Background
Epidermolysis bullosa (EB) is an inherited genodermatosis of variable severity characterised by skin and mucosal fragility commonly associated with altered gait patterns and hypermobility.
...Objectives
To define the altered gait pattern and identify possible causes in patients with EB.
Methods
Retrospective review of the EB database to identify children with EB with at least one physiotherapy assessment between 2009 and 2022.
Results
Forty‐eight children out of 59 referrals to physiotherapy with an altered gait pattern were identified (81.3%); 23 (48%) had recessive dystrophic EB (RDEB), 17 (36%) EB simplex, five (10%) Junctional EB (JEB) and three (6%) dominant dystrophic EB (DDEB). The patho‐mechanical altered gait patterns were characterised by altered load‐bearing surface in contact with the floor (63%), short shuffling pattern with high cadence and decreased single support (42%) and equinovarus (toe walking) (6%). Hypermobility (as defined by the Beighton score) was present in 67% of patients: 43% in RDEB, 88% in EBS, 100% in JEB and 67% in DDEB.
Conclusions
In this study, we provide the first accurate data for the causes of altered gait patterns in children with EB. Healthcare professionals should be aware of joint hypermobility and its effect on gait in this patient cohort.
We defined the altered gait pattern and identified possible causes in children across all types of epidermolysis bullosa. This is largely due to pain, bulky dressings, open wounds and scarring which leads to movement restriction and contractures. There is a high incidence of hypermobility which has a detrimental effect on gait pattern. The primary therapeutic goals aim to improve muscle strength, reduce pain and improve postural alignment by stabilising the joints as much as possible.
Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been ...implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.
Abstract
Background
Congenital haemangiomas are benign vascular tumours, typically solitary, categorised by their postnatal behaviour as rapidly involuting, non-involuting, or partially involuting. ...Histologically, they differ from infantile haemangiomas by the lack of immunostaining for GLUT-1. We present three infants with congenital, small, multifocal, non-progressive haemangiomas on the skin.
Cases
Our first patient was a male, born with 18 small vascular lesions. Abdominal ultrasound showed three vascular lesions in his liver and one in his left kidney, which were not visible on the repeated ultrasound in 3 months. MRI of the thorax showed a vascular lesion in the right hemithorax. He was completely asymptomatic, and the lung lesion was monitored annually with ultrasound.
The second patient was a male, born with eight vascular lesions. He had an abdominal ultrasound, which was clear. He was also asymptomatic, and the lesions disappeared in the first year.
The third patient was a female, born with 24 vascular lesions. Cranial ultrasound was clear; however, MRI head revealed nine punctate white matter lesions suggestive of vascular lesions. She had three small foci in the liver, consistent with haemangiomas, which were not detected after 6 weeks.
All three patients had skin biopsy, which showed thin-walled dilated vessels in the dermis, negative for GLUT1 and D240. None of the patients had coagulopathy.
Conclusion
These three cases expand the diagnosis of congenital haemangioma to include a multifocal phenotype and demonstrate their possible association with visceral and intracranial lesions/abnormalities.
Abstract
Mastocytosis is a rare and clinically heterogeneous disease characterized by abnormal accumulation of mast cells in various tissues. There are three major types of cutaneous mastocytosis ...(CM): diffuse cutaneous mastocytosis (DCM), urticaria pigmentosa and solitary mastocytoma, which is the most common form before the age of 3 months: 90% of CM cases present before 2 years of age, and congenital mastocytosis has been described in 23% of those. Solitary mastocytoma has been associated with a mutation of the KIT gene. A male infant was born at 39 weeks, with a large, indurated, blistering, ulcerated plaque containing yellow serous fluid affecting half his right calf. His nails and oral mucosa were normal. Our centre was contacted on suspected diagnosis of inherited epidermolysis bullosa (EB). There was no family history of EB, and the parents were not related. Initial testing showed a PCR positive for HSV type 1 and treatment with aciclovir and cefotaxime was initiated. There was no improvement after 2 weeks of treatment. Viral and bacterial skin swab were negative. A skin biopsy and ultrasound were performed showing extensive superficial hypoechoic lesion and reactive popliteal lymph nodes and the biopsy confirmed the diagnosis of mastocytoma. Bloods including tryptase level and abdominal ultrasound were normal. The lesion healed within 4 weeks with dressings and topical steroids. This case of a single isolated congenital mastocytoma shows the broad differential diagnoses that must be considered in the evaluation of bullous lesions in a newborn. It is key to biopsy early and always exclude infection.
Abstract
Ichthyosis follicularis alopecia and photophobia (IFAP) syndrome is a rare, X-linked inherited disorder caused by pathogenic mutations in the MBTPS2 gene. Seventy cases have been reported ...previously. The phenotypic spectrum varies, but IFAP consistently causes noninflammatory follicular keratoses, nonscarring alopecia and progressive corneal scarring. A 7-year-old boy, with IFAP syndrome associated with neurodevelopmental delay, chorioretinal coloboma and poor growth requiring gastrostomy, presented with a 4-week history of worsening flexural erythema and pain. Trials of topical steroids with fucidic acid, nystatin and oral penicillin had proven ineffective. On initial evaluation he had florid painful flexural erythema with surrounding crusting and scale. The Nikolsky sign was negative. He was systemically unwell with fever, dehydration and malaise requiring hospital admission. Laboratory evaluation demonstrated leucocytosis with neutrophilia and peak CRP of 100. He was treated empirically for bacterial superinfection including Staphylococcus scalded skin syndrome with intravenous clindamycin. With no appreciable improvement after 48 h, antimicrobial therapy was extended to include fluconazole and aciclovir. After 5 days, he continued to be febrile and systemically unwell with extensive yellow-brown crusting most marked at the flexural areas, and clindamycin was switched to piperacillin/tazobactam to provide antipseudomonal coverage. Skin swab cultures subsequently confirmed heavy growth of Pseudomonas aeruginosa. Within 48 h there was marked clinical improvement. He was discharged home to complete a course of oral antibiotics. This case highlights the importance of early consideration of Pseudomonas infection as a cause of subacute flexural exacerbations, particularly in those with skin barrier abnormalities, including inherited ichthyoses.
Abstract
Leukaemia is the most frequent malignancy of childhood, accounting for approximately 30% of all malignancies. Acute leukaemia may present in a variety of extramedullary manifestations, the ...commonest being leukaemia cutis (LC). LC is the infiltration of the epidermis, dermis or subcutis by neoplastic leukocytes with skin lesions preceding the development of leukaemia in the peripheral blood or bone marrow in just 2–3% of cases. A 6-month-old baby girl was reviewed due to multiple skin lesions which appeared on her left forearm 2 months previously, and spread widely, showing over 50 in the following weeks. They were well-circumscribed, nontender, violaceous nodules. She was clinically well and thriving with no lymphadenopathy or organomegaly. Blood tests and abdominal ultrasound were normal. A skin biopsy of a nodule demonstrated an infiltrate of medium-sized atypical cells involving the dermis and subcutis. Immunostaining showed CD45 expression and the Ki67 proliferation index was high, in keeping with a leukaemic infiltration. Cytogenetics performed on the skin biopsy showed KMT2A rearrangement by FISH. Bone marrow aspirate confirmed the diagnosis of acute myeloid leukaemia with monoblastic morphology, and cytogenetics confirmed the rearrangement as a KMT2A–MLLT10 fusion, which is classified as poor cytogenetic risk. Cerebrospinal fluid analysis was negative. It is vital to get a histological diagnosis (with cytogenetics) in a child presenting with violaceus nodular lesions even if the child is well. Importantly, LC can present with a normal full blood count. A bone marrow aspiration is paramount to confirm the diagnosis. Once leukaemia is diagnosed, cytogenetics plays a key role in stratifying treatment intensity.
Epidermolysis bullosa (EB) is a heterogeneous group of inherited blistering skin diseases. Severe forms of EB are associated with increased morbidity and mortality, and there is currently no ...effective treatment. To combat severe complications of EB, such as chronic erosions, scarring and malignancy, effective therapy needs to be given systemically and at an early age. One recent therapeutic advancement has been a clinical trial of whole bone marrow (BM) transplantation in children with the dystrophic form of EB. This led to correction of the inherent skin basement membrane defect and better skin integrity in some individuals. The challenge now is to precisely identify which BM cells contribute to skin recovery and what mechanisms are involved in tissue regeneration. An improved understanding of the key aspects of BM skin repair is likely to lead to significant health improvements for patients with EB and other skin diseases.
Abstract
TUFT1 encodes tuftelin-1, a glycoprotein thought to play a major role in mineralization and structural organization of enamel, but it has not been implicated in any monogenic enamel ...disorders.
Recently, Jackson et al. (2023) identified that tuftelin-1 has a role in desmosomal function. Pathology in desmosomal components causes disorders affecting the skin, hair, and heart. Newly described bi-allelic loss-of-function TUFT1 variants (OMIM600087) cause a novel skin fragility-woolly hair phenotype.
We present two siblings from non-consanguineous parents of Irish and British ancestry. Both had normal skin at birth and developed widespread blisters on day two of life, on the limbs, buttocks area and inside the mouth.
Although their skin fragility had improved with age, they still developed flare-ups with multiple small blisters, mainly on their limbs when viral illness. They had mild palmoplantar keratoderma and skin peeling.
Their most characteristic phenotype was slow-growing woolly hair that did not need cutting until the age of 5 years old in the older sibling. The eyebrows and eyelashes were unaffected. Recently, the older sibling has developed keratosis pilaris on her arms. The heart was unaffected with normal electrocardiogram and echocardiogram. Whole exome sequencing identified homozygous NM_020127:c.60+1G>A TUFT1 variants in both affected individuals.
These two cases reflect a novel condition. The predominant clinical phenotype is woolly hair and early signs of skin fragility. Despite having a role in desmosomal integrity bi-allelic loss-of-function TUFT1 variants do not appear to cause cardiac pathology.
Abstract
Erythrokeratodermia variabilis et progressiva (EKVP) is a clinically heterogeneous group of inherited disorders characterized by the coexistence of localized or generalized hyperkeratotic ...plaques and transient, stationary or migratory erythematous patches. EKPV is most often transmitted in an autosomal dominant manner. Causal pathogenic variants have been detected in the GJB3, GJB4, GJA1 KDSR and KRT83 genes encoding connexins 31, 30.3, 43, 3-ketodihydrosphingosine reductase and keratin 83, respectively. Connexins are expressed in almost all tissues and pathogenic variants in the connexin genes can cause skin diseases, cardiovascular disorders, myelin-related diseases, craniofacial disorders and hearing loss.
We present a 2-year-old girl who was referred to our centre with well-demarcated hyperkeratotic plaques symmetrically distributed with a predilection for the distal extremities and buttocks as well as erythematous plaques on her cheeks. The hyperkeratotic plaques were hyperpigmented, exhibited a geographic morphology and had prominent hypertrichosis. Her trunk and upper extremities were spared and her hair, teeth and nails were normal. There was family history of mild psoriasis in her mother and mild eczema in her father. Next generation sequencing confirmed she was heterozygous for the GJB3 c.625C>T p.(Leu209Phe) pathogenic variant which is associated with erythrokeratodermia variabilis et progressiva-1 (MIM 133200) and autosomal dominant deafness-2B (MIM 612644).
Erythrokeratodermia variabilis is largely a skin-limited condition however GJB3 pathogenic variants can cause haring loss and neuropathy due to its expression in peripheral nerves and the cochlea. Our patient’s hearing and development have been normal to date and will be monitored.
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