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.
Affected Females
Ectodermal manifestations. The most characteristic features of focal dermal hypoplasia are the skin manifestations (). 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 ( and ) [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 () [Gorlin et al 1963, Goltz et al 1970].
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.