Cantú Syndrome

Clinical characteristics.

Cantú syndrome is characterized by congenital hypertrichosis; distinctive coarse facial features (including broad nasal bridge, wide mouth with full lips and macroglossia); enlarged heart with enhanced systolic function or pericardial effusion and in many, a large patent ductus arteriosus (PDA) requiring repair; and skeletal abnormalities (thickening of the calvaria, broad ribs, scoliosis, and flaring of the metaphyses). Other cardiovascular abnormalities may include dilated aortic root and ascending aorta with rare aortic aneurysm, tortuous vascularity involving brain and retinal vasculature, and pulmonary arteriovenous communications. Generalized edema (which may be present at birth) spontaneously resolves; peripheral edema of the lower extremities (and sometimes arms and hands) may develop at adolescence. Developmental delays are common, but intellect is typically normal; behavioral problems can include attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, anxiety, and depression.

Diagnosis/testing.

The diagnosis of Cantú syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in ABCC9 or KCNJ8 identified by molecular genetic testing. Some individuals with a clinical diagnosis of Cantú syndrome have not had a pathogenic variant identified in either gene, suggesting the existence of another as-yet unidentified causative gene.

Management.

Treatment of manifestations: Surgical or device closure of PDA in infancy or early childhood as needed. Pericardiocentesis and pericardial stripping as needed to treat pericardial effusion. Compression stockings for peripheral edema; shaving and (in teenagers and adults) use of depilatories or laser hair removal for hypertrichosis; bracing and/or surgery as needed for scoliosis; individualized management for migraine headaches and developmental delays if present.

Surveillance: Yearly echocardiogram and electrocardiogram to monitor cardiac size and function, as well as for evidence of pericardial effusion. Clinical evaluation and cardiac biomarkers to monitor late development of high-output cardiac failure. Monitor for evidence of peripheral edema annually starting in adolescence and for scoliosis with physical examination, followed by spine radiographs as needed. Monitor for a history of persistent headaches or other neurologic symptoms, which may require brain imaging for cerebral vasculature abnormality and evaluation by a neurologist.

Evaluation of relatives at risk: If the pathogenic variant in an affected family member is known, relatives at risk who are suspected of having Cantú syndrome can be offered molecular genetic testing to clarify their genetic status. Family members who are affected should be evaluated and monitored for cardiac manifestations, scoliosis, and peripheral edema.

Genetic counseling.

Cantú syndrome is inherited in an autosomal dominant manner. Each child of an individual with Cantú syndrome has a 50% chance of inheriting the pathogenic variant and being affected. Prenatal and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

Cantú syndrome should be suspected in individuals with a combination of the following:

• Congenital hypertrichosis: excess hair growth on scalp, forehead, face, back, and limbs (see Figure 1 and Figure 2)
• Craniofacial dysmorphic features: coarse facial features, epicanthal folds, broad nasal bridge, anteverted nares, long philtrum, macroglossia, wide mouth, and full lips (see Figure 1)
• Enlarged heart with enhanced systolic function or pericardial effusion (see Figure 3 and Figure 4)
• Large patent ductus arteriosus (PDA) requiring repair
• Characteristic skeletal abnormalities: thickening of the calvaria (see Figure 3), broad ribs, platyspondyly, ovoid vertebral bodies, scoliosis, narrow thorax and shoulders, pectus carinatum, hypoplastic ischium and pubic bones, Erlenmeyer-flask-like long bones with metaphyseal flaring (see Figure 3 and Figure 4), narrow obturator foramen, and coxa vara

Figure 1.

Woman age 40 years (A, D), girl age 16 years (B, E), and girl age 11 years (C, F) with Cantù syndrome A, B, C. Facial appearance showing hirsutism of the forehead with low frontal hairline and coarse features

Figure 2.

Girl age 11 years (A, B) and girl age 16 years (C) with Cantù syndrome A. Narrow thorax and pectus carinatum deformity

Figure 3.

Woman age 40 years with Cantù syndrome A. Chest x-ray showing marked cardiomegaly

Figure 4.

Girl age 16 years with Cantù syndrome A. Chest x-ray showing cardiomegaly

Establishing the Diagnosis

The diagnosis of Cantú syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in ABCC9 or KCNJ8 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Cantú syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, approximately 150 individuals with a clinical diagnosis of Cantú syndrome have been identified; a pathogenic variant in ABCC9 or KCNJ8 has been identified in 107 individuals [Grange et al 2019]. The following description of the phenotypic features associated with this condition is based on this report.

Prenatal. Many pregnancies with a fetus with Cantú syndrome are complicated by polyhydramnios, leading in some instances to repeated amniotic fluid reductions as well as preterm labor and delivery.

Newborns. All newborns with Cantú syndrome have hypertrichosis with thick scalp hair and excessive hair growth on the forehead, face, back, and extremities. Some have thick and/or curly eyelashes. The hypertrichosis usually persists over time.

Many newborns have macrosomia (large birth weight and birth length) and macrocephaly.

Generalized edema at birth (observed on occasion) usually resolves spontaneously.

Growth. Ultimate adult height is usually within the normal range; however, short stature has been seen in a few individuals.

Macrocephaly, often present at birth, typically persists throughout life. Some individuals who do not have macrocephaly at birth have developed progressive macrocephaly in childhood.

Skeletal abnormalities are usually asymptomatic and identified on radiographs. Characteristic skeletal abnormalities have included thickening of the calvaria, broad ribs, platyspondyly, ovoid vertebral bodies, scoliosis, narrow thorax and shoulders, pectus carinatum, hypoplastic ischium and pubic bones, Erlenmeyer-flask-like long bones with metaphyseal flaring, narrow obturator foramen, and coxa vara.

Gastroesophageal reflux is reported by just under half of individuals. A smaller percentage report intestinal dysfunction characterized by chronic constipation or slow intestinal motility.

Cardiac findings include the following:

• Cardiac enlargement, with increased ventricular mass but normal chamber wall thickness and enlarged chambers of the heart, often present at birth. Despite the enlarged cardiac chambers, cardiac function is typically normal and ventricular contractility is increased on imaging studies [Grange et al 2006, Grange et al 2019]. Some patients note exercise intolerance, but others have been able to participate in organized sports without difficulty.
• Patent ductus arteriosus (PDA) in 58% (and described as extremely large in some), often requiring surgical closure in infancy or early childhood
• Bicuspid aortic valve with and without stenosis
• Pericardial effusion in about 25% of affected individuals. Small pericardial effusions may be asymptomatic; large fluid accumulations result in symptoms such as exercise intolerance and require intervention.
• Dilated aortic root and ascending aorta are present in about two thirds of individuals. The natural history is poorly understood. However, development of an aortic aneurysm is rare. Aortic aneurysm requiring surgical intervention was reported in one individual with an ABCC9 pathogenic variant [Hiraki et al 2014].

Tortuous vascularity including tortuous retinal vessels and multiple tortuous pulmonary arteriovenous communications have been reported [Scurr et al 2011, Grange et al 2019]. Abnormal tortuous vasculature in the brain is present in essentially all individuals who have been imaged specifically [Leon Guerrero et al 2016, Grange et al 2019].

Pulmonary hypertension has been reported in infants and young children, although the natural history is not well understood [Cantú et al 1982, Robertson et al 1999, Lazalde et al 2000, Kobayashi et al 2010, Scurr et al 2011]. In one child, pulmonary hypertension secondary to partial pulmonary venous obstruction was associated with severe mitral valve regurgitation that spontaneously resolved by age eight years [Kobayashi et al 2010]. In another individual, progressive (and ultimately fatal) pulmonary hypertension was reported [Park et al 2014]. In the majority of cases, pulmonary hypertension is mild and improves with age [Grange et al 2019].

Generalized edema, which may be present at birth, spontaneously resolves. Subsequently, edema involving the lower extremities and occasionally the arms and hands may develop over time, usually in adolescence or early adulthood. Puffiness of the eyelids is often observed. In one individual, lymphangiography demonstrated dilated lymphatic vessels in the legs with delayed lymphatic drainage [García-Cruz et al 2011]. In contrast, lymphatic studies were normal in another individual [Scurr et al 2011]. Therefore, it is unclear at this time whether the observed swelling is edema or lymphedema.

Intellect. Although the majority of affected individuals have normal intellect, mild learning disabilities and/or developmental delays have been observed, including delay in acquisition of early motor milestones (most likely related to decreased muscle tone) and delay in speech development. Ultimately, most affected individuals attend regular schools, and some are described as having a high IQ [Scurr et al 2011, Grange et al 2019].

Seizures are reported in about one quarter of individuals. Febrile, tonic-clonic, and absence seizure types have been observed as well as temporal lobe epilepsy.

Headaches are reported by many individuals, especially migraine-type headaches with associated aura, photophobia, and phonophobia, and occasionally with transient hemiparesis.

Behavioral problems have been reported in some individuals, including anxiety, mood swings, obsessive-compulsive disorder, and tics [Scurr et al 2011, Grange et al 2019]. Attention-deficit/hyperactivity disorder, autism spectrum disorder, and depression may also be present. Many individuals have self-reported these issues.

Features of a connective tissue abnormality are observed in many individuals with Cantú syndrome, including wrinkled or loose skin especially at birth, deep palmar and plantar creases, and joint hyperextensibility. Some have decreased subcutaneous fat with the appearance of a muscular build in childhood.

Less frequent features

• Umbilical hernia
• Pyloric stenosis
• Poor intestinal motility [Grange et al 2019]
• Ptosis
• Craniosynostosis involving the sagittal and coronal sutures in one individual [Hiraki et al 2014]
• Increased frequency of infections, raising the possibility of immune dysfunction [Scurr et al 2011, Grange et al 2019]
• Growth hormone deficiency in a few individuals [Cooper et al 2014, Grange et al 2019]
• Panhypopituitarism [Grange et al 2019, Theis et al 2019] and pituitary adenoma [Marques et al 2018] in a few individuals

The three individuals reported thus far with a pathogenic variant in KCNJ8 had typical clinical features seen in Cantú syndrome [Brownstein et al 2013, Cooper et al 2014, Chihara et al 2020]. The individual reported by Brownstein et al [2013] had the following additional abnormalities:

• Brain MRI: cerebral atrophy and thin corpus callosum
• Multiple tortuous venous collaterals and lack of flow in the inferior sagittal sinus
• Systemic vasculature: dilated hepatic and celiac arteries, dilated and tortuous intrahepatic arteries and veins

Genotype-Phenotype Correlations

Current information about genotype-phenotype correlation in Cantú syndrome is limited.

No significant genotype-phenotype correlations for ABCC9 or KCNJ8 have been identified.

Penetrance

Penetrance for Cantú syndrome in familial cases reported thus far appears to be complete although with variable expression [Grange et al 2019]. In a few families, somatic mosaicism for an ABCC9 variant has been identified in one of the parents, resulting in much milder phenotypic manifestations [Grange et al 2019; DK Grange, unpublished].

Nomenclature

Cantú syndrome may also be referred to as hypertrichotic osteochondrodysplasia.

Prevalence

The prevalence of Cantú syndrome is unknown. To date, about 150 individuals have been reported with Cantú syndrome. Two previously reported conditions, acromegaloid facial appearance (AFA) syndrome and hypertrichosis with acromegaloid facial features (HAFF) syndrome, are now realized to be cases of Cantú syndrome with variable and sometimes milder phenotypic features. Cantú syndrome has been reported worldwide and in all ethnic groups.