Focal dermal hypoplasia (ORPHA:2092)
A rare multiple congenital anomalies/dysmorphic syndrome characterized by abnormalities in ectodermal- and mesodermal-derived tissues, classically manifesting with skin abnormalities, limb defects, ocular malformations, and mild facial dysmorphism.
Epidemiology
The exact prevalence of focal dermal hypoplasia (FDH) is unknown. To date, around 300 cases have been reported in the literature. Female to male ratio is 9:1, with no racial or ethnic predilection.
Clinical description
FDH usually manifests in the neonatal period and characteristic skin findings include congenital patchy skin hypoplasia, nodular, subcutaneous fat herniation, hyper/hypo-pigmentation in Blaschko linear distribution, telangiectasia and ridged, dysplastic or hypoplastic nails. Sparse hair/alopecia and later-onset, verrucoid, periorificial, skin and mucous membrane papillomas are also frequently associated. Characteristic limb malformations include ectrodactyly, syndactyly, oligodactyly and marked long bone reduction, as well as occasionally observed costovertebral abnormalities (e.g. fused or bifid ribs, hemi- or butterfly vertebrae), which may lead to kyphosis/kyphoscoliosis. Typical ocular abnormalities include congenital microphtalmia (occasionally anophtalmia), cataracts and iris and chorioretinal colobomas. Dental abnormalities are also frequently observed and include enamel defects, as well as abnormal number and form of the primary and secondary dentition. Craniofacial dysmorphism, including facial asymmetry, notched nasal alae, small, underfolded pinnae and a pointed chin, may be associated. Other system abnormalities, such as genital labial hypoplasia, abdominal wall defects, and, occasionally, malrotation of the gut may be additional features.
Etiology
FDH is caused by mutations in the PORCN gene (Xp11.23), which encodes the porcupine O-acyltransferase, involved in the secretion and signaling of WNT proteins, important for embryonic tissue development. Different types of PORCN mutations, including nonsense, missense, and frameshift mutations, as well as partial- or whole-gene deletions, have been described. In familial cases, affected parents usually display a milder form of FDH.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical findings and is confirmed or established, in cases of inconclusive clinical presentation, by molecular genetic testing which reveals a pathogenic variant in the PORCN gene.
Differential diagnosis
Differential diagnoses should include microphtalmia with linear skin defects (MLS) and incontinentia pigmenti (IP), as well as oculocerebrocutaneous syndrome and Rothmund-Thompson syndrome.
Antenatal diagnosis
Prenatal testing for at-risk pregnancies is possible when a mutation has been previously identified in the family.
Genetic counseling
FDH follows an X-linked dominant pattern of inheritance and is usually lethal in utero in hemizygous, non-mosaic male fetuses. Approximately 95% of females with FDH have a de novo PORCN pathogenic variant and only 5% inherit it from a parent. Live-born affected males are rare (about 10% of FDH cases) and are nearly always mosaic for a de novo postzygotic mutation. Genetic counseling should be offered to affected females informing them of the 33% risk of giving birth to an affected daughter, an unaffected son, or and unaffected daughter.
Management and treatment
Treatment is symptomatic and involves dermatological, orthopedic, ophthalmologic and dental care. Verrucous papillomas may require surgical intervention.
Prognosis
Prognosis is variable depending on severity on manifestations. Individuals with severe forms of the syndrome usually die during infancy, however, a normal life expectancy may be reached in patients with less severe findings.

                            Last update: 
                            April 2019


                            - Expert reviewer(s): 
                            Dr Maria Paola LOMBARDI