PORCN gene mutations and the protean nature of focal dermal hypoplasia

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder featuring developmental abnormalities of ectodermal and mesodermal tissues. Pathogenic mutations in the PORCN gene (locus Xp11.23) were identified in 2007 and thus far 27 different mutations have been reported. PORCN encodes a putative O -acyltransferase which facilitates secretion of Wnt proteins required for ectomesodermal tissue development. We investigated PORCN gene pathology and pattern of X-chromosome inactivation analysis in two unrelated Caucasian female patients who presented with multiple developmental abnormalities consistent with FDH. We also reviewed the clinical and molecular data for all reported PORCN mutations and assessed genotype–phenotype correlation for sporadic and familial cases of FDH. DNA sequencing revealed two new PORCN gene mutations: p.W282X and c.74delG (p.G25fsX51). X-chromosome inactivation analysis revealed a random pattern in one case but was uninformative in the other. Collectively, point/small mutations account for 24 out of the 29 PORCN mutations and are typically seen in sporadic cases; larger deletions are more common in familial cases. Identification of two new PORCN gene mutations confirms the importance of PORCN -associated Wnt signalling in embryogenesis. Both new cases showed Blaschko-linear dermal hypoplasia and extensive ectomesodermal abnormalities, including severe limb developmental anomalies and a giant cell tumour of bone in one patient. Clinical variability can be attributed to the degree of lyonization and postzygotic genomic mosaicism, which are important mechanisms in determining the clinical presentation.     

Urogenital presentation of a male patient with focal dermal hypoplasia

Focal dermal hypoplasia (FDH) is a rare X-linked dominant syndrome characterized by streaky cutaneous atrophy in a blaschkoid distribution, skeletal dysplasias, and ocular abnormalities. Here, we report hypospadias and chordee identified in a male patient with molecularly confirmed FDH. This report highlights a new clinical manifestation of male patients with FDH.     

A case of mosaic Goltz syndrome (focal dermal hypoplasia) in a male patient

We present the case of a boy with a clinical diagnosis of Goltz (focal dermal hypoplasia) syndrome. This is a rare genodermatosis characterized by widespread dysplasia of mesodermal and ectodermal tissues. It is inherited in an X-linked dominant fashion and is normally lethal in male patients. Mutations in the PORCN gene (Xp11.23), the proteins of which are key regulators in embryonic development, have been found to be responsible for the syndrome. Sequencing of the PORCN gene was negative in our patient. This case highlights some of the challenges of obtaining a molecular diagnosis in male patients with suspected Goltz syndrome in the clinical setting.     

Focal dermal hypoplasia in a male patient due to mosaicism for a novel PORCN single nucleotide deletion

Background Focal dermal hypoplasia (FDH) is an X‐linked dominant disorder caused by nonsense mutations and deletions in the PORCN gene coding for a transmembrane endoplasmic reticulum protein required for Wingless signalling. Symptoms consist mainly of linear atrophic skin defects, skeletal deformities and, in many cases, mental retardation. Osteopathia striata is a nearly constant feature. Approximately 90% of patients are women. A few instances of father‐to‐daughter transmission and a number of sporadic male cases presumably as a result of somatic mosaicism have been recorded. Objectives The aim of this study was to demonstrate the presence of somatic mosaicism for PORCN mutations in a male patient. Methods We sequenced the PORCN gene in different tissues from a boy with symptoms of FDH. Results We demonstrate post‐zygotic mosaicism for a novel deletion in the PORCN gene. Conclusions A novel PORCN deletion, present in a post‐zygotic mosaic, causes focal dermal hyplasia in a male patient.     

局灶性真皮发育不全一例

患者男,17岁,出生时即出现多发条纹状红色斑片和丘疹,红色斑片菲薄易破,愈后遗留色素减退斑片。右手第1、2指指甲发育不全。随年龄增长逐渐出现泛发线状或漩涡状色素沉着条纹,部分黄红色丘疹增大形成斑块。于儿童期始逐渐出现多发的乳头瘤样皮损,以口周为著。皮肤科检查：全身泛发线状或漩涡状的色素沉着斑片,以躯干为著,其间散在色素减退斑片与黄红色斑块。口周、下颌及右胭窝多发乳头瘤样皮损。皮损组织病理检查：表皮角化不全,真皮厚度显著变薄,真皮乳头层血管增多,皮下脂肪层上移。诊断：局灶性真皮发育不全。     

Focal dermal hypoplasia resulting from a new nonsense mutation, p.E300X, in the PORCN gene

BACKGROUND: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development. OBJECTIVES: To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata. METHODS: Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene. RESULTS: DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes. CONCLUSION: Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis.     

局灶性真皮发育不全综合征1例

患者女，19岁，临床表现为皮肤网状色素沉着，脂肪疝，乳头状瘤以及头颅，耳，牙齿，毛发，甲发育异常，上肢不对称，并指，脊椎裂，皮肤组织病理改变：表皮突消失，真皮胶原纤维减少，脂肪组织增生，诊断为局灶性真皮发育不全综合征。     

Mosaicism due to postzygotic mutations in women with focal dermal hypoplasia

Focal dermal hypoplasia (FDH, Goltz syndrome, MIM #305600) constitutes a rare multisystem genetic disorder of the skin, skeleton, teeth and eyes with considerable variation in the clinical features. FDH is transmitted as an X-linked dominant trait and is caused by mutations in PORCN. In male children, hemizygous PORCN mutations are lethal in utero. Around 300 cases have been reported in the literature to date. About 10% of them are male patients presenting with either Klinefelter syndrome (karyotype 47, XXY) or mosaicism of a postzygotic mutation. Here we describe four cases of women with typical features of FDH, in whom a PORCN mutation was found in DNA from affected cutaneous tissue but not in DNA from peripheral blood. This study suggests that mosaicism caused by a postzygotic mutation occurs more often than assumed to date in female patients with FDH. A negative analysis performed on peripheral blood DNA does not exclude the diagnosis of FDH and it is therefore of practical importance to analyse DNA from the affected skin in order to identify low-level mosaicism and thus to improve diagnostic precision. In total, we found two missense variants, one novel indel and one novel splice-site variant. Individuals harbouring postzygotic mosaicism run a risk of transmitting the disorder to their daughters, because the maternal mosaic could also affect the gonads.     

Histopathological study of focal dermal hypoplasia (Goltz syndrome)

We report a case of focal dermal hypoplasia, or Golz syndrome in a 13-year-old girl. The patient presented with a variety of cutaneous defects, including atrophy-like depressions, striations, a verrucous papilloma, and lipomas. Histopathological examination showed deposits of fat cells or adipose tissue in the dermis, which were subepidermal, mid-dermal, perivascular, or involved the whole dermis. These findings indicate that the adipose tissue in the dermis is a result of dermal dysplasia and not hypoplasia.     

Three cases of focal dermal hypoplasia (Goltz syndrome)

Focal dermal hypoplasia or Goltz syndrome is a rare genodermatosis, characterized by multiple abnormalities of ectodermal and mesodermal origin. It is found predominantly in females and is characterized by hypoplasia of skin and papillomas. Three cases of focal dermal hypoplasia in infancy with unusual inheritance patterns are reported. Cutaneous features were atrophic reticulated scars involving the trunk and extremities following the lines of Blaschko. Papillomas were present on the genitalia and in a periorificial distribution. Skeletal abnormalities included syndactyly, polydactyly and lobster claw deformities. Ophthalmological examination revealed strabismus and retinal colobomas.     

Case of unilateral focal dermal hypoplasia (Goltz syndrome)

Focal dermal hypoplasia (FDH) is a rare multisystem condition in which developmental defects of the skin are associated with ocular, dental and skeletal abnormalities. Herein, we report an 8-year-old girl with FDH. Her body halves were asymmetric and she had linear cutaneous atrophy with yellow nodules on her extremities. Syndactylies of the third and fourth fingers of the right hand and second and third toes of the right foot were also observed. Histological examination revealed dermal hypoplasia and upward extension of the adipose tissue. Based on these observations, she was diagnosed with unilateral FDH.     

Cutaneous defects of focal dermal hypoplasia: an ectomesodermal dysplasia syndrome

The 5 major cutaneous defects of development found in focal dermal hypoplasia, an ectomesodermal dysplasia syndrome, are: aplasia cutis congenita, multiform atrophy-like areas, striate, papillomatous, and lipomatous lesions of skin. Subepidermal lipomatosis, present in some lesions, has been reported to be due to absence of dermis or a striking underdevelopment of connective tissue with replacement by adipose tissue from herniation of subcutaneous fat through multiple areas of hypoplasia. We believe this theory to be a major error in interpretation of the microscopic findings. We have had the unique experience of studying 2 patients periodically for 27-30 years and 2 additional patients for a shorter time. Biopsy specimens were removed at intervals for analysis from the same or similar lesions (43 specimens) from these 4 individuals. Our evidence strongly supports the concept that the cutaneous defects of development involving fat cells represent heterotopic fat i.e. a fat nevus resulting from dysplasia, not hypoplasia followed by herniation of subcutaneous fat.     

Progression and flaring of focal dermal hypoplasia during an acute illness

Focal dermal hypoplasia (FDH), or Goltz syndrome, is a rare genodermatosis affecting tissues of mesodermal and ectodermal origin. The characteristic skin changes have been reported to symptomatically flare in response to certain triggers as well as to progress over time in some cases. We present the case of a 5-year-old girl with cutaneous flaring and progression of FDH in the setting of septic shock. This case adds to the growing body of literature on both flaring and progression of the cutaneous manifestations of FDH.     

Osteochondroma of humerus in focal dermal hypoplasia (Goltz) syndrome

Focal dermal hypoplasia (Goltz) syndrome was diagnosed in a 26-year-old female subject and her 5-year-old daughter. The mother had been treated surgically for syndactyly in early childhood, and at the age of 12 years had developed a large osteochondroma of the proximal humerus. This is a further bone tumour which should be added to the skeletal manifestations of this syndrome.