Mitochondrial dysfunction in Stüve–Wiedemann syndrome in a patient carrying an ND1 gene mutation

Episodes of hyperthermia, liver failure, anemia, and mitochondrial dysfunction has been observed previously in Stüve–Wiedemann syndrome (SWS; OMIM 601559) [Stüve and Wiedemann, 1971; Chabrol et al., 1997; Cormier-Daire et al., 1998; Di Rocco et al., 2003]. Since noother patientwith a proven LIFR (OMIM 151443; [Dagoneau et al., 2004]) gene mutation in combination with a respiratory chain dysfunction has been reported, the casual relationship between the metabolic disorder and SWS remained hypothetical. We describe a patient with SWSandadisorder of theoxidativephosphorylation, carrying a LIFR mutation and a heteroplasmic mitochondrial ND1 gene (OMIM 516000) mutation. The index patient (V-1) was born at 40 weeks of gestation with a birth weight of 3,450 g ( 0.5 SD), length of 44 cm ( 4 SD), and head circumference of 32 cm ( 1.5 SD) as the first male child of healthy, non-consanguineous Dutch parents. The mother (IV-1) and the maternal grandmother (III-2) had had frequent episodes of migraine; the latter suffered from normochromic anemia and hypothyroidism as an adult. The maternal great-grandmother (II-4) was also known to have hypothyroidism. Two distant maternal relatives (III-1 and III-4), with known psychomotor retardation and epilepsy died in childhood. A maternal third cousin (V-4) was diagnosed with a mitochondrial encephalomyopathy and mitochondrial complex I deficiency with a heteroplasmic (80%) ND1 gene mutation confirmed in a muscle biopsy (Fig. 1). The propositus had campomelia and camptodactyly, severe generalized muscle hypotonia, a loud systolic heart murmur, episodes of hyperthermia (42.58C), and neonatal respiratory failure, requiring mechanical ventilation for 3 weeks. Transient neonatal seizures were treated successfully with phenobarbital. The brain MRI showed small symmetrical lesions of high-signal intensity in the caudate nucleus on T2 images. An echocardiography demonstrated tricuspid insufficiency, patent foramen ovale, and non-obstructive hypertrophic cardiomyopathy. He also had a convergent strabismus of the left eye, telecanthus, apparently low set ears, retrognathia, short neck, narrow chest, short ribcage, a protruding abdomen, hypotonic abdominal muscles, campomelia, camptodactyly, ulnar deviation of fingers, long big toe, and partial syndactyly of second to third toes. The skeletal survey showed characteristic findings of SWS (Fig. 2). The patient received gastric tube feeding due to feeding difficulties. His motor developmentwasdelayedwithhead lag and inability to roll over till age 8 months. He developed corneal ulcerations. At 12 months he was already able to sit, had head control, he fed himself, and his gastric tube was removed. The cardiomyopathy improved significantly and required no further medication. He suffered frommultiple ear infections, early caries due to abnormal tooth development, and from spontaneous femur fractures without pain. He started walking at 15 months but continued to have exercise intolerance with decreased muscle mass, muscle tone, and decreased deep tendon reflexes. Logopedic treatment was initiated due to an obvious speech