A rare combination of hydronephrosis, megaureter, and hyperphosphatasia

A female term-born infant presented with muscular hypotonia, brachydactyly, and dysmorphic features, such as deep-seated ears, submucosal cleft palate, and hypertelorism (Supplementary Figure S1). She developed acute kidney injury and abdominal distention, without meconium evacuation for 48 hours. Moreover, laboratory findings showed a 5-fold increase in alkaline phosphatase levels (normal range, 1.61–5.3 μkat/l), without liver or bone metabolism disorder. Abdominal magnetic resonance imaging revealed bilateral dysplastic multicystic kidneys with right-sided massive hydronephrosis and bilateral megaureters with ectopic urethral insertions (Figure 1). Acute urinary stasis was alleviated through a right-sided percutaneous nephrostomy. Subsequently, a ureterocutaneous diversion was performed, resulting in partial recovery of kidney function. Further diagnostics revealed genital malformations, including uterus didelphys and vagina duplex. Moreover, rectal biopsy and histologic findings determined Hirschsprung disease. The symptom complex consisting of facial dysmorphism, congenital abnormalities of the kidney and urinary tract, Hirschsprung disease, and neurodevelopmental disorder indicated an underlying genetic disease; and potential differential diagnosis, such as Smith-Lemli-Opitz syndrome (Mendelian Inheritance in Man [MIM] number 270400) and Mowat-Wilson syndrome (MIM number 235730), was considered. However, the significantly elevated alkaline phosphatase level observed immediately after birth strongly suggested the presence of hyperphosphatasia mental retardation syndrome (HPMRS; MIM number 239300; Mabry syndrome). In line with our hypothesis, next-generation sequencing panel analysis detected compound heterozygous, pathogenic missense variants in PIGV (NM_017837.3; c.607C>T, p.[Arg203Cys] and c.1022C>A, p.[Ala341Glu]) causing HPMRS. At 11 months, she developed an intractable epilepsy with prolonged, general seizures and neurodevelopmental regression. Following septic pyelonephritis, the patient succumbed to multiorgan failure at the age of 4 years. HPMRS is an ultrarare, inherited disorder caused by mutations affecting proteins of the glycophosphatidylinositol pathway. PIGV mutations disrupt the glycophosphatidylinositol transamidase function, leading to reduced cell surface anchoring of alkaline phosphatase and its increased release into the bloodstream. The phenotype of patients with HPMRS is widely heterogeneous and includes, besides hyperphosphatasia, neurologic symptoms and congenital malformations, including congenital abnormalities of the kidney and urinary tract. To date, a total of 13 disease-causing variants in PIGV have been published, among whom 7 patients presented a congenital abnormalities of the kidney and urinary tract phenotype, including hydronephrosis, duplication of kidneys, megaureter, ureteral ectopia, megacystis, and vesicoureteral reflux. All the authors declared no competing interests. Download .jpg (.33 MB) Help with files Supplementary File (TIFF) Supplementary Figure S1. (A) Facial abnormalities, including triangular mouth, hypertelorism, deep-seated ears, brachydactyly, and submucosal cleft palate (clockwise) of a newborn patient with hyperphosphatasia mental retardation syndrome (HPMRS; Mabry syndrome). (B) Clinical course over a duration of 4 years with elevated alkaline phosphatase (normal range, 1.61–5.3 μkat/l) and cystatin C (normal range, 0.65–1.04 mg/l) levels. Black arrows indicate critical events.