Focal Dermal Hypoplasia
DISEASE CARD
| Disease group | FOCAL DERMAL HYPOPLASIA |
|---|---|
| DISEASE NAME | FOCAL DERMAL HYPOPLASIA |
| Synonymous | Goltz Syndrome |
| Estimated prevalence | - |
| OMIM | 305600 |
| Inheritance | X-linked Dominant |
| Gene (s) | PORCN (300651) |
Definition
Focal Dermal hypoplasia (FDH) is a rare X-linked dominant ecto-mesodermal disorder. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic / atrophic dermis with nodular lipomatous lesions and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene. 90% of affected individuals are female, because this disease is lethal in hemizygous males and males only survive in case of a somatic mosaicism (10%).1
Clinical Description
The skin signs are the key presenting features, and are present in nearly all patients at birth. Linear streaks of hypo- or hyperpigmentation and/or teleangiectasias are typical. Those lesions can be slightly raised or depressed and initially (in the first 6 months of life) may show signs of inflammation (oedema, blistering, scaling, crusting), similar to the lesions in incontinentia pigmenti. Development of depressed linear streaks (red, brown, white or pink) due to dermal atrophy (focal lack of dermis) is a classical feature, often occurring along Blaschko's lines. Fat nodules or lipomatous lesions - initially referred to as fat herniations - are further typical skin signs. They are usually yellow to brown colored and may be present at birth. During childhood they tend to increase in size and number. Xerosis cutis, poikiloderma, (verrucoid) papillomas around mouth, eyes and genital area as well as aplasia cutis congenita are further cutaneous features. Hypoplasia of the labia minora as well as vulvar papillomas have been observed females.2
Skeletal pathologies mainly affect hands and feet in an asymmetrical pattern. Digital deformities, such as syndactyly, ectrodactyly or polydactyly are frequently seen. Some affected individuals develop striated areas of reduced bone density, which is visible on X-rays of long bones (osteopathia striata). Other findings include scoliosis, spina bifida (occulta), deformities of ribs/clavicles, ospeoporosis and cystic bone lesions or tumours. Bony tumours, including osteoclastomas, are usually not malignant, but can grow locally invasive and may result in pathological fractures.3
Involvement of other ectodermal structures is common. Dystrophic nails, sparse wiry hair and a variety of dental (e.g. notched incisors, longitudinal grooving, enamel defects, anodontia, delayed eruption) and ocular abnormalities (e.g. chorioretinal colobomas, microphthalmia, microcornea, anophthalmia, iris colobomas) can occur. Facial asymmetry or broad nasal tip, pointed chin and maxillary hypoplasia is frequently present. Ear malformations, together with hearing problems have been reported. Intellectual disability of varying severity is present in about 15% of affected individuals. CNS anomalies as well as respiratory, genitourinary, cardiovascular and digestive tract abnormalities have been reported.3-6
Significant clinical variability exists depending on the degree of lionization (in females) and somatic mosaicism (in males). Mild cases may remain unrecognized whereas most severe forms may not be compatible with life.
Pathogenesis
In 2007, mutations in the PORCN gene were identified as the molecular basis of FDH. PORCN (human porcupine locus MG61/PORC) is a member of the porcupine (porc) gene family and is located on chromosome Xp11.23. The gene is thought to encode an O-acyltransferase that catalyses cysteine N-palmitoylation and serine O-acylation in the endoplasmic reticulum, which allows membrane targeting and secretion of several Wnt proteins that have key roles in embryonic tissue development. However, further research is required to elucidate the underlying pathogenic mechanism of this pleiotropic disease. 1, 7-9
Diagnosis
Diagnosis is usually made by assessment of the clinical features (skin and skeletal findings) either at, or soon after birth. In those individuals who have milder phenotypic features, the diagnosis may become evident when hair, teeth or nails fail to develop normally. Genetic testing of the PORCN gene is recommended to confirm the diagnosis. Histopathologic features usually show dermal hypoplasia or fat herniation, although an absence of those features does not exclude the diagnosis. Decrease and fragmentation of elastic fibres of the upper dermis has also been described.10
Treatment
Management depends on the clinical severity of each affected individual. Those with milder phenotypes and only cutaneous features may profit from topical emollients to manage erosive or pruritic lesions as well as laser therapy for papillomatous lesions that can also occur enoral, oesophageal or laryngeal. However, those with (extensive) systemic abnormalities will require a multidisciplinary approach that includes dermatology, orthopaedic, opththalmology, otorhinolaryngology and plastic surgery as well as further specialists depending on the individual manifestations. Frequently, surgical procedures are necessary to correct limb, teeth, eye and ear defects. Many individuals require successive dentures as a child with addition of dental implants and bridges later in adult life.