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Epidermal nevus syndrome associated with hypophosphatemic rickets

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Letter: Epidermal nevus syndrome associated with hypophosphatemic rickets
Ana Isabel Moreira MD1, Graça Ferreira MD2, Mafalda Santos MD3, Armando Baptista MD1, Eduarda Osório Ferreira MD1
Dermatology Online Journal 16 (9): 14

1. Dermatology Department
2. Pediatrics Department
3. Orthopedics Department
Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.


Epidermal Nevus Syndrome (ENS) is characterized by epidermal nevi associated with abnormalities involving the nervous, skeletal, and other systems. Rarely, hypophosphatemic rickets has been observed in association with epidermal nevi. A patient with ENS with right-sided serpiginous skin lesions, generalized weakness, and diffuse osteopenia associated with hypophosphatemic rickets is described. Medical management was enough to correct the clinical picture. The pathogenic mechanism involved in the onset of hypophosphatemic rickets in ENS is not fully clarified. Different studies suggest that phosphaturia, caused by circulating factor(s), called “phosphatonin(s),” may be secreted by an epidermal nevus. The nature of the phosphaturic factor(s) is not well understood, but elevated levels of circulating FGF-23 were recently reported in one patient with hypophosphatemic rickets. The authors suggest that serum FGF-23 measurement be included in the workup of this kind of rickets because there is growing evidence that in these situations the epidermal nevi produce a phosphaturic factor.


Epidermal Nevus Syndrome (ENS) is a rare dermatological condition characterized by epidermal nevi associated with abnormalities in the central nervous system, skeleton, eyes, and cardiovascular and genitourinary systems. It is a sporadic, congenital disorder of unknown etiology featuring a complex and highly variable phenotype [1, 2, 3, 4, 5].

Hypophosphatemic rickets is an uncommon finding in ENS and only 15 cases have been reported [1, 2]. We describe a new case of ENS associated with hypophosphatemic rickets, non-vitamin D-resistent.

Case report

A 12-month-old Caucasian girl was observed in our Dermatology Department for extensive brown-yellow, verrucous plaques on the right side of the body. The lesions were present at birth and enlarged as the child grew. They had a serpiginous distribution and followed Blaschko lines (Figures 1A and 1B). Vesicles or blisters were never reported. There were no lesions on the scalp, face, and mucous membranes. The clinical diagnosis of a verrucous epidermal nevus was made.

Figure 1AFigure 1B
Figure 1A. Verrucous epidermal nevus following Blaschko lines

Figure 1B. Verrucous epidermal nevus with a serpiginous distribution

The girl’s mother had had an uncomplicated term pregnancy and delivery. At birth the girl’s weight and length were 2910 g and 46.5 cm, respectively. The family history was non-contributory.

The ophthalmologic and neurologic examinations were normal.

At 14 months of age the child was evaluated in an orthopedic clinic for progressive muscle weakness, limb deformities, and irregular and painful walking. Wrist and ankle widening were also observed. Physical examination revealed asymmetry of the thighs and right knee extension limitation.

Laboratory studies demonstrated a phosphorus level of 1.9 mg/dL (normal range: 3.0 - 6.5) and an alkaline phosphatase level of 1192 U/L (normal range: 54 - 280). Serum levels of calcium, parathormone, vitamin D, electrolytes, creatinine, urea, and calcitonin were within normal limits. Renal tubular function studies revealed a low tubular reabsorption of phosphorus with a normal acidification test. The remaining blood analyses were normal.

Skeletal radiographs showed diffuse, moderate osteopenia, more evident on the right side of the body, particularly on the right lower member. Incurvation of lower long bones and a right fibula pathologic fracture were also observed.

The right femoral MRI showed a severe structural alteration with abnormal medullar signal, particularly evident at the femoral diaphysis. Multiple areas of central sclerosis with reactive periosteal new bone and a fracture of the proximal femoral diaphysis were also observed.

The femoral T1-weighted pos-gadolinium MRI, the brain MRI, and the brain angio-MRI were normal as well as the echocardiography and the abdominal and renal ultrasonography.

The diagnosis of hypophosphatemic rickets was made based on the abnormal radiograph study findings and the typical laboratory findings with phosphaturia and normal parathormone.

Treatment was initiated with calcitriol (0.75 μg/day), oral phosphorus (32 mL, divided in 4 doses) and amiloride with hydrochlorothiazide (1.25 + 12.5 mg/day). Follow-up evaluations did not show hypercalciuria or nephrocalcinosis. A progressive clinical and radiological improvement was observed with biochemical normalization of the rickets. Presently, the child is 4 years of age and has attained normal growth with good motor development with the established medical therapy.


In 1968 Solomon et al. described the occurrence of epidermal nevi combined with different extracutaneous organ disturbances and called it “Epidermal Nevus Syndrome” [2, 4]. Whether ENS represents a single syndrome, or a variety of distinct entities, continues to be debated [4, 6]. Most reported abnormalities associated with epidermal nevi concern organs derived from the ectoderm and mesoderm primordial matrix, in particular the skeleton, central nervous system, and eyes [4]. In fact, ENS has also been referred to as linear sebaceus nevus syndrome, Schimmelpenning syndrome, Jadassohn nevus phakomatosis, and Solomon syndrome [6, 7].

Epidermal Nevus Syndrome comprises involvement of different organs and congenital epidermal nevi. These nevi, consisting of epidermal cells with mainly sebocytic and keratinocytic differentiation, follow Blaschko lines and may also occur alone. The genetic base of these linear nevi is supposed to be a lethal gene surviving by mosaicism [4, 6]. Postzygotic mosaicism would also help to explain the highly variable expression of the disease that can have neurologic, ophthalmologic, renal, and cardiac manifestations, as well as malignant changes [6].

The association between epidermal nevus and hypophosphatemic rickets is seldom reported. There are just 15 cases described in the literature with some of them being vitamin D-resistant.

The proposed pathogenesis of rickets in ENS is generally accepted to be a variant of the tumor-induced (“oncogenic”) osteomalacia [2, 6, 8, 9]. In this last situation, typically benign neoplasms (nearly half are present in bone) [5] cause the same derangements in mineral homeostasis observed in our patient: hypophosphatemia caused by renal phosphorus wasting, together with paradoxically low plasma calcitriol levels. In typical tumor-induced osteomalacia, symptoms tend to resolve after removal of the tumor [1, 6, 8, 9]. Phosphaturia is caused by circulating factor(s), called “phosphatonin(s),” secreted by the tumor cells. These tumors are frequently of mesenchymal origin, are histologically polymorphous, and have a significant vascular component [5]. Some examples are osteoblastoma-like, nonossifying-like, and ossifying fibroma-like tumors.

The pathogenic mechanism involved in the onset of hypophosphatemic rickets in ENS is not fully clarified [1, 4]. Material from skin lesions in a patient with ENS reportedly produced a phosphaturic effect when injected into animals [6, 10, 11]. The nature of the phosphaturic factor(s) in ENS is not well understood, but elevated circulating FGF-23 levels were recently reported in one patient with hypophosphatemic rickets [6]. In addition, several case reports indicate that severe bone hypomineralization in ENS is partially corrected when skin lesions are removed [4, 5, 6]. However, in other patients, excision of epidermal lesions failed to heal rickets [1].

We report a new case of ENS with hypophosphatemic rickets, non-vitamin D-resistent. Because our patient is affected with a widespread epidermal verrucous nevus (nevus unius lateris) we can suppose that this nevus may be responsible for the production of a phosphaturic substance.

For technical reasons, we were not able to measure the circulating levels of FGF-23 but we think this measurement may be helpful in the workup of this kind of rickets.

Because our case is not resistant to vitamin D, the clinical, laboratory, and radiological findings were corrected with just the established medical therapy. It was not necessary to perform surgical procedures; we can not predict its impact in improving this metabolic disorder.

This case highlights the importance of meticulous examination of children with epidermal nevi and referring them for neurologic, ophthalmologic, and orthopedic consultations when abnormalities are suspected.


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