Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Focal dermal hypoplasia (FDH) is a rare congenital disorder characterized by dysplasia of the ectodermal- and mesodermal-derived structures. Many features are evident at birth, thus a patient history is not usually a vital part of the evaluation. A patient may complain of pain or pruritus associated with their skin lesions. Other portions of the presenting history depend on the organ systems involved and the degree of involvement. Areas of skin involvement may be painful and/or pruritic in some patients. A female patient may have an affected mother.

  • Characteristic findings on physical examination

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Abnormalities in FDH may occur in multiple organ systems; however, those that are most commonly affected are the skin and skeletal systems. The ocular, dental, and central nervous systems are also routinely affected. Abnormalities of the skin that may be seen on physical exam are areas of linear atrophy and hypo- or hyper-pigmentation along the lines of Blaschko (Figure 1).

Figure 1.

Hyperpigmentation seen along the lines of Blashko.

This may result in skin depression or fat herniation in those areas, which are evident as soft compressible flesh-colored papules or nodules. Early in life, these lesions along the lines of Blaschko may be more inflammatory and consist of blisters, erythema, erosions, and ulcers (Figure 2). These skin lesions may occur anywhere on the body.

Figure 2.

Erythema and erosions.

Patients may develop raspberry-like papillomas at mucocutaneous junctions that may erode, ulcerate, and bleed. Some may interfere with breathing or swallowing, if present in the aerodigestive tract. Those present in the genital or perianal areas may be mistaken for genital warts. Dysplastic or hypoplastic nails, partial or complete body and/or scalp alopecia, telangiectasias, and aplasia cutis have also been seen in FDH.

Approximately 80% of patients with FDH also have skeletal abnormalities. These can be varied in nature but those evident on physical exam may include syndactyly, polydactyly, oligodactyly, hypoplasia of the digits, and scoliosis. “Lobster-claw” deformity is a rare skeletal feature (Figure 3).

Figure 3.

The “lobster claw” deformity is a rarely seen finding.

Orofacial manifestations of FDH may be quite varied and are present in approximately half of all patients. Hypodontia, microdontia, malocclusion, high-arched palate, and cleft lip or palate may be seen on physical examination. There may also be facial asymmetry, notching of the nasal alae, pointed chin, and small ears (Figure 4).

Figure 4.

Small, slightly malformed ears.

  • Expected results of diagnostic studies

Genetic testing is available for FDH. PORCN is the only gene known to cause FDH, and more than 20 different mutations have been described. Females may be heterozygous for a PORCN mutation or have somatic mosaicism. Affected male patients have somatic mosaicism for a PORCN mutation.

Prevalence of identifiable PORCN mutations among those with FDH range from 80-100%. Available molecular genetic testing for FDH is by sequence analysis or deletion analysis using fluorescence in situ hybridization (FISH) or array-based genomic hybridization (GH). It is recommended that in female patients, the sequence analysis should be used. If there is a known disease-causing mutation in a family, then prenatal testing may be done via chorionic villous sampling or amniocentesis.

Osteopathia striata, or a striated appearance of the tubular bones, are characteristic of FDH. This can be seen with plain radiographic imaging (Figure 5).

Figure 5.

Osteopathic Striata

Histopathology (Figure 6) may also be used to support the diagnosis of FDH. Findings usually consist of a normal epidermis and a hypoplastic dermis with little to no dermal collagen. In addition, a narrow strand of dermis may be seen along the dermal-epidermal junction and in the peri-appendageal areas. Ulceration may be present in areas without dermis. Islands of adipose cells within the superficial dermis that impinge upon the epidermis are seen in biopsies taken from the areas of fatty tissue herniation.

Figure 6.

Hypoplastic dermis with adipose cells within the superficial dermis.

  • Diagnosis confirmation

FDH is a fairly unusual disease; however, several other disorders may be considered, particularly in cases of milder phenotypes. Microphthalmia with linear skin defects (MLS) can have similar skin and eye findings, however, skeletal abnormalities and malformations are uncommon.

Incontinentia pigmenti (IP) is an X-linked dominant condition that can have similar skin, eye, and nail changes, but skin lesions of FDH are more atrophic than those of IP. In addition, skin histopathology in IP tends to be more vesicular or verrucous. Nevus lipomatosus superficialis presents with areas of fatty herniation at birth, but lacks the other findings seen in FDH. Aicardi syndrome is also an X-linked dominant condition with agenesis of the corpus callosum, early-onset seizures, and eye changes. It lacks the other findings that are seen in FDH.

Who is at Risk for Developing this Disease?

FDH is a rare genetic disease inherited in an X-linked dominant fashion, with approximately 300 cases reported worldwide. Incidence or prevalence is unknown. It is lethal in males except in cases of post-zygotic mosaicism. Approximately 90% of all affected patients are female; however, that may be an underestimation due to relative over-reporting of males with the disease. The degree of expression of the disease is variable; however, females are generally more affected than males.

Girls born to a mother with FDH have a 50% risk of inheriting the disease if the mother’s mutation is not mosaic. Male fetuses with the mutant allele are usually spontaneously aborted. In the case of mosaic mutations in the mother, the risk is up to 50% for all offspring, depending on the level of mosaicism.

Girls born to a father with FDH have up to a 100% risk of inheriting the disease, depending on the level of mosaicism. Males born to a father with FDH are unaffected, as the X chromosome is not transmitted.

What is the Cause of the Disease?

  • Etiology

FDH is caused by heterozygous or mosaic mutations in the PORCN gene, which is located on the X chromosome. Greater than 20 mutations have been identified thus far.

  • Pathophysiology

The PORCN gene is a regulator of Wnt signaling. The Wnt pathway is involved in the regulation of embryologic development.

Systemic Implications and Complications

FDH is a multisystem genetic disorder, and while the skin is the most commonly involved organ system, many others may be involved. Workup and management should be guided by the type and extent of involvement.

Features evident on the skin are outlined in the physical exam section. At times, patients may have accompanying pruritus within their skin lesions. Topical steroids may be used to decrease inflammation and pruritus. A flashlamp-pumped pulsed dye laser has also been used to flatten lesions and thus control pruritus and erythema. Cryotherapy has been used to flatten lesions and thus control pruritus and erythema. Cryotherapy has been used to treat trunk and extremity papillomas.

Reconstructive surgical therapy may also be considered, particularly for lesions in cosmetically-sensitive areas.

Multiple different skeletal abnormalities have been seen with FDH. These include syndactyly, oligodactyly, lobster claw deformity, costovertebral segmentation abnormalities, kyphoscoliosis, fibrous dysplasia of the bone, and giant cell tumors of the bone. Costovertebral abnormalities and giant cell tumors of the bone should be evaluated by radiographic imaging. Osteopathia striata, which may be seen in up to 20% of patients with FDH, can also be seen with radiographic imaging. Referral to an orthopedic surgeon for management and possible surgical intervention of skeletal findings is indicated.

Oral manifestations may be seen in approximately half of patients with FDH. These may include cleft lip or palate, problems with tooth eruption and position, abnormal number of teeth, tooth ridging, and microdontia. Those with cleft lip and/or palate should be referred to a plastic surgeon and all patients should regularly see a dentist.

Developmental abnormalities of the eyes may be seen at birth in approximately 40% of patients. Reported eye abnormalities in those with FDH are anophthalmia or microphthalmia, microcornea, coloboma, lacrimal duct abnormalities, cataracts, and strabismus, amongst many others. All patients with FDH should be referred to an ophthalmologist.

Neurologic involvement may manifest as intellectual impairment, cortical atrophy, or seizures. These patients should be referred to a neurologist. Ear involvement may also be present–malformation of the ears, conductive or sensorineural hearing loss, cholesteatoma, and cochlear dysplasia. Appropriate referral to an otolaryngologist should be made in those cases.

Some patients may have gastrointestinal involvement, with abdominal wall defects, diaphragmatic hernia, or severe gastroesophageal reflux due to laryngeal papillomas. Patients have also been reported to have absent or horseshoe kidneys. These patients should be referred to a gastroenterologist or a nephrologist, respectively.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Medical Topical triamcinolone creamTopical clobetasol creamOral antihistaminesGenetic counseling
Surgical ExcisionOther surgical options as indicated:Plastic surgeryOrthopedic surgeryDental surgeryOtolaryngeal surgery
Physical CryotherapyPulsed dye laser

All need Ophthalmology, Urology, Genetic, Neurology, and Gastroenterology exams

Optimal Therapeutic Approach for this Disease

There is no cure for FDH, and treatment is supportive. The therapeutic approach should be tailored based upon evident signs and symptoms. From a skin perspective, one of the more common complaints will be that of pruritus. First-line treatment for pruritus should be topical steroids appropriate for the location of involvement.

For body involvement, it is reasonable to start with topical triamcinolone 0.1% cream. If this is not beneficial within several weeks, the strength of the topical steroids can be increased. Less potent topical corticosteroids, such as desonide 0.05% cream, should be used for the face or groin.

Oral antihistamines may also be used to control symptoms of pruritus. For sedating antihistamines, hydroxyzine 25-50mg by mouth up to 4 times daily may be used. If this is not beneficial, doxepin, starting at a dose of 10mg nightly, may be initiated. The dose may be increased if desired. For non-sedating antihistamines, cetirizine, 10mg daily; loratadine, 10mg daily; or fexofenadine, 180mg daily may be used.

If a patient complains of erythema, pulsed dye laser can be used. Settings are dependent on the area being treated but it is reasonable to use settings consistent with those used to treat telangiectasias. Papillomas present at mucocutaneous junctions may be treated first line with cryotherapy. If this is not beneficial, they can be surgically excised.

All other surgical therapies should be guided by the type of systemic involvement and the resulting symptoms.

All patients with FDH should be referred for genetic counseling.

Patient Management

Patients should have at least yearly follow-up with a dermatologist for skin surveillance and management of skin problems. Patients should also have regular follow-up with their primary care provider and, depending on which organ systems are involved, routine follow-up with other subspecialists.

At routine visits, the patient should be questioned about gastroesophageal reflux and swallowing problems. If these are present, the patient should be referred to an otolaryngologist for management as indicated. Those with skeletal abnormalities should be evaluated with routine physical exams and radiographs.

Unusual Clinical Scenarios to Consider in Patient Management

FDH is unusual in males, given the X-linked dominant inheritance. Such cases, however, do exist because of mosaicism, and the diagnosis must be considered in males when clinical features are apparent.

What is the Evidence?

Goltz, RW. “Focal dermal hypoplasia syndrome: an update”. Arch Dermatol. vol. 128. 1992. pp. 1108-11. (One of the original descriptors gives an update on the syndrome regarding mode of inheritance, histopathologic findings, and new clinical findings. The hypothesis of lyonization is discussed, as is the possibility that it may be a progressive disorder. New clinical findings such as aplasia cutis, apocrine gland abnormalities, papillomas, giant cell tumors of the bone, anomalies of the eye, and anomalies of the urinary tract are discussed.)

Maymi, MA, Martin Garcia, RF. “Focal dermal hypoplasia with unusual cutaneous features”. Pediatr Dermatol. vol. 24. 2007. pp. 387-90. (The authors describe less common features associated with FDH. They present a newborn girl with inflammatory lesions, incomplete cleft lip and palate, notching of the nasal ala, pointed chin, and low-set ears.)

Seoane, J, Gibson, RL, Almagro, M, Pintos, E. “Oral manifestations associated with focal dermal hypoplasia”. Dermatol. vol. 219. 2009. pp. 368-70. (The authors present the case of a 15-year-old girl with focal dermal hypoplasia, and describe associated oral manifestations. Specific oral manifestions mentioned are hypodontia, microdontia, irregular spacing and malocclusion, enamel defects, high arched palate, cleft lip and palate, and mucocutaneous papillomas.)

Sutton, VR, Van den Veyver, IB. “Focal dermal hypoplasia”. National Center for Biotechnology Information (NCBI) Bookshelf. 2008. (This is a National Institutes of Health publication in which the authors review the literature regarding FDH. Clinical diagnosis, genetic testing, clinical description, systemic findings, differential diagnosis, management, and genetic counseling are discussed and up-to-date data are presented.)

Tollefson, MM, McEvoy, MT. “Goltz syndrome in a moderately affected newborn boy”. Int J Dermatol. vol. 48. 2009. pp. 1116-8. (The authors present the case of a male newborn with FDH and review the syndrome, clinical findings, histopathologic findings, pathogenesis, and treatment.)

Van den Veyver, IB. “Microphthalmia with linear skin defects (MLS), Aicardi, and Goltz syndromes: are they related X-linked dominant male-lethal disorders?”. Cytogen Genome Res. vol. 99. 2002. pp. 289-96. (Three X-linked dominant disorders [MILS, Aicardi, and Goltz syndrome] are reviewed. Clinical findings are reviewed, and similarities and differences of all three phenotypes are discussed. While the disorders have some similarities, they are distinct disorders.)

Wang, X, Sutton, VR, Peraza-Llanes, O, Yu, Z, Rosetta, R, Kou, YC. “Mutations in X-linked PORCN,a putative regulator of Wnt signaling, cause focal dermal hypoplasia”. Nat Genet. vol. 39. 2007. pp. 836-8. (The authors present a novel mutation identified in two female patients with FDH. Comparative genomic hybridization was used to identify the deletion, and gene sequencing found similar heterozygous and mosaic mutations in other affected patients.)

Peters, T, Perrier, R, Haber, RM. “Focal dermal hypoplasia: report of a case with myelomeningocele, Arnold-Chiari malformation and hydrocephalus with a review of neurologic manifestations of Goltz syndrome”. Pediatr Dermatol. vol. 31. 2014. pp. 220-224.