RESUMO
Differences of sex development (DSDs) are a heterogeneous group of congenital conditions in which chromosomal, gonadal, or anatomical sex does not match. The broad spectrum of phenotypes associated with DSDs requires accurate diagnosis, which influences the care and quality of life of affected patients. The decreasing costs of next-generation sequencing (NGS) and international research collaborations in rare diseases have allowed the identification of new genes associated with DSDs. Recently, Hughes et al. in 2020 reported the association of loss-of-function (LoF) variants in PPP1R12A with morphological anomalies of the midline, including holoprosencephaly and urogenital malformations, also known as genitourinary and/or brain malformation syndrome (OMIM #618820). In this report, we describe a Mexican individual with hypertelorism, multiple skin hemangiomas, testicular atrophy, and sex reversal, in whom a c.1880delC frameshift variant in PPP1R12A was detected by exome sequencing. Segregation analysis confirmed it as a de novo variant through Sanger sequencing. The main objective of this report is to expand PPP1R12A-related urogenital and/or brain malformation syndrome.
RESUMO
Pantothenate kinase-associated neurodegeneration (PKAN, OMIM: 234200) results from biallelic pathogenic variants in PANK2 which encodes pantothenate kinase 2, a crucial mitochondrial enzyme involved in coenzyme A biosynthesis. Pantothenate kinase-associated neurodegeneration patients typically exhibit the distinctive "eye of the tiger" sign on brain magnetic resonance imaging in the globus pallidus, along with psychiatric symptoms, extrapyramidal movements such as parkinsonism and dystonia, eventual speech and gait impairments, and the presence of dysphagia. An 11-year-old girl, with fifth-degree consanguinity, demonstrated typical psychomotor development and growth until the age of 5, when she began experiencing psychiatric symptoms. At the age of 9, she developed hand tremors, progressing to generalized muscular dystonia. By age 10, she exhibited gait and speech impairment. Physical examination revealed extensive generalized dystonia, hand tremors, speech impairment, dysphagia, inability to walk, and heightened osteotendinous reflexes. Metabolic analysis identified dyslipidemia with partial response to statin treatment and normocalcemic hypercalciuria. Exome sequencing revealed a novel likely pathogenic variant in PANK2 (NM_001386393.1:c.526C > G) in a homozygotic state. Pantothenate kinase-associated neurodegeneration typically manifests with generalized dystonia and psychiatric symptoms. Here, we present a Pantothenate kinase-associated neurodegeneration patient with dyslipidemia and hypercalciuria as potentially previously undescribed metabolic phenotype.