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doi:10.1111/jpc.12472
INSTRUCTIVE CASE
Epidermal nevus syndrome with hypophosphatemic rickets in a young girl Dabuswinee Sukkhojaiwaratkul, Pat Mahachoklertwattana and Preamrudee Poomthavorn Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Abstract: Epidermal nevus syndrome (ENS) is a rare congenital disorder. It is characterised by epidermal nevi and abnormalities of multiple organs, including central nervous system, skeleton, cardiovascular and genitourinary systems and eyes. Hypophosphatemic rickets-associated ENS has rarely been reported. We report a 46-month-old girl who presented with a classical feature of hypophosphatemic rickets. Examination of skin revealed multiple melanocytic nevi at her trunk, face and both arms with verrucous plaques at both axillae and neck, and yellow plaques at the back along Blaschko’s lines. Histopathology of the skin lesions was compatible with epidermal nevi and nevus sebaceous. Therefore, the diagnosis of ENS was made. Apart from typical rickets, the skeletal X-rays interestingly displayed fibrous dysplasia-like lesions along right femur, tibia and fibula. Hypophosphatemic rickets was treated with alfacalcidol and phosphate solution. After 3 months of treatment, clinical improvement of hypophosphatemic rickets was clearly demonstrated. Her blood chemistries were normalised at 5 months following the treatment. In conclusion, hypophosphatemic rickets is a rare presentation of ENS. Our patient also demonstrated an additional abnormal bone finding, fibrous dysplasia-like lesions, associated with rachitic changes. This highlights heterogeneity of this condition and importance of thorough evaluation of patients with ENS. Key words:
dermatology; endocrinology; general paediatrics.
Epidermal nevus syndrome (ENS) is a rare congenital disorder. It is characterised by epidermal nevi and abnormalities of multiple organs, including central nervous system, skeleton, cardiovascular and genitourinary systems and eyes.1 Hypophosphatemic rickets-associated ENS has rarely been reported. We report a young girl with ENS who presented with hypophosphatemic rickets.
Case Report A 46-month-old girl presented with leg deformity and pain as well as walking refusal during the past 9 months. She was born at term to an uneventful pregnancy and non-consanguineous parents. Her birthweight and length were 3500 g and 50 cm, Key points 1. Hypophosphatemic rickets associated with epidermal nevi and/or nevus sebaceous suggests the diagnosis of epidermal nevus syndrome (ENS). 2. ENS is a rare congenital disorder with multisystem abnormalities. Therefore, evaluation of various systems abnormalities is needed in ENS patients. 3. Skeletal involvement in ENS could be heterogeneous. Correspondence: Associate Professor Preamrudee Poomthavorn, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand. Fax: +66 2201 1850; email: [email protected] Conflict of interest: None Accepted for publication 24 September 2013.
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respectively. Her developmental milestones had been normal until the presentation. She had three meals and approximately 750 mL of whole milk daily. No family history of rickets and bone disease was noted. Physical examination revealed weight of 9.3 kg (−4 SDS) and height of 87 cm (−3.7 SDS). Both wrists were widened and varus deformity of right leg was demonstrated. An examination of skin revealed multiple melanocytic nevi at her trunk, face and both arms with verrucous plaques at both axillae and neck, and yellow plaques at the back along Blaschko’s lines (Fig. 1). Parents reported that skin lesions were present at birth and increased with age. Cardiovascular, respiratory and neurological systems were unremarkable. Skeletal X-rays revealed poor mineralisation with rachitic changes, including flaring, cupping and fraying of metaphyses of both wrists and ankles. In addition, scattered areas of poorly defined lucency fibrous dysplasia-like lesions at right femur, tibia and fibula were shown on the skeletal X-rays (Fig. 2). Blood chemistries are shown in Table 1. Tubular reabsorption of phosphate was 75% and renal threshold phosphate concentration (TmP/GFR) was 0.46 mmol/L, indicating urinary phosphate loss despite being hypophosphatemic (Table 1). Serum fibroblast growth factor 23 (FGF 23) level, a phosphaturic factor, was not measured because the assay was not available. Hypophosphatemic rickets was diagnosed and then treated with alfacalcidol and phosphate solution. Vitamin D2 was also administered to raise her serum 25-OHD level to above 75 nmol/L. To exclude a familial form of hypophosphatemic rickets, her parental blood and urine chemistries were undertaken and found to be normal. After 3 months of treatment, she started walking without pain and difficulty. Her blood
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
D Sukkhojaiwaratkul et al.
Epidermal nevus syndrome
(a)
(b)
Fig. 1 Skin lesions of the patient: (a) multiple melanocytic nevi at face, (b) multiple melanocytic nevi at back and yellow plaques along Blaschko’s lines.
chemistries were normalised at 5 months following the treatment (Table 1). However, skin lesions and leg deformity persisted. Other system abnormalities which may be present in ENS were sought. Echocardiography, ultrasonography of genitourinary system and eye examination were all unremarkable. Concerning the skin lesions, skin biopsies at right arm and back were performed. Pathological results demonstrated epidermal nevi and nevus sebaceous, respectively. Hypophosphatemic rickets-associated ENS was, therefore, consistent with her presentation. The girl has now been followed for 15 months. She weighs 13 kg (−2 SDS) and is 95 cm tall (−3 SDS). No new skin lesions have been observed. Her blood chemistries have been well within the normal ranges since 5 months of treatment.
Discussion Our patient presented with hypophosphatemic rickets. Thorough physical examination revealed multiple epidermal nevi and nevus sebaceous throughout the body. This ultimately led to the diagnosis of hypophosphatemic rickets-associated ENS in our patient. Hypophosphatemic rickets is caused by a defect in phosphate reabsorption at the proximal renal tubule. The disorder may be caused by mutations of genes involved in the complex regulation of phosphate metabolism or associated with the other specific conditions. ENS is characterised by congenital anomalies affecting multiple systems of the body. Its manifestations are the results of genomic mosaicism.2 Specific genetic defects and timing of mutation during fetal development influence the varied phenotypes of ENS. Central nervous system, cardiac and ocular involvements in ENS patients were reported.1 Precocious puberty was also reported.1 Hypophosphatemic rickets is a rare presentation of ENS. To our knowledge, there have been reports of only 26 patients with ENS who had associated hypophosphatemic rickets in the English literature. It usually develops within 5 years of age. Our patient had developed signs and symptoms of hypophosphatemic rickets
Fig. 2 Skeletal X-rays of both legs, showing rickets changes of left knee and scattered areas of poorly defined lucency (fibrous dysplasia-like lesions) at right femur, tibia and fibula.
since the age of approximately 3 years. The main proposed mechanism of hypophosphatemic rickets found in this condition is a renal phosphate wasting owing to FGF 23, which is produced and released from the skin nevi.3 Sethi et al. reported a 5-year-old boy who had hypophosphatemic rickets-associated ENS and the boy had an elevated serum FGF 23 level.3 Hypophosphatemic rickets treatment generally comprises phosphate solution, and active vitamin D, that is, calcitriol is added to prevent secondary hyperparathyroidism and also enhance intestinal phosphate absorption. There was a study of a 12-year-old boy who had hypophosphatemic rickets-associated ENS. He had an improvement of hypophosphatemia after the excision of skin lesions on his face and left leg.4 Furthermore, that study demonstrated hyperphosphaturia after inoculation of the extract from the boy’s skin lesions into a puppy. Hoffman et al. reported a boy with hypophosphatemic rickets-associated ENS
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Epidermal nevus syndrome
D Sukkhojaiwaratkul et al.
Table 1 Blood chemistries, TRP and TmP/GFR of the patient at pre- and post-treatments Parameters
At diagnosis
5 months after treatment
Blood chemistries Calcium (NR, 2.2–2.7 mmol/L) Phosphorus (NR, 1.2–1.8 mmol/L) iPTH (NR, 3.7–15.9 pmol/L) 25-OHD (NR, >50 nmol/L) ALP (NR, 169–372 U/L) TRP (%) TmP/GFR (mmol/L)
2.3 0.6 12.4 61.2 2,877 75 0.46
2.5 1.2 5.5 107.0 370 75 0.90
25-OHD, 25-hydroxyvitamin D; ALP, alkaline phosphatase; iPTH, intact parathyroid hormone; NR, normal range; TmP/GFR, ratio of the renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate; TRP, tubular reabsorption of phosphate
who had an elevated serum FGF 23.5 Following administration of octreotide which possesses antiproliferative and antiangiogenesis effects, serum FGF 23 and phosphorus levels were normalised.5 In addition, both serum levels were maintained after excision of nevus concomitant with calcitriol and phosphate solution treatment. Therefore, excision of nevi in patients with ENS may be another optional treatment for hypophosphatemic rickets. However, our patient had extensive skin lesions which excision was not possible. Therefore, supplementation with phosphate solution and active vitamin D was administered and this resulted in normalisation of her blood chemistries (Table 1). Serum 25-OHD level of the patient was aimed to above 75 nmol/L which is greater than the recommended threshold level for deficiency of 50 nmol/L in the general population. In fact, high serum FGF 23 level attenuates 1α-hydroxylase activity. Thus, higher serum 25-OHD level may be needed to optimise the production of calcitriol (1,25(OH)2 vitamin D). Apart from hypophosphatemic rickets, there were other skeletal abnormalities reported. These included primary osseous change, fibrous dysplasia, aplasia of ribs and kyphoscoliosis. Our patient’s radiographs showed fibrous dysplasia-like lesions along right femur, tibia and fibula. Riminucci et al. demonstrated that FGF 23 mRNA was expressed in fibrous dysplasia tissue of patients with McCune–Albright syndrome (MAS).6 Production of FGF 23 from these tissues caused greater serum FGF 23 level in patients with MAS as compared with that of normal age-matched controls. Therefore, we hypothesized that the fibrous dysplasialike bone lesions found in our patient may produce FGF 23, and thus resulted in hypophosphatemia. Herman and Siegel reported a 6-year-old boy with sexual precocity who had an epidermal nevus on the left shoulder and fibrous dysplasia on the skull.7 The diagnosis of MAS with ENS was made. However, hypophosphatemic rickets was not observed in this patient. Cutaneous lesions which were reported in ENS patients included epidermal nevi along the Blaschko’s lines, café au lait macules and hypopigmented macules. Malignant transformation of epidermal nevi has rarely been reported. One study reported malignant transformation of verrucous lesions at right ear pinna.8 The lesions were noticed shortly after birth and basal cell carcinoma was diagnosed at the age of 35 years. The girl in our report had no evidence of malignant transformation of her skin lesions from histopathological results. However, long-term 568
follow-up is needed for monitoring of malignant transformation of her skin lesions. As multisystem abnormalities are typical for patients with ENS, therefore, other abnormalities were sought in our patient but no additional abnormalities were found. In conclusion, the girl of this report presented with a classical feature of hypophosphatemic rickets. Additional evaluation revealed a diagnosis of ENS. Fibrous dysplasia-like lesions of the right leg were interestingly found in association with rachitic changes. To our knowledge, there were only a few previous reports of this bony abnormality in patients with ENS.
Multiple Choice Questions 1. Which of the following statements is true regarding hypophosphatemic rickets-associated epidermal nevus syndrome? A. Hypophosphatemic rickets is the most common presentation of epidermal nevus syndrome. B. Hypophosphatemic rickets usually develops during puberty. C. Gross motor development regression is one of the presentations of hypophosphatemic rickets. D. Persistent bone pain is characteristic even after resolution of hypophosphatemia. E. Excision of nevi does not normalise serum phosphate level. Answer A. Incorrect: Hypophosphatemic rickets is a rare presentation of epidermal nevus syndrome. B. Incorrect: Hypophosphatemic rickets usually develops during the first years of life. C. Correct: Gross motor development regression can be a presentation of rickets. D. Incorrect: Bone pain is improved following normalisation of serum phosphate level. E. Incorrect: Some reports demonstrated that excision of the nevi could correct hypophosphatemia. 2. Which of the following evaluations is not useful in patients with epidermal nevus syndrome? A. Echocardiography B. Ultrasonography of genitourinary system C. Eye examination
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
D Sukkhojaiwaratkul et al.
D. Chromosome karyotype E. Assessment of developmental milestones Answer A. Incorrect: Cardiac abnormalities such as TOF, PDA and coarctation of the aorta can be found in patients with epidermal nevus syndrome. B. Incorrect: Wilms’ tumour, horseshoe kidney and cystic kidney can be found in patients with epidermal nevus syndrome. C. Incorrect: Eye abnormalities such as ptosis, esotropia and nystagmus can be found in patients with epidermal nevus syndrome. D. Correct: Epidermal nevus syndrome resulted from postzygotic mosaicism; therefore, the chromosome karyotype is usually normal. E. Incorrect: Developmental delay can be found in patients with epidermal nevus syndrome. 3. Which of the following treatment modalities is not helpful for hypophosphatemic rickets-associated epidermal nevus syndrome? A. Phosphate supplementation B. Calcitriol supplementation C. Debulking of the nevi D. Optimization of vitamin D status E. Parathyroidectomy Answer A, B. Incorrect: Administration of phosphate solution and calcitriol is the treatment of choice of hypophosphatemic rickets. C. Incorrect: Debulking of nevi may help in normalisation of serum phosphate level.
Epidermal nevus syndrome
D. Incorrect: Optimisation of vitamin D status can avoid renal phosphate loss, secondary to hyperparathyroidism, and can augment intestinal phosphate absorption. E. Correct: Parathyroidectomy is not helpful in hypophosphatemic rickets.
References 1 Grebe TA, Rimsza ME, Richter SF, Hansen RC, Hoyme HE. Further delineation of the epidermal nevus syndrome: two cases with new findings and literature review. Am. J. Med. Genet. 1993; 47: 24–30. 2 Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch. Dermatol. 1993; 129: 1460–70. 3 Sethi SK, Hari P, Bagga A. Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets. Pediatr. Nephrol. 2010; 25: 1577–8. 4 Aschinberg LC, Solomon LM, Zeis PM, Justice P, Rosenthal IM. Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. J. Pediatr. 1977; 91: 56–60. 5 Hoffman WH, Jueppner HW, Deyoung BR, O’dorisio MS, Given KS. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am. J. Med. Genet. A 2005; 134: 233–6. 6 Riminucci M, Collins MT, Fedarko NS et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J. Clin. Invest. 2003; 112: 683–92. 7 Herman TE, Siegel MJ. McCune Albright syndrome: epidermal nevus syndrome. Clin. Pediatr. (Phila) 2010; 49: 1164–6. 8 Goldblum JR, Headington JT. Hypophosphatemic vitamin D-resistant rickets and multiple spindle and epithelioid nevi associated with linear nevus sebaceus syndrome. J. Am. Acad. Dermatol. 1993; 29: 109–11.
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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doi:10.1111/jpc.12472
INSTRUCTIVE CASE
Epidermal nevus syndrome with hypophosphatemic rickets in a young girl Dabuswinee Sukkhojaiwaratkul, Pat Mahachoklertwattana and Preamrudee Poomthavorn Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Abstract: Epidermal nevus syndrome (ENS) is a rare congenital disorder. It is characterised by epidermal nevi and abnormalities of multiple organs, including central nervous system, skeleton, cardiovascular and genitourinary systems and eyes. Hypophosphatemic rickets-associated ENS has rarely been reported. We report a 46-month-old girl who presented with a classical feature of hypophosphatemic rickets. Examination of skin revealed multiple melanocytic nevi at her trunk, face and both arms with verrucous plaques at both axillae and neck, and yellow plaques at the back along Blaschko’s lines. Histopathology of the skin lesions was compatible with epidermal nevi and nevus sebaceous. Therefore, the diagnosis of ENS was made. Apart from typical rickets, the skeletal X-rays interestingly displayed fibrous dysplasia-like lesions along right femur, tibia and fibula. Hypophosphatemic rickets was treated with alfacalcidol and phosphate solution. After 3 months of treatment, clinical improvement of hypophosphatemic rickets was clearly demonstrated. Her blood chemistries were normalised at 5 months following the treatment. In conclusion, hypophosphatemic rickets is a rare presentation of ENS. Our patient also demonstrated an additional abnormal bone finding, fibrous dysplasia-like lesions, associated with rachitic changes. This highlights heterogeneity of this condition and importance of thorough evaluation of patients with ENS. Key words:
dermatology; endocrinology; general paediatrics.
Epidermal nevus syndrome (ENS) is a rare congenital disorder. It is characterised by epidermal nevi and abnormalities of multiple organs, including central nervous system, skeleton, cardiovascular and genitourinary systems and eyes.1 Hypophosphatemic rickets-associated ENS has rarely been reported. We report a young girl with ENS who presented with hypophosphatemic rickets.
Case Report A 46-month-old girl presented with leg deformity and pain as well as walking refusal during the past 9 months. She was born at term to an uneventful pregnancy and non-consanguineous parents. Her birthweight and length were 3500 g and 50 cm, Key points 1. Hypophosphatemic rickets associated with epidermal nevi and/or nevus sebaceous suggests the diagnosis of epidermal nevus syndrome (ENS). 2. ENS is a rare congenital disorder with multisystem abnormalities. Therefore, evaluation of various systems abnormalities is needed in ENS patients. 3. Skeletal involvement in ENS could be heterogeneous. Correspondence: Associate Professor Preamrudee Poomthavorn, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand. Fax: +66 2201 1850; email: [email protected] Conflict of interest: None Accepted for publication 24 September 2013.
566
respectively. Her developmental milestones had been normal until the presentation. She had three meals and approximately 750 mL of whole milk daily. No family history of rickets and bone disease was noted. Physical examination revealed weight of 9.3 kg (−4 SDS) and height of 87 cm (−3.7 SDS). Both wrists were widened and varus deformity of right leg was demonstrated. An examination of skin revealed multiple melanocytic nevi at her trunk, face and both arms with verrucous plaques at both axillae and neck, and yellow plaques at the back along Blaschko’s lines (Fig. 1). Parents reported that skin lesions were present at birth and increased with age. Cardiovascular, respiratory and neurological systems were unremarkable. Skeletal X-rays revealed poor mineralisation with rachitic changes, including flaring, cupping and fraying of metaphyses of both wrists and ankles. In addition, scattered areas of poorly defined lucency fibrous dysplasia-like lesions at right femur, tibia and fibula were shown on the skeletal X-rays (Fig. 2). Blood chemistries are shown in Table 1. Tubular reabsorption of phosphate was 75% and renal threshold phosphate concentration (TmP/GFR) was 0.46 mmol/L, indicating urinary phosphate loss despite being hypophosphatemic (Table 1). Serum fibroblast growth factor 23 (FGF 23) level, a phosphaturic factor, was not measured because the assay was not available. Hypophosphatemic rickets was diagnosed and then treated with alfacalcidol and phosphate solution. Vitamin D2 was also administered to raise her serum 25-OHD level to above 75 nmol/L. To exclude a familial form of hypophosphatemic rickets, her parental blood and urine chemistries were undertaken and found to be normal. After 3 months of treatment, she started walking without pain and difficulty. Her blood
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
D Sukkhojaiwaratkul et al.
Epidermal nevus syndrome
(a)
(b)
Fig. 1 Skin lesions of the patient: (a) multiple melanocytic nevi at face, (b) multiple melanocytic nevi at back and yellow plaques along Blaschko’s lines.
chemistries were normalised at 5 months following the treatment (Table 1). However, skin lesions and leg deformity persisted. Other system abnormalities which may be present in ENS were sought. Echocardiography, ultrasonography of genitourinary system and eye examination were all unremarkable. Concerning the skin lesions, skin biopsies at right arm and back were performed. Pathological results demonstrated epidermal nevi and nevus sebaceous, respectively. Hypophosphatemic rickets-associated ENS was, therefore, consistent with her presentation. The girl has now been followed for 15 months. She weighs 13 kg (−2 SDS) and is 95 cm tall (−3 SDS). No new skin lesions have been observed. Her blood chemistries have been well within the normal ranges since 5 months of treatment.
Discussion Our patient presented with hypophosphatemic rickets. Thorough physical examination revealed multiple epidermal nevi and nevus sebaceous throughout the body. This ultimately led to the diagnosis of hypophosphatemic rickets-associated ENS in our patient. Hypophosphatemic rickets is caused by a defect in phosphate reabsorption at the proximal renal tubule. The disorder may be caused by mutations of genes involved in the complex regulation of phosphate metabolism or associated with the other specific conditions. ENS is characterised by congenital anomalies affecting multiple systems of the body. Its manifestations are the results of genomic mosaicism.2 Specific genetic defects and timing of mutation during fetal development influence the varied phenotypes of ENS. Central nervous system, cardiac and ocular involvements in ENS patients were reported.1 Precocious puberty was also reported.1 Hypophosphatemic rickets is a rare presentation of ENS. To our knowledge, there have been reports of only 26 patients with ENS who had associated hypophosphatemic rickets in the English literature. It usually develops within 5 years of age. Our patient had developed signs and symptoms of hypophosphatemic rickets
Fig. 2 Skeletal X-rays of both legs, showing rickets changes of left knee and scattered areas of poorly defined lucency (fibrous dysplasia-like lesions) at right femur, tibia and fibula.
since the age of approximately 3 years. The main proposed mechanism of hypophosphatemic rickets found in this condition is a renal phosphate wasting owing to FGF 23, which is produced and released from the skin nevi.3 Sethi et al. reported a 5-year-old boy who had hypophosphatemic rickets-associated ENS and the boy had an elevated serum FGF 23 level.3 Hypophosphatemic rickets treatment generally comprises phosphate solution, and active vitamin D, that is, calcitriol is added to prevent secondary hyperparathyroidism and also enhance intestinal phosphate absorption. There was a study of a 12-year-old boy who had hypophosphatemic rickets-associated ENS. He had an improvement of hypophosphatemia after the excision of skin lesions on his face and left leg.4 Furthermore, that study demonstrated hyperphosphaturia after inoculation of the extract from the boy’s skin lesions into a puppy. Hoffman et al. reported a boy with hypophosphatemic rickets-associated ENS
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Epidermal nevus syndrome
D Sukkhojaiwaratkul et al.
Table 1 Blood chemistries, TRP and TmP/GFR of the patient at pre- and post-treatments Parameters
At diagnosis
5 months after treatment
Blood chemistries Calcium (NR, 2.2–2.7 mmol/L) Phosphorus (NR, 1.2–1.8 mmol/L) iPTH (NR, 3.7–15.9 pmol/L) 25-OHD (NR, >50 nmol/L) ALP (NR, 169–372 U/L) TRP (%) TmP/GFR (mmol/L)
2.3 0.6 12.4 61.2 2,877 75 0.46
2.5 1.2 5.5 107.0 370 75 0.90
25-OHD, 25-hydroxyvitamin D; ALP, alkaline phosphatase; iPTH, intact parathyroid hormone; NR, normal range; TmP/GFR, ratio of the renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate; TRP, tubular reabsorption of phosphate
who had an elevated serum FGF 23.5 Following administration of octreotide which possesses antiproliferative and antiangiogenesis effects, serum FGF 23 and phosphorus levels were normalised.5 In addition, both serum levels were maintained after excision of nevus concomitant with calcitriol and phosphate solution treatment. Therefore, excision of nevi in patients with ENS may be another optional treatment for hypophosphatemic rickets. However, our patient had extensive skin lesions which excision was not possible. Therefore, supplementation with phosphate solution and active vitamin D was administered and this resulted in normalisation of her blood chemistries (Table 1). Serum 25-OHD level of the patient was aimed to above 75 nmol/L which is greater than the recommended threshold level for deficiency of 50 nmol/L in the general population. In fact, high serum FGF 23 level attenuates 1α-hydroxylase activity. Thus, higher serum 25-OHD level may be needed to optimise the production of calcitriol (1,25(OH)2 vitamin D). Apart from hypophosphatemic rickets, there were other skeletal abnormalities reported. These included primary osseous change, fibrous dysplasia, aplasia of ribs and kyphoscoliosis. Our patient’s radiographs showed fibrous dysplasia-like lesions along right femur, tibia and fibula. Riminucci et al. demonstrated that FGF 23 mRNA was expressed in fibrous dysplasia tissue of patients with McCune–Albright syndrome (MAS).6 Production of FGF 23 from these tissues caused greater serum FGF 23 level in patients with MAS as compared with that of normal age-matched controls. Therefore, we hypothesized that the fibrous dysplasialike bone lesions found in our patient may produce FGF 23, and thus resulted in hypophosphatemia. Herman and Siegel reported a 6-year-old boy with sexual precocity who had an epidermal nevus on the left shoulder and fibrous dysplasia on the skull.7 The diagnosis of MAS with ENS was made. However, hypophosphatemic rickets was not observed in this patient. Cutaneous lesions which were reported in ENS patients included epidermal nevi along the Blaschko’s lines, café au lait macules and hypopigmented macules. Malignant transformation of epidermal nevi has rarely been reported. One study reported malignant transformation of verrucous lesions at right ear pinna.8 The lesions were noticed shortly after birth and basal cell carcinoma was diagnosed at the age of 35 years. The girl in our report had no evidence of malignant transformation of her skin lesions from histopathological results. However, long-term 568
follow-up is needed for monitoring of malignant transformation of her skin lesions. As multisystem abnormalities are typical for patients with ENS, therefore, other abnormalities were sought in our patient but no additional abnormalities were found. In conclusion, the girl of this report presented with a classical feature of hypophosphatemic rickets. Additional evaluation revealed a diagnosis of ENS. Fibrous dysplasia-like lesions of the right leg were interestingly found in association with rachitic changes. To our knowledge, there were only a few previous reports of this bony abnormality in patients with ENS.
Multiple Choice Questions 1. Which of the following statements is true regarding hypophosphatemic rickets-associated epidermal nevus syndrome? A. Hypophosphatemic rickets is the most common presentation of epidermal nevus syndrome. B. Hypophosphatemic rickets usually develops during puberty. C. Gross motor development regression is one of the presentations of hypophosphatemic rickets. D. Persistent bone pain is characteristic even after resolution of hypophosphatemia. E. Excision of nevi does not normalise serum phosphate level. Answer A. Incorrect: Hypophosphatemic rickets is a rare presentation of epidermal nevus syndrome. B. Incorrect: Hypophosphatemic rickets usually develops during the first years of life. C. Correct: Gross motor development regression can be a presentation of rickets. D. Incorrect: Bone pain is improved following normalisation of serum phosphate level. E. Incorrect: Some reports demonstrated that excision of the nevi could correct hypophosphatemia. 2. Which of the following evaluations is not useful in patients with epidermal nevus syndrome? A. Echocardiography B. Ultrasonography of genitourinary system C. Eye examination
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
D Sukkhojaiwaratkul et al.
D. Chromosome karyotype E. Assessment of developmental milestones Answer A. Incorrect: Cardiac abnormalities such as TOF, PDA and coarctation of the aorta can be found in patients with epidermal nevus syndrome. B. Incorrect: Wilms’ tumour, horseshoe kidney and cystic kidney can be found in patients with epidermal nevus syndrome. C. Incorrect: Eye abnormalities such as ptosis, esotropia and nystagmus can be found in patients with epidermal nevus syndrome. D. Correct: Epidermal nevus syndrome resulted from postzygotic mosaicism; therefore, the chromosome karyotype is usually normal. E. Incorrect: Developmental delay can be found in patients with epidermal nevus syndrome. 3. Which of the following treatment modalities is not helpful for hypophosphatemic rickets-associated epidermal nevus syndrome? A. Phosphate supplementation B. Calcitriol supplementation C. Debulking of the nevi D. Optimization of vitamin D status E. Parathyroidectomy Answer A, B. Incorrect: Administration of phosphate solution and calcitriol is the treatment of choice of hypophosphatemic rickets. C. Incorrect: Debulking of nevi may help in normalisation of serum phosphate level.
Epidermal nevus syndrome
D. Incorrect: Optimisation of vitamin D status can avoid renal phosphate loss, secondary to hyperparathyroidism, and can augment intestinal phosphate absorption. E. Correct: Parathyroidectomy is not helpful in hypophosphatemic rickets.
References 1 Grebe TA, Rimsza ME, Richter SF, Hansen RC, Hoyme HE. Further delineation of the epidermal nevus syndrome: two cases with new findings and literature review. Am. J. Med. Genet. 1993; 47: 24–30. 2 Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch. Dermatol. 1993; 129: 1460–70. 3 Sethi SK, Hari P, Bagga A. Elevated FGF-23 and parathormone in linear nevus sebaceous syndrome with resistant rickets. Pediatr. Nephrol. 2010; 25: 1577–8. 4 Aschinberg LC, Solomon LM, Zeis PM, Justice P, Rosenthal IM. Vitamin D-resistant rickets associated with epidermal nevus syndrome: demonstration of a phosphaturic substance in the dermal lesions. J. Pediatr. 1977; 91: 56–60. 5 Hoffman WH, Jueppner HW, Deyoung BR, O’dorisio MS, Given KS. Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am. J. Med. Genet. A 2005; 134: 233–6. 6 Riminucci M, Collins MT, Fedarko NS et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J. Clin. Invest. 2003; 112: 683–92. 7 Herman TE, Siegel MJ. McCune Albright syndrome: epidermal nevus syndrome. Clin. Pediatr. (Phila) 2010; 49: 1164–6. 8 Goldblum JR, Headington JT. Hypophosphatemic vitamin D-resistant rickets and multiple spindle and epithelioid nevi associated with linear nevus sebaceus syndrome. J. Am. Acad. Dermatol. 1993; 29: 109–11.
Journal of Paediatrics and Child Health 50 (2014) 566–569 © 2013 The Authors Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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