Introduction 9 1 4H SYNDROME - Clinical spectrum Leukodystrophies are a large and heterogeneous group of genetic brain white matter disorders. Often they are diagnosed in childhood and have a progressive nature that leads to early death (van der Knaap et al., 2019). One of the more prevalent leukodystrophies is 4H syndrome (OMIM 612440) which is named after its characteristic clinical symptoms: hypomyelination, hypogonadotropic hypogonadism and hypodontia (Schmidt et al., 2020; Wolf, 2014). The first symptom, hypomyelination, is defined as a reduced amount or lack of normal myelin in the central nervous system (CNS), which can be diagnosed using MRI (Wolf et al., 2021). Patients often show cerebellar atrophy as well (Takanashi et al., 2014). Hypogonadotropic hypogonadism means that the hypothalamus or pituitary gland is not stimulating the testes or ovaries to produce sufficient sex hormones, leading to absent or abnormal puberty development (Fraietta et al., 2013). The last of the three typical symptoms is hypodontia, the absence of one or multiple primary or permanent teeth (Al-Ani et al., 2017). Even though these symptoms are characteristic for 4H, they are not always all present. The presentation of 4H ranges from very severe to mild and even asymptomatic young adults are described. The mildest patients present with isolated hypogonadotropic hypogonadism (Richards et al., 2017) while more severe patients seem to have a predominant neurological phenotype sometimes without typical hypomyelination (DeGasperis et al., 2020; Harting et al., 2020; La Piana et al., 2016; Wolf, 2014). There is not only heterogeneity in the presentation of the characteristic symptoms, there is also a wide spectrum of other symptoms and signs of the disease amongst which are other neurological presentations such as delay in motor development in early life and/or regression of motor development later in life, often resulting in wheelchair dependence. Additionally, many patients show cerebellar features such as ataxia and dysarthria. Later, pyramidal features such as the development of spasticity can be seen but this is more rare. Also non-neurological symptoms such as short stature, caused by endocrine abnormalities, and myopia (shortsightedness) are observed. Furthermore additional dental abnormalities like natal teeth, delayed dentition, and unusual order of tooth eruption are not uncommon. (Pelletier et al., 2021; Wolf, 2014). Craniofacial features may also be seen (Mirchi et al., 2023). A graphical representation of the wide spectrum of clinical symptoms is depicted in Figure 1.
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