JMedGenet 1990; 27: 315-319

Restrictive dermopathy: a report of three cases

Q Mok, R Curley, J L Tolmie, R A Marsden, M A Patton, E G Davies

AbstractWe report three infants with a rare syndrome ofrestrictive dermopathy, in which rigidity of the skinat birth is associated with characteristic facialanomalies, generalised arthrogryposis, bonyabnormalities, and lung hypoplasia. The skin has adistinctive pathology with compaction of the dermalcoliagen and fibrosis of the subcutaneous tissue.The inheritance is likely to be autosomal recessiveand the condition appears to be fatal in the earlyneonatal period.

Several cases of the fetal akinesia/hypokinesiadeformation syndrome have been described, wherefacial anomalies, arthrogryposis, and lung hypoplasiaare associated. Examples include Pena-Shokier, Neu-Laxova, cerebro-oculo-facio-skeletal, and lethal

Departments of Child Health, Dermatology, and MedicalGenetics, St George's Hospital Medical School, London.Q Mok, R Curley, R A Marsden, M A Patton, E G Davies

Duncan Guthrie Institute of Medical Genetics, Glasgow.J L TolmieCorrespondence to Dr Mok, Queen Mary's Hospital forChildren, Carshalton, Surrey SM5 4NR.

multiple pterygium syndromes. Restrictive dermo-pathy is a distinctive and recendy described disorderin which the primary defect appears to be rigidity ofthe skin, causing secondary generalised flexioncontractures and restriction of respiratory move-ments, thus leading to early death.

Case reportsCASE 1Case 1 was the first child of healthy, non-consan-guineous, Caucasian parents. The mother, aged 24years, did not smoke or drink and was not exposed toany known teratogens. The family history is otherwiseunremarkable. The pregnancy proceeded normallyuntil spontaneous rupture of membranes at 28+weeks' gestation, when an ultrasound scan showed anormal amount of liquor and no fetal breathingmovements. Despite treatment with ritodrine anddexamethasone labour progressed and five days later amale infant was delivered with difficulty by forceps.He had an Apgar score of 2 at one minute and wasintubated at two minutes with difficulty because of asmall, tight mouth and restriction in neck extension.The placenta weighed 530 g and had three vessels.The infant weighed 1080 g (above the 10th centile)

with an occipitofrontal circumference (OFC) of 27 cm(below the 50th centile). He had a dorsal kyphosis,rockerbottom feet, and contractures of all the joints(fig 1) including the fingers and mandible. The facial

Figure I Case I showing severecontractures ofall thejoints.

Received for publication 12 October 1989.Revised version accepted for publication 18 December 1989.

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appearance was distinctive with an antimongoloidslant and hypertelorism, small pinched nose, micro-stomia with a small, open, 0 shaped mouth, andmicrognathia (fig 2). The anterior fontanelle was largewith wide sutures. At birth he was noted to havesmooth, shiny skin which felt rigid and tethered. Thecutaneous vasculature was easily visible, suggestingthinning of the dermis. Within hours of birth, fragile ...blisters had developed over the anterior abdominal .s#wall and extensor aspect of the elbows, and theselater ruptured to leave superficial erosions (fig 3). The 2:,hair and nails were normal. Initially adequate gasexchange was easily obtained on low pressureventilation but his lungs became progressively moredifficult to ventilate. The skin continued to breakdown readily and became more rigid.

Karyotyping showed normal 46,XY chromosomes.X rays showed deficient ossification of the distalclavicles with segmentation, and the long bones,especially the humeri, showed 'overmodelling' (fig 4).A skin biopsy from the edge of a blister showedparakeratosis of the epidermis and a subepidermal ..f -split. The dermis appeared compacted with loss of the t .normal space between collagen bundles, and therewere striking downward projections of fibrous tissueextending from the dermis into the subcutaneous fat.

Figure 3 Close up of the skin showing the superficial erosions.

The adipose tissue itself was increased in amount andcontained proliferating fibroblasts (fig 5).

Supportive treatment was withdrawn in view of thedeteriorating condition and poor prognosis, and theinfant died aged 1 week.

CASE 2Case 2 was the second child of consanguineousPakistani parents. His mother, aged 21 years, tooktriiodothyronine for hypothyroidism and remainedeuthyroid throughout pregnancy. The pregnancy wasnormal until 32 weeks' gestation when spontaneousrupture of membranes was followed by a vaginaldelivery. The infant had an Apgar score of 2 at oneminute with no response to intubation and resus-citation. He died at 30 minutes. The placenta weighed450 g and was uniformly pale, thick, and oedematous.

.....:.-.:.: tThe infant weighed 1300 g (below the 10th centile)with an OFC of 27 cm (below the 3rd centile). He hadan antimongoloid slant, pinched nose, microstomia,and micrognathia. The skin was taut and shiny, and ahorizontal split in the skin over the thyroid cartilagehad been noted even before attempts at intubation (fig

Fgure2 The distinctivefacialappearanceofacaseof 6). There were fixed flexion deformities of the hips,restrictive dermopathy. Note the antimongoloid slant and knees, elbows, and fingers. The ankles and the third,hypertelorism, small pinched nose, microstomia with a small, fourth, and fifth toes were dorsiflexed. He was notedopen, 0 shaped mouth, and micrognathia. to have long nails and normal hair.

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Restrictive dermopathy: a report of three cases

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Figure 4 The x ray illustrates thesegmentation ofthe clavicles andovermodelling ofthe humeri, also thetypical appearance ofhypoplasticlungs.

Figure 5 The skin biopsy shows acompacted dennis with downwardprojections offibrous tissue into thethickened subcutaneous layer ofadipose tissue.

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Karyotyping (Giemsa banded) showed 46,XYchromosomes. X rays showed decreased ossificationof the distal ends of the clavicles, and 'overmodelling'of the long bones. A skin biopsy was not performed.

CASE 3Case 3 was the sib of case 2. She was born at 32 weeksafter an uneventful pregnancy. Apgar scores were 5 atone minute and 7 at five minutes. She weighed 1500 g(10th centile) with an OFC of 29 cm (10th centile).

She had exactly similar dysmorphic features to theprevious infant (fig 7). The skin was of similarappearance and texture, the nails were long, and therewere flexion contractures of the joints.

She had a normal 46,XX karyotype. X ray findingswere similar to the previous infant. A skin biopsyshowed acanthosis and hyperkeratosis ofthe epidermiswith reduction in papillary dermis, widespreadtelangiectasia, and poorly formed hair and sweatgland elements.The infant required tube feeds and over the

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Mok, Curlev, 7olmie, Marsden, Patton, Davies

Figure 6 A close up ofcase 2 showing the typicalfacial featuresand the split in the skin over the thyroid cartilage that was present

from birth.

Figure 7 The postmortem photograph ofcase 3 showing all thefeatures of the condition previously described.

following six weeks the skin became progressively lesselastic. Three primary teeth erupted prematurely.Cyanotic attacks became more frequent and the infantdied aged 7 weeks.The parents had a previous healthy male child and a

subsequent healthy female child. They also had twosubsequent intrauterine deaths at 16 and 26 weeks,respectively.

Necropsy was refused in all three cases.

DiscussionThe term 'restrictive dermopathy' was first used byWitt et all to describe two sibs from consecutivepregnancies, both born prematurely at 32 weeks.They shared the clinical, radiological, and histologicalfeatures of our three infants with the characteristicfacial anomalies (microstomia, micrognathia, hyper-telorism, pinched nose, low set ears, wide sutures andfontanelles), arthrogryposis, pulmonary hypoplasia,and intrauterine growth retardation. Polyhydramnioswas noted in both pregnancies and the infants hadshort umbilical cords. X ray examination showedovertubulation of the long bones with segmentationdefects of the clavicles.

In a more extensive study of the two sibs and afurther unrelated infant, Holbrook et a12 definedhistological, ultrastructural, and biochemicalabnormalities of the skin. They, like our infants, hadshiny, rigid skin with distinctive histology showingparakeratotic hyperkeratosis, epidermal acanthosis, adermis composed of dense parallel connective tissue,and a thickened and fibrotic layer of subcutaneous fat.Hair follicle development appeared to have beenarrested at a stage corresponding to the follicledevelopment in the first or early second trimesterfetus. Epidermal extracts, when examined by gelelectrophoresis and stained with antikeratin mono-clonal antibodies, showed a pattern suggestive of ahyperproliferative state with an increased expressionof 48 and 56 kD keratins. Immunohistochemistry ofthe epidermis showed a distinctive staining patternwith the monoclonal antibody AE1, which normallystains basal cells, but in the two affected infantsstained only suprabasal cells.A number of other infants with very similar

features have been reported previously. All showedthe typical facial anomalies, joint contractures, andskin fragility. Although Toriello et a13 described twosibs as having aplasia cutis congenita, their descriptionand photographs closely resemble our cases. Necropsyshowed evidence of prematurity with patent arterialducts, immature brain gyral pattern, and fetal lobu-lations of the kidneys. Toriello4 subsequentlyreported a third sib born to the same family with allthe typical anomalies. Studies of the skin by Holbrooket a12 clearly showed that the infant has the samecondition as the two sibs described by Witt et all and

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Restrictive dermopathy: a report ofthree cases

termed restrictive dermopathy. The four infantsreported by Lowry et a15 showed no internal abnor-malities apart from pulmonary hypoplasia. One oftheir cases also showed premature eruption of teethand had two central incisors. Toriello4 noted remark-able consistency in the facial phenotypes in the casesdescribed, while the skin anomaly exhibits morevariable expression. The striking similarity of thecases caused Gillerot and Koulischer6 to review theirpatient's diagnosis and recall the family five yearslater to correct recurrence risk figures and proposeprenatal diagnosis.

Schnur et a17 identified large amounts of prolineand hydroxyproline containing small peptides in theskin of an affected infant, and suggested a primarydefect of collagen or its metabolism. Lowry et a15 andWitt et all postulated that all the abnormalities wererelated to a basic disorder of skin differentiation.Rigidity of the skin caused severe restriction ofmovement in utero, and consequent contractures.The facial changes may be the result of the intrinsicallyabnormal mechanical effects ofthe skin, the pulmonaryhypoplasia the result of limitation of chest excursionand breathing movements, and the polyhydramniosthe result of abnormal swallowing. Toriello4 suggestedthat it is a more complex dysplasia affecting severaltissues and, owing to its effect on fetal movement,numerous deformations are caused.

Restrictive dermopathy is a universally fatalcondition in the neonatal period. Efforts shouldtherefore be directed towards confirming the diagnosisrapidly after birth and minimising trauma to theinfant and family.

All the reported cases suggest autosomal recessiveinheritance, which is supported by a history of

parental consanguinity in many of the families. Inview of the high risk of recurrence in subsequentpregnancies, there is a clearneed for prenatal diagnosisin potentially affected infants. Regular detailed ultra-sound scanning after 16 weeks could identify decreasedfetal movement and joint contractures, but may be toonon-specific in determining affected cases for thera-peutic abortions.

All the epithelial structural proteins are expressedby 14 to 16 weeks' gestation. Examination of fetal skinobtained after this time for morphological abnormal-ities and for the increased expression of the 48 and 56kD keratins might be used for prenatal diagnosis. Theprospects for prenatal diagnosis will improve if thespecific gene defectin this condition can be determined.

We thank Dr T L Turner for permission to reportcases 2 and 3.

1 Witt DR, Hayden MR, Holbrook KA, Dale BA, Baldwin VJ,Taylor GP. Restrictive dermopathy: a newly recognized auto-somal recessive skin dysplasia. Am J Med Genet 1986;24:631-48.

2 Holbrook KA, Dale BA, Witt DR, Hayden MR, Toriello HV.Arrested epidermal morphogenesis in three newborn infantswith a fatal genetic disorder (restrictive dermopathy). J InvestDermatol 1987;88:330-9.

3 Toriello HV, Higgins JV, Waterman DF. Autosomal recessiveaplasia cutis congenita-report of 2 affected sibs. Am J MedGenet 1983;15:153-6.

4 Toriello HV. Invited editorial comment: restrictive dermopathyand report of another case. Am J Med Genet 1986;24:625-9.

5 Lowry RB, Machin GA, Morgan K, Mayock D, Marx L.Congenital contractures, edema, hyperkeratosis, and intra-uterine growth retardation. Am J Med Genet 1985;22:531-43.

6 Gillerot Y, Koulischer L. Letter to the editor. Restrictivedermopathy. Am J Med Genet 1987;27:239-40.

7 Schnur RE, Ashmead J, Kelley RI. A lethal ichthyosis variantwith arthrogryposis. Am J Hum Genet 1985;37:76A.

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