Rickets with Alopecia Signals Vitamin D Dependent Rickets Type II

Vitamin D-dependent rickets type II is a rare autosomal recessive disorder. We report 27 months female child with classical rachitic changes, very high level of 25-hydroxy Vitamin D, 1,25 (OH)2D and markedly elevated serum Alkaline phosphatase. Very high dose of oral calcium and vitamin D3 was prescribed with minor improvement in skeletal features and alopecia. This case report hints the physician to diagnose and manage Vitamin D-dependent rickets type II, when rachitic changes are associated with alopecia.


Introduction
P a ents with vitamin D dependent rickets (VDDR) type 2 have muta ons in the gene encoding the vitamin D receptor, preven ng a normal physiologic response to 1,25-D.The mode of inheritance is autosomal recessive.Most pa ents present during infancy, although rickets in less severely aff ected pa ents might not be diagnosed un l adulthood.Less-severe disease is associated with a par ally func onal vitamin D receptor.Approximately 50-70% of children have alopecia,which tends to be associated with a more severe form of the disease. 1 The intriguing disease generally presents with a clinical picture of rickets, hypocalcaemia, hypophosphatemia, growth retarda on, hyperparathyroidism along with extremely elevated circula ng levels of 1,25(OH) 2 D. 2 Resource poor countries, where es ma on of parathyroid hormone and 1,25(OH) 2 D are not readily available, alopecia in the se ng of resistant rickets could be an important cue for the diagnosis of this rare condi on. 3Since the me, Brooks, et al reported the fi rst case in 1978, 4 only few cases have been reported in the world literature.We report one such case with alopecia.

The Case
A 27 months old female child presented with acute respiratory illness.This was her fi rst visit to our department.On history we found that she had delayed gross motor development milestones as she started standing without support at 24 months and at 27 months she could just walk with unstable gait.She had short stature and lack of hair on scalp.Family history revealed that she was born of nonconsanguineous marriage.She had two elder sisters; the eldest one was alive and healthy while the other died at 6 years.No medical consulta on was obtained for the deceased child but she has features similar to the case being reported.
The personal history of our index case depicted that she had uneven ul prenatal, natal and post-natal period.The child has normal teeth erup on but her anterior fontanelle was open.On examina on she has classical features of craniotabes, frontal bossing, pigeon chest, Harrison groove, bow legs, knock knees and widening of wrists and ankles (Fig. 1).
She has diff use alopecia also.On anthropometric examina on, her head circumference was 45.5 cm, between -2 to -3 z score.Her weight was 12 kg, normal for age and height of 84 cm between -2 and -3 z score.No abnormality was detected on systemic examina on of cardiovascular, gastrointes nal and central nervous system examina on.On view of systemic manifesta on of rickets and alopecia VDDR type II rickets was suspected.25-hydroxy Vitamin D level was 86.4 ng/ml (normal 30.0-74.0 ng/ml) and 1,25 (OH) 2 D was found to be 445pg/ml (normal 19.6 to 75 pg/ml).Serum Alkaline Phosphatase level was 2163 IU (markedly raised), total calcium level of 8.4 mg/dl (9-11mg/dl), Phosphorus level of 2 mg/dl(4.5-6.7mg/dl) and serum crea nine level of 0.5 mg/dl.X-Ray of wrist and knee revealed metaphyseal widening, fraying, cupping, decrease bone density and bowing of long bones sugges ve of rickets (Fig. 2).
High doses of Vitamin D 3 and calcium were started.Vitamin D3 was prescribed in dose of 60,000 IU(1500mcg) per day and oral calcium of1800 mg per day, much above the daily requirements.A er six months of follow-up, we observed that the physical, biochemical and radiological features showed mild improvement and sparse hair growth was no ced on the scalp (Fig. 3).

Discussion
Vitamin D-dependent rickets Type II is a rare autosomal recessive disorder.It usually presents with rachi c changes not responsive to Vitamin D treatment with elevated circula ng levels of 1,25-Dihydroxyvitamin D 3 , thus diff eren a ng it from Vitamin D-dependent rickets Type I. Alopecia of the scalp or the body is seen in some families with Vitamin D-dependent rickets Type II.This is usually associated with more severe resistance to Vitamin D. 5 The basic defect involves the unresponsiveness of vitamin D receptors to 1,25 dihydroxy vitamin D. 6 Eilet al demonstrated defec ve nuclear uptake of 1,25-dihydroxyvitamin D in cultured fi broblasts from these pa ents. 7ff erent studies indicate the heterogeneous nature of the defects leading to VDDR II.The defect could be an absent 8 , or a truncated 9 receptor, or a point muta on in the steroid binding domain 10 or in one of the zinc fi ngers in the DNA binding domain of the receptor 11 , or s ll a defec ve nuclear localisa on of hormone receptor complex. 12The cause of alopecia is postulated to be the lack of ligand-independent func on of the vitamin D receptor in kera nocytes which is necessary for proper anagen ini a on (Sakai  et al. 2001). 13e pa ent was suspected as VDDR type II with classical presenta on of alopecia and clinical feature of rickets and diagnosed by blood and x-ray inves ga ons.The other causes of rickets such as nutri onal, malabsorp on, drug induced, hepa c, renal and familial hypophosphatemic were excluded on clinical and laboratory evalua on.Presence of high levels of 1,25-(OH) 2 D 3 ruled out VDDR type I.
There is no consensus on the treatment of VDDR type II.A case report revealed two siblings with VDDR II with alopecia reported by Takeda et al. (1989) who responded to treatment with 50,000 IU of Vitamin D2, daily for 2 years without any recurrence for 14 years a er cessa on of therapy. 14lsan et al. (1986) demonstrated healing of rickets by long-term calcium infusions. 15Manandhar et al. (1989) reported a child with rickets and alopecia who did not respond to high doses of vitamin D 3 but did respond to a small dose of 1-alpha-hydroxyvitaminD 3 .Treatment was con nued for 2 years, and the pa ent did not show any signs of relapse 1 year a er stopping treatment.However, the alopecia did not resolve, and she con nued to have increased serum 1,25-dihydroxycholecalciferol. 16esent case had classical clinical and radiological features of rickets along with alopecia and showed some response to high dosage of Vitamin D 3 and Calcium.Substan al hair growth was noted a er 6 months of treatment.In such type of presenta on clinician should always think of vitamin D resistant rickets type II.

Conclusion
VDDR type II is a rare disorder.In a child with clinical and radiological features poin ng towards rickets, presence of alopecia heralds the clinician to think towards this condi on.High dosage of oral Vitamin D 3 and calcium supplementa on does show some benefi ciary eff ect.

Fig 3 :
Fig 3: Hair growth over scalp a er Vitamin D 3 and Calcium therapy