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Título

Multiple Congenital Anomalies Hypotonia Seizures Syndrome (MCAHS) - multiple genes, one phenotype? A case series

RESUMO

Case presentation: We report 3 patients from two unrelated families with Multiple Congenital-Anomalies-Hypotonia Seizures Syndrome (MCAHS) due to pathogenic variants in different genes and discuss phenotype-genotype associations. Case 1: A 26-year-old woman with a history of myoclonus in both hands during breastfeeding, generalized seizures, delayed milestones, hypotonia and dysmorphisms. She also had recurrent flu and pneumonia because of an immunodeficiency. Parents were not related but both were of Lebanese descent. Case 2: Female patient, sibling of Case 1, died 6 years ago, was diagnosed with tetralogy of Fallot and had a similar history of generalized seizures, myoclonus, global delayed milestones, dysmorphisms, hypotonia, urinary infections and recurrent flu and pneumonia also because of an immunodeficiency. Whole exome sequencing in both sisters disclosed two pathogenic variants in heterozygosis (Chr20:44.047.933 A>G and Chr20:44.047.955 C>T) in PIGT (OMIM* 610272). Case 3: 9-year-old male, presented with a history of epilepsy, delayed milestones, gastroesophageal reflux disease and myoclonus since birth. He also exhibited obstructive sleep apnea syndrome. Immunodeficiency was not present. Brain Magnetic Resonance Imaging showed cortical and cerebellar atrophy. Whole exome sequencing revealed a missense variant in homozygosity (Chr18:62.157.747 G>A) in PIGN (OMIM* 606097).
Discussion: MCAHS is a heterogeneous autosomal recessive disorder characterized by global developmental delay, hypotonia and early-onset seizures, as well as variable congenital anomalies in urinary, cardiac and gastrointestinal systems. MCAHS has also been classified under the more encompassing term of “glycosylphosphatidylinositol biosynthesis defects” (GPIBD). It can result from variants in different genes (PIGN, PIGA, PIGT, PIGQ), and MCAHS1 and MCAHS3 are related to PIGN and PIGT mutations respectively. Despite some information in the literature about the clinical spectrum, it is still unclear if the phenotypes are really similar between the different gene mutations. Immunodeficiency was the atypical finding in our two cases of mutation in PIGT, which can suggest some particularities related to the different genes.
Final considerations: Immunodeficiency is a symptom not yet described in patients with PIGT mutation and, despite the visible similarities between our 3 cases, further studies may demonstrate phenotypic specificities in different patients with MCAHS/GPIBD.

Palavras Chave

MCAHS. Multiple Congenital Anomalies Hypotonia Seizures Syndrome. PIGT. PIGN. GPIBD. Immunologic Deficiency Syndromes. Phenotype.

Área

Neurogenética