Ichthyosis associated with rickets in two Indian children.

We wish to report two cases of rickets due to vitamin D deficiency secondary to underlying ichthyotic skin disorder. The first case is of an 8-year-old male with history of multiple fluid-filled lesions over the body that would rupture to heal with thickening and scaling of skin, suggestive of epidermolytic hyperkeratosis, and the second is of a 14-year-old female with thick, large, quadrilateral scales over the extremities and back clinically consistent with lamellar ichthyosis. Both showed improvement with parenteral vitamin D3 and oral calcium supplements in addition to topical emollients.

What was known?

1. Rickets is a constitutional disease with vitamin D deficiency being the most common cause of rickets in infancy and dietary calcium deficiency as an important cause of nutritional rickets in young children in India.

2. Defective synthesis of vitamin D in the diseased epidermis and excessive loss of calcium through skin in turn puts the children with ichthyosis at increased risk of rickets.

Introduction

Rickets is a vitamin D deficiency disorder caused by failure of the osteoid to calcify in the growing bones of children and adolescents. Type 1 rickets is vitamin D dependent, whereas type 2 rickets is vitamin D non-dependent. Occurrence of rickets in patients of ichthyosis is an uncommon but preventable complication. Dark-skinned children with ichthyosis are prone to develop rickets since poor penetration of sun rays leads to reduced synthesis of vitamin D for the given amount of sun exposure.[1]

Case Reports

Case 1

An 8-year-old boy born of non-consanguineous marriage was brought with thick, dark skin lesions all over the body since 1.5 months of age and inability to walk since the past 5 months. The mother gave history of multiple fluid-filled lesions over the bilateral thighs at birth, which ruptured to heal with thickening and scaling of skin. This process continued to occur all over the body till the age of 7 years. There was history of fracture of the left forearm, followed by that of the right forearm 1 year back, causing deformities of both upper extremities. There was no history of similar complaints in other family members.

Cutaneous examination revealed generalized hyperkeratotic, verrucous and velvety plaques all over the body with predominant involvement of the axillae, wrists, buttocks and popliteal fossae [Figure 1]. There was relative sparing of the face and complete sparing of the palms and soles. Mucosae, hair, teeth and nails were normal. Bony examination revealed mild left-sided scoliosis and deformity of the left hand. There was a bowline deformity of the right forearm and bowing of both the legs.

Figure 1

Generalized hyperkeratotic verrucous plaques predominantly over the bilateral wrist and knee in the first case

Blood investigations including complete hemogram, renal function tests and liver function tests inclusive of serum proteins were within normal limits. Serum calcium (7.2 mg/dL) and 25-OH vitamin D3 (11.3 ng/mL) levels were low, whereas serum alkaline phosphatase level (1396.80 IU/L) was markedly high. Ultrasonography of the abdomen and pelvis was normal. X-ray of the limbs showed marked cupping and fraying of the distal metaphyses with coarse tubercular pattern and osteopenia. There was bilateral pseudo-fracture of the ulna, radius and tibia along with malunion of the radius, ulna and bowing of tibia [Figure 2]. Skin biopsy showed features of epidermolytic hyperkeratosis [Figure 3].

Figure 2

X-ray of upper limb showed marked cupping and fraying of distal metaphyses and tibia along with malunion of radius and ulna and bowing of tibia

Figure 3

Skin biopsy from the hyperkeratotic plaque over the arm shows lamellar orthokeratoses and epidermolytic hyperkeratosis on H and E, stain (×20)

On the basis of clinicopathologic correlation, the diagnosis of epidermolytic hyperkeratosis associated with active nutritional rickets was reached.

Case 2

A 14-year-old girl born of non-consanguineous marriage presented with thick, dark skin lesions since birth and pain in both knee joints since the past 4 years. She also had deformities of both the knees with difficulty in getting up from squatting position since the last 3 years. A history of collodion membrane at birth, followed by its spontaneous shedding a few days later, was elicited. This was followed by appearance of thick large scales all over the body, which was associated with periodic shedding. There was history of similar skin findings in the younger 11-year-old male sibling without any skeletal signs and symptoms. The mother also gave a history of avoidance of going out of the house during daytime due to social embarrassment and heat intolerance.

On cutaneous examination, there was diffuse thickening and hyperpigmentation of the skin with thick, large, quadrilateral scales that were free at the edges and adherent in the center. The lesions were distributed over the extremities and the back [Figure 4]. Hyperkeratosis of palms and soles was seen. Hair, teeth, nails and mucosa were un-involved. Bilateral genu valgum [Figure 4], wrist widening, double malleoli and rachitic rosary were noted.

Figure 4

Thickening and hyperpigmentation of the skin with few quadrilateral scales over the dorsa of the hands and legs with genu valgum in the second case

Blood investigations including complete hemogram, renal function tests and liver function tests, inclusive of serum proteins, were within normal limits. Serum calcium (7.79 mg/dL) and 25-OH vitamin D3 were low (12.25 ng/mL), whereas serum alkaline phosphatase (3090.00 IU/L) and parathyroid hormone levels (530.0 pg/mL) were significantly raised. X-rays of the limbs showed marked cupping and fraying of distal metaphyses with coarse trabecular pattern, osteopenia, pseudo-fracture of bilateral ulna, radius and tibia along with bowing of both the tibia [Figure 5]. Skin biopsy showed compact ortho-hyperkeratosis with focal parakeratosis, normal granular layer, papillomatosis and mild perivascular lymphocytic infiltrate in papillary dermis [Figure 6].

Figure 5

X-ray of the lower limb showed coarse tubercular pattern, pseudofracture, osteopenia and bowing of tibia

Figure 6

Skin biopsy from the scaly plaque on the shin shows compact ortho-hyperkeratosis with focal parakeratosis, normal granular layer and mild acanthosis on H and E, stain (×10)

On the basis of clinical features and investigations, a diagnosis of lamellar ichthyosis with active nutritional rickets was reached in the second case.

Rickets was treated in both these cases with parenteral vitamin D3, 6 lac IU single dose and 1500 mg of oral calcium daily for 1 month, showing gradual clinical improvement like reduction in joint pain and performance of activities of daily living. Serum calcium (8.8 mg/dL) and alkaline phosphatase (564 IU/L) improved over a period of 2 months in the first case, whereas serum calcium (8.43 mg/dL) and alkaline phosphatase (1480 IU/L) improved within 1 month in the second. Both the cases are currently orally taking 400 IU of vitamin D3 along with 500 mg of calcium salt daily.

For the treatment of ichthyosis, the first case was started on capsule isotretinoin 10 mg daily for 6 months, followed by 15 mg daily for 4 months for the underlying skin condition. Topically, 3% salicylic acid, white soft paraffin and liquid paraffin were applied daily.

In view of thin scales, the second patient was treated with only topical application of liquid paraffin and white soft paraffin with evidence of partial improvement in skin condition over the next 2 months.

Discussion

Rickets is a constitutional disease of infancy and childhood, characterized by impairment of general health, arrested growth and abnormalities of the developing bone. While vitamin D deficiency is the most common cause of rickets in infancy, dietary calcium deficiency is an important cause of nutritional rickets in young children in India.[23]

Rickets has been previously reported to occur in association with lamellar ichthyosis,[4] epidermolytic hyperkeratosis,[5] X-linked ichthyosis,[6] ichthyosis vulgaris[6] and non-bullous ichthyosiform erythroderma.[6] In a series of 41 Sudanese children with nutritional rickets, three were found to have ichthyosis.[7]

Epidermis is rich in 7-dehydrocholesterol, which is present in the cell membrane of keratinocytes. On sun exposure, 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3) in keratinocytes. Cholecalciferol undergoes hydroxylation in two steps, first in the liver to produce calcidiol and then in the kidney to produce calcitriol, which is the active product of vitamin D3. This conversion requires 25-hydroxyvitamin D 1α hydroxylase, which is highly regulated by parathyroid hormone.[8] Monocytes and keratinocytes are also capable of converting calcidiol to calcitriol. The keratinocytes are the only cells in the body having the entire pathway of vitamin D synthesis. However, its contribution toward total body calcitriol levels is minimal. Calcitriol increases the concentration of calcium and phosphorus in the extracellular fluid and maintains calcification of bones, primarily at the growing metaphysical end and later throughout all osteoids of the skeleton.

In hypocalcemic stage, serum parathyroid hormone (PTH) secretion increases, which in turn increases the renal phosphorus loss leading to decreased deposition of calcium in the bones. Due to defective synthesis of vitamin D in the diseased epidermis and excessive loss of calcium through skin, stimulation of PTH secretion occurs, which in turn puts the children with ichthyosis at increased risk of rickets.[9]

In a country like ours, where lack of fortification of dairy products and food fats with vitamin D contributes to nutritional vitamin D deficiency,[4] a low calcium and high phytate diet along with reduced vitamin D synthesis in dark-complexioned skin further increases the risk of occurrence of rickets.

The contributing factors proposed for development of rickets in underlying ichthyotic skin disorders are: (i) increased keratinocyte proliferation resulting in poor penetration of sunlight,[10] (ii) defective vitamin D synthesis in the diseased epidermis causing vitamin D-dependent rickets,[11] (iii) excessive loss of calcium through skin shedding,[4] (iv) limited sun exposure[10] due to heat intolerance as well as due to social constraints resulting from cosmetic reasons[7] and (v) use of systemic retinoids, which reduces the calcium absorption from the gut. A table differentiating ichthyosis-associated rickets with nutritional rickets has been given below Table 1.

Table 1

Differences between ichthyosis-associated rickets and nutritional rickets

Hence, the occurrence of rickets in our cases can be attributed to both nutritional vitamin D deficiency and the underlying ichthyotic disorders.

Epidermolytic hyperkeratosis and lamellar ichthyosis are life-long conditions and the most refractory forms of ichthyosis. All such patients should be considered for lifelong “rickets prophylaxis” with vitamin D supplements periodically along with counseling, pertaining to adequate exposure to sunlight.

Treatment of skin manifestations of EHK and LI is not usually very satisfactory, and includes keratolytics, antiseptic washes, topical calcipotriol, alfa hydroxy acids and oral retinoids, all of which lead to partial improvement. However, treating the underlying ichthyotic condition is important as it may probably contribute in restoring back the normal vitamin D metabolism.[12]

What is new?

1. Lack of food fortification with vitamin D, along with reduced vitamin D synthesis in dark-complexioned skin further increases the risk of occurrence of rickets in children with ichthyosiform disorders in our country.

2. Children with ichthyosis may require life-long prophylaxis of calcium and vitamin D.