JMed Genet 1998;35:763-766

Familial craniosynostosis, anal anomalies, andporokeratosis: CAP syndrome

N Flanagan, S A Boyadjiev, J Harper, L Kyne, M Earley, R Watson, E W Jabs,M T Geraghty

AbstractWe report on the occurrence of coronalcraniosynostosis, anal anomalies, and po-rokeratosis in two male sibs. A third malesib was phenotypically normal as were theparents. The occurrence of these threeclinical features has, to our knowledge, notbeen reported before. Cutaneous or analanomalies or both have been reported in anumber of syndromes associated withcraniosynostosis, including Crouzon,Pfeiffer, Apert, and Beare-Stevenson syn-dromes. These syndromes are associatedwith mutations in the fibroblast growthfactor receptor genes FGFR1, FGFR2, andFGFR3. They are inherited in an auto-somal dominant fashion. In contrast, thecases we report do not carry any of thecommon FGFR mutations and the pedi-gree suggests autosomal or X linkedrecessive inheritance.(7Med Genet 1998;35:763-766)

Keywords: craniosynostosis; anal anomalies; porokera-tosis; fibroblast growth factor receptor

Department ofDermatology, St JamesHospital, Dublin,IrelandN FlanaganL KyneR Watson

Center for MedicalGenetics, Blalock 1004,Johns HopkinsUniversity School ofMedicine, 600 N WolfeStreet, Baltimore, MlD21287-4922, USAS A BoyadjievE W JabsM T Geraghty

The Hospital for SickChildren, GreatOrmond Street,London, UKJ Harper

The Children'sHospital, TempleStreet, Dublin, IrelandM Earley

Correspondence to:Dr Geraghty.

Received 5 August 1997Revised version accepted forpublication 2 February 1998

Porokeratosis is a chronic progressive diseasecharacterised clinically by the formation ofannular, flat lesions with raised scaly borders.Several clinical types have been describedincluding disseminated superficial actinic, pal-moplantar, and Mibelli types.' Little is knownof the genetics of porokeratosis. It may occursporadically or be inherited in an autosomaldominant fashion. Instability of chromosome 3has been reported and may be a factor in thetendency to develop squamous cell carcinomaof the skin.2 Apart from an association withDown syndrome, we are unaware of any otherreports of porokeratosis in association withother congenital anomalies.3 Craniosynostosishas not been reported in porokeratosis. How-ever, cutaneous and anal anomalies have beendescribed in other syndromes associated withcraniosynostosis, for example, Apert, Crouzon,Pfeiffer, and Beare-Stevenson syndromesrespectively." We present two male sibs suffer-ing from craniosynostosis, anal anomalies, anddiffuse porokeratosis. These patients are thefirst reported cases of this clinical triad. Theaffected boys have one normal sib and bothparents are phenotypically normal. This sug-gests that the disorder is inherited in anautosomal or X linked recessive fashion, butnon-penetrance and gonadal mosaicism can-not be excluded.

Case reportsCASE 1A male infant was born at term by normalvaginal delivery following a normal pregnancy.He was the third child of healthy, unrelatedparents. The oldest boy in the family (de-scribed below) had a history of craniosynosto-sis, anal anomalies, and porokeratosis. Thesecond male sib was phenotypically normal.Clinical examination of both parents wasnormal. An extended family history did notindicate any other abnormalities, in particularthere was no history of craniosynostosis, limb,anal, or skin anomalies. The infant's birthweight was 3500 g and he had good Apgarscores. At birth he was noted to havemicrocephaly (head circumference 22 cm),brachycephaly, and a high forehead. The ante-rior fontanelle was widely patent with normalsagittal sutures. The coronal sutures were fusedand the posterior fontanelle was absent. He hada bifid scrotum and an anterior, ectopic, low,imperforate anus (fig 1). The latter requiredtreatment by anoplasty followed by regulardilatations. The skin was normal at birth.At 3 months of age he developed erythema-

tous, scaly plaques on the cheeks, ears, fingers,toes, and posterior scalp. Examination showedtwo 4 cm scaly, crusted plaques on both cheekswith some central clearing (fig 2). There wasscaling of the posterior scalp, crusting of thehelix of his ear, and erythema of the nail fold ofthe left thumb and index fingers without anyassociated nail dystrophy. Skin biopsy showed amild, perivascular, chronic inflammatory cellinfiltrate in the upper dermis, a number ofnecrotic keratinocytes in the epidermis, andvacuolation of the basal cell layer, but nocornoid lamella. He had a number of normalinvestigations including full blood count, elec-trolytes and biochemistry, immunoglobulinlevels, complement assays, and neutrophil andlymphocyte function tests. Chromosomeanalysis was normal. Total genomic DNA was

Figure 1 Case 1, aged 3 months, showing the anteriorposition of the anus and bifid scrotum.

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Figure 2 Case 1, aged 3 months, showing scaly, crusted,erythematous plaques on both cheeks with some centralclearing. (Photographs reproduced with permission.)

extracted from the patient's blood. Exon IIIa ofthe FGFR1 gene,9 exons IIIa, IIIc, and 10 ofthe FGFR2 gene,5 6 exons IIIa and 10 of theFGFR3 gene,' " and exon 1 of the TWISTgene were amplified by PCR.i 12 The amplifiedproduct was surveyed by direct sequencing forthe presence of mutations as previously pub-lished. None was found. Mutations in theseexons are the only ones reported to date ascausing Crouzon, Pfeiffer, Jackson-Weiss,Beare-Stevenson, Apert, and Saethre-Chotzensyndromes respectively.5 18 No mutation wasfound in FGFR2 exon IIIb, which is alterna-tively spliced in, to code for the KGFR isoformthat is expressed in epithelial cells.

CASE 2

The oldest brother of case 1, now aged 8, wassimilarily found at birth to have craniosynosto-sis with fusion of his coronal and sagittalsutures. Other anomalies noted were anteriorposition of the anus, hypospadias, and incurv-ing of his fourth toes bilaterally. His presenta-tion and early course have been describedpreviously.'9 At 4 weeks of age he developed ascaly facial eruption and lesions similiar toparonychia on his fingers and toenails. His rashslowly extended with the development oflesions on the arms, legs, and perineum. By 6months of age he had a symmetrical eruptionaffecting the face (fig 3), limbs, and perineum,but sparing the trunk. The facial rash wasreticulate, scaly, and erythematous with areasof poikiloderma over the cheeks and chin.There was focal crusting on the scalp and themargins of the pinnae. The acral rash wasstrikingly symmetrical with figurate and annu-lar patterns. Individual lesions were well

Figure 3 Case 2, aged 6 months. A symmetrical,reticulate, erythematous eruption is seen on both cheeks,similiar to case 1 (reprinted with permission of the BritishJ7ournal of Dermatology).

demarcated, erythematous, hyperkeratoticplaques with raised, brown, hyperpigmentedmargins. He had hypotrichosis of the scalp andeyebrows, delayed primary dentition, and nor-mal nails. Skin biopsies were performed at 7, 9,and 13 months. The first two biopsies werenon-diagnostic. The third biopsy, through theedge of a lesion, showed epidermal changeswith parakeratosis, acanthosis with several dys-keratotic cells, and an increase in the numberof mitotic figures. It also showed a cornoidlamella and focal vacuolar degeneration of thebasal layer, characteristic of porokeratosis (fig4). Normal investigations included full bloodcount, immunoglobulins, T cell subsets, andzinc levels. Magnesium levels were reduced onone occasion but were normal on subsequenttesting. Chromosome analysis and DNA repairstudies on cultured fibroblasts were normal.

Before confirmation of the diagnosis, theoldest sib was treated with zinc supplements,biotin, topical steroids, antifungal agents, anti-bacterial agents, and emollients. None of theseagents resulted in any benefit. Followingconfirmation of the diagnosis of porokeratosisat the age of 13 months, he was treated with atrial of etretinate at a dose of 1 mg/kg/day fortwo months. There was no response. At the ageof 14 months, koebnerisation was seen at themargins of his nappy area and at the scar siteafter surgical correction of his craniosynostosis.Wound healing was normal after further surgi-cal correction of his craniosynostosis in 1994and after correction of hypospadias in 1995.Over time, the lesions on his limbs and nappyarea have become much paler but the charac-teristic raised border of porokeratosis hasbecome more prominent (fig 5). Poikiloderma

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CAP syndrome

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Figure 6 Case 2, aged 8years, showing a reticulatepoikilodermatous eruption on his cheeks and chin.

Figure 4 Case 2,H & E, low power. This shows a cornoid lamella co?diagnosis ofporokeratosis (reprinted with permission of the British JrourDermatology).

Figure S Case 2, aged 8years. The chraised border ofporokeratosis (consisten;lamella histologically) has become moreincreasing age.

has become apparent on the fa6). Sunshine appears to imprand erythema of the skin on

aggravates the facial erythema.is of fine texture but normal voland eyelashes remain thin andon his trunk or limbs. His teethhas had no other medical prolnormal intelligence.

DiscussionPorokeratosis is a chronic progrsis characterised clinically by t]annular plaques with centrasurrounded by a raised keratotiorarely a furrow. The characteris

ogy is seen only at the edge of the lesion wherea column of poorly staining parakeratotic stra-

nsistent with a tum corneum cells is seen, the cornoid lamella.rnal of It is important to note that, as in our case, sev-

eral biopsies ideally taken from the edge of alesion may be needed before the diagnosis isconfirmed. It has been suggested that the cor-noid lamella marks the border between anexpanding clone of mutant keratinocytes andthe normal epidermis.20 Although the cornoidlamella is characteristic of porokeratosis, it mayalso be seen in a number of other disorders,such as verruca vulgaris and solar keratosis.2'Development of porokeratotic lesions has beenfound to follow exposure to ultraviolet radia-tion, infectious disease, mechanical trauma,and following immunosuppressive therapy.Autosomal dominant inheritance has beendescribed in the various types of porokeratosisin several families.222' Clinically a number ofvariants of porokeratosis have been described.Those reported in children include linearporokeratosis, punctate porokeratosis, and po-rokeratosis of Mibelli. Our patients do not fitany classic variant but most closely resembleporokeratosis of Mibelli. An atypical feature isthe poikiloderma on the face. However, therewere no other features suggestive ofRothmund-Thompson or Bloom syndromes,respectively.

Craniosynososis is the premature fusion ofthe bones of the skull that disrupts coordinategrowth and often results in abnormal skull

taracteristic sharply shape. It is an aetiologically and geneticallytwith the cornoid heterogeneous condition. It may be primary,prominent with owing to some unspecified defect in the suture

itself or secondary to some underlying prob-Lce and ears (fig lem. Primary craniosynostosis may be associ-ove the texture ated with other anomalies such as limb anoma-his limbs, but lies in Saethre-Chotzen, Pfeiffer, and Jackson-The scalp hair Weiss syndromes. Craniosynostosis has been

lume. Eyebrows reported in association with a number of cuta-he has no hair neous disorders, such as acneiform eruptionsare normal. He in Apert syndrome, acanthosis nigricans inblems and is of Crouzon syndrome, and cutis gyrata in Beare-

Stevenson syndrome.26-28 Mutations in theFGFR genes have been reported in thesesyndromes. Most patients with Crouzon syn-

*essive dermato- drome have a mutation that is thought to affecthe formation of the bacterially expressed kinase isoform (BEK)1 atrophy and of FGFR2, which is expressed in the develop-c wall and more ing skeleton. However, a mutation in thestic histopathol- FGFR3 gene (A391Glu) has been reported in

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a number of families with Crouzon syndromeand acanthosis nigricans."2 Although notwidely appreciated, anal anomalies are alsoknown to occur in some of the above disorders.Imperforate anus has been described in apatient with Crouzon syndrome who had aW290G mutation in exon IIIa of the FGFR2gene.6 This mutation affects both isoforms ofFGFR2, that is, BEK and keratinocyte growthfactor receptor (KGFR). The latter is ex-pressed in skin and the epithelial linings ofinner spaces such as the anus.30 31 Anal anoma-lies, such as anterior placement, are alsofindings in the Beare-Stevenson syndrome,which results from mutations in the FGFR2gene, proximal to the transmembrane domainand thus affecting both isoforms of this gene.5Finally, anal anomalies have been reported intwo of 36 patients with Apert syndrome.6 All ofthe above craniosynostosis syndromes areinherited in an autosomal dominant fashion.While we cannot exclude non-penetrance of adominant gene in our pedigree, the normalexamination of the parents and lack ofreportedanomalies in the extended family do notsupport this mode of inheritance. Finally, whilemutations in the genes for fibroblast growthfactor receptors (FGFRs) have been associatedwith Crouzon, Apert, and Pfeiffer syndromes,we were unable to find any of the mutationscurrently reported in association with thesedisorders.

In summary we report a unique family inwhich two ofthe three male sibs presented withporokeratosis, anal anomalies, and craniosyn-ostosis. The pedigree suggests the disorder isinherited in an autosomal recessive fashion, butX linked inheritance or gonadal mosaicismcannot be excluded.

This work was in part supported by the NIH, T32 GM7471(SAB),RO I DE11441 (EWJ).

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