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The perinatal phenotype of Troyer syndrome: Case report and literature review

To the Editor, Troyer syndrome (TS) is an autosomal recessive form of complex hereditary spastic paraplegia (HSP). TS was initially described by Cross and McKusick (1967), who reported an Old Order Amish family with 20 individuals affected by muscle wasting in childhood, followed by progressive spastic paraplegia and associated with intellectual disability. TS was named after the family in which it was first identified. Since the initial description, TS has been further characterized, particularly within the Amish population and in other communities with high levels of consanguinity. The precise incidence is not known but has been estimated to be 1 in 10,000,000 (Liang et al., 2020). While the diagnosis may be recognized promptly in some families with a known history, a recent review determined the median age of diagnosis of TS in reported cases to be 20 years old (Liang et al., 2020). Affected individuals are typically described as presenting around 1– 2 years of age with developmental delay (Proukakis et al., 2004). Progressive spastic paralysis of the legs and dysarthria were seen in almost all patients previously described. Other common features include distal muscle atrophy, learning disability, skeletal abnormalities, drooling, and emotional lability (Bizzari et al., 2017; Cross & McKusick, 1967; Farag et al., 1994; Tawamie et al., 2015). Neurological features present later in childhood, progress insidiously and significantly affect mobility in adulthood (Proukakis et al., 2004). TS is typically associated with short stature, with heights in some older children and adults described approximately in the range of 3 to 7 standard deviations from the mean (Butler et al., 2016; Dardour et al., 2017; Liang et al., 2020). In a handful of cases, concerns were raised in pregnancy regarding growth restriction (Diquigiovanni et al., 2019; Spiegel et al., 2017), though growth parameters in the prenatal period and early childhood are not well-described. Short stature is typically accompanied by relative macrocephaly, though microcephaly has also been reported (Dardour et al., 2017; Manzini et al., 2010). Abnormalities visible on MRI of brain, most commonly T2 hyperintensity affecting the periventricular white matter, are also described (Auer-Grumbach et al., 1999; Liang et al., 2020; Proukakis et al., 2004). Biallelic pathogenic variants in SPART (formerly designated SPG20) were first identified as the cause of TS in 2002 (Patel et al., 2002). SPART lies at chromosome position 13q12.3 and encodes the Spartin protein. This protein shares sequence similarity to Spastin, which is commonly associated with an autosomal dominant form of HSP. Like Spastin, Spartin is thought to play a role in endosomal trafficking and regulating microtubule stability and dynamics. Spartin may be involved in metabolic processes in the mitochondria and regulating lipid conversion. It has been found to be widely expressed especially in the developing brain (in particular in the amygdala, cortex, and thalamus), limbs, and face (Manzini et al., 2010). Despite the phenotype of TS in later childhood being relatively well-characterized, to date, little published data exist to describe its phenotype in the perinatal period (Table S1). In particular, the timing of onset of growth failure and the expected trajectory of growth in early life is poorly defined. In this context, we present a case of TS identified prenatally through testing that was prompted by abnormal scan findings. This case confirms TS as a disorder that should be considered within the differential diagnosis of shortened fetal long bones, and also highlights key issues relating to the application of genomic tests in the prenatal context. The present case was a male child, the first child of healthy nonconsanguineous, white Scottish parents. His mother had a history of cleft palate, which was diagnosed at age 4. She was otherwise in good Received: 27 June 2022 Revised: 23 August 2022 Accepted: 24 August 2022