Al-Owain, Mohammad

AbstractWe report successful heart transplantation in a phosphoglucomutase 1 deficient (PGM1‐CDG) patient. She presented with facial dysmorphism, bifid uvula and structural heart defects. Newborn screening was positive for classic galactosemia. The patient was on a galactose‐free diet for 8 months. Eventually, whole exome sequencing excluded the galactosemia and revealed PGM1‐CDG. Oral D‐galactose therapy was started. Rapid deterioration of the progressive dilated cardiomyopathy prompted heart transplantation at the age of 12 months. Cardiac function was stable in the first 18 months of follow‐up, and hematologic, hepatic, and endocrine laboratory findings improved during D‐galactose therapy. The latter therapy improves several systemic symptoms and biochemical abnormalities in PGM1‐CDG but does not correct the heart failure related to cardiomyopathy. Heart transplantation has so far only been described in DOLK‐CDG.

Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss‐of‐function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype–phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing.