BRIEF REPORT Pediatric Dermatology 1–2, 2014
Hereditary Vitamin D–Resistant Rickets Presenting as Alopecia Abstract: Hereditary vitamin D–resistant rickets (HVDRR) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor (VDR) gene. We report the case of an infant presenting with alopecia, growth failure, and gross motor developmental delay. Serum biochemistry and skeletal survey were consistent with rickets. After a poor response to standard treatment, genetic testing confirmed a c.147–2A>T novel mutation in the VDR gene consistent with HVDRR. It is important for dermatologists and pediatricians to recognize alopecia as a presenting sign of HVDRR because appropriate treatment leads to better growth and development of the child.
A 15-month-old boy was referred to dermatology with alopecia. His parents, ﬁrst cousins of Pakistani descent, reported normal hair at birth that failed to regrow after his scalp was ritually shaved at 1 week of age. At 2 weeks of age he developed myocarditis secondary to enterovirus infection, requiring ventilation, from which he made a complete recovery. Subsequent failure to thrive and lack of new hair growth had been attributed to this severe illness. Examination at 15 months of age revealed a few coarse hairs over the crown of his scalp (Fig. 1) and sparse eyebrows (Fig. 2) but normal eyelashes. There were no milia, papular lesions, erythema, or other ectodermal abnormalities. Histopathology of the scalp was not performed. Height and weight were in the 0.4th percentile, but head circumference was in the 25th percentile. He was just able to crawl but was not walking. Over the following months, persistent growth failure and gross motor developmental delay prompted rereferral to the pediatrician. At 2 years of age, rickets was diagnosed on the basis of hypocalcemia (1.34 mM, normal 2.12–2.62 mM), hypophosphatemia (0.82 mM, normal 0.9–1.8 mM), high alkaline phosphatase (2,618 IU/L, normal 250–720 IU/L) and high
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Figure 1. Hereditary vitamin D–resistant rickets with scalp alopecia.
Figure 2. Sparse eyebrows but normal eyelashes in hereditary vitamin D–resistant rickets.
parathyroid hormone (36.1 pM, normal 1.3–7.6 pM). Total 25-hydroxyvitamin D was low (13.9 nM, normal 80–150 nM) and 1a,25-dihydroxyvitamin D3 was markedly high (>550 pM, normal 43–144 pM). He also showed clinical and radiographic features of rickets, including a healing midshaft femur fracture. The rickets were thought to be nutritional and he was started on oral ergocalciferol 6,000 IU/day and calcium 8.1 mmol/day, but poor clinical and biochemical response after 3 months prompted further investigation. A diagnosis of hereditary vitamin D–resistant rickets (HVDRR) with alopecia (Online Mendelian Inheritance in Man [OMIM] 277440) was suspected because of resistance of his rickets to standard
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treatment coupled with consanguinity and alopecia. The ﬁnding of a novel homozygous splice acceptor mutation (c.147–2A>T) in intron 2 of the vitamin D receptor (VDR) gene conﬁrmed this. He was started on a 24-hour intravenous infusion of diluted 10% calcium gluconate, equivalent to 2 mmol/kg/day of calcium, with oral phosphate 3 mmol/kg/day. He responded well, showing catchup growth and radiologic healing of his rickets after 8 months of treatment. He is now maintained on oral calcium supplementation. His alopecia has not responded to therapy. DISCUSSION HVDRR, also known as vitamin D–dependent rickets type IIA, is a rare autosomal recessive disorder characterized by alopecia, rickets, and resistance to vitamin D therapy. It was ﬁrst described in 1978 (1), and mutations in the VDR gene were found to be causative in 1988 (2). Alopecia, typically aﬀecting the scalp, is a feature of some patients with HVDRR. Hair is normal at birth, indicating normal hair follicle development, but is lost permanently at approximately 4 weeks of age. At least 34 VDR mutations have been identiﬁed and a genotype–phenotype correlation has emerged (3). Individuals with HVDRR with alopecia have been found to have mutations causing the absence of VDR or defects in the DNA-binding domain or retinoid X receptor heterodimerization, indicating that a functional VDR, DNA binding, and heterodimerization are essential in regulating the normal hair cycle (4). The eﬀect of the intron mutation on VDR in our patient is unknown, although it was hypothesized that it aﬀected one of these aforementioned sites. Mutations in the hairless gene (atrichia with papular lesions (OMIM 209500) and alopecia universalis
congenita (OMIM 203655) can present with clinically and histologically indistinguishable alopecia from HVDRR and are important diﬀerential diagnoses. Pediatric dermatologists should be aware of the association between alopecia and HVDRR because early diagnosis and correction of the metabolic defect leads to better growth and development, although improvement of the alopecia is rare. REFERENCES 1. Brooks MH, Bell NH, Love L et al. Vitamin-D-dependent rickets type II. Resistance of target organs to 1,25dihydroxyvitamin D. N Engl J Med 1978;298:996–999. 2. Hughes MR, Malloy PJ, Kieback DG et al. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 1988;242: 1702–1705. 3. Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clinics North Am 2010;39:333–346. 4. Malloy PJ, Feldman D. The role of vitamin D receptor mutations in the development of alopecia. Mol Cell Endocrinol 2011;347:90–96. Genevieve Casey, M.B.B.S.* Tess McPherson, M.D., M.R.C.P.* Usha Kini, M.D., M.R.C.P.† Fiona Ryan, M.D., M.R.C.P.‡ Saleem M. Taibjee, M.D., M.R.C.P.§ Celia Moss, M.D., F.R.C.P.¶ Susan Burge, M.D., F.R.C.P.* Departments of *Dermatology, †Clinical Genetics, and ‡Paediatric Endocrinology, Oxford University Hospitals, Oxford, UK, §Department of Dermatology, Princess of Wales Hospital, Bridgend, South Wales, UK, ¶Department of Dermatology, Birmingham Children’s Hospital, National Health Service Foundation Trust, Birmingham, UK Address correspondence to Tess McPherson, M.D., M.R.C.P., Department of Dermatology, Churchill Hospital, Old Road, Headington, Oxford, UK OX3 7LJ, or e-mail: [email protected]