Hypertrophic cardiomyopathy (HCM) is defined as the presence of increased left ventricular (LV) wall thickness or LV mass that is not solely explained by abnormal loading conditions [1]. In children, it has an estimated prevalence of ~3/100,000 live births [2]. Sarcomeric disease is the most common etiology in adult HCM and remains the most common underlying cause of pediatric HCM [3]. However, in childhood, there is bigger heterogeneity with other causes including inborn errors of metabolism, RASopathy syndromes and neuromuscular disease. The morbidity and mortality as well as the treatment can vary greatly depending on the underlying etiology, making specific and timely diagnosis crucial. 
The diagnostic approach in a child with left ventricular hypertrophy (LVH), while having many similarities to an adult approach, has some important and distinct differences. Imaging, and specifically echocardiography as a first line, remains the cornerstone for the identification of the phenotype, clinical examination, ECG and detailed, phenotype-guided laboratory investigations are used to aid in the differential diagnosis (Table 1). Age at presentation also plays an important part in this process as different etiologies are more prevalent in different ages.

Family history, inheritance pattern and age of patient
A detailed family tree, including information about consanguinity, developmental and neuromuscular disorders is crucial. If there are signs of X-linked inheritance pattern, with males affected more severely and earlier than females, Danon disease should be at the top of the list of differentials. Conversely, matrilinear inheritance should point to a mitochondrial aetiology.
Even in the absence of family history, sarcomeric disease should be excluded and in cases presenting in infancy with severe HCM or heart failure or early in childhood with a SCD event, the possibility of a double or compound gene variants should be considered.
In infantile HCM cases, RASopathy syndromes, mainly Noonan syndrome and Noonan syndrome with multiple lentigines, as well as inborn errors of metabolism, are most common, representing up to 42% and 16% of cases diagnosed respectively [3,4]. In a neonate, reversible causes should also be considered – infant of a diabetic mother, twin-to-twin syndrome, use of corticosteroids, sepsis or other hemodynamic instabilities.
In the adult patient, an autosomal dominant transmission could be associated with sarcomeric HCM or cardiac amyloidosis.[1] However, in cardiac amyloidosis the disease onset rarely occurs before 60 years old.  Sarcomeric HCM has an age-related penetrance and the onset can be in infancy (<1 year), in teenage/early adulthood or mid-adulthood.[5] An X linked inheritance, on the other hand, is characteristic of Fabry disease, in which the cardiomyopathy commonly develops after 30 years of age.[6] 

Clinical examination
Clinical examination should be detailed when assessing neonates and children with HCM. The clinician should look for signs of dysmorphic features, stigmata, developmental delay, learning difficulties, poor muscle tone or gait disturbances to help direct the diagnosis to a malformation syndrome (RASopathies), inborn error of metabolism or neuromuscular or neurodegenerative conditions. 
In the elderly the presence of signs of muscoloskeletal infiltration (carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, trigger finger) is highly suggestive for cardiac amyloidosis.[7] Furthermore, in the variant form the phenotype varies according to the genotype. Variants such as early onset Val50Met are endemic in Japan, Portugal and Sweden and present between 30 and 40 years with length-dependent, small fiber sensory peripheral neuropathy and dysautonomia. Late onset Val50 Met, on the other hand, presents at 50 years of age with a mixed cardiac-neurological phenotype. Val142Ile is the most common variant in the United States and has a predominantly cardiac phenotype.[8] Each variant has a predicted age of disease onset (PADO) that can help program the allele carriers clinical screening. Indeed, a yearly clinical screening is recommended in allele carriers approaching the PADO to achieve the earliest diagnosis possible.[9]  The shoulder pad sign, macroglossia and periocular bruising are signs of AL amyloidosis. [10]
In Fabry disease the clinical presentation depends on the genotype. The disease is caused by variants in the GLA gene, which encodes for the lysosomal enzyme alpha-galactosidase A. Frameshift/nonsense variants associated with absent/very low alpha-Gal A activity (<5%) are associated with the classic phenotype of the disease characterized by childhood-onset systemic manifestations like neuropathic pain, febrile crisis, gastrointestinal symptoms, and angiokeratomas. The development of cardiac, renal and central nervous system complications occurs during early adulthood.[6] 
Missense variants associated with less severe enzymatic deficits are associated with the non-classic phenotype. The latter is characterized by the development of cardiomyopathy in the 3rd-4th decade, however renal and neurologic involvement may still be present. 
The phenotype in women is highly heterogeneous ranging from mild disease to severe forms resembling the ones of the classic male patients. This phenomenon depends on several epigenetic factors including X inactivation and DNA methylation.[6]
In Friedreich’s ataxia the onset is usually in early adolescence. The disease is due to GAA sequence expansion in the FXN gene, encoding for the mitochondrial protein frataxin, whose haploinsufficiency leads to impaired mitochondrial function. The neurological progressive ataxia, spasticity, sensory neuropathy, followed by diabetes and hypertrophic cardiomyopathy[11].

Electrocardiograhy
Specific ECG features can aid in directing clinicians towards an aetiological diagnosis [12]. An extreme superior (North-West) ECG axis can help point towards a RASopathy syndrome. AV block is more common Danon disease. Danon disease, along with glycogenosis, PRKAG2, Anderson-Fabry and mitochondrial disease can present with pre-excitation on ECG. If there are extreme voltage criteria for LVH, with or without a short PR interval, it can direct the differential towards Pompe or Danon disease. Atrial arrythmias are prominent in older children with Friedreich’s ataxia [11].
The ECG abnormalities that are more frequent in HCM include pathological Q waves and T wave inversion in the infero-lateral leads. Several characteristics differ in Fabry disease, in which a prolonged QRS duration, incomplete or complete right bundle branch block and inferior ST segment depression are frequently reported[13].
In cardiac amyloidosis electrocardiography is dominated by the signs of infiltration of the extracellular space of the myocardium and conduction system. Low/normal QRS voltage in the presence of left ventricular hypertrophy, atrioventricular blocks, atrial fibrillation, and T wave inversion can be present and help in the differential diagnosis of the hypertrophic phenotype. [7]

Echocardiography
It is important to define, along with the pattern of hypertrophy (asymmetric, concentric, biventricular), the presence of LVOTO, diastolic and/or systolic dysfunction, and RV involvement.
In infants with HCM, in the presence of biventricular outflow tract obstruction even in the absence of red flags for a malformation syndrome (dysmorphisms, cutaneous abnormalities, skeletal anomalies, etc.), as these can be difficult to diagnose at a neonatal stage by a non-specialist, a diagnosis of RASopathies should be strongly suspected. An additional ‘red flag’ for RASopathy syndromes would be the presence of concomitant congenital heart defects, specifically pulmonary valve stenosis (8, 9).
The presence of early severe biventricular hypertrophy, often presenting with systolic dysfunction (4), should raise suspicion of inborn errors of metabolism, including glycogenosis type II (Pompe disease), fatty acid oxidation defects, and mitochondrial disorders.
Concentric LVH in an older child with muscle weakness or ataxic features should additionally raise suspicion of a neuromuscular or neurodegenerative disorder such as Friedreich’s ataxia.
The amyloid fibrils deposit in every cardiac structure determining the development of concentric left ventricular hypertrophy, with a deposition gradient from the base to the apex that can lead to the typical “apical sparing pattern”, in which the contractility is reduced at the base but preserved at the apex. Furthermore, valvular infiltration may be evident and aortic stenosis is a common feature in this condition[7].
In sarcomeric HCM the classical phenotype is characterized by asymmetric left ventricular hypertrophy, associated with elongated mitral valve leaflets, abnormalities in the position and dimension of the papillary muscles related to various degrees of diastolic dysfunction[14]. 
In approximately 40% of patients with sarcomeric HCM, the conjunction of these anatomical abnormalities may cause LVOTO, a leading cause of heart failure in HCM[1].
Fabry disease is usually characterized by concentric left ventricular hypertrophy associated with hypertrophic papillary muscles[6].

Laboratory investigations
Additional laboratory investigations can help confirm the aetiological diagnosis of a patient with paediatric HCM.
Biochemical screening can help support the diagnosis of an inborn error of metabolism with tests such as blood glucose, metabolic acidosis on gas, transaminases, urine ketones, organic aciduria, acylcarnitine, free fatty acid profiles, calcium and vitamin D metabolism, or CK for neuromuscular conditions if suspected from clinical examination.
In elderly patients, a constant elevation in NTproBNP and troponin may be suggestive of cardiac amyloidosis[7].
In Fabry disease lyso-Gb3 the use of lyso-Gb3 is debated, however its use could be helpful with diagnostic and prognostic purposes[6]. 
Employing the aid of a clinical geneticist can help guide genetic investigations and specific panels to be sent, in conjunction with history, examination, imaging and laboratory findings.
Overall, it is essential to involve a multidisciplinary team in the diagnosis of patients with HCM so as to guide specific testing to reveal the aetiology and help guide management when reversible or specific diseases are present.