LAUSR

Genetic syndromes associated with cutis laxa (CL) and wrinkled skin are multisystem disorders with progeroid features, including sagging, lax and wrinkled skin [1, 2]. Metabolic CL is genetically heterogeneous. We previously reported on the frequently overlapping clinical phenotypes, including X-linked and autosomal recessive forms [2]. However, recently new forms of CL have been described. “Metabolic” CL is related to different inborn errors of metabolism; the historic example is the X-linked defect in ATP7A (MIM 309400). Autosomal recessive metabolic CL types are ARCL2 and ARCL3. ARCL2 patients present with a characteristic face, skeletal and joint abnormalities, developmental and growth delay due to mutations in different genes, including ATP6V0A2 (MIM 219200, 278250), RIN2 (MIM 613075), COG7(MIM 608779), GORAB (MIM 231070), and PYCR1 (MIM 612940, 614438) [2–4]. These encode endosomal and Golgi proteins (ARCL2A), and affect trafficking and glycosylation, except for PYCR1, which is involved in mitochondrial proline synthesis (ARCL2B). ARCL3 patients have parchment-like, progeroid skin, cataracts, corneal clouding, and significant neurologic disease [5], caused by mutations in PYCR1 or ALDH18A1 (MIM 616603, 219150), also involved in mitochondrial proline synthesis [2]. Additional inborn errors can also be associated with CL without a clear designation to ARCL2 or ARCL3; Transaldolase deficiency (TALDO MIM 606003) and Lenz-Majewski syndrome (MIM 151050) and Cantu syndrome (MIM 239850). ATP6V0A2-CDG related CL has been described both with normal elastin histology (wrinkly skin syndrome MIM 278250) and abnormal elastin histology (ARCL2A MIM 219200). COG7-CDG is another CDG with CL and normal elastin morphology. Recently, novel metabolic CL syndromes were added to the growing list of ARCL. Their clinical presentation highly overlaps with the phenotypic spectrum of ARCL2A [6, 7] and ARCL2B [8]. Mutations in ATP6V1A (MIM 617403) and ATP6V1E1 (MIM 617402), two components of the VATPase complex, were shown to cause ARCL2A, and a very similar phenotype to that seen in ATP6V0A2-CDG [7]. They have a type II pattern on transferrin isoelectric focusing (TIEF) similar to defects involving the V-ATPase complex in the Golgi, affecting glycosylation [3, 7]. In another new ARCL, lactic acidemia is the diagnostic clue for mitochondrial ECHS1 (MIM 616277) [8] deficiency. Here we report on the previously unreported finding of CL due to a hemizygous mutation in the gene ATP6AP1 (MIM 300972), a component of the V-ATPase complex that was recently described to cause an X-linked N-glycosylation disorder with liver disease [9]. A male patient was born at term (birth weight 3.66 kg (P50), length 51 cm (P10), and head-circumference 35 cm (P25)). He had CL with excess skin in the neck, axilla and groin and unilateral cryptorchidism (Fig. 1). At 2 weeks of age he had a urinary tract infection with sepsis due to Escherichia Coli. There were no underlying structural abnormalities of the urinary tract. At 2 months he developed conjugated jaundice (bilirubin direct/total 4.49/13.77 mg/d, AST 401 IU/L, ALT 73 IU/L, gammaGT and alkaline phosphatase were normal, ceruloplasmin was 0.03 mg/dL (normal range: 0.22–0.58 g/L). Stools were pigmented. Liver ultrasound showed normal bile ducts, hyperechogenic liver parenchyma, normal liver size but enlarged spleen (+3.7 SD). Urinary polyols showed an increased galactitol * Peter Witters [email protected]