Physical examination: milia, slanted palpebral fissures, hypoplasia of the nasal wings, dental crowding, prognathism, clinodactyly and brachydactyly in hands and feet, and hallux valgus.

The head MRI identified agenesis of the corpus callosum and hypoplasia of the cerebellar vermis.

Genetic testing found a de novo pathogenic variant with deletion in exon 12: c.1193_1196delAATC (p.Q398LfsX1) on the OFD1 gene, giving rise to a truncated protein, previously reported as associated with OFDSI.Case 2

Thirty-two-year-old woman with chronic kidney disease and GFR of 47ml/min, in the context of non-steroidal anti-inflammatory drug abuse due to herniated disc. Treated surgically in childhood for accessory gingival frenulae and extraction of supernumerary teeth due to malocclusion.

After being referred to nephrology in 2015, polycystic kidneys were observed on ultrasound: right kidney 13cm and left 13.4, with no changes in the liver, spleen, or pancreas.

Family history: mother with kidney transplant due to chronic consumption of non-steroidal anti-inflammatory drugs due to rheumatoid arthritis. The rest of the family (father, sister, son and daughter) have normal kidney function. All underwent ultrasound with kidneys normal in size with no cysts.

On physical examination: fissure of the upper lip, micrognathia, narrow palate and lobulated tongue, and brachydactyly-clinodactyly with marked difference in size between both hands.

During follow-up, onset of hypertension and rapid deterioration of GFR: 37ml/min at six months and GFR: 30ml/min at one year. On a new ultrasound, increase in kidney size (right 14.7 and left 15.1cm). Clinically diagnosed with de novo rapidly progressing ADPKD and a candidate for tolvaptan. Head and face MRI ordered due to vertigo and headaches, with no abnormalities found. Currently 37 years old and GFR: 14ml/min.

The Next Generation Sequencing (NGS) massive sequencing testing for cystic kidney diseases identified a pathogenic variant on exon 2 of the OFD1 gene: c.71dup, (p.Try24*), not previously reported, giving rise to a truncated protein changing the diagnosis from ADPKD to OFDSI. Family testing confirmed the same variant in her daughter, ruling it out in the rest of the family members.Case 3

Twelve-year-old girl, daughter of case 2. With no history of interest, except the extraction of a supernumerary canine at six years old. On physical examination: accessory frenula and hands with brachydactyly and clinodactyly (like her mother, although affected to a lesser degree) (Fig. 1). On ultrasound, the kidneys were normal in size with no cysts.

Figure 1.

Comparison of hands between case 2 (mother) and case 3 (daughter). In the mother (left), we observe brachydactyly and clinodactyly, while in the daughter (right), they are present to a lesser extent.

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OFDSI (OMIN #311200; ORPHA 2750) is a ciliopathy,2 with a prevalence: 1/50,000–1/250,000 in live newborns.

In 1998, De Conciliis3 identified the cause as the OFD1 gene on the X chromosome, which codes for a protein with 1,011 amino acids, expressed in the centrosome and basal body of the primary cilia.4 In the OFDSI, the embryogenesis process is altered, causing dysmorphias and kidney cysts. There are up to 18 types of oral-facial-digital syndrome, but type I is the most common.5

Up to 75% of the pathogenic variants of the OFD1 gene are sporadic or de novo. In family cases, the inheritance pattern is X-linked dominant, being lethal in males affected during gestation,6 therefore it would be transmitted from mothers to daughters.

The clinical diagnosis for suspected OFDSI is established after birth via orofacial and digital dysmorphias; or in adults by being associated with polycystic kidneys (Table 1).7 Annual blood pressure and kidney function checks and abdominal ultrasound are recommended because polycystic kidneys occur8 in 50%, or even the majority of women according to other authors,6 and may be the only manifestation.

Due to its great phenotype variability, genetic confirmation is required. NGS panels for cystic kidney disease, which identify the molecular cause in 80%, are the test of choice.9

In conclusion, all women with OFDSI must receive annual follow-up by nephrology, because they may develop polycystic kidneys and progressive chronic kidney disease, which determines their prognosis.10 OFDSI brings up the differential diagnosis with ADPKD, with the search for orofacial and digital dysmorphias being key during the physical examination.