Goltz syndrome: report of two severe cases

Abstract

Goltz syndrome is a rare, X-linked dominant congenital disorder with abnormalities in derivatives of each of the three embryonic germ layers. Its clinical phenotype varies widely, ranging from isolated skin defects to absence of limbs and/or organs. The rarity and wide range of presentation contribute to delayed or missed diagnosis.

BACKGROUND

This report describes a clinical entity, Goltz syndrome, which has not appeared in the general paediatrics literature in the past. It has been our experience that Goltz syndrome, also known as focal dermal hypoplasia, remains a little known diagnosis. Because of variable presentation (non-descript skin lesions to dramatic body wall and limb defects), diagnosis can be challenging. The first case described was initially published in a peer reviewed journal and thought to possibly represent a new syndrome. Retrospective analysis of the records, in light of the similarities with the second case, led us to the conclusion that the first patient described had Goltz syndrome. The gene causing the disease has very recently been identified, and these patients can now be tested. Our primary aim in presenting this article for publication is to expand the breadth of knowledge of those who read the general literature and may be able to use this information in their daily work.

CASE PRESENTATION

Goltz syndrome, also known as focal dermal hypoplasia, was first described in 1962.¹ Since then more than 300 cases have been reported in the specialty literature, primarily affecting females without ethnic or racial predilection, suggesting an X-linked genetic defect. Recently, heterozygous and mosaic loss-of-function mutations and large genomic deletions in the X-linked PORCN gene have been described in patients with Goltz syndrome.^2,3 Most cases are caused by de novo mutations, although there have been a small number of familial cases with father-to-daughter and mother-to-daughter transmission.

Goltz syndrome is characterised by a spectrum of congenital defects in tissues that arise from endoderm, mesoderm and ectoderm. Most afflicted individuals with Goltz syndrome have atrophic, often linear, skin defects with reticular pigmentation and cutaneous deposits of subdermal fat. Skeletal defects are common and include lobster claw deformity of the hands or feet, absence of the distal portion of a limb and diastasis pubis.⁴ Other variable features include skeletal striations known as osteopathia striata, aplasia cutis, ophthalmologic defects (microphthalmia, anophthalmia, coloboma and ectopia lentis), dental anomalies (enamel hypoplasia, hypodontia, oligodontia and microdontia), and midline body wall defects. Intelligence is usually normal, although mental retardation has been reported.

We present two cases, one of which was presented previously as a midline thoracoabdominal schisis with limb defects⁵ that on re-evaluation was reclassified as Goltz syndrome. Because the genetic defect has now been identified^2,3 a molecular diagnostic test can be obtained to confirm the diagnosis, facilitating improved genetic counselling and prenatal diagnosis in familial cases.

Case 1

An infant Caucasian girl was delivered by caesarean section at 38 weeks’ gestation due to a large omphalocele that was originally noted at a routine prenatal screening ultrasound at 20 weeks’ gestation. High resolution ultrasonography revealed further abnormalities, including a chest wall defect, possible bladder extrophy, scalp defects, unilateral microphthalmia, and an absent left foot. Chromosomes were normal: 46,XX obtained through amniocentesis. The mother was healthy throughout the pregnancy. There is a healthy 3-year-old full brother.

Shortly after an uneventful delivery, with Apgar scores of 5 and 8, the infant had respiratory difficulties and was intubated. Physical exam was notable for a grossly dysmorphic infant with a large midline abdominal wall defect extending from the upper third of the sternum down to the symphysis pubis with an overlying membrane (fig 1A). She had an absent left foot, two patches on the scalp that lacked skin, subcutaneous tissue and bone (but over which dura was present), numerous yellow, white and red skin defects, some of which lay in a linear array, and a hairy tuft at the midline sacrum. She had low set posteriorly rotated ears with floppy pinnae and pronounced tragus, hypoplastic left orbit, ruggated nasal bridge and nasal tip, abnormally long third digits on the hands, and hypoplastic nails. There was a patent anus and apparent bladder extrophy with urine visibly spilling from the suprapubic area.

Figure 1.

Two cases of Goltz syndrome. (A) Case 1, first week of life: large midline thoraco-abdominal wall defect with bladder extrophy with overlying membrane and unilateral phocomelia; linear skin defects, left thigh. (B) Case 2, postmortem exam: midline thoraco-abdominal defect and unilateral phocomelia; large skin defects of right side of upper chest (not shown) and of face.

The scalp lesions were closed on the second day of life and the omphalocele was closely monitored for maturation of the membrane overlying the abdominal and chest contents and expansion of surrounding tissue for planned closure.

Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain revealed no abnormalities other than microphthalmia on the left. Skeletal survey revealed overlying sutures of the skull, butterfly vertebral body at T4, multiple hypoplastic left ribs, diastasis of the pubic symphysis and absent left fibula and tapered left tibia with no distal bones present. Ultrasound examination of the kidneys was within normal limits.

Chromosomes from blood lymphocytes revealed a normal 46,XX karyotype. An X inactivation study showed a random X inactivation pattern. PORCN mutation analysis was performed as described³ and resulted in identification of a heterozygous loss-of-function nonsense mutation [c.479dupA (p.Y160X)] in the patient, but not in her parents. At 3 ½ months of age, after a period of using skin expanders, the infant’s midline defect and bladder extrophy were repaired, as well as a bifid uterus noted at the time of surgery. The infant developed pulmonary hypertension soon after and later expired.

Case 2

This case was previously reported by one of the authors (EKP) in 1998.⁵ Upon review of the case it is felt that this infant had Goltz syndrome. While skin defects were not noted in the published case, a review of the patient’s record reveals there was an atrophic skin lesion overlying the right clavicle at the point of foreshortening. At the time, the skin findings were not appreciated to significantly contribute to the diagnosis of the case.

This female African American infant was born full term to healthy parents with neither personal nor family history of miscarriages, stillbirths or congenital abnormalities (fig 1B). The pregnancy was complicated by polyhydramnios and intrauterine growth retardation. Congenital abnormalities included midline thoracoabdominal defect from the upper third of the chest to the umbilicus, ectopia cordis, multicystic left kidney, absence of the right fibula and foot, ectrodactyly of the right hand and left foot, right anophthalmia, left microphthalmia, incomplete bilateral cleft lip, minor ear anomalies and pronounced nuchal fold. No aggressive measures were taken and the infant expired soon after birth due to poor respiratory efforts.

Postmortem radiological exam noted the absence of sternum (the manubrium was present), 11 right sided ribs, absence of the middle third of the right clavicle, opaque right hemithorax, hypoplastic right tibia with absent right fibula and foot, and ectrodactyly of the right hand and left foot. Autopsy revealed separation of rectus abdominus muscles and two diaphragmatic defects. No molecular studies were performed, as the infant expired before identification of the molecular defect that causes Goltz syndrome.

DISCUSSION

These cases and many others demonstrate the difficulties with identification of Goltz syndrome at initial presentation, especially in severe or atypical cases. The clinical overlap with other rare syndromes may also complicate the diagnosis. Overlap with microphthalmia with linear skin defects (MLS syndrome) and Aicardi syndrome has been previously reported.⁶ These conditions are now known not to be molecularly related to Goltz syndrome. MLS is caused by heterozygous deletions or point mutations in the HCCS gene in Xp22.3.⁷ Patients with Aicardi syndrome do not have point mutations in PORCN (unpublished data). Van Allen–Myhre syndrome has been suggested to be a severe form of Goltz syndrome,⁸ but this awaits molecular confirmation. Other conditions with potential overlap in clinical characteristics with Goltz syndrome are oculocerebrocutaneous syndrome, Adams-Oliver syndrome and others.⁶ Clearly, the discovery of the gene for Goltz syndrome and the capacity to perform molecular diagnosis will improve the clinical diagnosis and its differentiation from other phenotypically similar conditions. It will also allow a better description of all clinical conditions caused by mutations in PORCN.

In summary, Goltz syndrome is a spectrum of congenital defects affecting tissues that arise from all three embryonic germ layers. Affected patients are usually female, with heterozygous mutations or deletions of the X-linked PORCN gene found in at least two thirds of patients, or males with mosaic mutations in this gene. Unfortunately, the number of focal dermal hypoplasia patients currently described with PORCN mutations is too small to allow genotype–phenotype correlation, although it is interesting that a patient with a nonsense mutation and random patterns of X chromosome inactivation had a severe phenotype. There is variation in X chromosome inactivation between different patients, as well as somatic mosaicism in some affected males and likely also females. Although it is mostly sporadic, familial cases are inherited in an X-linked fashion. Greater and timelier identification of patients with Goltz syndrome and molecular genetic diagnosis may positively affect families by facilitating accurate genetic counselling.

LEARNING POINTS

• Presentation of Goltz syndrome varies widely, ranging from minor skin lesions to body wall defects incompatible with long term survival, making diagnosis difficult at times.

• Clinical characteristics may overlap with other conditions.

• Genetic diagnosis of X-linked Goltz syndrome may allow for accurate genetic counselling.