DiagnosisClinical DiagnosisFocal dermal hypoplasia is a multisystem disorder primarily involving the skin, skeletal system, eyes, and face. The diagnosis of focal dermal hypoplasia should be considered in individuals with either of the following:Multiple skin manifestationsOne typical skin manifestation in conjunction with characteristic limb malformationsSkin manifestations include the following (see Figure 1 and Figure 2):FigureFigure 1. Skin manifestations include yellowish-pink areas representing fat herniation (white arrowheads), aplasia (black arrowheads), hyperpigmentation following lines of Blaschko (black arrows indicating the border) and hypopigmented areas of poikiloderma (more...)FigureFigure 2. Left great toe showing underdevelopment and ridging of the nail Atrophic and hypoplastic areas of skin that often follow the lines of Blaschko and appear as depressed regions of pink or white color, often with a fibrous texture.
Note: The lines of Blaschko correspond to cell migration pathways evident during embryonic and fetal skin development. Like dermatomes, the lines of Blaschko are linear on the limbs and circumferential on the trunk. Unlike dermatomes, the lines of Blaschko do not correspond to innervation patterns.Hypo- or hyperpigmented changes that usually follow the lines of BlaschkoCutis aplasia that may occur on the scalp or any part of the bodySoft, yellow-pink nodules on the skin (which represent fat nodules in the dermis) that are typically seen on the trunk and extremitiesVerrucoid papillomas of the skin and mucous membranesRidged and dysplastic (abnormal)/hypoplastic (small) nailsSparse or absent hair on the scalp and in areas of abnormal skin on the body (may be present at birth and may evolve with time)Telangiectasias (may be seen on the face, trunk, and extremities)Limb malformations include the following (see Figure 3):FigureFigure 3. Hands showing syndactyly (black arrow) and split-hand malformation (black arrowhead) with only four digits (oligodactyly) on the left hand. The appearance of the left hand has been somewhat modified by partial surgical repair. Oligodactyly (<5 digits on a hand or foot) and/or syndactyly (joining or webbing of ≥2 fingers or toes), which may be seen in one or both hands or feet. Central digits are more frequently involved.Split hand/foot malformation that may occur on one or more extremitiesWhen the diagnosis of focal dermal hypoplasia is unclear, a skeletal survey may be helpful to evaluate for the following:Osteopathia striata, a striated appearance of the bones evident on plain x-rays and of no clinical or medical significance [Larrègue et al 1972]. It is not clear if the striations reflect increased or decreased bone density.Costovertebral segmentation abnormalities, including fused ribs, bifid ribs, hemivertebrae, and/or butterfly vertebraeIn most cases, molecular genetic testing will confirm the clinical diagnosis of focal dermal hypoplasia. Molecular Genetic TestingGene. PORCN is the only gene in which mutations are known to cause focal dermal hypoplasia:Affected females are germline heterozygous for a PORCN mutation or have somatic mosaicism for a PORCN mutation.Affected males have somatic mosaicism for PORCN mutations [Grzeschik et al 2007, Wang et al 2007, Lombardi et al 2011].Evidence for locus heterogeneity. In initial studies, only 80% (12/16 females and 4/4 males) of individuals with a clinical diagnosis of focal dermal hypoplasia had mutations in PORCN [Wang et al 2007]; however, phenotypic information was limited. The diagnosis in those without mutations in PORCN could not be confirmed, even though two were described by the referring clinician as “typical” focal dermal hypoplasia. Subsequent studies of individuals with better-characterized phenotypes found mutations in PORCN or deletions affecting the gene in nearly all affected females [Maas et al 2009, Lombardi et al 2011]. However, when diagnostic laboratories analyze samples submitted to rule out a diagnosis of FDH (including cases with atypical findings), mutations are found in only 40%-62% [Fernandes et al 2009, Lombardi et al 2011]. No evidence suggesting locus heterogeneity exists at this time.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Focal Dermal HypoplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1, 2, 3Test AvailabilityAffected MalesCarrier FemalesPORCNSequence analysisSequence variants 415/17 reported 5142/155 reported 6ClinicalDeletion analysis 7Large deletions 80/17 reported13/155 reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Estimates based on 155 individual positive test results which are curated in the PORCN @ LOVD database [Lombardi et al 2011] 3. The exact detection rate is uncertain, however of those with positive findings, deletions represent 8.4% and other mutations represent 91.6%. Males with mosaic mutations represent 9.7% of all described cases with mutations in PORCN @ LOVD [Bronholdt et al 2009, Froyen et al 2009, Fernandes et al 2010, Lombardi et al 2011]. It has been suggested that mutations can be identified in nearly all well-characterized cases of FDH [Lombardi et al 2011], but that diagnostic yields are lower when samples from clinical cases with less defined phenotypes are submitted to clinical diagnostic labs to rule out FDH, varying from 34% [Fernandes et al 2010] to 62.5% [Lombardi et al 2011].4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.5. All males reported thus far where a mutation in PORCN has been confirmed have been mosaic for the mutation. Mutations have not been found or described in all reported affected males [Tollefson & McEvoy 2009, Lasocki et al 2011].6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.8. Reported deletions have ranged from an intragenic deletion (exons 1-4) [Bornholdt et al 2009] to large genomic deletions including PORCN and neighboring genes of up to 0.5 Mb [Wang et al 2007, Lombardi et al 2011].Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.Females may be mosaic for mutations in PORCN. In sequence analysis, mosaicism for a missense or other non-frameshifting mutation can be difficult to detect and may produce a false negative test result [Grzeschik et al 2007, Bornholdt et al 2009].46,XY males with an identified mutation thus far have been mosaic for mutations in PORCN [Wang et al 2007, Grzeschik et al 2007, Bornholdt et al 2009, Maas et al 2009, Fernandes et al 2010, Vreeburg et al 2011, Yoshihashi et al 2011]. In sequence analysis, mosaicism for a missense or other non-frameshifting mutation can be difficult to detect and may produce a false negative test result [Wang et al 2007, Maas et al 2009, Lasocki et al 2011]. Testing of affected tissues in these cases can result in increased detection of the mutation [Maas et al 2009]. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a female proband1.Perform sequence analysis.2.In females, if no mutation is identified on sequence analysis, test for large deletions by deletion/duplication analysis. This can be achieved by fluorescence in situ hybridization or other targeted methods to search for a PORCN-including deletion. The locus is also well covered on most clinical CMA tests. To confirm/establish the diagnosis in a male probandSequence analysis. No male has been reported to have a germline mutation and careful attention may be required to detect low levels of mosaicism. Analysis of affected tissues (e.g., skin biopsy) can be considered in males if the results performed on DNA from other sources (e.g. blood sample, saliva) do not detect a mutation [Maas et al 2009]. Males with a 47,XXY karyotype can have a heterozygous mutation on one of their two X chromosomes [Alkindi et al 2012].Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersAccording to Van Allen & Myhre [1991], Van Allen-Myhre syndrome is either a severe form of or allelic to focal dermal hypoplasia. This has been confirmed in a report in which an individual with Van Allen-Myhre syndrome [Hancock et al 2002] was found to have a pathogenic mutation in PORCN [personal observation; case reported by Wang et al 2007]. Angioma serpiginosum has been hypothesized to be allelic to focal dermal hypoplasia [Blinkenberg et al 2007]. A deletion of PORCN was subsequently reported in one affected individual [Houge et al 2008], but this was later disputed and proposed to be a case of FDH instead of a case of angioma serpiginosum [Happle 2009] Severe presentations of FDH with abdominal wall closure defects that are in the spectrum of pentalogy of Cantrell or limb-body wall complex anomaly have been reported [Hancock et al 2002, Maas et al 2009, Scott et al 2009, Smigiel et al 2011]. In some of these affected individuals, PORCN mutations have been detected [Maas et al 2009, Lombardi et al 2011, Smigiel et al 2011]. Whether mutations in PORCN can cause isolated forms of these conditions has not been established.}

Natural HistoryFocal dermal hypoplasia is a multisystem disorder caused by developmental abnormalities in mesodermal and ectodermal structures and thus primarily involves the skin, skeletal system, eyes, and face. The manifestations vary among affected individuals and many have only a subset of the characteristic features. Nearly all individuals have at least a few of the skin manifestations.Females account for 90% of individuals with focal dermal hypoplasia. Affected males have somatic mosaicism for mutations in PORCN and are generally more mildly affected than females [Grzeschik et al 2007, Wang et al 2007, Lombardi et al 2011].Affected FemalesSkin manifestations. The most characteristic features of focal dermal hypoplasia are the skin manifestations. The cutaneous findings typically follow the lines of Blaschko, cell migration pathways that are linear on the limbs and circumferential on the trunk. Hypoplastic areas are usually evident at birth; the distribution and severity may change over time. Unilateral involvement has also been reported [Tenkir & Teshome 2010, Asano et al 2013, Maalouf et al 2012].Papillomas are typically not present at birth but develop with age. Common sites for verrucoid papillomas include around the mouth and nose, in the esophagus and larynx (where they may cause obstruction), and in the genital and anal region (where they may be confused with genital warts).Other integumentary system and ectodermal appendage findings include sparse and brittle hair, sometimes accompanied by patchy alopecia. The nails can be hypoplastic or dysplastic with longitudinal grooving. There can be absent or supernumerary nipples. Dental abnormalities and eye findings, both of which result from abnormalities in ectodermal appendage development, are described separately below. Skeletal system. Most females with focal dermal hypoplasia have limb malformations noted at birth, including syndactyly, oligodactyly, and split-hand/foot malformation [Gorlin et al 1963, Goltz et al 1970]. These malformations, which do not change over time, may impair function.Less common limb malformations that may be present at birth and impair function include camptodactyly (contraction deformities of the digits) and reduction defects of the long bones, such as transverse deficiency of distal radius/ulna or tibia/fibula.Osteopathia striata, a striated appearance of the bones evident on plain x-rays, is common and may be seen in childhood, adolescence, and adulthood.Giant cell-like tumors of long bones, reported on occasion, may develop in childhood, adolescence, or adulthood. They typically become evident when a pathologic bone fracture occurs at the site of the lesion [Selzer et al 1974, Joannides et al 1983, Tanaka et al 1990]. In the small number of reports to date, none of these tumors have been malignant.Costovertebral segmentation abnormalities, including fused ribs, bifid ribs, and hemivertebrae and butterfly vertebrae, are present at birth but are often not evident on physical examination and may only be seen on x-ray of the chest and/or spine. Although these malformations do not typically cause problems in infancy or early childhood, they may cause scoliosis as the child grows. More often, these segmentation abnormalities do not cause health issues.Diastasis pubis, an abnormal separation of the symphysis pubis, may be an incidental finding or may present in adolescence or adulthood with pain. The gap between the pubic bones in the average non-pregnant adult is 4-5 mm. An abnormal gap is considered to be 1 cm or more, sometimes with the two bones being slightly out of alignment. In some individuals with focal dermal hypoplasia, diastasis pubis may cause pain with walking or in the symphysis pubis, legs, groin, and lower abdomen.Fibrous dysplasia of bone (i.e., replacement of medullary bone with trabeculae of woven bone containing fluid-filled cysts embedded in a fibrous matrix) may affect any bone at any time. On x-ray the bone appears radiolucent, with what is classically described as a “ground-glass” appearance. Fibrous dysplasia may be asymptomatic or become evident when it is the site of a pathologic fracture.Eye findings. Developmental abnormalities of the eyes are common and are evident at birth. Depending on the severity of the manifestations, vision can range from normal to blindness. Reported eye abnormalities include anophthalmia/microphthalmia, microcornea, iris, chorioretinal and eyelid colobomas, lacrimal duct abnormalities, and cataracts (cortical and subcapsular) [Gorlin et al 1963, Goltz et al 1970].Strabismus and/or nystagmus can be observed when visual impairment in infancy is significant.Craniofacial findings. Facial features are variable and include facial asymmetry, notched alae nasi, pointed chin, and small underfolded pinnae. These facial characteristics are not typically evident at birth but develop with time (see Figure 4) [Gorlin et al 1963, Goltz et al 1970].FigureFigure 4. Note facial features of pointed chin and small right ear. Cleft lip and palate can be present and may lead to difficulty with feeding. More severe facial clefting can cause feeding, breathing, and vision problems, as well as significant cosmetic concerns [Ascherman et al 2002].Dental. Oral manifestations are seen in more than half of affected individuals. Enamel hypoplasia that predisposes to dental caries is the most common problem. Other findings include: hypodontia; oligodontia; supernumerary teeth and crowding, leading to malocclusion of both primary and secondary dentition; vertical grooving of the teeth; microdontia (small teeth); taurodontia (prism-shaped molars); fused teeth; and abnormal root morphology [Balmer et al 2004, Tejani et al 2005, Murakami et al 2011]. Affected individuals may also have problems with the eruption and position of teeth. Natal teeth were described in one affected individual [Dias et al 2010]. Gastrointestinal. Developmental abnormalities of the digestive system are rare but may have severe consequences. These are typically evident at birth (abdominal wall defects) or cause significant problems with breathing or feeding (diaphragmatic hernia) (see Congenital Diaphragmatic Hernia Overview).Severe gastroesophageal reflux (GER) has been reported in infancy and childhood, leading to feeding difficulties with frequent vomiting and/or discomfort/distress. The GER likely results from esophageal papillomas [Brinson et al 1987].Urogenital. Structural abnormalities of kidneys and urinary system that may lead to recurrent urinary tract infections and urinary reflux include unilateral absent kidney, hypoplastic kidney, cystic renal dysplasia, hydronephrosis, and fused/horseshoe kidney [Suskan et al 1990]Occasional affected individuals with müllerian anomalies, including bicornuate uterus, have been described [Reddy & Laufer 2009, Lopez-Porras et al 2011].Other. Most affected individuals with focal dermal hypoplasia are reported to be small at birth and have mild short stature, although this has been poorly characterized [Goltz et al 1970].Development is usually normal; some individuals with focal dermal hypoplasia may have cognitive impairment. Structural brain abnormalities and spina bifida [Goltz et al 1970, Almeida et al 1988] have been reported but are uncommon. Epilepsy has been reported [Kanemura et al 2011].Mixed conductive and sensorineural hearing loss has been reported on occasion.Affected MalesBecause relatively few affected males have been reported, no comprehensive data exist about a “typical” male phenotype. Affected males may have any of the features seen in affected females including typical skin findings; sparse, brittle hair; nail dystrophy; microphthalmia; syndactyly; split-hand/foot malformation; costovertebral segmentation abnormalities; osteopathia striata; and diastasis pubis [Wang et al 2007, Maas et al 2009, Bornholdt et al 2009, Lombardi et al 2011, Lasocki et al 2011, Vreeburg et al 2011, Yoshihashi et al 2011].PathologyHistopathologic and ultrastructural studies of the skin have shown the following:A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [Kanitakis et al 2003]Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [Howell & Freeman 1989, del Carmen Boente et al 2007]. Whether these represent herniation of fat into a thinned dermis or ectopic aggregation of fat within a dysplastic dermis is unclear [Howell & Freeman 1989].Verrucoid papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucoid papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [Rosen & Bocklage 2005].

Genotype-Phenotype CorrelationsInformation on genotype-phenotype correlations in focal dermal hypoplasia is limited.Available data suggest that the level of X-chromosome inactivation correlates with severity of the phenotype in some (familial) cases [Grzeschik et al 2007, Wang et al 2007]. Note: All females with deletions in PORCN have extremely skewed X-chromosome inactivation, whereas females with point mutations can have random or skewed X-chromosome inactivation [Grzeschik et al 2007, Wang et al 2007, Lombardi et al 2011].All males reported to date are mosaic for mutations in PORCN and are generally more mildly affected than females, although more severe cases have been reported [Maas et al 2009, Bornholdt et al 2009, Lombardi et al 2011].

Differential DiagnosisMicrophthalmia with linear skin defects (MLS). Similar skin and ophthalmologic manifestations may be seen in MLS; however, limb and skeletal malformations are uncommon in MLS. MLS is caused by deletions and point mutations of HCCS [Wimplinger et al 2006]; thus, as was previously proposed [Van den Veyver 2002], MLS and focal dermal hypoplasia are not allelic conditions [Harmsen et al 2009; Author, unpublished data]. Incontinentia pigmenti (IP) is a disorder that affects the skin, hair, teeth, nails, eyes, and central nervous system. Characteristic skin lesions evolve through four stages: (I) blistering (birth to age ~4 months); (II) a wart-like rash (for several months); (III) swirling macular hyperpigmentation (age ~6 months into adulthood); (IV) linear hypopigmentation. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Neovascularization of the retina, present in some individuals, predisposes to retinal detachment. Neurologic findings including cognitive delays/intellectual disability are occasionally seen. IKBKG (NEMO) is the only gene known to be associated with IP. IP is inherited in an X-linked manner and is lethal in many males.The combination of focal dermal hypoplasia, morning glory anomaly, and polymicrogyria has been observed in one individual [Giampietro et al 2004]; the eye abnormalities and polymicrogyria make this disorder seem distinct from focal dermal hypoplasia (i.e., Goltz syndrome), the subject of this GeneReview.Oculocerebrocutaneous syndrome predominantly affects males and can be distinguished from focal dermal hypoplasia by the former having characteristic brain malformations, including frontal polymicrogyria, periventricular nodular heterotopia, and agenesis of the corpus callosum [Moog et al 2005].Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, eyelashes, and/or eyebrows/lashes, small stature, skeletal and dental abnormalities, cataracts, and an increased risk for cancer, especially osteosarcoma. The skin is typically normal at birth; the rash of RTS develops between ages three and six months as erythema, swelling, and blistering on the face and subsequently spreads to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectases, collectively known as poikiloderma. Hyperkeratotic lesions occur in about one-third of individuals. Skeletal abnormalities include dysplasias, absent or malformed bones (such as absent radii), osteopenia, and delayed bone formation. RECQL4 is the only gene associated with Rothmund-Thomson syndrome to date. Inheritance is autosomal recessive.Papillomas of the genital and anal region are common and should not be confused with genital warts.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with focal dermal hypoplasia, the following evaluations are recommended:Chest x-ray to evaluate for costovertebral defects and evidence of diaphragmatic herniaEye examination to evaluate for colobomasConsideration of abdominal MRI to evaluate for diaphragmatic herniaRenal ultrasound examination to evaluate for structural anomalies of the kidneys and urinary collecting systemHearing evaluationMedical genetics consultationTreatment of ManifestationsSkin. For individuals with significant areas of dermal aplasia, regular care with a dermatologist and use of occlusive dressings and antibiotic creams may help prevent secondary infections as erosive lesions may be painful, pruritic, and therefore prone to infection. Some individuals report that lotion is helpful in managing pruritic erosions. Pulsed dye laser or other photodynamic therapy has been successful in managing skin lesions [Alster & Wilson 1995, Liu et al 2012].Verrucoid papillomas can cause significant morbidity. Large papillomas of the larynx can obstruct swallowing and cause severe GER. Affected individuals should be asked frequently about swallowing problems and, when present, should be referred to an otolaryngologist for evaluation and management with surgical or laser therapy.An individual with refractory exophytic granulation tissue received significant benefit from a combination of curettage and photodynamic therapy [Mallipeddi et al 2006].An adult individual with multiple cutaneous basal cell carcinomas has been reported. Whether this is more prevalent in FDH is currently unknown, but heightened surveillance and appropriate treatment for such lesions may be indicated [Patrizi et al 2012].Skeletal system. Impaired functionality associated with syndactyly, oligodactyly, and split-hand/foot malformation may improve with occupational therapy, assistive devices, or surgical intervention.Camptodactyly often improves with physical and occupational therapy.Reduction defects of the long bones, such as transverse deficiency of distal radius/ulna or tibia/fibula, may be managed with prostheses as appropriate.Individuals with scoliosis secondary to costovertebral defects should be referred to an orthopedist when other medical providers are unfamiliar with guidelines for routine monitoring and management.Management of pain related to diastasis pubis with anti-inflammatory medications and/or physical therapy usually resolves the pain. Individuals with pain refractory to these interventions should consult an orthopedist.Individuals with FDH can have osteopathia striata of long bones, which are streaks of hypodensity; it is currently unclear if such individuals are at increased risk for general osteoporosis. A spontaneous patella fracture related to osteoporosis in a patient with FDH has been reported [Altschuler et al 2012].Dental. Abnormalities in the structure and number of teeth may cause dental malocclusion and dissatisfaction with the appearance of the teeth. Orthodontic care may be indicated when dental malocclusion is present. Composite veneers and other aesthetic procedures may be used to improve the appearance of abnormal teeth [Tejani et al 2005, Murakami et al 2011].Other. Consultation with:An otolaryngologist prior to general anesthesia for evaluation for papillomas of the tonsils or pharynx that would complicate endotracheal intubation
Note: These lesions may change significantly over time, so the evaluation should be within a few months of the procedure. The papillomas may be friable and prone to bleeding; when papillomas are present the airway must be handled as gently as possible, which may include fiberoptic bronchoscopy for intubation rather than direct laryngoscopy [Rhee et al 2006].A pediatric surgeon for the treatment of diaphragmatic hernia and abdominal wall defectsA urologist or nephrologist for treatment of structural malformations of the kidneys and urinary collecting systemPrevention of Secondary ComplicationsIn individuals with structural renal malformations, standard measures are used to reduce risk for urinary tract infections.Regular care of a dentist and promotion of good oral hygiene, diet counseling, and consideration of fissure sealants are important to minimize the risk of dental caries [Tejani et al 2005, Murakami et al 2011].SurveillanceThe following should be considered as part of routine medical care for individuals with focal dermal hypoplasia:Routine follow-up with a dermatologist to anticipate and manage common skin problemsPreoperative evaluation by an otolaryngologist for hypopharyngeal and tonsillar papillomasQuestioning about gastroesophageal reflux and swallowing difficulties at routine health visits, and, when present, referral to an otolaryngologist for evaluation of possible verrucoid papillomas and management with surgical or laser therapy as neededRoutine physical examinations and/or spine radiographs to evaluate for scoliosis, particularly in individuals with costovertebral segmentation abnormalitiesRegular dental examsEvaluation of Relatives at RiskFemale and male sibs of females with maternally inherited mutations should be offered testing, and only female sibs of females with paternally inherited mutations should be offered testing.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Preconception and/or prenatal genetic counseling should be offered to all women with FDH who are or desire to become pregnant, or when the father of the pregnancy has FDH, to discuss recurrence risk and preimplantation or prenatal genetic testing options. For affected women, management of pregnancy should be guided by standard obstetric principles taking into account potential complications of FDH. Skeletal abnormalities including scoliosis or diastasis pubis may be present in some affected women, and may affect delivery management. Women with significant scoliosis will benefit from evaluation of respiratory status and feasibility of epidural analgesia. Obstetricians should be aware that verrucous papillomas in genital areas in women with FDH are unlikely to be viral in origin and thus, there is no risk for transmission to the newborn during vaginal delivery. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Focal Dermal Hypoplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPORCNXp11​.23Probable protein-cysteine N-palmitoyltransferase porcupinePORCN @ LOVDPORCNData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Focal Dermal Hypoplasia (View All in OMIM) View in own window 300651PORCUPINE, DROSOPHILA, HOMOLOG OF; PORCN 305600FOCAL DERMAL HYPOPLASIA; FDHNormal allelic variants. PORCN has 15 exons, 14 of which are coding exons. It undergoes alternative splicing, resulting in five transcript variants.Pathologic allelic variants. Disease-causing mutations include nonsense, frameshift, and missense mutations as well as genomic deletions that delete the entire PORCN locus. The deletions also delete a variable number of flanking genes [Grzeschik et al 2007, Wang et al 2007].Normal gene product. PORCN encodes the human homolog of Drosophila porcupine [Caricasole et al 2002]. The gene product, human probable protein-cysteine N-palmitoyltransferase porcupine, has five isoforms that result from alternative splicing and in mouse studies was found to be expressed in a wide variety of tissues. Most information about its function is derived from studies of its highly conserved mouse, Drosophila, and recently also zebrafish homologs, where porcupine has been shown to be required for secretion and signaling of most WNT proteins from WNT-producing cells [van Amerongen & Nusse 2009, Chen et al 2012, Clevers & Nusse 2012] and may play a role in fine-tuning Wnt protein levels. WNTs are important morphogens that are secreted from producing cells and interact with specialized receptors and co-receptors (FZD/LRP5 or 6) on target cells. This activates the canonical WNT pathway, resulting in intracellular stabilization and translocation into the nucleus of β-catenin, where it activates specific target genes that are important for normal development [Clevers & Nusse 2012]. It may also be required to activate other non-canonical Wnt signaling [Proffitt & Virshup 2012]. Wnt-3a is retained in the endoplasmic reticulum of cultured cells when Porcn is inactivated [Takada et al 2006, Clevers & Nusse 2012]. Wnt signaling is required for induction, proliferation, morphogenesis, and maintenance of most organs. Abnormal gene product. Focal dermal hypoplasia is caused by loss-of-function mutations and deletions of PORCN. Loss of function of orthologs in mouse cells and Drosophila results in failure of WNT proteins to be secreted from the endoplasmic reticulum in WNT-producing cells, with defective downstream WNT signaling [Tanaka et al 2000, Takada et al 2006]. Inactivation of Porcn in mouse embryos has resulted in early embryonic lethality and revealed that it is required for gastrulation and normal development of mesoderm and ectoderm-derived structures [Barrott et al 2011, Biechele et al 2011, Liu et al 2012]. Conditional inactivation of Porcn in developing skin causes alopecia because hair follicles do not form [Liu et al 2012] and in developing limbs causes skeletal defects reminiscent of those seen in human patients with FDH [Barrott et al 2011, Liu et al 2012]. Inactivation in zebrafish has resulted in defects that are consistent with a role of protein-cysteine N-palmitoyltransferase porcupine in non-canonical Wnt-signaling in this organism [Chen et al 2012]. Inactivation in a tumor cell line, has suggested that porcupine may also function in other pathways in these transformed cells [Covey et al 2012]. Whether these last two new findings are relevant to the function in normal human cells or contribute to the defects found in FDH is currently unknown. The new mouse models will be helpful in the future to further understand the normal function of porcupine and to test potential new therapies for those symptoms that are progressive or first present after birth.