Clinical characteristics.

Focal dermal hypoplasia is a multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face. Skin manifestations present at birth include atrophic and hypoplastic areas of skin; cutis aplasia; fat nodules in the dermis manifesting as soft, yellow-pink cutaneous nodules; and pigmentary changes. Verrucoid papillomas of the skin and mucous membranes may appear later. The nails can be ridged, dysplastic, or hypoplastic; hair can be sparse or absent. Limb malformations include oligo-/syndactyly and split hand/foot. Developmental abnormalities of the eye can include anophthalmia/microphthalmia, iris and chorioretinal coloboma, and lacrimal duct abnormalities. Craniofacial findings can include facial asymmetry, notched alae nasi, cleft lip and palate, and pointed chin. Occasional findings include dental anomalies, abdominal wall defects, diaphragmatic hernia, and renal anomalies. Psychomotor development is usually normal; some individuals have cognitive impairment.

Diagnosis/testing.

Focal dermal hypoplasia can be diagnosed based on clinical findings in individuals with classic ectodermal findings and characteristic limb malformations. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are inconclusive.

Management.

Treatment of manifestations: Care by a dermatologist for painful and pruritic erosive lesions that are prone to infection; referral to an otolaryngologist or gastroenterologist for evaluation and management of large papillomas of the larynx and/or trachea or esophagus causing gastroesophageal disease (GERD); referral to a physical/occupational therapist and hand surgeon for management of hand and foot malformations; standard protocols for management of structural abnormalities of the eyes and kidneys and diaphragmatic hernia and abdominal wall defects.

Prevention of secondary complications: Preoperative evaluation by an otolaryngologist for hypopharyngeal and/or tonsillar papillomas.

Surveillance: Routine follow up with a dermatologist; routine evaluations for scoliosis, particularly in individuals with costovertebral segmentation abnormalities; routine monitoring of growth and body composition to determine need for nutritional intervention; regular eye examinations; routine screening for cognitive, emotional, behavioral, and adaptive issues.

Genetic counseling.

Focal dermal hypoplasia is inherited in an X-linked manner. Females (90% of affected individuals) are heterozygous or mosaic for a PORCN pathogenic variant; live-born affected males (10% of affected individuals) are mosaic for a de novo PORCN pathogenic variant. It is presumed that non-mosaic hemizygous males are not viable. Approximately 95% of females with focal dermal hypoplasia have a de novo pathogenic variant; ~5% inherited the pathogenic variant from a parent. The risk that the PORCN pathogenic variant will be transmitted by an affected heterozygous female is 50%; however, because most male conceptuses with a PORCN pathogenic variant are presumed to be spontaneously aborted, at delivery the expected sex ratio of offspring is: 33% unaffected females; 33% affected females; 33% unaffected males. If the affected female is mosaic for a PORCN pathogenic variant, the risk to her female offspring of inheriting the pathogenic variant depends on the level of mosaicism in her germline and can be as high as 50%. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.

Suggestive Findings

Focal dermal hypoplasia, a multisystem disorder primarily involving the skin, skeletal system, eyes, and face, should be considered in an individual with following clinical findings.

Major Findings

Characteristic ectodermal manifestations include the following (see Figure 1):

Figure 1.

Ectodermal manifestations include yellowish-pink areas representing fat herniation (white arrowheads), patchy aplasia (black arrowheads), hyper-/hypopigmentation following lines of Blaschko (black arrows indicating the border), and hypopigmented areas (more...)

• Congenital patchy skin aplasia (95% of individuals) evidenced by 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.
• Congenital skin hypo- or hyperpigmentation (90%-100%) often following a Blaschko linear distribution
• Congenital nodular fat herniation (60%-70%), evidenced by soft, yellow-pink nodules on the skin (which represent fat nodules in the dermis) that are typically seen on the trunk and extremities
• Congenital ridged, dysplastic, or hypoplastic nails (80%-90%)
• Telangiectasias (~80%) (may be seen on the face, trunk, and extremities)

Characteristic limb malformations [Smith & Hunt 2016] include the following (see Figure 2 and Figure 3):

Figure 2.

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.

Figure 3.

Highly variable limb malformations Feet showing syndactyly (black arrow), split-hand malformation or ectrodactyly (black arrowhead), oligodactyly (3, 6, 7, 8, 10, 11, 12), and distal transverse limb defect (13)

• Syndactyly (70%-90% of individuals) joining or webbing of ≥2 fingers or toes, occurring variably on one or more extremities
• Ectrodactyly (75%), a split hand/foot malformation that may occur on one or more extremities
• Oligodactyly (20%-40%) – <5 digits on a hand or foot, which may be seen in one or both hands or feet. Central digits are more frequently involved.
• Transverse limb defect (15%) – congenital absence of the hand, wrist, forearm, or elbow with no distal remaining portions, including acheiria or hemimelia
• Long bone reduction defect (50%-80%) – hypoplasia or shortening of the long bones in one or more extremities

Establishing the Diagnosis

Focal dermal hypoplasia can be diagnosed based on clinical findings in individuals with classic ectodermal findings and characteristic limb malformations. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are inconclusive.

The diagnosis of focal dermal hypoplasia is established in a female or male proband with the following clinical and/or molecular genetic findings.

Clinical Description

Focal dermal hypoplasia is a highly variable multisystem disorder caused by developmental abnormalities in mesodermal and ectodermal structures primarily involving the skin, limbs, eyes, and face. The manifestations vary among affected individuals and many have only a subset of the characteristic features.

Females account for 90% of individuals with focal dermal hypoplasia.

The phenotypes in both males and females are highly variable due to tissue mosaicism: females have random X-chromosome inactivation (functional mosaicism) while males nearly always have postzygotic somatic mosaicism.

Affected Females

Ectodermal manifestations. The most characteristic features of focal dermal hypoplasia are the skin manifestations (Figure 1). The cutaneous findings typically follow the lines of Blaschko and include patchy areas of skin aplasia/hypoplasia, skin hypo- and/or hyper-pigmentation, and nodular fat herniation. The lines of Blaschko represent cell migration pathways that are linear on the limbs and circumferential on the trunk. The lines are classically described as V-shaped overlying the upper spine, S-shaped on the abdomen, and an inverted-U shape from the breast area to the upper arms. These findings are typically evident at birth, but the distribution and severity may change over time. Unilateral involvement has also been reported [Tenkir & Teshome 2010, Maalouf et al 2012, Asano et al 2013].

Other integumentary system abnormalities include wiry hair, sparse hair, patchy alopecia of the scalp, and abnormal nails. The nails can be absent (anonychia), small (micronychia), hypoplastic, or dysplastic, often with longitudinal ridging, splitting, or V-nicking [Bree et al 2016].

Papillomatosis. Papillomas and telangectasias are typically not present at birth but develop with age.

• Verrucoid papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe GERD.
• The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.

Dental abnormalities and eye findings, both of which result from abnormalities in ectodermal appendage development, are described separately below.

Limb and skeletal manifestations. Most individuals with focal dermal hypoplasia have limb malformations noted at birth, including syndactyly, oligodactyly, and split-hand/foot malformation or ectrodactyly (Figure 2 and Figure 3) [Gorlin et al 1963, Goltz et al 1970]. These malformations, which do not change over time, may impair function.

Additionally, reduction defects of the long bones ranging from leg length discrepancies to transverse defects of the distal radius/ulna or tibia/fibula are commonly seen.

Less common limb malformations that may be present at birth and impair function include camptodactyly (contraction deformities of the digits) and brachydactyly (shortening of the digits).

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. Kyphosis or kyphoscoliosis is seen in approximately 10% of affected individuals [Smith & Hunt 2016]. 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.

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 has been malignant.

Osteopathia striata, a striated appearance of the bones evident on plain x-rays, is common and may be seen in childhood, adolescence, and adulthood. It is currently unclear if individuals with this finding are at increased risk for general osteoporosis. Of note, a spontaneous patella fracture related to osteoporosis in a patient with FDH has been reported [Altschuler et al 2012].

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 20/20 to no light perception. 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 (Figure 4) [Gorlin et al 1963, Goltz et al 1970].

Figure 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].

Oral and dental findings. Oral manifestations are seen in more than half of affected individuals and include both soft tissue and hard tissue abnormalities.

Enamel hypoplasia that predisposes to dental caries is the most common problem. Other findings include: hypodontia, oligodontia, supernumerary teeth, and dental 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].

Soft tissue abnormalities include generalized gingivitis and intra-oral lipomas and papillomas.

Gastrointestinal and nutrition. Problems include poor weight gain (77% of individuals), short stature (65%), oral motor dysfunction (41%), gastroesophageal reflux (24%), gastroparesis (35%), and constipation (35%) [Motil et al 2016]. Food allergies – primarily to milk, soy, and shellfish – are present in 12% of affected individuals.

Other developmental abnormalities of the digestive system are rare but may have severe consequences; they include abdominal wall defects and diaphragmatic hernia (see Congenital Diaphragmatic Hernia Overview).

Severe gastroesophageal reflux disease (GERD) has been reported in infancy and childhood, leading to feeding difficulties with frequent vomiting and/or discomfort/distress. GERD likely results from esophageal papillomas [Brinson et al 1987].

Renal and urogenital. Genital labial hypoplasia is present in most females [Adeyemi-Fowode et al 2016]. Occasional affected individuals with müllerian anomalies, including bicornuate uterus, have been described [Reddy & Laufer 2009, Lopez-Porras et al 2011].

Renal structural abnormalities are uncommon, but previous case reports include unilateral absent kidney, hypoplastic kidney, fused/horseshoe kidney, or cystic renal dysplasia. If present, these abnormalities may lead to recurrent urinary tract infections and urinary reflux [Suskan et al 1990].

Cognitive and psychological. Development and intellectual ability is normal in most individuals. Intellectual impairment (15%-20% of individuals), behavioral problems (~20%), emotional lability (40%-50%), and withdrawn behavior (65%) have been reported [Deidrick et al 2016]. In those with emotional, behavioral, adaptive, and intellectual impairment, the spectrum of severity varies widely.

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].

Other. Mixed conductive and sensorineural hearing loss has been reported on occasion.

When the first affected female in the family has milder manifestations than affected females in subsequent generations [Wechsler et al 1988, Kilmer et al 1993], it is most likely that she has either mosaicism for the PORCN pathogenic variant or skewing of X-chromosome inactivation. Alternative explanations could be reduced reproductive fitness in severely affected females, such that only mildly affected females reproduce.

Genotype-Phenotype Correlations

Information 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 a single-nucleotide variant can have random or skewed X-chromosome inactivation [Grzeschik et al 2007, Wang et al 2007, Lombardi et al 2011].

Nearly all affected males to date have somatic mosaicism for a PORCN pathogenic variant, with males being generally more mildly affected than females; however, some severely affected males have been reported [Maas et al 2009, Bornholdt et al 2009, Lombardi et al 2011]. One notable exception is two brothers who were hemizygous for an inherited novel PORCN missense variant thought to contribute to syndromic microphthalmia [Brady et al 2015]. The phenotypic severity in female relatives harboring the same variant ranged from mild to unaffected, suggesting a probable hypomorphic allele.

Penetrance

Focal dermal hypoplasia appears to be highly penetrant in females, but the phenotypic severity can occasionally be mitigated by skewed X-chromosome inactivation.

Males are nearly always mosaic for a hemizygous somatic PORCN pathogenic variant and can be so mildly affected as to not come to medical attention until adulthood.

Nomenclature

Focal dermal hypoplasia is also known by the following eponyms:

• Goltz syndrome
• Goltz-Gorlin syndrome

Note: Gorlin-Goltz syndrome is another name for nevoid basal cell carcinoma syndrome.

Note that not all individuals with the disorder focal dermal hypoplasia have focal areas of skin hypoplasia.

Prevalence

Focal dermal hypoplasia is an uncommon disorder with about 300 reported affected individuals worldwide [Goltz 1992, Tadini et al 2015]. The exact prevalence is unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with focal dermal hypoplasia, the following evaluations are recommended.

• Ectodermal manifestations. Evaluation by a dermatologist for identification of dermal aplasia or erosive skin that may benefit from treatment with dressings or lotion
• Papillomatosis
  • Evaluation by an otolaryngologist for evidence of laryngeal or peri-tonsillar verrucoid papillomas, which can cause obstructive sleep apnea
  • Sleep study to evaluate for obstructive sleep apnea (often due to airway papillomas)
• Limb and skeletal manifestations. Chest x-ray to evaluate for costovertebral defects and evidence of diaphragmatic hernia
• Eye findings. Eye examination to evaluate for iris colobomas, chorioretinal colobomas, nystagmus, strabismus, or cataracts
• Oral and dental findings
  • Evaluation by a cleft palate team if relevant
  • Examination by a dentist beginning with the first teeth around age one year
• Gastrointestinal and nutrition
  • Consideration of abdominal ultrasound examination to evaluate for diaphragmatic hernia
  • Evaluation by a gastroenterologist if gastroesophageal reflux disease (GERD) is an issue
• Renal and urogenital
  • Renal ultrasound examination to evaluate for structural anomalies of the kidneys and urinary collecting system
  • Evaluation by a pediatric gynecologist prior to puberty. Imaging studies of the reproductive tract should be considered as anomalies can affect fertility.
• Cognitive and psychological. Hearing evaluation
• Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Skin. For individuals with significant areas of dermal aplasia, regular care by a dermatologist and use of occlusive dressings and antibiotic creams may help prevent secondary infections as erosive lesions may be painful and 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 excessive granulation tissue [Alster & Wilson 1995, Liu et al 2012].

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].

Papillomatosis. Verrucoid papillomas can cause significant morbidity, including breathing problems (which could reflect the presence of laryngeal and/or tracheal papillomas) and GERD symptomatology (which could reflect the presence of esophageal papillomas). When possible, individuals should be referred to an otolaryngologist or gastroenterologist depending on the anatomic location of the papillomas.

Symptomatic papillomas of the esophagus can be removed endoscopically [Kashyap et al 2011] or with balloon-assisted radiofrequency ablation [Bertani et al 2014]. Airway (hypopharyngeal, tonsillar, and tracheal) papillomas can be managed with surgery or laser therapy.

Skeletal. Impaired functionality associated with syndactyly, oligodactyly, and split-hand/foot malformation may improve with occupational therapy, assistive devices, or surgical intervention.

Reduction defects of the long bones, such as transverse deficiency of distal radius/ulna or tibia/fibula, may be managed with prostheses as appropriate.

Camptodactyly often improves with physical and occupational therapy.

Individuals with scoliosis secondary to costovertebral defects should be referred to an orthopedist 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.

Eye. Colobomas of the eyelid may be repaired by an oculoplastic surgeon.

Iris colobomas can be aesthetically treated with colored contact lenses to give the appearance of a round pupil.

The photophobia that often accompanies iris colobomas can be reduced by use of tinted glasses.

Because retinal detachment leading to blindness is a potential complication of retinal coloboma, any acute changes in vision should be evaluated urgently by an ophthalmologist.

In patients with microphthalmia, an ocularist using prosthetic intervention can work to expand the palpebral fissures. Additional surgical corrections can be discussed with an oculoplastic surgeon.

Children with reduced vision may benefit from visual aids or other visual resources as part of an early intervention program to increase visual-spatial development.

Dental. 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].

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:

• A pediatric surgeon for the treatment of diaphragmatic hernia and abdominal wall defects.
• A urologist or nephrologist for treatment of structural malformations of the kidneys and urinary collecting system and their sequelae. In individuals with structural renal malformations, standard measures are used to reduce risk for urinary tract infections.
• A developmental pediatrician for evaluation and management of behavioral problems, emotional lability, or withdrawn behaviors. Those with intellectual impairment or developmental delay should receive early intervention in occupational, speech, and physical therapies.

Prevention of Secondary Complications

Preoperative evaluation by an otolaryngologist for hypopharyngeal and tonsillar papillomas [Rhee et al 2006] is indicated prior to general anesthesia. Any papillomas that would complicate endotracheal intubation should be surgically removed or communicated to the anesthesiologist prior to the procedure.

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].

Surveillance

The following should be considered as part of routine medical care for individuals with focal dermal hypoplasia:

• Skin. Routine follow up with a dermatologist to anticipate and manage common skin problems
• Papillomatosis
  • Monitoring for symptoms of gastroesophageal reflux disease and swallowing difficulties at routine health visits. When present, refer to an otolaryngologist for evaluation of possible verrucoid papillomas and management with surgical or laser therapy as needed.
  • Routine monitoring for symptoms of obstructive sleep apnea (snoring, gasping, breathing pauses). If present, a sleep study should be performed [Bostwick et al 2016].
• Skeletal. Routine physical examinations and/or spine radiographs to evaluate for scoliosis, particularly in individuals with costovertebral segmentation abnormalities
• Dental. Regular examinations
• Other
  • Routine monitoring of growth and body composition to determine if early nutritional intervention is needed [Motil et al 2016]
  • Regular eye examinations to monitor for changes in visual acuity and risks for retinal detachment in individuals with retinal colobomas. Any acute changes in vision should be considered a medical emergency as retinal detachment can lead to total blindness.
  • Routine screening of cognitive, emotional, behavioral, and adaptive ability, with appropriate referrals to therapeutic interventions as indicated [Deidrick et al 2016]

Agents/Circumstances to Avoid

Because some individuals with severe skin manifestations may have hypohidrosis (and thus be at increased risk for heat intolerance), care should be taken to prevent exposure to extreme heat.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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 Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Focal dermal hypoplasia (FDH) is inherited in an X-linked manner.

Females account for 90% of individuals with FDH; they may have heterozygous or mosaic pathogenic variants in PORCN. Males account for 10% of individuals with FDH; nearly all live-born affected males who have had molecular testing are mosaic for a PORCN pathogenic variant [Lombardi et al 2011]. It is presumed that non-mosaic, hemizygous males are not viable.

Risk to Family Members

Parents of a proband

• Approximately 95% of females with FDH have a de novo pathogenic variant.
• Approximately 5% of affected females have inherited a PORCN pathogenic variant from a parent, usually the mother; such women may be more, equally, or less affected than their mothers [Wang et al 2007, Shimaoka et al 2009].
  Less frequently, an affected female may have inherited the pathogenic variant from a father mosaic for a PORCN pathogenic variant [Wang et al 2007]; fathers with FDH are typically more mildly affected than their daughters [Burgdorf et al 1981].
• Female proband. An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
  • If the PORCN pathogenic variant has been identified in a female proband, molecular genetic testing of the parent who has manifestations of FDH is appropriate.
  • If neither parent has clinical manifestations of FDH, molecular genetic testing of both parents should be considered because: (1) the father or mother may have low-level mosaicism or (2) the mother may be a mildly affected heterozygote secondary to extremely favorable skewing of X-chromosome inactivation.
• Male proband. Live-born affected males are rare and nearly always have somatic mosaicism for a de novo, presumably postzygotic pathogenic variant. The mother of a severely affected male should be examined for subtle features of FDH. Maternal testing is indicated as two hemizygous males have been reported as offspring of a seemingly asymptomatic mother with a presumed hypomorphic pathogenic variant and favorable skewing of X-chromosome inactivation [Brady et al 2015].

Sibs of a proband

• Female proband. The risk to sibs of a female proband depends on the genetic status of the mother and father:
  • If the mother is affected and/or heterozygous for the PORCN pathogenic variant, the risk at conception of a sib inheriting the variant is 50%. However, the risk at delivery that a sib will be affected is lower than 50% because nearly all male conceptuses with the variant are presumed to be spontaneously aborted. The expected ratio in live-born sibs is 33% unaffected females, 33% affected females, and 33% unaffected males.
  • If the father has the PORCN pathogenic variant, the risk to female sibs of inheriting the variant at conception is as high as 100% depending on the level of mosaicism in the father's germline. Male sibs are not at risk of inheriting the pathogenic variant from their father.
• Male proband. Because evidence from both molecular studies and clinical reports indicates that nearly all live-born males are mosaic for a postzygotic pathogenic variant, the risk to the sib of an affected male is similar to the population risk for this disorder.

Offspring of proband

• Female proband. The risk to the offspring of females with FDH must take into consideration the presumed lethality to males during gestation.
  • At conception, the risk that the PORCN pathogenic variant will be transmitted is 50%; however, most male conceptuses with the PORCN variant are presumed to be spontaneously aborted. Thus, at delivery the expected ratio of offspring is 33% unaffected females, 33% affected females, and 33% unaffected males.
  • If the affected female is mosaic for a PORCN pathogenic variant, the risk to her offspring is as high as 50%, depending on the level of mosaicism in her germline.
• Male proband. Males with focal dermal hypoplasia have somatic mosaicism for a PORCN pathogenic variant.
  • The risk to an affected male of having an affected daughter is as high as 100% depending on the level of mosaicism in his germline.
  • Males do not transmit their X chromosome to their sons and thus their sons are not at risk of inheriting the PORCN pathogenic variant.

Other family members. If the mother of the proband also has a PORCN pathogenic variant, her female family members may also be at risk of having the pathogenic variant (asymptomatic or symptomatic) and her father may be at risk of being mosaic for the pathogenic variant.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to affected individuals.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the PORCN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for FDH are possible.

Literature Cited

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Author Notes

Dr. Sutton's website

Dr. Van den Veyver's website

Revision History

• 21 July 2016 (bp) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 15 May 2008 (me) Review posted live
• 6 February 2008 (vrs) Original submission