AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Focal dermal hypoplasia (FDH) is an uncommon genetic disorder characterized by distinctive skin abnormalities and a wide variety of defects that affect the eyes; teeth; and skeletal, urinary, gastrointestinal, cardiovascular, and central nervous systems. The mnemonic FOCAL can be used to remember some of the key features of this syndrome: female sex; osteopathia striata; coloboma; absent ectodermis-, mesodermis-, and neurodermis-derived elements; and lobster claw deformity. FDH is also known as Goltz syndrome or Goltz-Gorlin syndrome. These eponyms should not to be confused with Gorlin syndrome or Gorlin-Goltz syndrome, which is basal cell nevus syndrome. FDH is identified as entry 305600 in the Online Mendelian Inheritance of Man database.

Affected individuals are often recognized at birth or occasionally prenatally, but cases involving a minor expression of the syndrome may be diagnosed later in life. The name focal dermal hypoplasia is somewhat of a misnomer because the skin lesions appear to evolve as accumulations of fat rather than hypoplasia of the dermis.

Pathophysiology

The underlying genetic basis for FDH is not clear. Because skin and bone lesions generally follow the lines of Blaschko and the clinical anomalies are consistent with dysplasia of ectodermal, neuroectodermal, endodermal, and mesodermal elements, dermal mosaicism with random X-chromosome inactivation (lyonization) is probable.

On the basis of common findings of syndactyly, oligodactyly, and polydactyly, the fetal expression of FDH is postulated to occur before the eighth week of gestation; by the eighth week, the hands and feet have differentiated and developed separate and elongated digits.

Various in vitro observations of fibroblasts from lesional skin reveal abnormal growth kinetics of fibroblasts (increase in the fibroblast doubling time), abnormal glycosaminoglycan metabolism (decreased accumulation of hyaluronic acid), and an absence of basement membrane type IV collagen. These findings have led to the hypothesis that aberrant dermal fibroblast growth and altered collagen fibers are the bases of the skin defects in FDH. Various loci on the X chromosome and the long arm of chromosome 9 are targeted as possible gene sites; however, no definitive sequences have been identified.

Frequency

United States

FDH is an uncommon disorder.

International

FDH is an uncommon but not rare disorder. Worldwide, 200-300 cases are reported, and new cases continue to be reported. The exact incidence and prevalence are unknown.

Mortality/Morbidity

• A high incidence of miscarriages and stillbirths indicates lethality in utero, particularly in males.
• Severely affected individuals die in infancy, but those with a minor expression can expect to have a normal life span.

Race

Persons of any race can be affected.

Sex

FDH almost exclusively occurs in females. Usually, FDH is lethal in males. (X-linked dominance with male lethality is the favored inheritance pattern; the genetic basis is still unknown.)

Age

This condition is present at birth.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

FDH derives its name from the characteristic skin changes.

• The lesions are present at birth, but they may progress and evolve over time.
• The patient may have a history of skin ulcerations.

Physical

• Skin features
• • Symmetric, linear, reticulated, frequently tender, pink or red, thin skin is characteristic. Involved areas may be angular, atrophic, slightly raised, or depressed macules. The lesions generally follow the lines of Blaschko and can be a few millimeters to several centimeters in width.
  • In pigmented skin, the lesions may be hypopigmented or hyperpigmented instead of erythematous.
  • Telangiectasias are common.
  • Rarely, inflammation is reported with vesicular lesions.
  • The skin lesions may appear anywhere on the body; they are prominent on the legs (especially the thighs), the forearms, and the cheeks (where lines radiate from the angles of the mouth).
  • • In mild cases, FDH involves only limited usually unilateral areas of skin.
    • In severe cases, all areas of the body are involved.
  • The dermis may be replaced by accumulations of adipose cells, which appear as striking hernialike outpouchings of fatty tissue; this feature is unique to FDH.
  • A striking abnormality is the appearance of raspberrylike papillomas.
  • • These papillomas are multiple, arising at junctions between the mucosa and the skin (ie, perioral, perivulvar, perianal, periocular junctions). Less commonly, the ears (pinnae and external auditory canal), fingers and toes, groin, umbilicus, gums, and base of the tongue are involved.
    • Such papillomas may cause obstruction in the larynx, esophagus, and stomach.
    • New papillomas may continue to appear throughout childhood and into adulthood.
    • Not infrequently, these lesions are mistaken for warts.
    • Recently, a case report described lentigolike pigmented macules occurring at the periphery of atrophic skin lesions and periorificial papillomas. These lesions have been described to develop progressively during adolescence and do not follow the lines of Blaschko.
• Adnexal features
• • Adnexal abnormalities, such as apocrine nevi, multiple hydrocystomas, hypohidrosis, and anhidrosis, are occasional features.
  • Scalp and body hair is usually sparse, and the hair may be brittle. Complete absence of hair on the scalp or pubic area is reported. Sparse eyebrows and eyelashes have also been observed.
  • A variety of nail abnormalities occur (such as atrophy, dystropy, spooning, grooving); they often accompany skeletal abnormalities.
• Facial features
• • Asymmetry of the face with mild hemiatrophy may be noted.
  • Sparse eyebrows and eyelashes may be observed.
  • The ears, which are often simple and low set, may protrude. Sometimes, they are asymmetric.
  • A narrow nasal bridge and a broad nasal tip with a unilateral notch of the nasal alae may be present.
  • The chin is commonly pointed.
• Stature
• • Patients are of short stature.
  • Sloping shoulders are observed.
  • Truncal and limb asymmetry are observed.
• Skeletal features
• • Abnormalities are often severe and numerous. The spectrum is variable and ranges from short stature to aplasia of the bones with complete or partial absence of an extremity. 60% of the cases report syndactyly.
  • Split hands and feet, claw hands, clinodactyly, adactyly, polydactyly, oligodactyly, and syndactyly are common.
  • Abnormal vertebrae with kyphoscoliosis, sloped shoulders, abnormal clavicles and ribs, spina bifida occulta, hypoplasia of the pelvic bones, and generalized osteopenia may be present.
  • Multiple bone lesions that resemble giant cell tumors, osteochondromas, and vertebral bone cysts are reported.
  • Osteopathia striata is a radiographic finding commonly seen (approximately 20% cases) in patients with FDH, but it is not a diagnostic feature of FDH (see Imaging Studies).
  • • When osteopathia striata occurs as an isolated finding, with no associations, it is known as Voorhoeve disease. This is an asymptomatic finding that is often an incidental radiologic finding.
    • Osteopathia striata can be associated with other skeletal disorders, such as the autosomal dominant genodermatosis Buschke-Ollendorf syndrome, in which the striations are associated with the mottling of bones (ie, osteopoikilosis). Osteopathia striata can also be associated with bone condensation and osteopetrosis.
• Central nervous system features
• • Mental impairment is not uncommon; however, the severity of the cutaneous lesions is not correlated with central nervous system involvement. Normal mentation is noted in many otherwise severely affected individuals.
  • Diffuse cortical cerebellar atrophy can occur with microcephaly, postencephalitic cysts, and meningomyelocele with congenital hydrocephalus.
  • Seizures are rare.
• Aural features
• • Malformation, protrusion, and asymmetry of the ears may be noted.
  • Auricular appendages and hypoplasia of the helix may be observed.
  • Cholesteatoma may be observed.
  • Neurosensory and conductive hearing loss may be noted.
  • Cochlear dysplasia may be present.
  • Papillomas may be observed.
  • The auditory nerve may be affected.
• Ocular features
• • Ocular abnormalities are present in 40% of cases. Colobomata have been reported in one third of cases, then, less frequently, microphthalmia, strabismus, nystagmus, and ectopia lentis. Other findings reported include the following:
  • • Heterochromia
    • Irregularity of the pupils
    • Aniridia
    • Colobomas of the iris, choroid, retina, or optic disc
    • Corneal defects
    • Cloudiness of the vitreous
    • Blue sclerae
    • Blockage of the tear ducts with tearing
    • Widely spaced eyes
    • Anophthalmia
    • Optic nerve hypoplasia
    • Ectropion
    • Ptosis
    • Photophobia
    • Papillomas at the lid margin or conjunctiva
    • Retinal neovascularization (new finding in Goltz syndrome)
• Oral and dental defects
• • A variety of oral and dental defects include prognathism, overbite, agenesis or dysplasia of the teeth, delayed tooth formation/eruption, microdontia, irregular spacing and malocclusion, enamel defects, and notching of the incisors or extra incisors.
  • Other oral findings include a high arched palate; double lingual frenulum; cleft lip, cleft palate, absence of a labial sulcus, hypertrophy of the gums; taurodontism; and papillomas of the gums, tongue, palate, and buccal mucosa.
• Cardiopulmonary features
• • Anomalous pulmonary venous drainage may be present.
  • Mediastinal dextroposition may be observed.
• Gastrointestinal features
• • Malrotation of the intestine may be observed.
  • Papillomatous lesions of the esophagus can lead to obstruction, gastric polyps, gastric reflux with laxity of the hiatus, diaphragmatic hernia, and omphalocele.
  • Hernias, rectal prolapse, and perianal papillomas may be observed.
• Genitourinary: Abnormalities of the kidneys or ureters (eg, bifid ureter, renal pelvis), horseshoe kidney, and hypoplastic or absent kidney can be present.
• Infection-related features: Recurrent respiratory infections, cellulitis, conjunctivitis, otitis media, and urinary tract infections are reported. These have been secondary consequences of the organ systems affected; no primary regulatory dysfunction of the immune system has been identified.

Causes

The underlying genetic basis for FDH is not clear. Different inheritance patterns are considered: X-linked dominance and autosomal dominance with sex limitation.

• Most cases (approximately 90%) affect females and are lethal in males. This is consistent with an X-linked dominant inheritance pattern. Since the short arm of the X chromosome is prone to terminal deletions that cause X-linked dominantly inherited developmental syndromes, it is thus implicated in this syndrome.
• Molecular genetic investigations have focused on this area. Studies have been conducted to compare FDH with various syndromes with similar inheritance patterns and phenotypic findings.
• • FDH, microphthalmia with linear skin defect (MLS) syndrome (also known as microphthalmia, dermal aplasia, and sclerocornea syndrome [MIDAS]), and Aicardi syndromes share similar patterns of X-linked, male, lethal inheritance.
  • These 3 syndromes share phenotypic abnormalities such as microphthalmia and atrophic skin lesions.
  • These syndromes are postulated to be linked, and they may be caused by involvement of the same genes with different patterns of X inactivation.
  • Findings of molecular genetic analysis do not support this hypothesis; the syndromes do not share contiguous loci.
  • Deletions of the genes involving the Xp22 regions have been demonstrated in patients with MLS syndrome, but these deletions have never been observed in FDH.
  • Preliminary results indicate that the Aicardi and MLS syndromes are caused by neighboring genes; therefore, a contiguous gene syndrome may be present.
  • Many investigators believe that the gene responsible for FDH will be found at an X-linked locus distant from band Xp22.3.
• To account for the approximately 10% cases that occur in male patients, autosomal dominance with sex limitations is considered. The 9q31 locus is implicated for the autosomal dominant inheritance pattern with sex limitation. Family pedigree analysis has revealed the presence of this deletion in affected males, who are always the first affected patients in their pedigree.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Incontinentia pigmenti (Bloch-Sulzberger syndrome)

Initially, a number of FDH cases were reported as variants of incontinentia pigmenti because of the marked predilection for females with probable male mortality in utero, the linear nature of the skin lesions that follow the Blaschko lines, and an initial inflammatory phase.

As more cases of FDH were reported, the 2 syndromes were noted to be distinct. The clinical history of incontinentia pigmenti includes cutaneous vesiculation and verrucous lesions with persistent whorled hyperpigmentation, which differ from the red linear atrophic areas of FDH. The histopathologic findings of incontinentia pigmenti are highly characteristic in the early vesicular and verrucous phases. Eye abnormalities characteristically involve the posterior chamber, with microphthalmos as the late end-stage result. In addition, a higher proportion of patients have convulsions and neurologic deficits in incontinentia pigmenti than in FDH. Incontinentia pigmenti is caused by mutations in the gene NEMO/IKK-gamma on chromosome Xq28.

Aicardi syndrome (MIM 304050)

Aicardi syndrome is an X-linked dominant condition. Mild skin involvement is noted on the head and neck and, sometimes shoulders, chest, and limbs. Microphthalmia, corneal opacity, and agenesis of the corpus callosum are observed.

MIDAS syndrome (MIM 309801)

Microphthalmia, dermal hypoplasia, and aplasia may be confined to the head and neck, and sclerocornea. Microphthalmia occurs with linear skin defects in individuals with distal Xp segmental monosomy. The phenotype overlaps with those of both Aicardi syndrome and FDH.

Delleman syndrome (oculocerebrocutaneous syndrome)

This syndrome is characterized by orbital cysts of microphthalmia, cerebral malformations, and FDH (rare).

Goldenhar syndrome

This syndrome is associated with the first and second branchial syndrome. Hemifacial hypoplasia, ocular, oral, aural, and vertebral malformations are observed. Cardiac anomalies and frequent mental deficiencies are observed.

Proteus syndrome

Patchy dermal hypoplasia may be seen in the other numerous features of this syndrome. The hallmark of Proteus syndrome is hemihypertrophy, cerebriform plantar lesions, and macrodactyly.

Deletion of band Xp22.2

Cases in 4 patients are described. This condition involves microphthalmos, normal intelligence, and acute weeping linear skin lesions of the face and neck that heal to become hyperpigmented streaks. The hair, teeth, and skeletal system in these patients were normal, except for the occasional finding of mild soft-tissue syndactyly. All probands have a deletion of the short arm of the X chromosome that involves band Xp22.2.

Adams-Oliver syndrome

Adams-Oliver syndrome is an autosomal dominant condition that involves an association of scalp and skull bone aplasias with distal limb reductions. The skin and eyes are normal. This condition is often associated with cutis marmorata telangiectasia congenita.

Nevus lipomatosus superficialis (Hoffmann-Zurhalle syndrome)

Nevus lipomatosus superficialis is a developmental anomaly of the skin that involves localized groups of soft fleshy nodules, most commonly on the lower trunk; these nodules are generally present at birth. Histologically, the lipomatous nodules of FDH are similar; but in the lesions of FDH, the collagen is more attenuated. Furthermore, the clinical presentation assists in the differentiation because the other characteristic abnormalities in FDH are not present in nevus lipomatosus superficialis.

Aplasia cutis congenita

In aplasia cutis congenita, areas of the skin are absent at birth, but none of the other findings of FDH occur.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Imaging Studies

• Radiography may reveal osteopathia striata.
• • Osteopathia striata consists of longitudinal striations in the metaphyses of the bones.
  • The lesions are usually bilateral and symmetric, mainly involving the long bones and the sacral bone. In contrast, the vertebrae and iliac bones are typically spared.
  • Osteopathia striata is an idiopathic finding, which radiographically is manifested by linear vertical opacities that originate at an articular surface and extend into the diaphysis, where they gradually narrow and disappear.
  • The thickened striations of lamellar bone are parallel to the axis of the long bones.
  • The shape, density, and cortex of the affected bones are normal.
  • Osteopathia striata is commonly (approximately 20% cases) seen in patients with FDH; however, it is not a specific diagnostic feature of FDH.
  • When osteopathia striata occurs as an isolated finding, with no associations, it is known as Voorhoeve disease. This is an asymptomatic finding that is often an incidental radiologic finding.
  • The radiographic diagnosis of osteopathia striata is a useful clue in individuals who have minimal phenotypic disease. A careful clinical history taking and dermatologic examination may lead to the diagnosis of FDH.
• Prenatal ultrasonographic findings are variable. Imaging studies may reveal findings that range from nonspecific fetal growth delay to specific organ and/or developmental anomalies; all findings are contingent on the degree to which an individual is affected.

Other Tests

• Parents and siblings of patients with new, apparently sporadic cases of FDH should be closely examined for subtle skin findings or other abnormalities. Prenatal testing/karyotype analysis is not available since the genetic defect is unknown.

Procedures

• Biopsy of the skin may be performed.

Histologic Findings

The atrophic reticulated patches of skin reveal attenuation of dermal collagen fibers with partial-to-complete absence of significant portions of the dermis. An accompanying change is the appearance of adipose cells in the dermis. In mild cases, adipocytes may be noted only around blood vessels; in severe cases, they may replace all or part of the dermal connective tissue. A layered effect sometimes occurs, with attenuated collagenous connective tissue lying both above and beneath an adipose layer. If the accumulation of adipose tissue is pronounced, it may cause the apparent herniation of subcutaneous tissue through the thinned skin.

The papillomatous lesions typically consist of a fibrovascular stalk composed of loose connective tissue with dilated vessels and a variable perivascular admixture of inflammatory cells.

The lentigolike pigmented macule lesions describe increased amounts of melanin deposition in the basal epidermal keratinocytes, with an underlying mild dermal infiltrate of lymphocytes with numerous dermal melanophages.

TREATMENT

Section 6 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Regular surveillance, with frequency increased as needed during and after adolescence, facilitates early detection of anomalies and timely preventative and/or corrective treatment planning.

• Medical management is targeted toward the various soft-tissue, dental, and skeletal anomalies, with the goal of achieving optimal functional and aesthetic results.
• Treatment with a flashlamp-pumped pulse dye laser may ameliorate the pruritic symptoms that sometimes are noted in affected skin and improve the clinical appearance of the telangiectatic and erythematous skin lesions.

Surgical Care

• Surgical management is targeted toward the various soft-tissue, dental, and skeletal anomalies, with the goal of achieving optimal functional and aesthetic results.
• Periorificial fibrovascular papillomas may continue to appear during adulthood; these papillomas require repeated surgical intervention.

FOLLOW-UP

Section 7 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• The presence of fibrovascular papillomas around, near, or within body orifices may result in functional or aesthetic problems. Large perianal papillomas may cause difficulties in defecation and hygiene. Rarely, papillomas in the esophagus or stomach wall cause obstruction.
• Perioral and genital papillomas can be mistaken for viral warts and inappropriately managed.

Prognosis

• Most of the numerous organ abnormalities in the syndrome are present at birth and remain essentially unchanged thereafter.
• The morbidity and mortality depend on what organ systems are affected.
• In the skin, an initial inflammatory stage may occur, but this usually subsides in the first few months after birth.
• Older patients complain that the atrophic skin lesions are tender and sore.
• Periorificial fibrovascular papillomas may continue to appear during adulthood; these papillomas require repeated surgical intervention.

MISCELLANEOUS

Section 8 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• No potential teratogenic exposures (medicinal or environmental) have been associated with the development of FDH.

MULTIMEDIA

Section 9 of 10  

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• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Typical facial features are asymmetry of the face with mild hemiatrophy, low-set protruding ears, a narrow nasal bridge, a broad nasal tip with unilateral notch of the sal alae, and a pointed chin. Also note the reticular hyperpigmentation of the skin, sparse hair, and raspberrylike papillomas on the lips.
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Media file 2:  Photograph shows characteristic linear, erythematous, raised and depressed macules that follow the lines of Blaschko. Also note oligodactyly of the hand (entire rays are absent).
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Media file 3:  Photomicrograph shows the histopathologic findings in a skin biopsy sample. The image depicts the characteristic absence of dermal collagen and the accompanying appearance of adipose tissue in the dermis.
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Media file 4:  Characteristic lobster claw deformity.
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Media file 5:  Syndactyly.
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Media file 6:  Image shows oligodactyly of the feet. Also note the reticular erythematous hyperpigmentation on the limbs.
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Media file 7:  Characteristic lesions that follow the lines of Blaschko.
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Media file 8:  Hyperpigmentation that follows the lines of Blaschko on the upper extremity.
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Media file 9:  Slightly raised and pigmented macules and soft tumors are noted on this extremity.
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Media file 10:  Close-up view of reticulate, mildly atrophic, erythematous macules and soft, rounded nodules.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Feb 16, 2006