Lethal congenital erythroderma: a newly recognised genetic disorder

Case Report

Lethal congenital erythroderma: a newly recognised genetic disorder Shield JPH, Judge MR, Reardon W, Baraitser M, Nohria M, Malone M, Harper JI. Lethal congenital erythroderma: a newly recognised genetic disorder. Clin Genet 1992: 4 I : 273-277. We report 4 patients and their extended families comprising 17 cases, all of whom had congenital exfoliative erythroderma resistant to treatment, associated with failure to thrive and hypoalbuminaemia. All died in the first year of life. This condition appears to be inherited in an autosomal recessive manner and the underlying defect remains unknown.

J. P. H. Shield’, M. R. Judge’, W. Reardon*, M. Baraltre?, V. Nebria’, M. Malone4 and J. 1. Harper’ Departments of ‘Dermatology, ’Genetics and ‘Histopathdopy, The Hospitals tor sick Children, Great Ormond Street. and 30epartment of Child Health, Queen Elizabeth Hospital tor Children, Hackney Road, London, U K

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Key words: congenital diarrhoea - erythroderma failure to thrive hypoalbuminaemia Dr J. I. Harper, Department of Dermatology, The Hospital tor Sick Children, Great Ormond Street, London W l N 3JH, UK

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Received 4 October 1990, revised 31 May, accepted tor publition 7 June 1991

The congenital erythrodermas are a group of distinct diseases that in the past have been included under the heading of ‘Leiner’s disease’ ( McKusick No. 22710) (McKusick 1988). ‘Leiner’s’ is a term used to describe the association of erythroderma in infancy with failure to thrive and diarrhoea. It, in fact, encompasses a heterogeneous group of disorders covering a spectrum of causes of erythroderma including atopic eczema, infantile seborrhoeic dermatitis, ichthyosiform erythrodexma, Netherton’s syndrome and immunodeficiency syndromes. We would propose that the term ‘Leiner’s’ is no longer used as it is a descriptive rather than diagnostic term, and that a determined effort be made to characterise more accurately the distinct subgroups of the congenital erythrodermas. reports Case 1 Cat8

This boy was fourth child of Turkish first-cousin parents. He was born at 38 weeks’ gestation weighing 3.4 kg (50th centile). The baby was born by ventouse extraction for fetal distress. At delivery he was noted ‘to be covered in thick vernix. When this was removed, the child was noted to be intensely erythrodermic with areas of superficial erosion. Due to respiratory distress, the child was ventilated for a total of 8 days and required oxygen supplementation throughout life. Laboratory findings were as follows: haemo-

globin 16.5 g/dl (normal range 10-15 g/dl), white cell count 10.5 x 10/ I , with 60% neutrophils (within the normal range); serum IgG, IgM and IgA were normal, as were the ‘T’ cell subsets; PHA response (a test of ‘T’ cell function) was normal; C3b opsonins (a test for yeast opsonisation) 1% binding (normal 20-120”/0) and low C3 component of complement. The earliest albumin level aged 2 weeks was 22 g/l, which fell to 13 g/l (normal range 35-55 g/l). Liver function and renal function tests were normal. The stool alpha- I-antitrypsin level was within normal limits. Chromosomal analysis revealed a normal 46,XY karyotype. The skin was treated with emollients only and the erosions healed, but the skin retained an erythrodermic appearance (Fig. 1). The stools remained loose throughout the child’s life but were not excessive in number. He was fed modified cow’s milk at 140 k/cal/kg/day but his weight gain remained poor, at 5 weeks 3.2 kg (below 3rd centile), and hypoalbuminaemia persisted. His respiratory problems never settled, despite the use of broadspectrum antibiotic cover. At 5 weeks of age he developed heart failure, but an echocardiogram identified no cardiac structural abnormality. His condition deteriorated gradually and he died aged 2 months. There had been three previous siblings, one male, two female, all of whom had died within 1 month of a desquamative erythroderma. Within this pedigree, the mother’s sister is married to the father’s 273

Shield et al.

Fig. 1. Case 1. aged 2 weeks, with generalised crythroderrna.

spectrum intravenous antibiotics were started but he became increasingly tachypnoeic with stridor. Streptococcusfaecalis was grown from blood culture and he died 2 weeks after admission. Two of his four siblings had died of an erythrodermic skin disorder, aged 2 months and 6 weeks, respectively. A third sibling had died aged 6 months of an unspecified illness not associated with any skin complaint. The fourth sibling, aged 6 years, is alive and well (Fig. 3). This boy’s uncle and his unrelated wife had two children who died of an apparently similar skin condition in Oman. Case 3

brother and this couple have had five live births. Three of these children, two males and one female, are alive and well. The two other children, one male, one female, died at 4 and 8 weeks respectively of the same condition described above (Fig. 2). Case 2

This boy was the fifth child of Omani secondcousin parents. He was born at 40 weeks’ gestation weighing 3 kg (3rd centile). When first seen aged 8 weeks he was irritable and lethargic with a generalised erythroderma and encrusted eczema covering his scalp. Initial investigations revealed a white count of 21.5 x 10 911 (normal range 5-19 x 10 9/1) and an albumin of 18 g/l (normal range 35-50 g/l). Liver function tests were normal. The serological tests for congenital infection were negative. Immunological tests were not performed. His skin condition was treated with mild topical steroids, emollients and oral antibiotics, and initially improved. Low birth-weight bottle milk was used to supplement breast feeding as he had frequent loose stools and was failing to thrive with a weight below the third centile at 4.2 kg. However, 4 days after admission he developed a fever and his liver function tests became deranged. Broad

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Fig. 2. Pedigree of family of Case 1.

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This boy was born at 36 weeks’ gestation weighing 2.5 kg (between 10th and 50th centile). At birth he was covered in thick yellow vernix, underneath which the infant was erythrodermic with skin peeling off in sheets. Initial laboratory results were haemoglobin 15.9 g/dl (normal range 14.5-22.5 g/dl) and white cell count 23.9 x 10 (84% neutrophilia). Serum IgA, cell subsets, IgG and IgM were normal, as were ‘T’ PHA response (a test of ‘T’cell function) and neutrophil function tests. Liver and renal function tests were normal but the albumin was low at 29 g/l (normal range 36-54 g/l). Chromosomes showed a normal karyotype of 46,XY. Emollients were used for the skin, which continued to scale. Four days after birth, this child developed abdominal distension associated with profuse diarrhoea. This settled on initial intravenous feeding and the subsequent gradual reintroduction of enteral feeds, but his weight continued to be a problem and he remained hypoalbuminaemic at 15 g/l. Weight gain was very inadequate and at 7 weeks he weighed only 2.3 kg (below 3rd centile). At 8 weeks he was readmitted shocked

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Fig. 3. Pedigree of family of Case 2.

Lethal congenital erythroderma

Fig. 4. Pedigree of family of Case 3.

and tachypnoeic. A rapid antigen screen revealed a strongly positive test for group B haemolytic streptococcus, but despite appropriate antibiotic therapy he died the following day. This boy was the fifth child of an unrelated Turkish Cypriot couple from the same village; their four previous children had died within the first month of life, also with erythroderma (Fig. 4). Case 4

This girl was born to first-cousin Pakistani parents at term weighing 1.76 kg (below 3rd centile) (Fig. 5). At birth she had erythematous dry skin with extensive peeling. Erythroderma and failure to thrive, with persistent diarrhoea, resulted in frequent admissions to her local hospital. Her condition did not respond to antibiotics, topical steroids or emollients. At 9 months of age she was seen for further evaluation at our hospital. Initial investigations were: haemoglobin 12.3 g/ dl, and white cell count 24x 10 g/l (normal range 6-17.5 x 10 911). Serum IgA, IgM, IgG were normal, as were 'T' cell subsets. However, the PHA response was suboptimal, indicating poor 'T' cell function. Total haemolytic complement levels were normal, but the C4 component of complement was low at only 60% of normal serum. Reduced neutrophi1 mobility was also found. Chromosomal analysis revealed a 46,XX normal karyotype. Her skin condition was treated with topical steroids and emollients but without significant improvement. She was discharged home on pregestermil (a low birth-weight supplemented milk feed) and caloreen

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Fig. 5. Pedigree of family of Case 4.

6. Skin biopsy from Case 1.

supplements, and had started to gain some weight when she suddenly died of a Hurmophilus influenz ~ respiratory e infection. Histopathology Skin

Skin biopsy in three patients (Cases 1, 3, and 4) showed similar features (Fig. 6): a poorly maturing squamous epithelium with mild spongiosis, parakeratosis and occasional mitoses above the basal layer. The granular layer was prominent. The biopsy from Case 4 showed mild acanthosis, but this was not present in Case 3 and the biopsy from Case I showed a mildly atrophic epidermis with few rete pegs. Hair follicles and eccrine sweat glands showed no abnormality. There was no evidence of inflammation. Post mortem

In all cases there were reduced numbers of lymph nodes in the mesentery and mediastinum. Occasional small lymphoid follicles could be iden-

Fig. 7. The thymus in one case, showing prominent Hassall's corpuscles and depletion of lymphoid tissue.

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Shield et al. Table 1. Patient data ~

Case no. Sex

Nationality

Age at onset of rash

1 2 3

male male

4

female

Turksh Omani Turkish-Cypriot Pakistani

congenital congenital congenital congenital

male

Immunological abnormalities low yeast opsonisation: low C3 component of complement tests not performed none found suboptimal PHA response; low c4 component of mplement reduced neutrophil mobility

tified. The thymus glands appeared small and, in Case 1, atrophic (Fig. 7). The condition of the spleens appeared normal.

Discussion

Leiner in 1908 described an illness, in 43 children of unspecified gender, of generalised erythroderma, diarrhoea and failure to thrive, developing at the end of the first or beginning of the second month of life. He named it ‘Erythroderma desquamativea’ (Leiner 1908).Three male siblings with this clinical presentation were subsequently described by Simon et a]. (1975). These three children all died in the first year of life, and post-mortem examination was unremarkable except for lymphatic hypoplasia. Since that time, ‘Leiner’s disease’ has been used to describe various different conditions that lead to the above triad of symptoms. In 1988, Glover et al. suggested that the term ‘Leiner’s disease’ should be avoided, and they described five children (two siblings, the other three unrelated) with various different immunological abnormalities. Two of these children, one a sporadic case, the second a member of the sibling pair, died within 6 months of birth. It is now known that one of these children had Netherton’s syndrome and that one had Omen’s syndrome, highlighting the fact that this clinical presentation can represent a number of different disease entities. Much effort has been put into the search for the unifying defect in children with ‘Leiner’s disease’. Defective opsonisation, originally felt to be due to a deficiency in the C5 component of complement and later to a C3 deficiency, has been postulated in the past (Miller & Koblenz 1972, 1974, Sonea et al. 1981). However, defective opsonisation (now felt to be due to low levels of a serum lecithin, mannan binding protein (Super et al. 1989), affects 5-7% of the general population (Soothill & Harvey 1976). In the series described by Glover, yeast opsonisation was normal and immunodeficiency in various forms was postulated as the cause. In our series the immunological deficiencies were vaned and minimal, and in one patient none was deter278

Lowest albumin

Outcome

13 g/i 18 e/l 15 g/l 29 g/l

died aged 8 week died aged 10 weeks died aged 8 weeks died aged 9 months

mined (Table 1). The relevance of these findings is as yet unclear. All our patients were erythrodermic from birth, with no obvious nail or hair-shaft abnormalities. A consistent finding was hypoalbuminaemia resistant to any attempt at correction by enteral or intravenous supplementation. This was not the result of any excessive renal or gastro-intestinal loss. There may well be metabolic defects associated with this condition which are yet undefined. Certainly there have been cases of children with ‘Leiner’s disease’ with persistent, unexplained metabolic acidosis, described previously (Goodyear & Harper 1989). In 1975, Scott et a]. described a child with total infantile dermatitis and a yeast opsonisation defect. Based on observation of similar opsonisation defects in the patient’s mother and maternal grandfather, neither of whom has skin problems, an autosomal dominant inheritance was proposed for this case. This is the only reported case with clinical features and course resembling this current report in which an inheritance pattern was postulated, the evidence resting entirely on the opsonisation findings. That three of the four index cases in this report had multiple affected siblings and were the offspring of consanguineous marriages strongly suggests an autosomal recessive condition which presents with congenital erythroderma, diarrhoea and failure to thrive. The outcome of this condition in all cases we have observed has been lethal. If infantile erythroderma represents a spectrum of disease conditions with unifying symptomatology, then our cases with a specific inheritance, congenital presentation, associated with failure to thrive and hypoalbuminaemia and poor prognosis, are certainly at the far end of this spectrum and should be regarded as a distinct entity. Ackaowltdgeetnts The authors wish to thank the following who were also involved in the care of these patients: Dr. D. Atherton (The Hospitals for Sick Children, Great Ormond Street, London); Professor C.Wood (Queen Elizabeth’s Hospital, Hackney. London); Dr K. Costeloe (The Homerton Hospital, London); Dr S. Rom

Lethal congenital erythroderma (The Portland Hospital, London); Dr G. S. Gau (Department of Histopathology, Queen Charlotte's Hospital, Goldhawk Road, London); Dr G. Morgan and the Department of Immunology (Institute of Child Health, Guilford Street, London) and the Department of Medical Illustration (The Hospitals for Sick Children, Great Ormond Street, London).

Rstsrsncss Glover MT.Atherton DJ, Levinsky R. Syndrome of erythroderma, failure to thrive and diarrhoea in infancy: a manifestation of immunodeficiency. Paediatrics 1988: 8 1: 6 6 7 2 . Goodyear HM, Harper J1. Leiner's disease associated with metabolic acidosis. Clin Exp Dermatol 1989: 14364-366. Leiner C. Erythroderma desquamativa (universal dermatitis of children at the breast). Br J Dis Child 1908: 5: 244-251. McKusick VA. Mendelian inheritance in man. 8th ed. Baltimore and London: The Johns Hopkins University Press, 1988.

Miller ME, Koblenzer PJ. Leiner's disease and deficiency of C5. J Paediatr 1972: 80: 879-880. Miller ME, Nilsson UR. A major role of the fifth component of complement (C5) in the opsonisation of yeast particles. Partial dichotomy of function and immunochemical measurement. Clin Immunol lmmunopathol 1974: 2: 246255. Scott H. Moynihan EJ, Risdon RA et at. Familial opsonisation defect associated with fatal infantile dermatitis, infections and histiocytosis. Arch Dis Child 1975: 50: 31 1-317. Simon C, Becker V. Wiedemann HR. uber ein unter dem Bilde der Erythroderma desquamativa Leiner vcrlaufenes tiidliches Leiden bei drei Briidern. 2 Kinderheilk 1965: 94: 12-24. Sonea MJ, Moroz BE, Reece ER. Lciner's disease associated with diminished third component of complement. Paediatr Dermatol 1987: 2: 105-107. Soothill JF, Harvey BAM. Defective opsonisation: a common immunity deficiency. Arch Dis Child 1976: 51: 91-99. Super M, Thiel S, Lu J, Levinsky RJ, Turner MW. Association of low levels of mannan binding protein with a common defect of opsonisation. Lancet 1989: i: 12361239.

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