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Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is an ultrarare autosomal recessive heterogeneous ciliopathy caused by pathogenic variants in one of six genes including IFT43, IFT52, IFT122, IFT140, WDR19 and WDR35, all encoding proteins that are part of the intraflagellar transport complex A which is involved in retrograde ciliary transport. Sensenbrenner syndrome is a multiple anomaly syndrome with distinctive craniofacial findings (forehead bossing, dolichocephaly), metaphyseal dysplasia (short limbs, small thorax), ectodermal anomalies (sparse hair, small and missing teeth, short nails), connective tissue abnormalities (loose skin, joint laxity), retinal dystrophy, and chronic kidney and liver disease. Nephronophthisis has been reported in some patients with Sensenbrenner syndrome.
We present a 5-year-old male patient diagnosed with Sensenbrenner syndrome as a typical craniofacial, skeletal and ectodermal anomalies, with kidney disease and progressive decline in kidney function.
The boy is a second child of healthy non-consanguineous parents. His birth weight was 3390 g and birth length 51 cm. Clinical examination performed directly after birth, revealed typical characteristics of Sensenbrenner syndrome, including craniofacial, skeletal and ectodermal abnormalities (dolichocephaly, wide forehead, epicanthic folds, telecanthus, narrow thorax, short limbs, brachydactyly, syndactyly of 3-4 toes of both feet). Postnatal kidney ultrasound (US) showed normal-sized kidneys without parenchymal changes. At the age of 14 months the boy underwent a surgical correction for scaphocephaly.
At the age of 2 years the child presented with failure to thrive, kidney US revealed bilateral solitary parenchymal cysts (<1 cm) in both kidneys.
At the first admission at the age of 4 years the boy had short stature (height and weight <3P), lumbar scoliosis, metabolic acidosis (pH 7.33, HCO3 18 mmol/l), proteinuria (up to 1.0 g/l) with elevated urinary β-2 microglobulin level (15.4 mg/L) and microalbuminuria (90 mg/ mmol creatinine), decreased calcium excretion (Ca/Cr = 0.02), increased of fractional excretion of potassium (15.7%), sodium (1.6%) and magnesium (6.5%). His eGFR was decreased to 54.7 ml/min/1.73 m2. Kidney US revealed a few cysts (RK 1.3х1.6 cm, LK 0.8х0.6 cm) and single medullary calcifications in both kidneys. Echocardiography and liver US showed no abnormalities. Oral sodium bicarbonate was given to the patient to correct metabolic acidosis. Treatment with ACE inhibitor (enalapril, 0.125 mg/kg/d) was started for antiproteinuric and nephroprotective purposes. NGS identified a pathogenic homozygous variant c.G2907T (p.K969N) in exon 25 of WDR35 gene. Both parents were found to be heterozygous carriers of this WDR35 variant. 12‐month therapy with sodium bicarbonate led to normalization of the acid-base state, treatment with ACE inhibitor led to decreasing of proteinuria (0.1 g/L) and microalbuminuria (50.5 mg/mmol creatinine), however, his kidney function continued to decline (eGFR 50.1 ml/min/1.73 m2).
Our case with Sensenbrenner syndrome caused by pathogenic variants in the WDR35 gene presented with nephronophthisis-like phenotype and early-onset progression to chronic kidney disease. Treatment with ACE inhibitor led to marked decreasing of glomerular proteinuria, but kidney function continued deteriorate. Investigation of efficacy of treatment with ACE inhibitors in patients with Sensenbrenner syndrome requires further studies.