Pediatric Dermatology Vol. 29 No. 4 463–472, 2012 Poikiloderma with Neutropenia: Report of Three Cases Including One with Calcinosis Cutis Rattanavalai Chantorn, M.D.,* and Tor Shwayder, M.D. *Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Department of Dermatology, Henry Ford Hospital, Detroit, Michigan Abstract: Poikiloderma with neutropenia (PN), Clericuzio type (OMIM #604173) is a new, unique genodermatosis first described by Clericuzio et al (Am J Med Genet A, 2011, 155, 337) in Navajo Indian population. This disease is characterized by poikiloderma that usually develops in the first year of life and is associated with nail abnormality, palmoplantar hyper- keratosis, chronic neutropenia, and recurrent infections. The rash typically starts from the extremities and spreads centripetally to involve the trunk, face, and ears. Recently, a homozygous mutation in the C16orf57 gene on chromosome 16q13 was identified as a strong candidate as the gene responsible for PN. We report three cases of PN whose clinical presenta- tions, laboratory investigations, and C16orf57 mutation support the diag- nosis of PN. One child has developed multiple painful calcinosis cutis lesions. Early-onset poikiloderma should prompt a complete blood count as a screening test. Poikiloderma consists of epidermal atrophy, telangi- Navajos and non-Navajos in the literature (1–9). Patients ectasia, and reticulated dyspigmentation (hyperpigmen- with PN usually present with early onset of poikiloder- tation and hypopigmentation). Poikilodermatous ma; noncyclic neutropenia, neutrophil dysfunction, or skin changes may be seen in many genodermatoses, both; nail abnormalities; palmoplantar hyperkeratosis; including Rothmund-Thomson syndrome (RTS), and recurrent infections. Autosomal recessive inheri- Bloom syndrome, xeroderma pigmentosum, dyskerato- tance has been reported in several consanguineous sis congenita, and Kindler syndrome. (The clinical dif- affected siblings. Mutation in the C16orf57 gene has been ferences between the causes of poikiloderma of infancy recently reported in many cases of PN (6–10). For a are shown in Table 1.) Clericuzio et al (1) first described a diagnosis of PN, patients should have the classic rash of new hereditary poikiloderma, named poikiloderma with poikiloderma, chronic neutropenia, no mutation in neutropenia (PN: OMIM 604173) in 14 Navajo Indians. RECQL4, and if possible, detection of a C16orf57 Approximately 36 cases of PN have been identified in gene mutation. In this report, we comprehensively Addresss correspondence to Tor Shwayder, M.D., Pediatric Dermatology, Henry Ford Hospital, Detroit MI 48202, or e-mail: [email protected]. DOI: 10.1111/j.1525-1470.2011.01513.x Ó 2011 Wiley Periodicals, Inc. 463 464 TABLE 1. Clinical Differences Between the Causes of Poikiloderma of Infancy Pediatric Dermatology Vol. 29 No. 4 July Clinical Poikiloderma Rothmund-Thomson Bloom Dyskeratosis Xeroderma presentation with neutropenia syndrome syndrome congenital pigmentosum Kindler syndrome Mode of inheritance AR AR AR XR, AD, and AR AR AR Cutaneous Photosensitivity + ⁄ ) ++ ) ++ Poikiloderma Develops from Typically first Erythematous Reticulated History of Neonatal peripheral noticed on face patches and hyperpigmentation acute sunburn trauma-induced extremities and and progresses telangiectasia and atrophy on face, reaction, skin blistering, spreads centripetally peripherally; arise on sun-exposed neck, chest, arms marked progressive to involve upper tends to spare area freckling of poikiloderma extremities, trunk, trunk and abdomen sun-exposed on sun-exposed face, earlobes areas, dry and areas, especially parchment-like dorsal aspects with poikiloderma of hands and feet ⁄ on sun-exposed August 2012 areas Nail Pachyonychia, Atrophic nails ) Nail dystrophy, ) Nail ridging and abnormalities thickened, longitudinal ridging grooving excessive curving, and subungual splitting, hyperkeratosis, pterygium, onychodystrophy nail loss Palmoplantar Hyperkeratosis of )) ))Hyperkeratosis involvement heels or soles, of palms and keratoderma soles Mucosa ))Blisters and fissures Oral leukoplakia ) Gingivitis, involvement of the lower lip periodontitis, orogenital leukokeratosis Hair ) Sparse hair, eyebrows, Loss of lower Sparse eyelashes, )) lashes; alopecia; eyelashes hair loss, premature graying premature graying Systemic Growth Normal or growth Short stature Severe pre-and Short stature Dwarfism in ) retardation postnatal growth DeSanctis-Cacchione retardation syndrome Recurrent Recurrent viral ) Repeated otitis Opportunistic )) infections and bacterial media and infections infections in pneumonia due (cytomegalovirus, respiratory tract, to gastroesophageal pneumocystis, otitis media, diarrhea, reflux and low candida) urinary tract, sinusitis, plasma immunoglobulin dental abscess TABLE 1. (Continued.) Clinical Poikiloderma Rothmund-Thomson Bloom Dyskeratosis Xeroderma presentation with neutropenia syndrome syndrome congenital pigmentosum Kindler syndrome Mode of inheritance AR AR AR XR, AD, and AR AR AR Ophthalmic ) Cataracts, ) Conjunctival Conjunctivitis, Conjunctivitis microphthalmia, leukoplakia, ectropion, entropion, microcornea, epiphora, keratitis, corneal strabismus, glaucoma conjunctivitis, opacification and blepharitis, vascularization, Chantorn and Shwayder: Poikiloderma with Neutropenia and Calcinosis Cutis strabismus, epithelioma, cataract, squamous cell optic atrophy carcinoma, melanoma of the eyes Skeletal ) Radiographic ) Osteoporosis ) Digital webbing, abnormalities of pseudoainhum the bone (dysplasia, of toes absent or malformed bones, delayed bone formation), radial ray hypoplasia, osteoporosis Endocrine Cryptorchidism Hypogonadism Type II diabetes, Testicular Immature sexual ) early menopause hypoplasia, development in in women, cryptorchidism DeSanctis-Cacchione infertility in men syndrome Neurologic Delay development Mental retardation ) Microcephaly, ) 5–13% deafness, hyporeflexia, progressive intellectual deterioration, spasticity, ataxia, seizure in some subtypes, especially DeSanctis-Cacchione syndrome Abdomen Hepatomegaly, Annular pancreas Gastroesophageal Cirrhosis, )) splenomegaly reflux esophageal stricture, anal mucosal leukoplakia Hematology Prominent ))Myelodysplasia, )) neutropenia, pancytopenia leukopenia, transient thrombocytopenia 465 466 Pediatric Dermatology Vol. 29 No. 4 July ⁄ August 2012 describe the clinicopathologic features of three cases. (Clericuzio et al (9) have recently reported the novel C16orf57 mutations of these cases). carcinoma Squamous cell CLINICAL REPORTS: PATIENTS 1 AND 2 Clinical History A4-year-oldSouthAsianIndianboywasbornattermby spontaneous vaginal delivery. There were no immediate problems after birth. There was no history of consan- guineous marriage in the parents. His birth weight, length, and head circumference were all normal. The parents noted a rash on his lower legs and feet at risk of cutaneous basal cell carcinoma, squamous cell carcinoma, melanoma Xeroderma pigmentosum Kindler syndrome 1,000 times greater approximately 10 months of age. It spread centripetally along the hands, forearms, thighs, and buttock and also involved the ears and face (Fig. 1A,B). The lesions spared the trunk, abdomen, and popliteal and antecubital fos- sae.Theskinwasmottledbrownwithdepigmentedpat- ches and telangiectasias. The palms and soles also showed poikilodermatous changes but no hyperkeratosis. His rash never became vesicular or bullous and was not carcinoma (skin or mucosa), acute myeloid leukemia, Hodgkin’s lymphoma, pancreatic carcinoma Dyskeratosis congenital Squamous cell associated with sun exposure. Nails, hair, teeth, palms, and soles were all normal. He had no hepatospleno- megaly. All his bony structures were normal. Neurolog- ically, his family first noticed an abnormal waddling gait at approximately 12 months of age. Social and cognitive development were within normal limits. This patient also had a history of multiple infections, including rhinitis, otitis media, and pneumonia since the age one of 1. leukemia occur 150–300 times as frequently as normal, carcinomas of the gastrointestinal tract especially colorectal cancer, respiratory tract, skin, breast, liver, connective tissue sarcoma, retinoblastoma, brain tumor Bloom syndrome Lymphoma and Investigations Complete blood count demonstrated variably slightly low neutrophil count from 1,490 to 2,600 cell ⁄mm3 since the age of 15 months. Immunoglobulin levels were all normal. Neutrophil function test was not done. Sweat chloride tests done at 5 months and 1 year of age revealed 30%, basal cell carcinoma, squamous cell carcinoma, melanoma (estimated 5%) levels of 77 and 106.4 mEq ⁄L, respectively (nor- Rothmund-Thomson syndrome mal < 40 mEq ⁄L). He was initially diagnosed with cystic fibrosis and a comprehensive examination was commenced. The cystic fibrosis transmembrane conduc- tance regulator (CFTR) mutation panel, CFTR sequence analysis, and CFTR duplication and deletion analysis were all negative. Nasal biopsy showed normal ciliary ultrastructure. Stool elastase was normal, which indi- Poikiloderma with neutropenia cated normal pancreatic function, placing the diagnosis of cystic fibrosis in doubt. Magnetic resonance imaging (MRI) of the brain and spine were normal. Pediatric (Continued.) neurology diagnosed him with mild cerebral palsy. A skin biopsy was done from the poikilodermatous skin of the buttocks. It demonstrated foci of vacuo- Neoplasia Remains unknown Osteosarcoma TABLE 1.