LEOPARD syndrome with PTPN11 gene mutation in monozygotic twins: A case description and literature review

Abstract

Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is a rare autosomal dominant genetic disease with only over 200 reported cases worldwide.¹ LEOPARD is an acronym for its typical symptoms: L, lentigines (freckle-like spots); E, electrocardiogram abnormalities; O, ocular hypertelorism; P, pulmonary stenosis; A, abnormal genitalia; R, retardation of growth; and D, deafness (sensorineural). First described in 1969 by Gorlin et al.,² twin cases are particularly rare. This report describes a very rare case of NSML in monozygotic twins, involving diffuse myocardial thickening with left and right ventricular outflow tract obstruction. Using imaging methods for early diagnosis can facilitate timely interventions to prevent heart damage and adverse outcomes.

The monozygotic twins, aged 9 years, were diagnosed with hypertrophic obstructive cardiomyopathy at birth by the local hospital. Initially, they exhibited no significant discomfort and did not receive systematic treatment. Over the past 2–3 years, and particularly in the last 6 months, they began experiencing post-activity dyspnoea, which progressively worsened. The symptoms of the first-born twin were similar to those of the second, but slightly less severe.

Physical examination revealed short stature and an audible click and systolic murmur at the cardiac apex. Both twins had myopia and multiple freckle-like nevi on their head, face, trunk and limbs. The younger sister (Figure 1A–C) had slightly more nevi than the older sister (Figure 1D–F). Their hearing was normal, with no language disorders, and their intelligence levels were normal.

The younger twin underwent several tests: an electrocardiogram displaying sinus rhythm with abnormal P waves, ST-T changes and high voltage in the left ventricle. Transthoracic echocardiography results were similar to those from cardiac magnetic resonance (CMR) imaging (elder: Figure 1G, younger: Figure 1H). CMR showed diffuse cardiac hypertrophy, with the basal segment of the septum being the thickest at about 27–28 mm (Figure 1I), left and right ventricular outflow tract obstruction (Figure 1J), high-speed blood flow (Figure 1K), and a visible ‘SAM’ sign on the mitral valve. Late gadolinium enhancement (LGE) images displayed focus-like delayed enhancement of the left ventricular free wall (Figure 1L). T1 mapping (Figure 1M) indicated elevated T1 in the lesion area and the extracellular volume fraction (ECV) (Figure 1N) was increased. The decreased LVEF (ejection fraction 36%) is not specific for genetic metabolic disease. Finally, genetic testing revealed a mutation in the PTPN11 gene [chr12:112910827, NM_002834.5; exon 7, c.836A>G(p.Tyr279Cys)], inherited from their mother. This mutation is consistent with LEOPARD syndrome (or Noonan syndrome with multiple lentigines). Born-first twin underwent modified enlarged Morrow surgery and right ventricular outflow tract dredging. Postoperative ultrasound indicated patency of the left and right ventricular outflow channels and significant improvement in mitral valve closure (Figure 1O). He was discharged 15 days later, and the child recovered well.

NSML is characterized by freckles or moles, which are scattered flat dark brown spots on the face, head, neck and body, generally appearing by four to five years of age and gradually increasing.³ However, some individuals with NSML may not show freckles. Hypertrophic cardiomyopathy (HCM) is the most common cardiovascular abnormality associated with NSML.⁴ According to Limongelli et al.,¹ 73% of patients had left ventricular hypertrophy, and 34% of them had left ventricular outflow tract obstruction. Right ventricular hypertrophy occurred in 30% of patients. Current studies indicate that the pathological features of HCM in NSML patients are similar to other forms of HCM.⁵ It has been reported that HCM in patients with Noonan syndrome accelerates the risk of further deterioration and poor prognosis.^{6, 7} Cardiovascular system involvement in NSML can also manifest as coronary artery dilation.⁸ Mitral valve involvement is the most common among valve-related issues, and a few patients may also have pulmonary artery stenosis, left ventricular aneurysm, left ventricular non-compaction, isolated left ventricular dilation or atrioventricular canal defects.

Growth restriction after birth results in short stature in less than 50% of patients. About 20% of patients with NSML have sensorineural hearing impairment,⁴ which is not well characterized. Clinical diagnosis of NSML can be based on clinical criteria or molecular diagnosis involving variants in one of the following four genes: BRAF, MAP 2K1, PTPN11 and RAF1.³

The imaging features of NSML are primarily used to evaluate myocardial and cardiovascular involvement while coronary CTA can assess the cardiovascular involvement. CMR can not only evaluate cardiac structure and function but also perform myocardial tissue characterization using advanced gadolinium enhancement and T1 mapping techniques. Given the rare occurrence of NSLM, clinical history and physical examination are crucial for making diagnosis. The possibility of NSML should be considered in the presence of myocardial hypertrophy and multiple systemic lentigines.

The most common cardiac disorder in NSML is increased ventricular wall thickness.⁹ The pattern of left ventricular remodelling may be associated with an increased risk of death.¹⁰ As with patients with hypertrophic cardiomyopathy, patients with NSML can be treated with similar medications. Morrow surgery or alcohol septal ablation can effectively improve symptoms and prognosis. Diagnosing the disease early and taking appropriate preventive measures before myocardial hypertrophy reaches a severe and irreversible stage is essential to prevent the potential risk of heart damage.

Early diagnosis of NSML before heart damage reaches a serious irreversible stage is crucial for patients. Understanding the potential risks, complications and prognosis of the disease allows for appropriate measures to prevent heart damage and adverse outcomes.

Yingwen Zhou,^,Kai Yang, Kai Ma and^,Minjie Lu declare no competing interests.

This study has received funding by the CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-052).