Poikiloderma with Neutropenia: Report of Three Cases Including One with Calcinosis Cutis

Pediatric Dermatology Vol. 29 No. 4 463–472, 2012

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 hyperkeratosis, 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 presentations, laboratory investigations, and C16orf57 mutation support the diagnosis 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

2011 Wiley Periodicals, Inc. 463 464

TABLE 1. Clinical Diﬀerences Between the Causes of Poikiloderma of Infancy July 4 No. 29 Vol. Dermatology Pediatric

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 2012 August 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, hnonadSwye:Piioem ihNurpnaadClioi Cutis Calcinosis and Neutropenia with Poikiloderma Shwayder: and Chantorn 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 consanguineous 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. Clinical presentation Mode of inheritance AR AR AR XR, AD, and AR AR AR AR, autosomal recessive; XR, X-linked recessive; AD, autosomal dominant. lar degeneration at the dermoepidermal junction, Chantorn and Shwayder: Poikiloderma with Neutropenia and Calcinosis Cutis 467

A analysis of the RECQL4 gene was normal. Recently, he was identified to have a homozygous mutation in the C16orf57 gene (c.266-1G>A) (9). This family consists of two affected brothers and an unaffected sister. This patient has an affected younger brother who was a full-term, third pregnancy for the mother and was 1 year-old at the time of last follow-up. Poikilodermatous changes were noticeable before the age of 10 months. The rash initially presented on the cheeks and distal extremities (elbows to wrists and knee to ankles; Fig. 2). His nails, palms, and soles were all normal, without hyperkeratosis, at the last examination. He has not had infections. Mild hepatomegaly was detected. He has been found to have mild developmental delay. Initial investigations revealed low neutrophil count (1,300 cell ⁄mm3) and a slightly high aspartate amino- transferase (AST) level (107 U ⁄L).Hehadthesame homozygous mutations in the C16orf57 gene as his brother.

Figure 1. Patient 1, aged 5. (A) Poikilodermatous skin changes on the upper chest, arms, groin, and legs. (B)Pro- nounced poikiloderma on the earlobe and cheek. telangiectasia, and fibrosis in the dermis with lympho- cytic inflammation and pigmentary incontinence in the superficial and reticular dermis. These findings were consistent with poikiloderma. The tentative initial diagnosis was RTS, so a skeletal survey and RECQL4 mutation analysis were ordered. The skeletal survey Figure 2. Patient 2, aged 1 (younger brother of patient 1). showed no radiographic abnormality. The sequence Poikiloderma on cheeks, elbows to wrists, and knee to ankles. 468 Pediatric Dermatology Vol. 29 No. 4 July ⁄ August 2012

CLINICAL REPORT: PATIENT 3 A Clinical History This patient was a 6.5-year-old, one-quarter Navajo Indian girl. She was born at full term and was normal at birth. She is her father’s first child and her mother’s third. Her parents reported that she began to have skin mottling on her lower extremities at approximately 6 months of age, although her mother had noticed that she started to have some ‘‘blistering of the skin’’ at the age of 3 months. The relationship between the rash and sun exposure was not clear. She subsequently developed extensive hyper- and hypopigmented spots and telangiectasia on the cheeks, ears, arms, hands, buttocks, and upper and lower legs, with her back and upper chest spared (Fig. 3A). Several toenails were thickened, and she had convexity of the nail plates (Fig. 3B). Her fingernails were uninvolved. At the age of 4 years, she experienced calcified (assumed) cysts on both hands, elbows, knees, legs, and feet (Fig. 4A) that were usually painful and resolved spontaneously after discharge of a white gooey material from the lesions. A second type of cyst on her eyelid (chalazion-like cyst) was noticed, but it was not biopsied. The soles have a wrinkled appearance and extensive, even hyperkeratosis. (Fig. 4B). Her eyes B and hair were normal. A pediatric ophthalmologist confirmed that she had no cataracts. There was mild hepatomegaly. Her parents felt that her development was on the lower end of normal compared with her siblings, but there was no specific concern. She had a history of recurrent urinary tract infections and chronic diarrhea. She also had frequent respiratory infections with prominent wheezing, which was being kept under control with a bronchodilator and inhaled corticosteroid.

Investigations Constant leukopenia (3,400–3,540 cell ⁄mm3) and neu- 3 Figure 3. Patient 3, aged 6. (A) Generalized poikiloderma, tropenia (440–700 cell ⁄mm ) developed without anemia particularly on the arms. (B) Thickening and curvature of the or thrombocytopenia from the age of 20 months old. toenails. A liver function test demonstrated only mildly elevated AST (64–99 U ⁄L). Immunoglobulin (Ig) levels were measured at the age of 20 months and showed slightly large masses of calcium within the reticular dermis and high IgG (1,040 mg ⁄dL; normal 123–1005 mg ⁄dL) and no cyst detected, consistent with calcinosis cutis high IgA (150 mg ⁄dL; normal 14–85 mg ⁄dL). Ig levels (Fig. 5A,B). were normal at 5 years. Abdominal ultrasonography Although calcium and vitamin D levels were normal; showed an enlarged liver. A skin biopsy was done slightly low phosphate and mildly high intact parathy- twice. The first biopsy was performed at the poikilo- roid hormone (iPTH; 89.4 pg ⁄mL; normal 10–75 pg ⁄ dermatous changes and demonstrated parakeratosis mL) levels were detected. Because there was no evidence with superficial dermal inflammation, pigmentary of hypercalcemia, calcinosis cutis did not result from changes, and telangiectasia. The second biopsy of abnormal calcium metabolism in this patient. High iPTH the cyst-like lesion from over the right patella showed and slightly low phosphate levels might have been due to Chantorn and Shwayder: Poikiloderma with Neutropenia and Calcinosis Cutis 469

A A

Figure 4. Patient 3. (A) White paste-like material from lesions on the right knee during skin biopsy. (B) Widespread, evenly distributed plantar hyperkeratosis. Figure 5. (A) Histopathology from cystic lesion. Note large masses of calcium within the reticular dermis and no cyst detected consistent with calcinosis cutis. (B) Von Kossa stain unrecognized vitamin D deficiency, calcium deficiency, demonstrates large mass of calcium. or both, but these were investigated, and subsequent studies demonstrated normalcalcium,phosphate,iPTH, and 1,25-hydroxycholecalciferol levels. We do not have DISCUSSION an explanation for these multiple calcified cysts in our patient. Poikiloderma with neutropenia or Clericuzio-type Our initial working diagnosis was RTS, so a RECQL4 poikiloderma (OMIM #604173) is a rare autosomal gene sequencing analysis was done. There were no recessive disorder characterized by poikiloderma, neu- common sequence variant mutations. Compound het- tropenia, and recurrent infections. Cutaneous manifes- erozygous mutation of C16orf57 gene was subsequently tation typically starts from patchy eczematous eruption demonstrated (9). developing in the first year of life and gradually evolving TABLE 2. Summary of Clinical Presentations and Investigations of 22 Patients with Poikiloderma with Neutropenia 470

Van Hove Volpi and Arnold July 4 No. 29 Vol. Dermatology Pediatric Presentation Pianigiani (2) Wang (3) (4) Mostefai (5) Concolino (6) (8) Clericuzio (9) Our report Total, n (%)

Sex F F F F M F F M F F M M F F M M M F F M M F F:M = 13:9

European Mediter- Italian Navajo Turkish-British Scottish Turkish Morocco Italian ranean Navajo Apache Cherokee-Caucasian Asian-Indian Navajo- Caucasian

Cutaneous Photosensitivity ) ))) ))))+++ )))+ + NR NR NR ))) 5 (22.7) Poikiloderma + + + + ++++++++++++ + + + + ++ 22(100) Nail involvement + + ) ++) + ))))+ ))++ + ) + ))+ 11 (50) Palmoplantar + ))+ ) +++++ ) + ))+ + NR NR NR ))+ 11 (50) hyperkeratosis Calcinosis cutis NR ))) )+ NRNRNRNRNRNRNRNRNRNRNR NR + ))+ 3 (13.6) Systemic Dysmorphic + ))) )))))))+ )) NR NR NR ))) 4 (18.1) features Saddle-nose, Eyebrow hypertelorism hypoplasia, frontal ⁄ bossing, 2012 August wide-spaced eye, midfacial hypoplasia, prognathism, hypertelorism, hypermobile ﬁngers Growth retardation + ))) ))))++ ) +++++ NRNR NR ))) 8 (36.4) Developmental ) ))) ))++*++ )))))) NR NR NR Mild CP + + 7 (31.8) delay Recurrent infection + + + + ++++++++++++ + + + + ) + 21 (95.5) Hepatomegaly ) ))) )))+ ))))))+ + NR NR NR ) + + 5 (22.7) Splenomegaly + ))) ))++++ ) ++ ) + + NR NR NR ))) 9 (40.1) Retractile or ) ))) )))+ ))))))++ NR ))))) 3 (13.6) undescended testes Investigations Neutropenia + + + + ++++++++++++ + + + + ++ 22(100) Leukopenia + ))) ))))++ ) +++ )) NR NR NR ))) 6 (27.2) Thrombocytopenia ) ))) ))+, tran- ))+ )))+, transient NR NR ))) 3 (13.6) sient High low-density NR NRNRNR NRNR++NRNRNR+++++ NRNR NR NRNRNR 7(31.8) lipoprotein cholesterol High creatine NR NR NR NR NR NR + NR NR NR NR + + + NR NR NR NR NR NR NR NR 4 (18.1) phosphokinase Immunoglobulin NR NR NR NR Low IgM NR NR Polyclonal NR NR NR NR NR NR NR NR ) NR Transient 3 (13.6) level hypergamma- increase in globulinemia immunoglobulin Genetic study C16orf57 + +++ NRNRNRNRNRNRNR+++++ + + + + ++ 15(68.2) mutation identiﬁed

*Subject was born with preterm delivery complicated with perinatal asphyxia, hypoglycemia, seizure, intracerebral hemorrhage, and multicystic leukomalacia. NR, not reported. Chantorn and Shwayder: Poikiloderma with Neutropenia and Calcinosis Cutis 471 into poikiloderma. This rash tends to develop from the solitary lesion, although multiple lesions may occur. peripheral extremities and spread centripetally to involve They are usually asymptomatic but may be painful. The the upper extremities, trunk, face, and earlobe. It usually most common location is the face, but nodules can occur is not related to sun exposure, although a few patients anywhere. Calcinosis cutis has been reported in three experienced photosensitivity with blistering (5,8). No patients with PN; this finding may be one of the clinical hair, eye, or bone abnormality has been reported. Nail manifestations of this syndrome. Ours is the first case to involvement, including pachyonychia, thickened nails, be documented by biopsy. Our patient has had multiple excessive curving, and dystrophic nails, may be seen individual painful lesions that continue to occur. The (toenails more than fingernails). Hyperkeratosis of the other cases of ‘‘painful cysts’’ have circulated informally heels and soles frequently develops later in life. between PN investigators, but no formal examinations Palmoplantar keratoderma has been reported in some have been done before ours (personal communications patients, although neither the exact type of the kerato- with other investigators). derma nor biopsies were reported (2–6,8). Extracutane- In summary, we report three patients with a rare ous manifestation reported in the literature comprise genodermatosis PN. One of them was descended from a recurrent infection, especially in pulmonary infection Navajo Indian, but the other two were of South Asian (1–9); mild developmental delay (4,5); growth retarda- ancestry. All developed the classic rash of this disease tion (5–8); hepatomegaly (4,8); splenomegaly (2,4–8); early in life without evidence of postnatal growth defi- undescended testes (4,8); and facial dysmorphism (2,6,7). ciency or eye or skeletal abnormalities. Thickened and Low oxidative burst and killing capacity of neutrophils excessive curving of the nails presented in one patient that arealsoreported(4,5).Neutropenia and neutrophil wasfirstnoticedontoenails. Neurologic abnormality dysfunction may be responsible for recurrent infection in was detected in all three patients. Two patients have mild patients with PN. The clinical presentations and labo- developmental delay, and another has cerebral palsy ratory investigations of the 22 cases reported in literature without history of compromised delivery. Hepatomegaly are summarized in Table 2. with mild elevation of liver enzyme was found in two of Poikiloderma with neutropenia shares some clinical our three cases. Neither needed specific treatment. They features with RTS (OMIM #268400). This is an auto- also had history of recurrent pulmonary infections to- somal recessive disorder with poikiloderma, cataract gether with low neutrophil count. Immunologic abnor- formation, alopecia, small stature, bone abnormality, malities and other disorders causing recurrent infection and predisposition to malignancy. Many cases of PN such as cystic fibrosis were excluded. RECQL4 gene were previously initially diagnosed as RTS. There are mutation analysis in patients 1 and 3 and was negative. several distinctive differences between the two disorders. Mutations of the C16orf57 gene were identified in all Skin rash in PN tends to start from the extremities and patients (9). We also described a distinctive feature, spread centrally to the trunk and face, whereas RTS subepidermal calcified nodules, as a new clinical finding typically is first noticed on the face and progress in PN. One more general point: children with widespread peripherally, with sparing of the trunk and abdomen. poikiloderma should at least have a complete blood Alopecia, sparse hair, leukoplakia, and bony involve- count performed to screen for neutropenia. ment are seen rarely in PN but frequently in RTS. Unlike with RTS, PN has not been reported to be related to ACKNOWLEDGMENTS cancer. Neutropenia and susceptibility to infection are found in all cases of PN but not RTS. Mutations in the We would like to thank Dr. Thomas Wenker, who made RECQL4 (OMIM #603780), the DNA helicase gene on the initial diagnosis in the first patient, and Drs. 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