Her dermatologist noticed the freckling under both arms first. Combined with more than 10 café au lait macules scattered across her arms and legs, at least 10 of them measuring 15 millimeters or more, the picture pointed in one direction. Those two findings sit inside the formal diagnostic criteria for neurofibromatosis type 1.
She was referred to clinical genetics at age 56. Testing for NF1 came back negative. So did testing for SPRED1, the gene behind Legius syndrome, an NF1 lookalike. The appearance still fit. The genetics did not.
Three years later, genome sequencing produced an answer nobody was looking for. Writing in Kidney Medicine, clinicians reported that the 59-year-old woman carried a heterozygous pathogenic germline variant in GANAB, a gene associated with autosomal dominant polycystic kidney disease. The result prompted an abdominal MRI, which confirmed numerous liver cysts and multiple cysts in both kidneys.
A Rare Route to a Common Disease
Autosomal dominant polycystic kidney disease affects roughly one in a thousand people, making it the most common single gene cause of kidney failure. Most cases trace to variants in PKD1 or PKD2.
GANAB is a different and far rarer route. It sits among a handful of genes involved in protein processing inside the endoplasmic reticulum that can produce cystic kidney and liver disease, a group reviewed in the Clinical Journal of the American Society of Nephrology that also includes PRKCSH, SEC63, SEC61B, DNAJB11, ALG8, and ALG9. These minor genes generally cause milder kidney disease than PKD1 or PKD2, which is part of why they often escape detection until adulthood or later.
The picture is not uniform, though. Clinicians have also described severe GANAB-related disease in an 18-year-oldwith enlarged kidneys and normal blood work. The specific variant in the new report, c.181C>T producing p.Arg61 stop, has surfaced before as well, in a 12-year-old girl with early onset polycystic kidney disease who also carried a PKD1 variant of uncertain significance.
What has never been described as part of GANAB-related disease is anything on the skin.
Why the Skin Finding Is Not Being Overclaimed
This is where the report earns credit for restraint. The authors wrote that their findings suggest the phenotypic spectrum of GANAB-related disorders may include cafe au lait macules and armpit freckling. They then immediately added that because the observation rests on a single individual, the association may be coincidental and should be treated as hypothesis-generating.
That caveat matters. Cafe au lait macules are not rare in the general population, and one person can carry two unrelated things at once. A single case cannot separate a genuine expansion of a genetic syndrome from a coincidence.
The patient’s long medical history complicates matters further. It includes developmental speech delay, hearing loss, peripheral neuropathy, migraines, spinal stenosis, multiple basal cell carcinomas, and colonic polyps, which makes attributing any individual feature to one gene difficult. She also declined cascade testing for relatives, citing limited contact with her family, which closes off the most direct way to test whether the skin findings track with the variant. There was no known family history of kidney disease or of NF1 features among her close relatives.
The Argument for Sequencing Wider
The case fits a documented pattern. Targeted gene panels answer the question you ask. When the clinical picture is atypical, that can be the wrong question.
Researchers assessing real-world use of whole-genome sequencing in polycystic kidney disease, reported in the European Journal of Human Genetics, examined 144 samples sent to a clinically accredited diagnostic laboratory. The overall diagnostic rate was 70%. Among patients with typical disease, it reached 81%, with 98% of those explained by PKD1 or PKD2. Among patients with atypical features, the rate fell to 60%, and in that group only 56% involved PKD1 or PKD2. The remainder came from PKHD1, HNF1B, GANAB, DNAJB11, PRKCSH, and TSC2.
The authors of that analysis noted that most patients with atypical disease showed no clinical features predicting whether a genetic diagnosis would be found. Clinicians could not reliably guess in advance.
What Readers Should Take from a Single Case
Nobody should look at their own freckles and worry about their kidneys. Cafe au lait macules are common and usually mean nothing. This report describes one patient, and its own authors say the skin connection may be chance.
The transferable point concerns diagnostic dead ends. When a strong clinical picture returns negative targeted test results, the answer is sometimes a broader look rather than repeating the same test. Here, that broader look changed her care by triggering abdominal imaging. Her kidney function was reasonable but not pristine, with a creatinine of 0.88 mg/dL and an estimated filtration rate of 76 mL/min/1.73 m2, with a reference range above 90.
Anyone with unexplained skin findings, a family history of kidney cysts, or a suspected genetic condition that testing has not confirmed should raise the question of further evaluation with their clinician. Genetic testing decisions, including whether to test relatives, should be part of a conversation with a genetics professional.
Key Questions Answered
What was the patient originally thought to have? Neurofibromatosis type 1. She had multiple cafe au lait macules and freckling under both arms, both of which are formal diagnostic criteria for the condition.
What did the testing actually find? Targeted NF1 and SPRED1 testing was negative. Genome sequencing identified a heterozygous pathogenic variant in GANAB, a rare cause of autosomal dominant polycystic kidney disease.
Does this mean skin spots are a sign of this kidney disease? Not established. The authors explicitly stated the association may be coincidental in a single patient and should be considered hypothesis-generating.
How common is GANAB-related kidney disease? Rare. Polycystic kidney disease affects about one in a thousand people, and the great majority of cases involve PKD1 or PKD2 rather than GANAB.
Was her kidney function affected? Her creatinine was 0.88 mg/dL, and her estimated filtration rate was 76 mL/min/1.73m2, below the reference value of 90. Imaging showed numerous liver cysts and cysts in both kidneys.
Why did broader sequencing help? Targeted panels test only the selected genes. In atypical polycystic kidney disease, published data show a substantial share of diagnoses come from genes outside PKD1 and PKD2.
