Focal Dermal Hypoplasia Syndrome

Updated: Jun 24, 2019
  • Author: Wasim Haidari; Chief Editor: Dirk M Elston, MD  more...
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Focal dermal hypoplasia (FDH) is an uncommon genetic disorder affecting tissues of ectodermal and mesodermal origin. It is also known as Goltz syndrome or Goltz-Gorlin syndrome and was first described in 1962. Focal dermal hypoplasia is a multisystem disorder characterized by dermatologic, skeletal, ocular, urinary, gastrointestinal, cardiovascular, neurologic, and oral abnormalities. [1] It is usually, but not always, X-linked dominant (lethal in males except if male is mosaic). About 90% of affected individuals are female. Ninety-five percent are new mutations. Affected individuals often are recognized at birth or occasionally prenatally, but cases involving a minor expression of the syndrome may be diagnosed later in life. The mnemonic FOCAL can be used to remember some of the key features of this syndrome: female sex; osteopathia striata; coloboma; absent ectoderm-, mesoderm-, and neuroderm-derived elements; and lobster claw deformity. [2, 3, 4, 5, 6]

The eponyms of focal dermal hypoplasia should not to be confused with Gorlin syndrome or Gorlin-Goltz syndrome, which is the nevoid basal cell carcinoma syndrome. [7] Focal dermal hypoplasia is identified as entry #305600 in the Online Mendelian Inheritance of Man database.



The focal dermal hypoplasia (FDH) genetic defect has been associated with at least 80 different mutations in the PORCN gene of the X chromosome (Xp11.23). [8] Nonsense, frameshift, aberrant splicing, and missense mutations have all been identified in patients with focal dermal hypoplasia. [9] No genotype-phenotype correlation has been found thus far.

The biochemical functions of the human PORCN gene still are not completely characterized. However, much is known about PORCN signaling in the mouse and in humans. This gene provides instructions for making a protein that is responsible for modifying other proteins, including Wnt proteins. Wnt signaling is critical for normal embryonic development of the skin, bones, and other structures. Since Wnt signaling proteins cannot be released without the PORCN protein, and Wnt signaling is important for normal embryonic development, the defects found in this disorder are related to lack of Wnt signaling. [10, 11, 12, 13]

The severity of defects in focal dermal hypoplasia is variable, and this variability is due to random X-chromosome inactivation (lyonization) within cells. In females, one of the two X chromosomes is randomly inactivated in every cell. The result is functional mosaicism of cells. Tissues in which cells select for the defective PORCN gene show anomalies. In the skin, these abnormalities follow the embryonic lines of Blaschko.

Approximately 10% cases occur in males; postzygotic somatic mosaicism accounts for the findings in these affected males. Postzygotic somatic mosaicism is also postulated for the sporadic female cases with negative family pedigree analysis.



Studies indicate that focal dermal hypoplasia (FDH) is usually caused by mutations of the PORCN gene, mapped to locus Xp11.23. At least 80 different mutations have been identified. These include nonsense, missense, and frameshift mutations, as well as abnormal splicing. [9, 14, 15, 16, 17, 18] No genotype-phenotype correlation has been found. Somatic and germline mutations may occur.

PORCN, a member of the porcupine (PORC) gene family, encodes transmembrane endoplasmic reticulum proteins that target Wnt signaling proteins. Wnt proteins are key regulators of embryonic development.

Although biochemical functions of the human PORCN gene are not well characterized, Wnt signaling may be involved in the phenotypic expression of focal dermal hypoplasia where defective/deficient Wnt signaling could affect cell fate or result in failure of a progenitor cell line to expand.

Drosophila melanogaster porcupine and its mouse homologue PORCN gene encode transmembrane bound endoplasmic reticulum proteins needed for the secretion of Wnt (Wingless and INT-1) proteins. (In Drosophila melanogaster, the PORCN gene is involved in the processing of the wingless protein.)

Investigators have detected embryonic mouse expression of PORCN in cartilage, primordia of long bones and digits, calvaria, the facial skeleton, molar tooth buds, the petrous part of the temporal bone, as well as affecting developing skin of the anterior body wall and limbs; and in the developing cerebral cortex and retina. These findings correlate with the developmental defects seen in persons with focal dermal hypoplasia.

Deletion of the PORCN gene has been achieved in mice. Conditional inactivation of mouse PORCN early in development leads to increased embryonic lethality. Mesenchyme-specific inactivation leads to limb defects, while ectoderm-specific inactivation leads to thin skin, alopecia, and abnormal dentition. [8]

Cell culture assays show that knock down of expression of PORCN by siRNA causes retention of Wnt3a in cells. [8]

Disorders that may be subsets of focal dermal hypoplasia

Angioma serpiginosum (OMIM #300652)

This is an X-linked skin disorder characterized by nonpurpuric red punctate lesions seen histologically as capillary ectasias in the superficial papillary dermis. The lesions often follow Blaschko lines. In 2007, Blinkenberg et al suggested that the disorder may be a mild variant of focal dermal hypoplasia. [19] Blinkenberg et al (2007) and Houge et al (2008) identified a 112-kb deletion on Xp that removed the PORCN gene and four other genes. [19, 20]

Pentalogy of Cantrell (OMIM #313850)

This is an X-linked disorder characterized by the combination of midline supraumbilical abdominal wall defects and absent or cleft lip. Overlap cases have been described with patients displaying these typical features in association with more typical focal dermal hypoplasia features and mutation in PORCN. [21]

Van-Allen Myhre syndrome (Listed in OMIM under focal dermal hypoplasia)

These children described first in 1997 by Van-Allen and Myhre and then by Hancock in 2002 showed intrauterine growth restriction; bilateral split foot–split hand malformations; a broad-based, skin-covered periumbilical abdominal wall herniation; areas of cutis aplasia congenita and bullous vesicles; microphthalmia, and colobomata of the iris, retina, and optic nerve bilaterally. This is likely a severe phenotype of focal dermal hypoplasia. [22, 23]



Focal dermal hypoplasia (FDH) is an uncommon disorder. The exact prevalence is unknown. Only 200-300 cases have been reported in the literature. All races have been affected. The syndrome occurs predominantly in females. In males, it is usually X-linked and lethal in utero. A small number of male patients have been reported, mostly with postzygotic somatic mutations. Focal dermal hypoplasia is present at birth but may evolve thereafter and, in mildly affected individuals, may be recognized only later in life.



The prognosis is good; most individuals live to adulthood. However, many severely affected individuals die in infancy; family pedigree analysis shows a high incidence of miscarriages and stillbirths.

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 report that the atrophic skin lesions are tender and sore. Periorificial fibrovascular papillomas may continue to appear during adulthood; these papillomas require repeated surgical intervention.


Patient Education

Information for patients and families with focal dermal hypoplasia (FDH) can be found through the National Institutes of Health Genetics Home Reference: Focal dermal hypoplasia. The first international research symposium was held July 22-23, 2013. [24] Other organizations are as follows: