Focal Dermal Hypoplasia

A number sign (#) is used with this entry because of evidence that focal dermal hypoplasia is caused by heterozygous mutation in the PORCN gene (300651) on chromosome Xp11.23.

Description

Focal dermal hypoplasia is inherited as an X-linked dominant with in utero lethality in males. The features include atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, and multiple papillomas of the mucous membranes or skin. In addition, digital anomalies consist of syndactyly, polydactyly, camptodactyly, and absence deformities. Oral anomalies, in addition to lip papillomas, include hypoplastic teeth. Ocular anomalies (coloboma of iris and choroid, strabismus, microphthalmia) have also been present in some cases. Mental retardation occurs in some patients. Striated bones are probably a nearly constant feature (Larregue and Duterque, 1975; Happle and Lenz, 1977).

Reports from the International Research Symposium on Goltz Syndrome in 2013 were published in the American Journal of Medical Genetics; the authors and subjects of the reports are listed in an introduction by Fete and Fete (2016).

Clinical Features

Goltz et al. (1962) reported 3 females with a disorder that they called focal dermal hypoplasia. They described the defect as congenital linear areas of thinning of the skin and herniations of adipose tissue in the form of yellowish papules. They identified 2 similar previously reported female patients. Additional features in some of the patients included cleft palate, syndactyly, polydactyly, nail and tooth deformities, ocular anomalies, and sparse hair.

The mother of a female patient reported by Wodniansky (1957) had skin changes and a sister had bilateral syndactyly of the third and fourth fingers and toes. Warburg (1970) observed microphthalmos with bilateral coloboma of the iris and ectopia lentis in a patient with FDH. Ferguson-Smith (1981) observed a typically affected patient who had coloboma of the iris as a feature.

Goltz (1992) reviewed the disorder that carries his name. Patients with areas of total absence of skin at birth have been reported. Apocrine gland anomalies and hydrocystomas near the eyes have been described in patients with FDH. Fibrovascular papillomas, particularly in the perineal, vulvar, and perianal regions, have been mistaken for warts and aroused questions about sexual activity or sexual abuse. They may attain massive size, their surfaces may become eroded, and bleeding may occur. Laryngeal papillomas requiring tracheostomy in one case and esophageal papillomas associated with stricture have been described. Longitudinal striation of the long bones, crossing the epiphyses (osteopathia striata), is a frequent finding. The combination of split hand with syndactyly and absence of rays, the so-called lobster-claw hand, has come to be recognized as a striking feature of FDH. Similar deformity may affect the foot. Although 'focal dermal hypoplasia' does not describe all the protean manifestations of the disorder, it is difficult to devise a designation that is better and, as in the case of many genetic and other clinical disorders, the name for the part is used as the name for the whole.

Buchner and Itin (1992) described typical FDH in a 68-year-old man. He had complete syndactyly between the third and fourth fingers of the right hand from birth. Other than the findings in the skin, Buchner and Itin (1992) stated that 'results from the remainder of the physical examination were unremarkable.' Features consistent with Klinefelter syndrome were not described and karyotype was apparently not performed.

Landa et al. (1993) described an unusual patient in whom the diagnosis of FDH was first made at the age of 39 years. She showed atrophic erythematous and hyperpigmented linear streaks following Blaschko lines, some of which were in a reticular or cribriform arrangement. Yellow, soft nodules caused by fat herniation were visible mainly in skin folds. The patient had multiple bone anomalies, including longitudinal striation of long bones (osteopathia striata). The left side of the body was generally underdeveloped, and the skin on the left showed more extensive changes than the right. There was coloboma of the left iris, subluxation of the left lens, and bilateral lenticular opacities. Syndactyly affected the second and third fingers of the right hand and the first and second toes of the left foot. Spina bifida occulta of the cervical spine and a smaller left kidney were also observed.

Wellenreuther et al. (1994) reported the case of a 40-year-old woman who was thought to have typical Goltz syndrome except that no herniation of fatty tissue was observed. Others had suggested that such herniation is not a necessary feature of the disorder. The patient also had ulcerative colitis and obliterative cholangitis of unknown relationship to the skin disorder.

In a 14-year-old black girl and her mother with cutaneous manifestations of FDH and syndactyly, Lueder and Steiner (1995) found several discrete vascularized peripheral subepithelial corneal opacifications bilaterally with no other ocular abnormalities. They interpreted these corneal lesions as representing an unusual manifestation of FDH.

Irvine et al. (1996) reported a child with typical cutaneous, ocular, and skeletal manifestations of FDH, who had also preauricular sinuses, omphalocele, duodenal atresia, mediastinal dextraposition, patent ductus arteriosus (see 607411), esophageal reflux, and hydronephrosis. The X-inactivation pattern was markedly skewed in the proband but random in her mother.

Bellosta et al. (1996) reported a family with affected females in 3 generations. The grandmother, 72 years old, had typical manifestations of FDH, including multiple telangiectases of the legs, linear hyperpigmented macules, skin atrophy with focal herniations of subcutaneous tissue, dystrophic nails, erythematous lesions of the right leg and arm, and a large papilloma of the tongue. X-ray examinations showed osteopathia striata, scoliosis, and some esophageal papillomas. Karyotype analysis revealed chromosomal abnormalities in 5% of the metaphases examined. The pedigree is consistent with X-linked dominant transmission with lethality in the male.

Gorlin (1998) pointed to the occurrence of giant cell tumors of bone in this disorder.

In a woman with FDH, Traupe (1999) illustrated lines of Blaschko, suggesting the visual consequences of lyonization.

Patel et al. (1997) reported an unusually severe presentation of FDH in a fetus with typical defects of the hands and feet, anophthalmia, total anomalous pulmonary venous return, and diaphragmatic hernia, but with minimal skin defects. Han et al. (2000) described an infant girl of 36 weeks' gestational age who had cardiovascular and other lethal internal anomalies in addition to characteristic external anomalies of FDH. The internal anomalies included truncus arteriosus type II with truncal origin of hypoplastic pulmonary arteries, cardiac ventricular septal defect, severe hypoplasia of the lungs and pulmonary veins, massive diaphragmatic hernia, and absence of the right kidney. The infant showed an oblique facial cleft.

Hancock et al. (2002) described a girl diagnosed with severe Goltz syndrome at 8 months of age when fatty herniations or lipopapillomata were noted. At birth this child was thought to have the same condition as the child described by Van Allen and Myhre (1991), although the latter had ectopia cordis and died in the neonatal period. The child reported by Hancock et al. (2002) had intrauterine growth retardation, 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. No chromosomal deletion was found in the Xp22 region. Hancock et al. (2002) suggested that the child described by Van Allen and Myhre (1991) also had a severe form of Goltz syndrome.

Gordjani et al. (1999) described a 14-year-old girl with FDH who had extensive papillomatosis of the hypopharynx and larynx. These masses were resected subtotally by endoscopic laser treatment. Residual papillomas were left in the subglottic space but tracheotomy was avoided. Complete clinical recovery ensued. Histologic examination did not show morphologic signs of human papillomavirus as an etiologic agent.

Rodini et al. (2006) reported a newborn girl with a severe form of Goltz syndrome with atypical and extensive facial clefting. Oral anomalies included hypodontia, papillomas of the lip, and right-sided complex facial clefting involving maxilla, oral, nasal, and ocular structures.

Maas et al. (2009) described the clinical and molecular features of 17 patients with Goltz-Gorlin syndrome. Thirteen classically affected females had a mutation in the PORCN gene, including 2 sisters with germline mosaicism. In a male patient who was classically affected except for relatively mild limb anomalies, a mutation was identified in fibroblast samples from affected and unaffected areas, with a lower signal intensity at the mutation site in unaffected fibroblasts, suggestive of somatic mosaicism. No mutations were identified in the 3 remaining female patients, who were mildly affected, with features limited to focal dermal hypoplasia and hyperpigmentation following Blaschko lines. Two mutation-positive women had 1 and 2 female fetuses, respectively, with a phenotype resembling either the limb-body wall complex (217100) or the pentalogy of Cantrell (see 313850). Maas et al. (2009) suggested that some cases carrying the latter diagnoses may in fact be severely affected fetuses with Goltz-Gorlin syndrome.

Gnamey et al. (2010) reported a male infant with focal dermal hypoplasia who also had an extensive area of aplasia cutis congenita (ACC; 107600) of the scalp vertex, with cerebral structures visible through the defect. He had cutaneous atrophy with areas of hyperpigmentation on the right leg, hypoplasia of the first toe of the right foot, absence of the fifth toe of the left foot, and bilateral complete tissue syndactyly with fusion of the toes. Radiography revealed hypoplastic mandible, absence of left first and second metatarsals, absence of the right first metatarsal, and the femora and tibiae were dystrophic with flattened diaphyses. The patient died at 23 days due to neurologic complications. Gnamey et al. (2010) reviewed 18 previously reported cases of FDH and stated that this was the first in which there was associated aplasia cutis congenita.

Smigiel et al. (2011) reported an infant girl with a nonsense mutation in the PORCN gene, who had findings fitting both Goltz-Gorlin syndrome, including sparse hair, clinical anophthalmia, clefting, bifid nose, irregular vermilion of both lips, asymmetric limb malformations, caudal appendage, linear aplastic skin defects, and unilateral hearing loss, and the pentalogy of Cantrell, including absent lower sternum, anterior diaphragmatic hernia, ectopia cordis, and omphalocele. Smigiel et al. (2011) stated that this was the third patient reported to have this combination of features.

Inheritance

Ninety percent of individuals with FDH are female, with heterozygous or mosaic mutations in the PORCN gene. Males (mosaic mutations) account for 10% of affected individuals; heterozygous nonmosaic mutations are thought to be lethal in males. Approximately 5% of affected females inherit the gene defect from a parent; 95% of affected females have a new mutation (summary by Deidrick et al., 2016).

Goltz et al. (1962) noted that all 5 of their cases were female, that the disorder occurred only in female antecedents and other relatives, and that miscarriages are frequent in these families. They had affected females in 4 successive generations in 1 family and in 2 generations of another.

Toro-Sola et al. (1975) reported what they purported to be the eighth case in a male. From a review of published cases, they concluded that multifactorial inheritance is likely.

Wettke-Schafer and Kantner (1983) stated that that the inheritance of FDH as an X-linked dominant lethal in hemizygous males was not confirmed. At least 2 instances of father-to-daughter transmission had been reported (Larregue and Duterque, 1975; Burgdorf et al., 1981). In a review on FDH, Temple et al. (1990) suggested that the disorder in males may be the result of half-chromatid mutations. If the mutation occurs early enough in the developing embryo, the gonads would also be affected, and this may explain reports of father-to-daughter transmission. In keeping with this hypothesis, reported affected males have always been the first affected person in their families.

Gorski (1991) observed FDH in father and daughter. Study of somatic cell hybrids constructed by fusing HPRT-deficient rodent fibroblasts with either patient dermal fibroblasts or peripheral white blood cells showed that while hybrids constructed from skin fibroblasts contained an active X chromosome inherited from either of the patient's parents, hybrids constructed from white cells showed a skewed pattern of X inactivation; 11 of 11 hybrids contained an active maternal X chromosome (p = 0.001). These findings were interpreted as indicating that FDH was associated with nonrandom X inactivation consistent with X-linked inheritance and that the patient's father was mosaic for a mutant FDH allele.

Cytogenetics

Friedman et al. (1988) described a child with FDH who was found to have a terminal deletion of the short arm of the X chromosome with the breakpoint in Xp22.31. They suggested that this is the site of the gene. Zuffardi et al. (1989) observed a child with some of the manifestations of FDH in association with a deletion in 9q32-qter. They questioned whether FDH may in fact be autosomal, not X-linked, or whether there may be an autosomal form.

Naritomi et al. (1992) described 2 unrelated girls with deletion in the terminal portion of the short arm of the X chromosome. They had features interpreted as combining those of the Goltz and Aicardi syndromes. From this and the clinical and cytogenetic findings in similar cases, Naritomi et al. (1992) concluded that these may be contiguous gene syndromes in the region Xp22.31 (or, alternatively, caused by mutations in separate genes that are closely situated to each other). Gorlin (1998) stated that the condition described by Naritomi et al. (1992) was 'clearly MIDAS syndrome' (MLS; 309801), which has been mapped to Xp22.31.

Wang et al. (2007) cohybridized genomic DNA of girls with FDH with reference female DNA onto a genomewide oligonucleotide comparative genomic hybridization (CGH) array and identified a 219-kb region of copy number loss in 11p11.23 in DNA from 2 affected individuals. This region, which encompassed 5 genes, including PORCN, was not deleted in her unaffected parents. Another affected girl was found to have the nearly identical mutation. In both, there was 100% inactivation of the paternally inherited X chromosomes in peripheral blood leukocyte (PBL) DNA. The finding of 2 such nearly identical heterozygous genomic deletions may indicate that this is a common mutational mechanism for FDH, possibly mediated by low-copy repeat sequences.

Grzeschik et al. (2007) used CGH to study 6 affected members of 1 family segregating FDH and 10 unrelated affected individuals. In 2 of those affected, they identified deletion in Xp11.23 that overlapped by approximately 80 kb and included 4 genes, including PORCN. Grzeschik et al. (2007) concluded that FDH can be a component of a contiguous gene syndrome. They also noted skewed X-chromosome activation.

Molecular Genetics

Wang et al. (2007) amplified and sequenced all coding exons of the PORCN gene, using genomic DNA of 15 girls with confirmed or suspected FDH and identified heterozygous mutations in 10 of them (e.g., 300651.0001-300651.0002). None of the mutations were detected in available parental DNA samples, except for a duplication mutation in exon 12 in 1 individual (300651.0001). The sequencing profiles of her father's DNA showed very low signals for the mutant sequence superimposed on the wildtype sequence, suggesting somatic mosaicism.

In 8 individuals with FDH, Grzeschik et al. (2007) identified several heterozygous nonsense mutations and 1 splice site mutation (e.g., 300651.0003-300651.0004).

Leoyklang et al. (2008) reported 3 unrelated Thai girls with sporadic FDH in whom they identified mutations in the PORCN gene (see, e.g., 300651.0005), confirming that PORCN is the gene responsible for FDH across different populations. One of the girls displayed unilateral athelia, which the authors stated was previously unreported in this disorder.

In 24 unrelated FDH patients from different ethnic backgrounds, Bornholdt et al. (2009) identified 23 different PORCN mutations, including 3 microdeletions encompassing PORCN as well as neighboring genes, 12 nonsense mutations resulting in loss of function, 1 splice site mutation, and 8 missense mutations at highly conserved amino acids (see, e.g., 300651.0005). FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Bornholdt et al. (2009) noted that molecular characterization of PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families, since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Froyen et al. (2009) analyzed the PORCN gene in 6 Finnish and 2 Belgian patients with FDH and identified a 150-kb deletion, encompassing PORCN and at least 5 other genes in a 13-year-old Finnish girl. In addition, they identified 2 different missense mutations, 1 in a 6-year-old Belgian girl and the other in a 16-year-old Finnish girl; the latter mutation (R365Q; 300651.0005) had previously been identified in a Thai girl with a severe form of FDH by Leoyklang et al. (2008) and in a girl with a mild FDH phenotype by Bornholdt et al. (2009). Froyen et al. (2009) stated that these were the first causal PORCN mutations identified in the Finnish and Belgian FDH populations.