Expanding Phenotype of Hereditary Fibrosing Poikiloderma with Tendon

CASE SERIES

Expanding phenotype of hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis caused by FAM111B mutations: Report of an additional family raising the question of cancer predisposition and a short review of early-onset poikiloderma

Rapha€elle Goussot, MD,a Megana Prasad, MD,b Corinne Stoetzel, MD,b Cedric Lenormand, MD, PhD,a Helene Dollfus, MD, PhD,b and Dan Lipsker, MD, PhDa Strasbourg, France Key words: FAM111B; inherited poikiloderma; pancreatic cancer.

ereditary fibrosing poikiloderma with Abbreviations used: tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP [MIM#615704]) IPMN: intraductal papillary mucinous H neoplasm is an extremely rare syndromic form of autosomal POIKTMP: hereditary fibrosing poikiloderma dominant poikiloderma. This genetic disorder was with tendon contractures, myopathy, first identified in a South African family in 2006.1 To and pulmonary fibrosis date, 3 families and 9 independent sporadic cases RTS: Rothmund-Thomson syndrome have been reported.2-4 Here we report an additional family of POIKTMP and expand the clinical spectrum. We describe, for the first time to our knowl- early childhood. Clinical evaluation found a very edge, a pancreatic cancer in the clinical course in 1 severe case of poikiloderma, predominant in the patient. We also address the differential diagnosis of sun-exposed areas, resulting from the combination inherited poikiloderma and related disorders. of skin atrophy, mottled pigmentation with hyper- pigmented and hypopigmented lesions, and telan- CASE SERIES giectasia (Fig 1, A). He had a distinct intolerance for In 2007, at the Strasbourg University Hospital, the heat with marked hypohidrosis. Diffuse xerosis was department of medical genetics referred a family to combined with multiple depigmented macules on the dermatology department with a diverse clinical the trunk and limbs. The patient reported lymphe- skin picture, dominated by poikiloderma. The father, dema of the lower limbs (Fig 1, B) starting in a white 64 year old, was the sixth (I: 6) of sibship adolescence, complicated by recurrent erysipelas. born from nonconsanguineous parents. Very soon His feet and hands were small, both affected by after birth, his grandmother observed that ‘‘he was tendon contractures (Fig 1, B). His nails and teeth not like the others,’’ and he was described to have were normal. He did not have a history of cataract red cheeks and heat (but not sun) intolerance since formation or pulmonary disease. He also had

From the FacultedeM edecine, Universite de Strasbourg et JAAD Case Reports 2017;3:143-50. Clinique Dermatologique, Hopitaux^ Universitairesa and the 2352-5126 Laboratoire de gen etique medicale, Facultedem edecine de Ó 2016 by the American Academy of Dermatology, Inc. Published Strasbourg, Institut de gen etique medicale d’Alsace, Universite by Elsevier, Inc. This is an open access article under the CC BY- de Strasbourg.b NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ Funding sources: None. 4.0/). Conflicts of interest: None declared. http://dx.doi.org/10.1016/j.jdcr.2017.01.002 Correspondence to: Dan Lipsker, MD, PhD, Clinique Dermatologique, 1, Place de l’Hopital,^ F-67091 Strasbourg cedex, France. E-mail: [email protected].

143 144 Goussot et al JAAD CASE REPORTS MARCH 2017

Fig 1. A, Father. Poikiloderma, predominant in the sun-exposed areas but sparing in some zones the forehead and scalp. B, Father. Chronic lymphedema of the lower limbs with tendon contractures. recent-onset alopecia, which was subsequent to lesions to those of her father were observed: chemotherapy. The patient had pancreatic cancer poikiloderma mainly localized to the face; xerosis at the time of referral. The appearance of an and innumerable achromic or hypochromic mac- obstructive jaundice had led, several months earlier, ules, measuring between 1 and 2 mm, of the trunk to the diagnosis of pancreatic cancer. A thoraco- and the limbs (Fig 2, A); marked hypohidrosis; and abdominal pelvic computed tomography scan found lower-limb lymphedema. Her hands and feet were a diffuse infiltration of the pancreas, with peritoneal small, with atrophy of both thenar and hypothenar carcinosis. Magnetic resonance imaging of the eminences (Fig 2, B). A biopsy of the palm found pancreas found a tumor in the pancreatic isthmus, marked reduction in eccrine glands, and a biopsy of with numerous cystic lesions, most likely caused by an achromic macule found a clear decrease in an intraductal papillary mucinous neoplasm (IPMN). melanin pigment in the basal layer of the epidermis There was no fatty infiltration of the pancreas on without loss of melanocytes. She had mildly magnetic resonance imaging. The diagnosis of inva- elevated liver transaminases on repeat blood sam- sive adenocarcinoma originating from an IPMN was ples, but the search for an etiology was negative. established by scan-guided pancreatic biopsy. Pulmonary function tests and thoracic computed Because of locally advanced stage, only palliative tomography scan were normal. chemotherapy with gemcitabine was administered. Her daughter (III: 3) had facial telangiectatic The patient had none of the known risk factors of erythema since the age of 6 months. This family’s pancreatic cancer such as type 2 diabetes, obesity, phenotype, characterized by poikiloderma, hypo- pancreatitis, or smoking. hidrosis, small feet and hands with tendon contrac- His son (II: 1), age 30, had similar skin changes— tures or atrophy of the thenar and hypothenar red cheeks since 6 months old, developing into an eminences, was reminiscent of the case of a South essentially facial poikiloderma; hypohidrosis with African family reported in 20061 and recently found heat intolerance; lymphedema of the lower limbs to have a mutation in the FAM111B gene.5 Sanger starting in adolescence; guttate leukoderma; and sequencing of the family reported herein identified stiffness of the fingers. Teeth, hair, and nails were also a mutation in FAM111B: p.[Ser628Arg]; [=] normal. There was no pulmonary impairment. c.[1884T[A] (Fig 3) that segregated with the disease His 27-year-old daughter (II: 2) had erythema- confirming that the diagnosis belonged to the tous cheeks since she was 1 year old. Identical POIKTMP spectrum. JAAD CASE REPORTS Goussot et al 145 VOLUME 3, NUMBER 2

Fig 2. A, Daughter. Multiple, discrete round or oval, porcelain-white macules. B, Daughter. Atrophy of both thenar and hypothenar eminences with inability to extend the fingers fully. No loss of dermal ridges.

Fig 3. Chromatograms of Sanger sequencing of the FAM111B gene in the patients. The arrows indicate mutation sites.

DISCUSSION condition.2 The condition begins in early childhood, We report an additional family of POIKTMP typically in the first 6 months of age (Table I). It (Fig 4) in which a pancreatic cancer was discovered affects sun-exposed areas. It is a true poikiloderma in one of the members. POIKTMP is a recently and not a simple reticulated pigmentation disorder described entity of syndromic inherited poikilo- or a mottled pigmentation with atrophy. derma.2,5,6 In 2013, whole exome sequencing Poikiloderma is almost invariably combined with enabled identification of causative mutations in alopecia and hypohidrosis with heat intolerance.2 FAM111B-encoding a protein of still unknown We found that hypohidrosis could be explained by a function.5 This is a rare disorder; only 26 patients rarefaction of sweat glands. As in the family reported belonging to 12 independent families have been here, lymphedema of the extremities, complicated reported.1-4 These families were of South African, by recurring erysipelas, is often observed (Table I). Algerian, Northern European, French, Irish, Italian, The variability of dermatologic characteristics is Moroccan, Dominican Republic, and Kuwaiti ori- found in our cases: no alopecia, but diffuse xerosis gins.1-4 Congenital poikiloderma is a constant skin and depigmented macules, which do not usually 146 Goussot et al JAAD CASE REPORTS MARCH 2017

Fig 4. Pedigree of the family consistent with autosomal dominant inheritance. The proband is indicated by arrow. Asterisk indicates sequenced patients. occur in this syndrome. To our knowledge, this is the cancer has previously been described in first case of guttate hypomelanosis described in POIKTMP2,6; however, considering the relative POIKTMP. The skin lesions improve with age, young age of most patients reported to date, this whereas the extracutaneous manifestations become does not rule out any cancer-predisposing effect of worse.2 Musculo-tendinous impairments begin dur- FAM111B deleterious variants occurring later in life.6 ing the first 10 years of life5 consisting of muscle The length bias may also have played a role, as the contractures, progressive muscular weakness, and first case of cancer was reported in the oldest patient amyotrophy (Table I). Interstitial pulmonary fibrosis with a FAM111B mutation. Although the pancreatic is found in adulthood, and was found to be fatal in a adenocarcinoma could have been an incidental few individuals.1,2 No respiratory abnormalities were finding in this patient, to report a pancreatic cancer observed in our patients. Liver impairment,2 re- in a syndrome in which pancreatic manifestations do ported in one of our patients with transaminases occur3 is intriguing. Most congenital poikiloderma fluctuating between normal and abnormal, and syndromes are inherited cancer-prone diseases exocrine pancreatic dysfunction3 are also described. (Table I).8-11 Furthermore, 2 studies imply An extensive fatty infiltration of the pancreas is FAM111B as a cancer predisposition gene. The first12 reported.1 using a genomewide association study, identified In 2013, Mercier et al5 identified the causative several susceptibility loci for prostate cancer. One gene, FAM111B (NM_198947.3), on chromosome 11 locus was on chromosome 11q12 and FAM111B is a (11q12.1). The c.1884T[A heterozygous mutation of candidate gene. In the second study,13 transcrip- the FAM111B gene found in our 4 cases yields a tomic analysis on a pancreatic cancer cell line pre- p.Ser628Arg amino acid substitution at position 628 viously treated by antiproliferative drugs found (Fig 3). A mutation at the same position (serine: downregulation of FAM111B, raising the question p.Ser628Asn) was previously reported.2,5 This muta- as to the oncogenic activity of this gene. Further tion segregated with the disease in this large pedi- functional studies and the analysis of a broader cross- gree (Fig 4). section of patients are requested to address this Autosomal dominant POIKTMP has overlapping question and the putative cancer-promoting effects clinical ﬁndings with Rothmund-Thomson syndrome of FAM111B mutations. (RTS), which has a recessive inheritance pattern. Congenital poikiloderma presents a diagnostic Several patients were initially misdiagnosed with challenge for dermatologists.4 The differential diag- RTS in childhood,2,6 although the mode of inheri- nosis begins with a complete dermatologic exami- tance is different. Differential diagnoses that must be nation.9 Definite diagnosis relies on identification of considered in a child with poikiloderma are re- a pathogenic mutation in specific genes implicated in viewed in Table I.2,7-11 the broad group of the inherited poikiloderma, as Although the son (II: 1), the daughter (II: 2), and summarized in Table I.6 This report shows the the granddaughter (III: 3) had no personal history of variability of the clinical spectrum of POIKTMP.2 cancer, the proband died of pancreatic cancer. No The malignant transformation of IPMN in the index V C JAAD

Table I. Clinical and molecular data of the different types of syndromic inherited poikiloderma OLUME

FA #227645 #227646 #227650 #300514 ,N 3, ASE #600901 #603467

DKC #127550 #609053 #609054 R UMBER

#224230 #305000 XP #278700 #278720 #610832 #613390 EPORTS #613987 #613988 #278730 #278740 #613951 #614082 #613989 #613990 #278760 #278780 #614083 #615272 POIKTMP OMIM number RTS #268400 PN #604173 #615190 #616353 KS #173650 WHSK 173700 #610651 BS #210900 BGS #218600 #616435 #615704 2 Inheritance AR AR AD AR X-linked AR AD AR AR AR AR X-linked AD Onset of 3-6 mo 6 mo 3-5 y 2-3 y 2-4 y Late childhood 1-2 y Late onset Variable 6mo poikiloderma Prevalent Lacy Accentuated Abnormal freckling Butterfly (not in Poikilodermoid- acral reticular in flexural on the face distribution early infancy) brownish distribution pigmentation areas before age 2 y ; of face; pigmentation rather than true real poikiloderma initially and hypo poikiloderma is rare telangiectatic pigmentation erythema and not poikiloderma Palmoplantar About 30% of Frequent May be present 65% May be present Absent Absent Absent Absent May be keratoderma patients present Blister In early May be In areas of Acral; after Absent In neonate; Blister around In infancy Absent May be childhood; in present trauma trauma or in sun-exposed the mouth (face buttocks present sun-exposed sun exposure areas extremities) areas present at birth: fourth type of inherited epidermolysis bullosa Nail Pachyonychia is Pachyonychia Major feature Frequent Absent Absent Absent Absent Absent May be abnormalities common (lichen planus- present like changes) Dental Frequent (27% Dental Poor dentition; Periodontal Absent Absent Occasional Delayed Severe Absent defects e59%); wide eruption early dental loss disease absence of eruption generalized (rarely poor variety of delay; lateral incisors of teeth periodontitis dentition; malformations fragile recurrent carious gingivitis) teeth Mucous Absent Absent Major feature: Orogenital Absent Tongue Absent Anus anteposition; Oral leukoplakia No leukoplakia membrane leukoplakia, leukokeratosis; leukoplakia imperforated lesions stenosis mucous stenosis anus Other Hypotrichosis/ Photosensitivity; No Photosensitivity; Sclerosis of Photosensitivity; Photosensitivity; Swelling of Cafe-au-lait spots Hypohidrosis/ dermatologic alopecia sparse photosensitivity; skin fragility; palms and xerosis paucity of the extremities heat signs photosensitivity; eyelash- absent skin atrophy; soles; linear subcutaneous intolerance; cafe-au-lait eyebrows fingerprints; loss of dermal hyperkeratosis fat; loss of the hypotrichosis/

spots alopecia; ridges; and sclerotic lower eyelashes; alopecia; al et Goussot canities pseudosyndactyly bands in skin cafe-au-lait spots lymphoedema pseudoainhum; folds; calcinosis; of extremities; phimosis ; clubbing fingers; xerosis; eczema anhidrosis Raynaud’s or psoriasis-like phenomenon lesions; sclerosis of the digits; guttate hypomelanosis 147 Continued Table I. Cont’d 148

FA #227645 #227646 oso tal et Goussot #227650 #300514 #600901 #603467 DKC #127550 #609053 #609054 #224230 #305000 XP #278700 #278720 #610832 #613390 #613987 #613988 #278730 #278740 #613951 #614082 #613989 #613990 #278760 #278780 #614083 #615272 POIKTMP OMIM number RTS #268400 PN #604173 #615190 #616353 KS #173650 WHSK 173700 #610651 BS #210900 BGS #218600 #616435 #615704 Ocular Cataract Absent Epiphora Conjunctivitis; Absent Photophobia; Wide Ocular Microphthalmia May be abnormalities blepharitis corneal severe keratitis variety proptosis; present retinopathy erosion; hypertelorism (cataract) ectropion of the lower eyelids Skeletal Radial ray Craniofacial Microcephaly; Skull or Mandibuloacral Absent Microcephaly; Coronal cranio- Microcephaly; May be defects defects; dysmorphism; osteoporosis mandibular dysplasia; dolichocephaly; synostosis; absent or present Malformations patellar hypermobile abnormalities maxillary prominence of radial ray abnormal (scoliosis) hypoplasia; fingers with bossing; the nose and defects; patellar thumbs small feet frontal bossing; beak of swan micrognathia ears hypoplasia and radii saddle nose appearence Respiratory Bronchiectasis Recurrent Diffuse Normal No Normal Pneumonia Normal Pulmonary Interstitial system pulmonary interstitial pulmonary bronchiectasis infections pulmonary infections pulmonary involvement chronic fibrosis fibrosis pulmonary disease Hematologic Leukopenia Permanent High frequency of Absent Absent Absent Myelodysplasia; Absent Major feature Eosinophilia features anemia neutropenia bone marrow low (bone marrow failure; immunoglobulin failure); pancytopenia counts myelodysplasia Other Chronic diarrhea Recurrent Liver cirrhosis Severe colitis Cardiac Acquired Immunodeficiency Heart-hand Type 2 diabetes Muscle visceral in early otitis involvement; microcephaly; with recurrent syndrome: (adults); ear contractures abnormalities childhood media; cardiac valvular neuro- infections; radial abnormalities; (triceps surae); splenomegaly diseases; aortic degeneration diabetes mellitus; abnormalities hearing loss muscle atrophy; stenosis (30%) in some gastroesophageal and defects weakness of variants reflux; diarrhea; in the heart proximal and lower urinary distal muscles; tract obstruction liver involvement; pancreatic exocrine insufficiency Physical Pre- and Short stature Short stature Normal Growth Normal Pre- and postnatal Short stature Pre- and Growth retardation development postnatal retardation growth postnatal growth deficiency growth deficiency retardation ADC JAAD Mental Normal Normal or Mental retardation Normal Normal Intellectual Normal or limited Mental May be Normal development slightly deficiency retardation delayed delayed (30%) in some M patients ASE ARCH

Continued R EPORTS 2017 V C JAAD

Table I. Cont’d OLUME

FA #227645 #227646

#227650 #300514 N 3, ASE #600901 #603467

DKC #127550 #609053 #609054 R UMBER

Some of the discussed entities rather display a mottled disorder of pigmentation than true poikiloderma, which associates a reticulate hyperpigmentation, atrophy and telangiectases, but distinction between those 2 dermatologic phenotypes is not always done in published literature. Werner syndrome (OMIM #277700) is not mentioned because the symptoms appear in adulthood. It is associated with increased risk of malignancies (thyroid carcinoma, melanoma, soft-tissue sarcoma, meningioma). AD, Autosomal dominant; AR, autosomal recessive; BGS, Baller-Gerold syndrome; BS, Bloom syndrome; DKC, dyskeratosis congenita; FA, Fanconi anemia; KS, Kindler syndrome; PN, poikiloderma with neutropenia; POIKTMP, hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis; WHSK, Weary hereditary sclerosing poikiloderma; XP, xeroderma pigmentosum. *Mutations in RECQL4 are also associated with RAPADILINO syndrome, which overlaps clinically with RTS but without poikiloderma. oso tal et Goussot 149 150 Goussot et al JAAD CASE REPORTS MARCH 2017

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