Focal Dermal Hypoplasia

Disease Overview

Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is a rare multisystem disorder that principally involves the development of the skin, hands and feet and eyes. It is a type of ectodermal dysplasia, a group of heritable disorders causing the hair, teeth, nails and glands to develop and function abnormally. Most of the cases of FDH (about 90 percent) are seen in females. This disorder is characterized by skin abnormalities that develop into streaks or lines of tumor-like lumps on various parts of the body. This syndrome displays a wide array of symptoms and may affect almost any organ. FDH is caused by changes (variants or mutations) or duplications/deletions in the PORCN gene.

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Synonyms

• combined mesoectodermal dysplasia
• DHOF
• ectodermal and mesodermal dysplasia, congenital
• ectodermal and mesodermal dysplasia with osseous involvement
• FDH
• focal dermal dysplasia syndrome
• focal dermato-phalangeal dysplasia
• FODH
• Goltz-Gorlin Syndrome
• Goltz Syndrome

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Signs & Symptoms

An extremely wide range of symptoms characterizes FDH.

FDH is a rare disorder that primarily affects females and has extreme variability. It is characterized by skin lesions that look streaked, underdeveloped or “punched-out”, birth defects of the hands and feet and birth defects of the eyes. There may be inflammation, itching, reddening, blistering and crusting of the skin. Skin may be thinned, discolored or lack color (pigmentation) in some areas. The nails may be absent or appear abnormal. Enlargement of capillaries/veins under the skin (telangectasias) often develop with age. Wart-like growth (papillomas) are usually not present at birth but develop with age and are typically found on the gums, tongue, lips, nose, genetalia and anus. All individuals with focal dermal hypoplasia have at least a few of the skin abnormalities. The hair may be sparse, brittle and/or missing.

Eye differences are common and are present at birth and can include drooping eyelids (ptosis); clouding of the cornea; a cleft or keyhole-shaped defect in the iris or the retina (colobmas); small or missing eye (microphthalmia/anophthalmia); wide spacing between the eyes (hypertelorism); crossed eyes (strabismus) and/or exposure of the lining of the eyelid (ectropion).

Individuals with FDH may also have a variety of skeletal abnormalities, some of which may be present at birth. Curvature of the spine (scoliosis), fused vertebrae, underdeveloped or missing fingers or toes, extra fingers or toes (polydactyly), fingers or toes that have grown together (syndactyly), fingers that bend to the side (clinodactyly), permanently bent fingers (camptodactyly) and/or fusion of bones of the fingers and toes may be present. Other malformations of the skeleton may include a small skull, an underdeveloped jaw, a forward projection of the jaw, and/or uneven development of the face, limbs or trunk. Cleft lip and palate may be present and may cause feeding, breathing and vision problems.

Problems within the mouth are seen in more than 50 percent of patients affected. Failure of the teeth to develop properly often occurs in these patients. The teeth may be missing or underdeveloped and are unusually small or improperly spaced. Missing enamel may result in the development of cavities.

Abnormalities of the ears, the eyes, the heart, central nervous system, gastrointestinal system and the kidneys may also be present. Abnormalities within the gastrointestinal system may lead to problems with breathing and feeding. Intellectual disability can be found in some patients. Most patients with FDH are noted to be small at birth and have mild short stature.

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Causes

FDH is caused by changes (variants or mutations) in the PORCN gene that creates proteins important in the development of the skin, skeleton and eyes in a developing embryo and fetus. Recent studies of patients with symptoms consistent with FDH have found genetic changes in the PORCN gene in nearly all affected females.

The PORCN gene is found on the X chromosome and the syndrome is inherited in an X-linked dominant pattern. X-linked dominant disorders are caused by an abnormal gene on the X chromosome and occur mostly in females. Females with these rare conditions are affected when they have an X chromosome with the gene for a particular disease. Males with an abnormal gene for an X-linked dominant disorder are more severely affected than females and often do not survive. Living males with FDH are “mosaic” for a change in the PORCN gene. This means that the change is seen in some, but not all, of the cells in their body.

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Affected populations

Prevalence estimates are not available for FDH. Approximately 200 to 300 affected individuals have been reported worldwide, and only about 10 percent are live born males.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of focal dermal hypoplasia. Comparisons may be useful for a differential diagnosis:

Ectodermal dysplasias are a group of hereditary, non-progressive skin diseases in which the affected tissue derives primarily from the ectodermal germ layer. The skin, its derivatives, and some other organs are involved. Symptoms may include eczema, poorly functioning sweat glands, sparse or absent hair, abnormal hair, disfigured nails and difficulty with the nasal passages and ear canals. (For more information on these disorders, choose “ectodermal dysplasias” as your search term in the Rare Disease Database.)

Microphthalmia with linear skin defects (MLS) is associated with similar skin and eye abnormalities as is seen in focal dermal hypoplasia. However, limb and skeletal abnormalities are uncommon in MLS.

Incontinentia pigmenti (IP) is a rare genetic dermatological disorder affecting the skin, hair, teeth, nails, eyes and central nervous system. It is inherited in an X-linked dominant pattern. IP is characterized by four stages, some of which may overlap. The first stage may be present at birth or appear in early infancy and consists of redness or inflammation of the skin. This irritation includes the scalp as well as the extremities and can last from a few weeks to several months. In the second stage, blisters develop into a raised, wart-like appearance with lesions that look like pustules. The extremities are involved almost exclusively in this stage, which may last for several months but rarely as long as a year. In the third phase, the skin darkens in a swirled pattern sometimes described as a “marble cake” appearance. This phase occurs from approximately 6 months into adulthood. The fourth stage is called the “atrophic” stage. Pale, hairless patches in addition to abnormal tooth shape and nails appear among adolescent and adult patients. The skin changes may fade later in life. (For more information on this disorder, choose “incontinentia pigmenti” as your search term in the Rare Disease Database.)

Rothmund-Thomson syndrome (RTS) is a multisystem disorder characterized by skin abnormalities, sparse hair, eyelashes, and/or eyebrows, small stature, skeletal and dental abnormalities, cataracts, and an increased risk for cancer, mainly osteosarcoma. The skin typically presents normally at birth, however, the rash of RTS develops between the ages of three and six months as redness (erythema), swelling, and blistering of the face and subsequently spreads to the extremities. The rash typically evolves over the course of months to years into a chronic pattern of increased or decreased skin color, skin thinning, and presence of prominent blood vessels. (For more information on this disorder, choose “Rothmund-Thomson syndrome” as your search term in the Rare Disease Database.)

Proteus syndrome is a condition that involves the atypical overgrowth of skin, bones, and the body’s organs. Most medical scientists now agree that Joseph Merrick, known famously as the “Elephant Man”, suffered from Proteus syndrome. The overgrowth is progressive and limits the range of motion of affected joints making them massively overgrown and fixed. It usually begins with the fingers, toes, and knees but can occur in any part of the body. The spine is commonly affected, and the result is scoliosis. Other affected organs include the lungs, spleen, thymus, uterus and colon. Fatty tumors (lipomas) may invade the limbs, trunk and, in some instances, the spinal canal. Other serious complications are blood clots, and some patients have intellectual disability. (For more information on this disorder, choose “Proteus syndrome” as your search term in the Rare Disease Database.)

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Diagnosis

Diagnosis is based on clinical findings and affected individuals are usually recognized at birth. DNA testing for the PORCN gene is available to confirm the diagnosis.

The diagnosis of focal dermal hypoplasia should be considered in patients with either of the following: multiple skin manifestations or one typical skin manifestation in addition to characteristic limb malformations. To better establish the extent of the disease and the treatment of the patient diagnosed, the following evaluations are often recommended: chest x-ray, eye exams, abdominal MRI, kidney ultrasound, hearing evaluation and medical genetics consultation.

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Standard Therapies

Treatment
Treatment for patients with focal dermal hypoplasia is directed at the symptoms. Dermatological creams and protective dressings may relieve skin discomfort and prevent secondary infections. Dentures and hearing aids may be required. Heat and over-exercise should be avoided. Limb deformities may be treated with occupational therapy, assistive devices or surgery. Surgical or laser therapy may be recommended for patients demonstrating trouble swallowing due to large fat deposits in the throat.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Van den Veyver IB, Sutton VR. Goltz Syndrome (Focal Dermal Hypoplasia). In: Sheffield V, Wynshaw-Boris A, Erickson RP, eds. Inborn Errors of Development. Oxford University Press, 3rd edition, 2014.

Bostwick B, Sutton VR, Van den Veyver IB. Focal Dermal Hypoplasia In: Irvine AD, Hoeger PH and Yan AC, eds. Harper’s Textbook of Paediatric Dermatology 4th edition Wiley-Blackwell, 2019

Jones KL. ed. Smith’s Recognizable Patterns of Human Malformation. 5th ed. W. B. Saunders Co., Philadelphia, PA; 1997:532-33.
Gorlin RJ, Cohen MMJr, Levin LS, eds. Syndromes of the Head and Neck. 3rd ed. Oxford University Press, London, UK; 1990:472-74.

JOURNAL ARTICLES
Bostwick B, Fang P, Patel A, Sutton VR. Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals. Am J Med Genet C Semin Med Genet. 2016 Mar;172(1):9-20. doi: 10.1002/ajmg.c.31473. Epub 2016 Feb 7.

Bree AF, Grange DK, Hicks MJ, Goltz RW. Dermatologic findings of focal dermal hypoplasia (Goltz syndrome). Am J Med Genet C Semin Med Genet. 2016 Mar;172(1):44-51. doi: 10.1002/ajmg.c.31472. Epub 2016 Feb 9.

Smith A, Hunt TR 3rd. The orthopedic characterization of Goltz syndrome. Am J Med Genet C Semin Med Genet. 2016 Mar;172(1):41-3. doi: 10.1002/ajmg.c.31470. Epub 2016 Feb 11.

Wright JT, Puranik CP, Farrington F. Oral phenotype and variation in focal dermal hypoplasia. Am J Med Genet C Semin Med Genet. 2016 Mar;172(1):52-8. doi: 10.1002/ajmg.c.31478. Epub 2016 Feb 3.

Deidrick KK, Early M, Constance J, Stein M, Fete T. Cognitive and psychological functioning in focal dermal hypoplasia. Am J Med Genet C Semin Med Genet. 2016 Mar;172(1):34-40. doi: 10.1002/ajmg.c.31471. Epub 2016 Jan 28.

INTERNET
Sutton VR. PORCN-Related Developmental Disorders. 2008 May 15 [Updated 2023 Jun 15]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1543 Accessed August 23, 2023.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Focal Dermal Hypoplasia. Entry Number; 305600: Last Update: 06/17/2022. Available at: https://omim.org/entry/305600 Accessed August 23, 2023.

Goltz RW. Focal Dermal Hypoplasia Syndrome. Medscape Reference. Last Update: June 24, 2019. Available at: https://emedicine.medscape.com/article/1110936-overview Accessed August 23, 2023.

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