Her dermatologist saw a textbook picture. Bilateral freckling in the armpits. Ten flat brown patches spread across her arms and legs, each 15 millimeters or larger. Those two findings sit inside the formal diagnostic criteria for neurofibromatosis type 1, and they were enough to send her to clinical genetics at age 56.
The genetic test came back negative. So did the backup test.
A case report in Kidney Medicine describes what happened next. Sequencing eventually identified a heterozygous pathogenic germline variant in GANAB, a gene associated not with skin findings at all but with a rare form of autosomal dominant polycystic kidney disease. Imaging then confirmed numerous cysts in her liver and multiple cysts in both kidneys. She was 59 when the case was written up.
Two Negative Tests and a Diagnostic Odyssey
The workup followed exactly the path it should have. Next generation sequencing with deletion and duplication analysis was performed for NF1 and for SPRED1, the gene behind Legius syndrome, a well known neurofibromatosis mimic that produces the pigmentary features without the tumors. Both were negative.
Her broader medical history, laid out in the full report, was long and hard to unify: developmental speech delay, kidney cysts, early menarche, migraines, hearing loss, peripheral neuropathy, spinal stenosis with radiculopathy that had required a cervical fusion, multiple basal cell carcinomas and colonic polyps. There was no family history of kidney disease, of the skin findings, or of neurofibromatosis among her first and second degree relatives.
Genome sequencing returned GANAB c.181C>T, p.Arg61*, a nonsense variant that truncates the resulting protein. A stop codon this early in the sequence generally means little or no functional protein is made from that copy of the gene, which is why the variant is classified as pathogenic rather than as a change of uncertain significance.
The Gene Nobody Was Looking For
Polycystic kidney disease is common as inherited conditions go. About 500,000 people in the United States are affected, and the autosomal dominant form accounts for the large majority. Most of it traces to two genes: PKD1 in about 78% of cases, PKD2 in 15%.
GANAB is a rare cause, described in only a handful of published patients. It encodes a subunit of an enzyme involved in processing the polycystin proteins that PKD1 and PKD2 produce, which is why disrupting it produces a similar cystic picture. GANAB-related disease is generally milder in the kidneys than PKD1 disease, and liver cysts are often prominent, which matches this patient's imaging.
The clinical course also tends to differ. Where PKD1 disease often drives kidney function down steadily from midlife, GANAB-related disease has so far been reported with slower kidney decline and a heavier liver burden. That pattern is drawn from very few patients, and it is not absolute. Clinicians have reported one young patient with severe disease whose imaging predicted rapid progression to kidney failure despite a GANAB variant, which is a reminder that the milder label is a tendency rather than a rule.
What has never been part of the described phenotype is anything on the skin. Kidney and liver cysts are well documented in GANAB-related disease. Café au lait macules and axillary freckling are not.
Where the Authors Stop, and Why That Matters
The temptation with a case like this is to declare a new syndrome. The authors do not.
Their stated conclusion is that the phenotypic spectrum of GANAB-related disorders may include cafe au lait macules and axillary freckling. That is a carefully hedged sentence, and the hedge is the point. This is one patient. Café-au-lait macules are not rare in the general population, and a person can carry a pathogenic variant in one gene while having pigmentary findings that arose for entirely unrelated reasons. Co-occurrence in a single individual cannot distinguish a genuine expansion of a phenotype from coincidence.
Establishing a real link would require finding the same skin features in additional unrelated people with GANAB variants, ideally with a plausible biological mechanism connecting the enzyme to pigment cell behavior. Nothing of the kind exists yet. Related puzzles have appeared elsewhere in the literature, including a reported patient carrying both an NF1 variant and a separate cystic kidney disease variant, which illustrates how two conditions can travel together in one body without one explaining the other.
Why the Answer Still Changed Her Care
Even framed as hypothesis-generating, the diagnosis was not academic for this patient. Cysts in both kidneys and a confirmed pathogenic variant move her into structured nephrology follow-up, with monitoring of kidney function and blood pressure over time. It is an autosomal dominant condition, so first-degree relatives have a 50% chance of carrying the same variant and can be offered testing. And it closes a question that had been open since her fifties.
The broader lesson is about what happens when a clinical picture and a genetic test disagree. The skin findings were real, and they were suggestive, but they were not the diagnosis. Broad sequencing found something the targeted panels were never designed to look for. People with unexplained skin findings, a family history of kidney disease or a diagnosis that has never quite fit should raise genetic evaluation with their physician rather than assuming a negative panel closes the question.
Key Questions Answered
What was the patient's original suspected diagnosis? Neurofibromatosis type 1, based on bilateral axillary freckling and 10 cafe au lait macules each 15 millimeters or larger. Both features appear in the formal diagnostic criteria for the condition.
What did she actually have? A pathogenic germline variant in GANAB, a rare cause of autosomal dominant polycystic kidney disease. Imaging confirmed numerous liver cysts and multiple cysts in both kidneys.
What is GANAB-related kidney disease? An uncommon form of inherited polycystic kidney disease caused by variants in a gene involved in processing the polycystin proteins. Only a small number of patients have been reported.
Does this prove GANAB causes skin spots? No. The authors state only that the phenotypic spectrum may include these features. With a single reported patient, coincidence cannot be ruled out.
Why did the first genetic tests miss it? They were targeted panels for NF1 and SPRED1, the genes the skin findings pointed toward. GANAB is not on those panels. Genome sequencing looks far more broadly.
Should anyone with cafe au lait spots get genome sequencing? No. Cafe au lait macules are common and usually benign. Genetic evaluation is a decision to make with a physician based on the full clinical picture and family history.
