Neonatal dilated cardiomyopathy and cardiospondylocarpofacial syndrome linked to a novel MAP3K7 gene mutation

Abstract

Cardiospondylocarpofacial syndrome (CSCF) is a rare congenital disorder characterized by growth impairment, polyvalvular heart diseases, and skeletal anomalies caused by a mutation in the mitogen-activated protein three kinase seven (MAP3K7) gene. It encodes transforming growth factor-β activated kinase1 (TAK1), a member of the mitogen-activated protein kinase (MAPK) family, and is responsible for abnormal skeletal and cardiac morphogenesis. We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy (DCM) and congenital heart disease (CHD) and presented with acute heart failure (HF). DCM has not been reported before with CSCF. This case emphasizes the role of genetic testing in diagnosing the syndromic neonate with DCM.

INTRODUCTION

Cardiospondylocarpofacial syndrome (CSCFS) is caused by a heterozygous mutation in the mitogen-activated protein three kinase seven (MAP3K7) gene on chromosome 6q15. It is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal–tarsal fusion, extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, gastrointestinal dysmotility, and deafness with inner ear malformations.[1] The pathogenic variants of MAP3K7 encode transforming growth factor-β activated kinase1 (TAK1), a member of the mitogen-activated protein kinase (MAPK) family, and are responsible for abnormal skeletal and cardiac morphogenesis.[2] It is inherited as an autosomal dominant inheritance pattern. Depending on the types of MAP3K7 mutations, a homologous mutation can cause frontometaphyseal dysplasia type 2 (FMD2), while a heterozygous mutation results in CSCF.[3] We are reporting a novel heterozygous mutation of the MAP3K7 gene: c.710 T>C, resulting in the pathologic protein p.F237S in a neonate presenting with CSCFS, congenital heart disease (CHD), and dilated cardiomyopathy (DCM).

CASE REPORT

A female infant, who was the only child of healthy, nonconsanguineous, African American parents, was born at term but small for gestational age after an uneventful pregnancy. Her Apgar score at birth was 6 for 1 min and 7 for 5 min. Her birth weight, length, occipitofrontal circumference, and chest circumference were 1770 g (−3.35 standard deviation [SD]), 45.0 cm (−2.12 SD), 31 cm (−1.49 SD), and 30.0 cm, respectively. She presented with a heart murmur and respiratory distress on day 9 of life. At presentation, characteristic facial features include dolichocephaly, epicanthal folds, and low-set posteriorly rotated ears. She had constriction of the lower extremities below the knees [Figure 1a and b], absent middle three fingers on the right hand [Figure 1c], generalized hypotonia, and hypermobility. Her heart rate was 184 bpm, and she exhibited respiratory distress and metabolic acidosis on her first arterial blood gas test (pH 7.26, pCO₂ 16 mmHg, HCO₃ – 7.1 mmol/L, anion gap – 16 mmol/L with elevated lactate >16.8 mmol/L) and elevated N-terminal B-type natriuretic peptide (NT-proBNP) 69,747 pg/mL.

Figure 1.

Skeletal and cardiac abnormalities. (a) Constriction below the left leg and abnormal left foot due to fusion of tarsal bones. (b) Constriction below the right leg and abnormal right foot due to fusion of tarsal bones. (c) Right-hand brachydactyly and abnormal fusion of carpal bones. (d) 2-D Echocardiogram from parasternal short-axis view showing bicuspid aortic valve. (e) A patent foramen ovale with bi-directional shunting. (f) Calculated left ventricle (LV) ejection fraction. (g) Spectral Doppler showing abnormal LV global longitudinal strain. (h) Patent ductus arteriosus (PDA) occlusion by Amplatzer PDA Occluder

A cardiac examination showed tachycardia with an S3 gallop rhythm and a grade 2/6 systolic murmur at the left sternal border. Bibasilar fine crackles were present. She had hepatomegaly, with the liver 3 cm below the right subcostal margin. An echocardiogram revealed a bicuspid aortic valve [Figure 1d] without significant stenosis or regurgitation, a patent foramen ovale (PFO) with bidirectional shunting [Figure 1e], a moderate-sized patent ductus arteriosus (PDA) with left-to-right shunting, no coarctation of the aorta, normal coronaries, a dilated left ventricle (LV) with LV ejection fraction (LVEF) 22% [Figure 1f], and markedly decreased LV global longitudinal strain (GLS) – 9.5% [Figure 1g].

She was intubated due to acute decompensation and started on intravenous milrinone for inotropic support and treatment for metabolic acidosis. She was diagnosed with Ross stage IV heart failure (HF). Newborn screening tests were negative for common inborn errors of metabolism and storage disorders. Notably, she failed the hearing test. A comprehensive diagnostic process ruled out secondary causes for DCM due to metabolic and infectious etiologies. Her chromosome was 46XX. Whole-exome sequencing (WES) identified a heterozygous pathogenic variant in the MAP3K7 gene: c.710 T>C, resulting in the abnormal protein p.F237S, confirmed by Sanger sequencing. Other genetic tests for mitochondrial disorders by sequence analysis and deletion testing of the mitochondrial genome were negative. The patient’s father and mother were negative for the p.F237S variant in the MAP3K7 gene.

After stabilization of her HF, it was found that she had hemodynamically significant left-to-right shunting across a moderate-sized PDA. She underwent cardiac catheterization, and the PDA was occluded using an Amplatzer PDA occluder [Figure 1h]. She was successfully extubated and weaned off intravenous milrinone infusion and tolerated guideline-directed medical therapy (GDMT), including Carvedilol, Enalapril, Lasix, and Aldactone, with doses gradually up-titrated. Her echocardiogram showed improvement in LVEF to the 40s. She remained on enteral feeding with slow weight gain and no end-organ dysfunction. As of this report, her weight increased to 5.62 kg at 6 months follow-up, and she is at home on GDMT and gastric (G)-tube feeding due to upper gastrointestinal dysmotility. Written informed consent from the patient’s parent is obtained for reporting this case, but the photograph showing the face is not allowed for presentation.

DISCUSSION

The identification of the novel MAP3K7 p.F237S variant in this case is a significant discovery, as it has not been previously reported in patients with CSCFS. Our patient exhibited dysmorphic features, including abnormalities of extremities, facial anomalies, CHD, and DCM with acute decompensated HF. The family history, spanning three generations, was negative for familial cardiomyopathy, CHD, connective tissue disorder, Noonan syndrome, and CSCF. The differential diagnosis in this case includes FMD2, Noonan syndrome, and CHD, such as PDA and VSD, but they lack the skeletal and hearing anomalies seen in CSCF. CSCFS patients show a range of CHDs, mainly left-sided, from mitral valve prolapse to hypoplastic left heart syndrome.[4]

The genetic mutation of MAP3K7 encodes TAK1, a serine-threonine protein kinase, which associates with specific binding proteins to influence various downstream effectors, such as c-Jun N-terminal kinases, extracellular signal-regulated kinases, p38 MAP kinase, and nuclear factor-κB.[5,6] This modulation impacts various cellular processes, including cell growth and differentiation, immune response, stress reactions, oncogenesis, and apoptosis.[6,7] Previous studies have shown that MAP3K7 variants in FMD2 cause elevated TAK1 phosphorylation.[1] In contrast, in CSCFS, MAP3K7 variants have been shown to decrease TAK1 phosphorylation and disrupt downstream TAK1-dependent signaling pathways. The difference in phosphorylation of TAK1 may be due to homozygous and heterozygous mutations in MAP3K7, which may explain the difference between the phenotypes of the two disorders, CSCFS and FMD2. CSCF is a rare congenital malformation syndrome for which there is no effective treatment. Only a few cases have been reported,[1,3,8,9,10,11] and none of these prior reports have described DCM [Table 1].

Table 1.

Genetically proven cardiospondylocarpofacial syndrome cases reported in the literature

Author/year of publication	Patients	Genetic	Clinical features	Cardiom-yopathy
Le Goff et al., 2016[1]	6 cases: Father, daughter, and son in one family, an unrelated woman, and two girls, 6 years old (Moroccan) and 7 years old (French)	In-frame 3-bp deletion in the father and son, a missense mutation in the (G110C) in a Moroccan girl, heterozygosity for a missense mutation W241R in the MAP3K7 gene in the remaining patients	Facial dysmorphism, short stature, short hands, carpal-tarsal fusion, vertebral synostosis, and cardiac defects	None
Morlino et al., 2018[8]	7-year girl	Heterozygous splice site mutation in the MAP3K7 gene	Facial dysmorphism, soft/dystrophic skin, joint hypermobility, CHD (PFO, small muscular ventricular septal defect, mitral and tricuspid valve dysplasia, and mild aortic arch hypoplasia), and gastrointestinal dysmotility	None
Abubakr et al., 2020[9]	8-year boy	Heterozygous MAP3K7 variant (c. 125_127del, p.Val42del)	CHD (bicuspid aortic valve, dysplastic pulmonary valve), elbow flexion contracture, excessive wrinkled skin, joint laxity, mild global developmental delay, short stature, synostosis involving bones of the hand	None
Minatogawa et al., 2022[3]	10-year boy	Heterozygous MAP3K7 variant (c. 467A>T, p.Asp156Va)	Dysmorphic facial features, short stature, cryptorchidism, congenital heart disease, otitis media, hearing impairment, and mild intellectual disability	None
Shepherd et al., 2023[10]	8-year boy	Heterozygous MAP3K7 variant (c. 528dupT, p.G177WfsX5)	Facial dysmorphism Failure to thrive, gastroesophageal reflux, joint laxity, cleft palate, micrognathia, hypotonia, and recurrent otitis media	None
Nyuzuki et al., 2024[11]	1-day girl	Heterozygous MAP3K7 variant (p.Thr187Ile)	Facial dysmorphism, skin laxity, severe growth retardation, and developmental delay. CHD includes aortic stenosis, ventricular septal defect, mitral regurgitation, and tricuspid regurgitation	None

CHD: Congenital heart disease, MAP3K7: Mitogen-activated protein three kinase seven, PFO: Patent foramen ovale

Genetic testing of all children with cardiomyopathies is not only prudent but also holds significant clinical value when appropriate use criteria are satisfied [Table 2]. This case underscores the critical role of genetic testing in diagnosing, predicting, and guiding treatment strategies for syndromic children with cardiomyopathy.[12,13] WES in a parent-offspring trio is an effective method to identify the genetic basis of DCM in neonates, particularly when there is no family history.[14] It highlights the importance of genetic mutations in prognosis, as patients with genetic causes may respond less favorably to GDMT than those with reversible causes like viral infections or inflammation.[15]

Table 2.

Genetic testing is considered medically necessary when the following criteria are satisfied

Clinical appropriateness

The patient’s symptoms and presentation align with the suspected condition

The test results are anticipated to influence medical management decisions

The test is commonly accepted as clinically and technically suitable for diagnosing and/or treating the suspected condition

Benefit versus risk

The clinical benefits of the test outweigh potential psychological or medical harm to the individual being tested

Targeted testing

The test is as specific as possible for the clinical scenario (e.g., testing for known familial pathogenic or likely pathogenic variants, common variants, or genes related to the phenotype)

Validated methodology

The testing methodology has been clinically validated and is the most accurate method available, unless technical limitations (e.g., poor sample quality) require alternative testing strategies

The long-term prognosis for patients with CSCFS and DCM varies. However, early diagnosis and appropriate management, including medical therapy and interventions, can significantly improve outcomes. The presence of skeletal anomalies, developmental delay, and abnormal immune response in the future may pose ongoing challenges, necessitating multidisciplinary care and regular follow-up. This underscores the importance of proactive and comprehensive care for these patients.

Our case broadens the phenotypic spectrum of CSCFS and contributes to a new mutation in the MAP3K7 gene, which was not reported before. The MAP3K7 gene encodes TAK1, a kinase integral to various cellular processes, including heart development. Disruptions in MAP3K7 can lead to CHD and cardiomyopathy, in addition to the clinical features of CSCFS, as seen in our case. Future research should focus on elucidating the pathogenesis and genotype-phenotype correlations and accumulating more cases to enhance understanding of this rare but serious condition. In addition, the identified genes and pathways could pave the way for targeted therapies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient’s mother has consented to images and other clinical information being reported in the journal. The patient’s mother understands that his name, initials, and facial photograph will not be published. Every effort will be made to conceal the patient’s identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.