congenital heart disease or pulmonary hypertension. Hearing and eye evaluation was normal. Magnetic resonance imaging of the brain and pelvis did not show any arteriovenous malformation or vascular tortuosity. There was a T2 hyperintense nonenhancing lesion at the lower mesorectum and rectal wall thickening suggestive of a lymphatic malformation.

Whole-exome sequencing showed a heterozygous variation in ABCC9 (c.3746 G>A), which was classified as a variant of uncertain significance and is associated with Cantu syndrome. A heterozygous mutation in COL4A5 (c. 3203del) associated with Alport syndrome was also found, which was classified as pathogenic and found to be present in the patient's mother and younger brother.

Management and course

The patient was treated with furosemide for fluid retention and ramipril for proteinuria. Proteinuria responded fairly with ramipril with spot urine protein-to-creatinine ratio ranging from 0.95 to 2.54 mg/mg. Hydrocortisone replacement and growth hormone injection were commenced. Her latest height was at 10th percentile and her growth velocity improved with a height gain of 8.5 cm in 4 months.

The patient's mother was followed up in mainland China for her renal condition. She is on therapy with antihypertensive agents and sodium bicarbonate, and her serum creatinine level was 3.57 mg/dl, without any proteinuria. The patient's 8-year-old brother had intermittent proteinuria since the age of 4 years; the urine protein-to-creatinine ratio was 0.36–0.56 mg/mg. He had normal blood levels of creatinine and bilateral moderate sensorineural hearing impairment.

  Discussion Top

We report a 9-year-old girl with nephritis associated with a heterozygous variant in COL4A5 and histological findings suggestive of Alport syndrome. She was noticed to have dysmorphism and short stature, which was not a common feature in Alport patients. Investigations including whole-exome sequencing revealed a dual molecular diagnosis of Alport and Cantu syndrome.

Cantu syndrome is a rare disease caused by heterozygous pathogenic variant in ABCC9 or KCNJ8, which results in a gain of function of SUR2 or Kir6.1 subunits of KATP channels. These channels are mainly found in cardiac, skeletal, smooth muscle, and endothelial tissues. The diagnosis is based on clinical findings and confirmed by the detection of a pathogenic variant in the above genes. Clinical features of patients with Cantu syndrome include congenital hypertrichosis, distinctive facial features, cardiac and skeletal anomalies, and vascular malformation or tortuosity.[1] Our patient had some of the dysmorphic features without cardiac and skeletal abnormalities. Growth hormone deficiency and adrenal insufficiency in this patient are possibly related to Cantu syndrome, with a few cases reported to have pituitary dysfunction including growth hormone deficiency, pituitary hyperplasia, enlarged sella turcica, and nonfunctioning pituitary macroadenomata.[2] MRI did not reveal any vascular malformation but showed suspected lymphatic malformation at the mesorectum. Dilated lymph vessels or lymphedema has been reported in patients with Cantu syndrome.[3] SUR2 and Kir6.1 subunits were expressed in mouse lymphatic muscle and Kir6.1 subunits in lymphatic endothelium. The gain of function in these subunits could result in impaired lymphatic contractions and drainage.[4] By whole-exome sequencing, a novel missense variant c.3746G>A in ABCC9 gene was detected. This pathogenic variant is located at the ABC transporter type 1 transmembrane domain and is a de novo change.

During exome testing, a heterozygous pathogenic variant in the COL4A5 gene c.3203del was also detected. We suggest that the renal manifestations of this patient are due to Alport syndrome, which is also supported by features on renal biopsy. COL4A5-related Alport syndrome in our patient is inherited in an X-linked manner. The same genetic variation was also found in her mother and younger brother. Females with X-linked Alport syndrome are heterozygotes, so it is expected that our patient would present with a milder phenotype.[5] Heterozygous females do not have a significant genotype–phenotype correlation as compared to males and have variable disease outcomes from normal urinalysis to end-stage kidney disease (ESKD).[6] Her proteinuria improved with angiotensin-converting-enzyme inhibitor and she had no hearing and ocular involvement. In X-linked Alport syndrome, females have a lower risk of developing ESKD and hearing impairment compared to males. Female patients who have recurrent gross hematuria, proteinuria, and hearing impairment would have a higher risk of developing ESKD.[5]

Dual molecular diagnosis is now recognized in around 1%–2% of genome-wide testing.[7],[8] So far, there is no well-recognized explanation for dual syndromes. It was also found that consanguinity was not related to multiple genetic diagnoses as different studies have reported de novo variants in those patients from consanguineous families. For dual diagnosis with Turner syndrome, it was noticed that aneuploidies of autosomes were largely associated with non-mosaic patients. It was postulated that dual diagnosis may be caused by the same meiotic error.[9] Diagnosis of those patients is clinically challenging, as the overlapping features and additive effect result in a blended phenotype. Some may initially diagnose as an apparent atypical presentation of one of the diseases.

In summary, we present a young girl with both Alport and Cantu syndromes. She would require long-term follow-up with regard to her endocrine, nephrology conditions as well as cardiovascular surveillance. This case demonstrates the clinical utility of exome testing in patients with complex multisystem abnormalities.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Grange DK, Nichols CG, Singh GK. Cantú syndrome and related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle Gene Rev 2014. Available from: Cantú Syndrome - GeneReviews® - NCBI Bookshelf.  Back to cited text no. 1
Theis NJ, Calvert T, McIntyre P, Robertson SP, Wheeler BJ. Cantu syndrome and hypopituitarism: Implications for endocrine monitoring. Endocrinol Diabetes Metab Case Rep 2019;2019:EDM190103.  Back to cited text no. 2
García-Cruz D, Mampel A, Echeverria MI, Vargas AL, Castañeda-Cisneros G, Davalos-Rodriguez N, et al. Cantu syndrome and lymphoedema. Clin Dysmorphol 2011;20:32-7.  Back to cited text no. 3
Davis MJ, Kim HJ, Zawieja SD, Castorena-Gonzalez JA, Gui P, Li M, et al. Kir6.1-dependent KATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain-of-function. J Physiol 2020;598:3107-27.  Back to cited text no. 4
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, et al. X-linked Alport syndrome: Natural history and genotype-phenotype correlations in girls and women belonging to 195 families: A European Community Alport Syndrome Concerted Action study. J Am Soc Nephrol 2003;14:2603-10.  Back to cited text no. 5
Gong WY, Liu FN, Yin LH, Zhang J. Novel mutations of COL4A5 identified in Chinese families with X-linked alport syndrome and literature review. Biomed Res Int 2021;2021:1-10.  Back to cited text no. 6
Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014;312:1870-9.  Back to cited text no. 7
Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med 2017;376:21-31.  Back to cited text no. 8
Jones KL, McNamara EA, Longoni M, Miller DE, Rohanizadegan M, Newman LA, et al. Dual diagnoses in 152 patients with Turner syndrome: Knowledge of the second condition may lead to modification of treatment and/or surveillance. Am J Med Genet A 2018;176:2435-45.  Back to cited text no. 9


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