SG08 The phenotypic spectrum of MBTPS2 mutations: two illustrative cases
Authors: McCusker Sarah , Hamilton Mark , Beattie Paula 
Published: June 2024

Abstract
Mutations in the X-linked gene MBTPS2 are associated with a range of genodermatoses, including keratosis follicularis spinulosa decalvans, and ichthyosis follicularis with atrichia and photophobia (IFAP). Furthermore, some individuals with specific MBTPS2 mutations demonstrate features of IFAP, with additional findings including BRESHECK syndrome (brain anomalies, learning difficulties, ectodermal dysplasia, skeletal deformities, ear or eye anomalies, kidney dysplasia or hypoplasia, Hirschsprung disease, and cleft palate or cryptorchidism) (Bornholdt D, Atkinson TP, Bouadjar B et al. Genotype–phenotype correlations emerging from the identification of missense mutations in MBTPS2. Hum Mutat 2013; 34: 587–94). We present two cases, with different pathogenic MBTPS2 variants, demonstrating the wide clinical spectrum of disease. Case 1 is a 2-year-old boy, recently arrived in the UK, who was admitted to a general paediatric ward with poor growth, developmental delay, abnormal eye movements and an umbilical hernia. He was born at term to nonconsanguineous, Nigerian parents and was small for his gestational age. His parents described dry skin and alopecia affecting the head and neck since birth. Scoliosis was noted at 9 months. There was no significant family history. The reviewing dermatologist noted ichthyosis, alopecia and photophobia. A clinical diagnosis of IFAP was made. Next-generation sequencing confirmed a hemizygous p.Arg429His pathogenic variant in MBTPS2, previously reported in cases of IFAP with additional anomalies (Oeffner F, Fischer G, Happle R et al. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet 2009; 84: 459–67). Magnetic resonance imaging of the brain demonstrated partial dysgenesis of the corpus callosum, and cortical migration abnormalities. Spinal imaging revealed multiple segmentation anomalies. These findings were consistent with a diagnosis of IFAP with BRESHECK syndrome. Case 2 is a 6-year-old boy who presented to ophthalmology with photosensitivity. Electrodiagnostic tests were poorly tolerated and inconclusive, and referral was made to clinical genetics for consideration of oculocutaneous albinism (OCA). Examination was not suggestive of OCA, but the family history revealed a known diagnosis of MBTPS2 disorder in maternal male relatives. Targeted testing confirmed that the patient carried the familial, pathogenic p.Asn508Ser variant. Dermatology review noted mild ichthyosis, follicular prominence, nonscarring alopecia of the eyebrows, and photophobia. He had also experienced episodes of corneal ulceration. Clinical features were in keeping with IFAP. We report two cases with MBTPS2 disorders: one presenting with a severe multisystem developmental disorder, the other with much more subtle signs. MBTPS2 codes for a zinc metalloprotease enzyme, with roles involving cholesterol homeostasis and endoplasmic reticulum stress response. The variation in clinical phenotype of MBTPS2 disorders is likely related to varying effects of specific missense mutations on enzymatic function, with greater functional impact associated with more severe phenotypes (Bornholdt et al.).